PROCEEDINGS
The Symposium Organizing Committee would like to thank
the following organizations for their support of
the Progress Toward Rubella Elimination and
CRS Prevention in Europe symposium:
Abbott Diagnostics
Albert B. Sabin Vaccine Institute
BioMerieux
DiaSorin
World Health Organization Regional Office for Europe
March of Dimes Foundation
Merck
Roche
sanofi-pasteur
Serum Institute of India
U.S. Centers for Disease Control and Prevention
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Progress Toward Rubella Elimination And CRS Prevention in Europe Proceedings
Table of Contents
Executive Summary.............................................................. 4
Introduction........................................................................... 7
SESSION I:
Measles Elimination in Europe................... 8
SESSION II: Background Information........................... 19
SESSION III: Diagnostics................................................ 24
SESSION IV: Global Epidemiology................................. 28
SESSION V: Burden of Rubella and CRS in Europe.... 31
SESSION VI: Country Experiences................................. 36
SESSION VII: Strategies, Policy Implementation
and Documentation of Rubella/CRS........ 41
SESSION VIII: Surveillance Strategies............................. 47
SESSION IX: Issues to be Addressed............................ 52
Concluding Remarks.......................................................... 57
Speakers.............................................................................. 58
Delegates............................................................................. 59
Rome, Italy, 8-10 February 2012
3
Foreword
F
rom 8-10 February 2012, over 150 people from 47 countries met in Rome, Italy, to discuss the strategies and work
needed to eliminate measles and rubella from the European region by 2015. It was the first major global meeting on rubella
in 40 years. Participants shared lessons from the successes already achieved in rubella elimination around the world.
By bringing together public health authorities and pediatric societies, the conference embodied the types of partnerships
that will support successful elimination campaigns. Participants tackled the complexity of the immunization enterprise – from
the basic sciences to the laboratories, from the role of clinicians to the community and the media. As Dr. Louis Cooper said,
“It may seem on the surface very simple to vaccinate a child, but the truth is that it is exceedingly complex.”
Symposium Organizing Committee
Dr. Louis Cooper, American Academy of Pediatrics and International Pediatric Association
Dr. Nedret Emiroglu, World Health Organization Regional Office for Europe
Dr. Michael Katz, March of Dimes
Dr. Stanley Plotkin, University of Pennsylvania
Dr. Ciro de Quadros, Albert B. Sabin Vaccine Institute
Dr. Maria Grazia Revello, Fondazione IRCCS Policlinico San Matteo
Dr. Susan Reef, U.S. Centers for Disease Control and Prevention
Executive Summary
T
he rubella virus threatens children and adults, but poses the highest risk to pregnant women and their developing
fetuses. Once known as “German measles,” rubella infection early in pregnancy may result in miscarriage, fetal death, or
the birth of an infant with Congenital Rubella Syndrome (CRS). CRS can cause blindness, deafness, mental retardation,
heart defects and a range of other conditions from diabetes to autism.
An estimated 112,000 babies around the world are born with CRS every year. Many of these children need a life-time
of medical and social support. Although the European Region has significantly reduced cases of rubella and of CRS, it has
not eliminated them. Babies are still born with the condition, and expectant mothers must still make irrevocable choices
when learning of their infected status.
Yet, this situation is completely avoidable. For more than 40 years, a vaccine has been available to prevent rubella
and CRS. The Americas have succeeded in eliminating both rubella and CRS through mass immunization. “In countries
like the U.S., where we’ve eliminated congenital rubella, we’ve been able to close schools of the deaf,” Dr. Louis Cooper
told the gathering.
Rubella vaccine is most commonly administered as part of combination vaccines with measles (MR vaccine) or
with measles and mumps (MMR vaccine). The use of measles vaccine has already reduced measles deaths, which fell
78 percent between 2000 and 2008. Yet, this disease continues to claim the lives of nearly 164,000 people a year, and
sporadic outbreaks and imported cases threaten the progress already made.
Thus, the use of rubella- and measles-containing vaccines could eliminate these two viruses and their huge burdens of
disease, death, and disability.
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Progress Toward Rubella Elimination And CRS Prevention in Europe Proceedings
In 2010, the European Region set a goal of eliminating measles and rubella and preventing CRS by 2015. Dragan
Jankovic, with the World Health Organization Regional Office for Europe, described four strategies for achieving this goal:
•
•
•
•
Reach at least 95 percent coverage of the population with two doses of measles-containing vaccine and one
dose of rubella-containing vaccine (RCV);
Use mass campaigns and other supplementary vaccination activities to provide “catch-up” vaccination and
reach everyone who is susceptible;
Establish case-based surveillance with strong laboratory involvement component; and
Make evidence-based information on immunization’s benefits and risks available to experts and the public.
Throughout the two-and-a-half-day meeting, pediatricians, epidemiologists, and others involved in public health
and health policies shared information on progress in implementing these strategies in the European Region, and the
challenges that must be met to eliminate rubella.
Presenters reported on significant progress already made: between 2001 and 2010, the WHO Europe Region
achieved a 99 percent decline in reported cases of rubella. Major advances took place in the Central and Eastern parts
of the Region, and the Newly Independent States. Nonetheless, outbreaks continue, and some countries have coverage
of less than 80 percent. Pockets of susceptible populations are scattered throughout the region, and large gaps in
surveillance mean that the region does not yet have an accurate picture of the extent of rubella and CRS.
Every country is different, however. Representatives from Italy, Russia, Finland, Poland and France summarized their
own histories, current status and challenges in rubella elimination.
Consistent themes emerged in global, regional and national reports. One of the key challenges countries face is the
need to significantly improve surveillance. This surveillance must be case-based, allowing the investigation of contacts,
identification of cause (e.g. importation, failure to vaccinate, or vaccine failure); identification of populations at risk; and
ensuring a public health response. Strong surveillance is also essential for the verification of elimination.
Despite the importance of case-based surveillance reporting, in 2011 in the WHO European Region, it was provided by
only 28 countries; 10 provided aggregate data and 15 provided no data.
Once potential cases are identified, they need to be laboratory confirmed. But in 2010, only 22 percent of reported
cases were confirmed. Speakers addressed the challenges of diagnosis, the confounding factors in assessing immune
status, and the opportunities presented by molecular epidemiology.
Country representatives also shared lessons from their vaccination experience, including the impact of targeting
girls only for vaccination. Countries including Poland, Lithuania, Finland and France reported on the limitations of their
initial approaches of only vaccinating girls and young women. This left circulation of the virus intact, outbreaks affected
unvaccinated boys and men, and pregnant women who had not been vaccinated remained vulnerable to circulating virus.
More recently, countries have been grappling with the need for mass catch-up campaigns that vaccinate older children,
adolescents and even adults. Some fear that limited resources and competing public health demands may stand in the
way, despite the importance of such campaigns for achieving elimination.
Another common challenge was the ever-growing numbers of vaccine skeptics. “Vaccine safety is increasing, vaccine
coverage is increasing, disease incidence is decreasing, and then public trust is decreasing,” said Pier Luigi Lopalco from
the European Centre for Disease Prevention and Control (ECDC).
The source of opposition is not only largely unfounded fears about vaccine safety, but also suspicions aroused by
anything that appears to be a major change in policy from the top. Therefore, vaccine campaigns can bring their own
headwinds, said Jan Bonhoeffer from the Brighton Collaboration.
Discussants addressed the need for the public health community to utilize some of the same social and digital media
tools now used so adroitly by vaccine opponents, and the need for trusted health providers, starting with pediatricians, to
more visibly support the need for vaccination. To do so, however, they need access to the most up-to-date and credible
evidence of vaccine impacts, safety and risks.
Rome, Italy, 8-10 February 2012
5
The meeting also considered global issues of vaccine cost-effectiveness and vaccine demand, supply and cost. The
cost-effectiveness of rubella vaccine is apparent. Jon Kim Andrus from the Pan American Health Organization (PAHO)
reported on studies in the PAHO region that show the benefit-cost ratio was 10:1 – 12:1 with MR vaccination. Global
supply and demand for rubella-containing vaccine is shifting. Selenge Lkhagva reported that UNICEF expects demand
of MR and MMR vaccine to increase to 300 million doses by 2015. There are only a handful of manufacturers, with the
potential that increased demand will lead to higher prices. A roundtable of vaccine manufacturers emphasized their role as
partners in ensuring that the industry is able to reliably supply the needs of countries. All emphasized the need for accurate
forecasting of demand to ensure vaccine security.
By addressing the many challenges to eliminating measles and rubella in Europe, the conference laid the foundation
for success. Ciro de Quadros of the Sabin Vaccine Institute encouraged the European Region and its public health leaders
to take the steps needed, especially those that may seem most difficult. “ You will be surprised that you will succeed. Let’s
try it.”
“Why hold this meeting now? On the one side, many regions are already
moving towards elimination of measles and rubella. On the other side,
there is a major resurgence of both diseases here in Europe.
By the end of the Decade of Vaccines, we should set the target date
for the eradication of measles and rubella.”
Ciro de Quadros, Sabin Vaccine Institute
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Progress Toward Rubella Elimination And CRS Prevention in Europe Proceedings
Introduction
T
he symposium, “Progress Toward Rubella Elimination and CRS Prevention in Europe” brought together over 150
people from 47 countries, who together represented global health leaders, multilateral organizations, NGOs, pediatric
associations, and biomedical researchers.
It was designed to review the status of rubella elimination, and its close connection with the elimination of measles,
from understanding the science, economics, country experiences, and public health strategies, policies and documentation
necessary for success.
Organizers noted that last year in Europe there were more than 32,000 cases of measles, compared to 8,000 in 2008,
and that the true burden of rubella is unknown, given severe under-reporting of cases across the region.
Dr. Ciro de Quadros, Executive Vice President of the Sabin Vaccine Institute, highlighted the timeliness of the meeting.
First, Europe has made elimination of measles a goal, he said, along with another four of the six WHO regions. Second, the
global health community has recently initiated the Decade of Vaccines, with the goal of articulating and achieving a vision
for control of vaccine-preventable diseases by the end of the decade. The eradication of measles and rubella should be
part of this vision.
Introductory remarks from Dr. Stefania Iannazzo, representing the host country of Italy, called on all participants to
view the experiences of each country as a source of wealth, and to learn from them.
Dr. Sergio Cabral, President of the International Pediatric Association (IPA), infused the meeting with additional energy,
when he announced that the Association of 166 pediatric societies representing 600,000 members would launch and lead a
global initiative to eradicate rubella and measles.
Adding to the momentum, Dr. Helen Evans, the Deputy CEO of GAVI, detailed the organization’s commitment to
the control and elimination of measles and rubella. She noted that of the 112,000 cases of congenital rubella syndrome
occurring globally each year, 90,000 of those are in GAVI-eligible countries, and that GAVI is now backing the elimination of
rubella through supporting countries’ use of Measles Rubella (MR) vaccine.
Speaking on behalf of the WHO Regional Office for Europe, Dr. Nedret Emiroglu emphasized the commitment of the
WHO to work together with all interested partners – particularly pediatricians and healthcare workers – to eliminate measles
and rubella by 2015. The time was right to move vigorously ahead, she said, noting that political commitment is high as all
53 member states of the European Region had committed to the 2015 elimination target.
Noting the significance of both the IPA’s and GAVI’s announced commitments, Dr. de Quadros framed the opening day
of the symposium as “an historical day for the control and elimination of measles and rubella.”
“I am happy and proud to tell you that the IPA took the opportunity of this
meeting to announce that we’ll lead a global initiative that will ultimately
aim to eradicate rubella and measles all over the world.”
Sergio Cabral, International Pediatric Association
Rome, Italy, 8-10 February 2012
7
SESSION I:
Measles Elimination in Europe: A Necessary
Component Toward Rubella and CRS Elimination
The Measles Initiative: Global Progress and Challenges
Dr. Peter Strebel, Department of Immunization, Vaccines and Biologicals, World Health Organization (WHO)
Dr. Strebel described the remarkable achievements and outstanding challenges in the control and elimination of
measles since the founding of the Measles Initiative, an 11-year global partnership committed to reducing measles deaths
worldwide. Led by the American Red Cross, the United Nations Foundation, the U.S. Centers for Disease Control and
Prevention (CDC), UNICEF and the World Health Organization, the partnership has worked to reduce measles mortality, to
advocate for human and financial resources, and to support WHO/UNICEF measles control strategies, which include the
use of rubella vaccine.
Achievements: Strebel noted that since 2001, more than one billion doses of the measles vaccine have been
administered worldwide through mass campaigns. These campaigns have supplemented efforts to scale up routine
immunization with both the first and second doses of measles vaccine. The results have included an impressive two-thirds
reduction in cases, and three-quarters reduction in measles deaths. Between 1990 and 2008, the reduction in measles
mortality contributed over one-fifth of the total reduction in child under-five mortality.
Goals: This progress lays the basis for current global goals for measles control by 2015:
•
•
•
Vaccine coverage: 90 percent first dose coverage at the national level, and 80 percent in every district
Reported incidence: less than 5 cases of measles per million
Mortality reduction: 95 percent (2000 baseline)
Five out of the six WHO regions have measles elimination targets on or before 2020. The European Union has set
2015 as the target date to eliminate both measles and rubella.
While global eradication is considered feasible, based on the recommendation of the SAGE, an expert advisory group
to the WHO, the global health community has held off on setting a date for its achievement. SAGE advised that a target
date should be established only after measurable progress has been made toward existing regional elimination goals and
2015 targets. Also of concern was the need to focus on the current 11th hour global campaign to eradicate polio, according
to Strebel.
Challenges: Strebel highlighted four major challenges: low vaccine coverage in India, a resurgence of measles in
Africa, weak immunizations systems, and financing that is late, unpredictable and inadequate. For 2012, there is a funding
gap of approximately US$35 million for planned activities for reducing mortality due to measles.
India was the last country to initiate strategies for providing a second dose of vaccine. As of January 2012, some 90
million children in 14 high burden states in India had yet to receive measles vaccination through a catch-up campaign.
Therefore, major work remains in India’s catch-up vaccination activities.
“The opportunity to re-access older children through
a combined measles/rubella campaign will have a major impact
on reducing measles mortality.”
Peter Strebel, WHO
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Progress Toward Rubella Elimination And CRS Prevention in Europe Proceedings
In Africa, the progress made against measles in the early years of the new millennium is slipping away. “From a
low point of cases in 2008, we’ve seen about a fourfold increase of measles in Africa in the last two years,” Strebel said.
There have been large outbreaks in Burkina Faso; more than 100,000 cases and at least a thousand related deaths in the
Democratic Republic of Congo; and resurgence of disease in the Horn of Africa.
Strebel highlighted the problem and the implications of weak immunization systems in countries where first dose
measles coverage is below 80 percent. “If you don’t reach that child with the first dose on time, you rapidly accumulate
susceptible children, and of course these are the countries that are very prone to measles outbreaks.”
The Measles Initiative is developing a strategic plan that will address these challenges between 2012 and 2020. It
targets both measles and rubella; emphasizes activities to strengthen routine immunization and disease surveillance
systems; addresses outbreak preparedness and response; and emphasizes innovation and research and development to
enable breakthroughs in measles control. The strategy will also benefit from the decision by the GAVI Alliance to support the
51 GAVI-eligible countries in introducing the rubella vaccine, as well as a combined measles/rubella vaccine in a catch-up
campaign targeting children from 9 months to 14 years of age. The wide age range is particularly important to countries in
Africa, where outbreaks often include children from 10 to 15 years of age and older. “The opportunity to re-access older
children through a combined measles/rubella campaign will have a major impact on reducing measles mortality,” Strebel said.
Major Causes of Mortality Among Children <5 Years,
1990 vs. 2008
Measles accounts for ~23% of overall
decrease in child mortality
Malaria
5%
Malaria
8%
Measles
7%
Measles
1%
Other
47%
Pneumonia
21%
Diarrhoea
20%
1990: 12.1 mil
Other
58%
Pneumonia
18%
Diarrhoea
15%
2008: 8.8 mil
Source: M. van den Ent et al, J Infect Dis Suppl, July 2011, pp S18-S23
Rome, Italy, 8-10 February 2012
9
PAHO Measles Elimination Program Update
Dr. Jon Kim Andrus, Deputy Director, Pan American Health Organization (PAHO)
In 1980, measles was endemic across the region of the Americas, with more than 250,000 confirmed annual cases.
By 2002, endemic measles had been eliminated from the Americas. Dr. Jon Andrus described the strategies that led to its
elimination and the current challenges, particularly with imported cases of measles.
Beginning in 1994, PAHO worked with countries to eliminate the disease. Catch-up vaccination campaigns targeted
all children less than 15 years of age, and follow-up campaigns targeted children under five every four years. Routine
immunization strove to achieve the highest possible level of coverage, with special attention to high risk areas. This work
was reinforced through rigorous monitoring and surveillance, including virologic surveillance of the virus genotype.
Since 2002, imported cases of measles have caused limited disease outbreaks. CDC laboratories in the U.S. have
assisted with genotyping the rare cases of measles that have occurred; and sequence data has confirmed that these cases
are indeed the result of infections brought in by visitors to the region. The lesson, says Andrus, is that “As long as there’s
transmission anywhere in the world, we’re at high risk for importations.”
Measles Importations: Travel and tourism brought 150 million people to the Americas in 2010, an increase of 6
percent from 2009. Such travel is a major factor behind imported cases of measles, which constitute the biggest challenge
to maintaining the region as measles-free, according to Andrus. Data show that a cluster of countries—including Brazil,
Canada, the USA and Venezuela--repeatedly experience importations. Most of the cases come from Europe, Asia or Africa.
One outbreak, which began in July 2011, has yet to be fully contained. It is in Ecuador, and the most affected groups
are indigenous, high-risk populations engaged in trade and commerce. One country in the Americas that is now receiving
special attention is Haiti. In April 2012, PAHO will work with its partners to implement a measles/rubella/polio follow-up
vaccination campaign.
The biggest post-2002 outbreak occurred in Quebec, Canada, included more than 800 cases, and lasted eight months.
The outbreak was school-based, primarily affecting people 10 to 19 years old. While the virus was imported, its spread
was facilitated by gaps in vaccination: 79 percent of those affected were not vaccinated. Fortunately, the Quebec health
authorities were able to contain the outbreak before it could become endemic. By definition, once an outbreak has persisted
for more than a year, it is considered endemic, regardless of whether the cause was an imported case of measles.
To guard against the return of endemic measles, PAHO supports the strengthening of surveillance, and has launched
a documentation and verification process. Verification links each piece of evidence, from the molecular epidemiology to
analysis of vaccinated population cohorts and assessment of the sustainability of national immunization programs.
Disease surveillance efforts often focus on susceptible populations through Rapid Coverage Monitoring. Attention goes
to the highest risk areas within countries, including where there are marginalized and vulnerable populations; hightraffic borders; and areas dedicated to commerce and trade. PAHO also monitors mass gatherings in the Americas, and
elsewhere in the world. For example, PAHO monitored World Youth Day, held in Madrid, Spain, which brought together
more than a million young people, and was a potential source of measles cases.
To preempt importations, PAHO issues alerts that encourage travelers to check their immunization status and teach
the signs of measles. PAHO has made alliances with large airlines and travel agencies to put out alerts for passengers.
Going forward, PAHO expects all countries to implement high-quality follow-up vaccination campaigns, and to use measles
eradication activities to accelerate the control of rubella and the prevention of Congenital Rubella Syndrome (CRS). The
goal is to obtain high levels of immunity, and be able to confirm and verify the Americas free of endemic transmission of
measles and rubella by 2013.
“As long as there’s transmission anywhere in the world,
we’re at high risk for importations.”
Jon Kim Andrus, Pan American Health Organization
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Progress Toward Rubella Elimination And CRS Prevention in Europe Proceedings
Measles Elimination in The Americas, 1970 – 2011*
Catch-up campaigns
300,000
100
Speed-up campaigns
200,000
60
Follow-up campaigns
150,000
Last measles
case (D9)
Confirmed Cases
80
100,000
50,000
40
20
Routine infant vaccination coverage (%)
250,000
0
0
80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11
Measles cases
M coverage
MR coverage
*MR in children aged 1 year as countries introduced measles-rubella containing vaccines
Source: Country reports to FCH-IM/PAHO
Measles in Europe
Dr. Pier Luigi Lopalco, Head of Vaccine Preventable Diseases Programme, European Centre for Disease
Prevention and Control (ECDC)
Despite decades of vaccine use, measles has been endemic in many countries of the European Union (EU) for the
last seven years. Dr. Lopalco outlined the series of outbreaks: Bulgaria in 2010, France in 2011, followed by outbreaks in
Italy, Germany and Romania. Indeed, almost all EU countries had some measles cases in 2011, including a number that
had long been considered measles-free. During 2011, the EU saw 30,567 reported cases of measles.
The 2011 outbreak in France had the highest incidence of measles in children less than one year of age. Most had
been infected by their mothers, many of whom were never immunized, according to Lopalco. However, older children
and adults were also infected, demonstrating the accumulation of a large susceptible population, built up over many
years of low vaccine coverage. The ECDC calculates that up to 5 million children in the EU have missed out on measles
vaccinations over the last 10 years.
Throughout the EU, the vast majority of measles cases in recent years have been in unvaccinated people. “We are
not talking about vaccination failure. We are talking about a large part of the EU population that was not vaccinated,”
Lopalco said.
Analysis shows that in one year, 82 percent of cases were unvaccinated; 18 percent were vaccinated, but only 4
percent had been vaccinated with both the first and second doses of vaccine. Less than half of the European population is
estimated to have had two doses of measles containing vaccine.
“This is unbelievable because measles is not a mild disease… We know that last year eight children died from
measles in Western Europe.” In addition, the region had an incidence of one case of encephalitis per 1,000 cases, up
to one in five measles cases requires hospitalization, and almost 5 percent of pneumonia occurred as a complication of
measles.
Rome, Italy, 8-10 February 2012
11
Given that there is a safe and effective vaccine, Lopalco identified several main problems as responsible for low
coverage: the lack of an “active offer” of MMR vaccine; problems related to vaccination providers; and problems related to
vaccination recipients.
According to surveys, parents are often unaware of the need for MMR, Lopalco reported. Systematic offers of
vaccination are impeded by a lack of vaccine registries and reminder systems. Young doctors may not know what
measles and other previously rampant infectious diseases are. Other doctors and healthcare workers resist vaccination.
Underserved groups who are not included in the healthcare system cannot access vaccines.
Compounding all this, there is growing skepticism of vaccines among the public. Lopalco described this as the
“vaccine paradox.” “Vaccine safety is increasing, vaccine coverage is increasing, disease incidence is decreasing, and
then public trust is decreasing.” Even worse, the lack of support for vaccination among the public and in the medical
establishment effects political commitment. Opposition to vaccination exists even at the governmental level, Lopalco said.
Lopalco described several categories of vaccine skeptics: those who practice anthroposophic medicine and others
with religious beliefs that may predispose them to be against vaccines. However, dialogue with this group is possible,
he said. A second very large skeptic population is a portion of middle to high class people, especially women, who get
information from the Internet. Here, too, more communication is needed and dialogue is possible. However, the most
ardent anti-vaccine activists are followers of conspiracy theories, and with this group, “No dialogue is possible and we
should not waste our time to talk to these people,” he said. While these opponents are a very small group, they are very
active in promulgating their ideas.
To improve vaccination coverage and to succeed in eliminating measles, Lopalco stressed the need to address the
challenges as part of a “multiphase approach,” beginning with the active offer of vaccination.
“Vaccine safety is increasing,
vaccine coverage is increasing, disease incidence is decreasing,
and then public trust is decreasing.”
Pier Luigi Lopalco, European Centre for Disease Prevention and Control (ECDC)
Discussion
Discussion centered on two topics: 1) What lessons, if any, about age of vaccination can be drawn from recent
measles outbreaks in the Americas; and 2) The basis for strong political commitment to vaccination in the Americas, and
how this might be different in Europe.
Outbreaks and Age of Vaccination
During the large measles outbreak in Quebec, Canada, in 2011, a number of the cases were in people who had been
vaccinated. According to one participant, vaccinated children who had received the first dose of vaccine at or before 12
months of age were more susceptible than children who had received the vaccine at 15 months of age or later. Therefore,
there is a push in Canada to give the first dose later in life.
This contrasts, however, with findings in some resource poor countries. In Guinea-Bissau in West Africa, for example,
public health workers are advocating for giving the first vaccine at four or six months of age because of weak transplacental
antibodies from mothers. “We have two different forces moving, and whether the Quebec experience is unique or will be
repeated anywhere else we’re waiting to see,” the participant said.
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Progress Toward Rubella Elimination And CRS Prevention in Europe Proceedings
Basis for Strong Political Commitment in the Americas
One participant asked why it is that the political and social commitment to vaccination is very high in the Americas, and
what Europe might be able to apply from this experience. Respondents noted several important factors:
•
•
•
•
•
•
Awareness of huge economic and health disparities in the Americas. Although the extent of poverty in
the region is not as severe as in parts of South Asia and sub-Saharan Africa, the World Bank has defined the
Americas as having the greatest disparities.
Public health leadership and partnerships in Latin America and the Caribbean: Dr. Ciro de Quadros
and other public health leaders have nurtured the commitment of national political leaders, based on
recognition of the right of all children to have equal access to vaccination services.
Country ownership in the PAHO Region: Public health leaders have worked for the development and
implementation of vaccine laws, which in turn reinforce a sense of country ownership.
Visibility of political leaders: Political leaders’ direct involvement in vaccination activities inspires further
commitment. Presidents will go on national TV to support or launch a vaccination campaign. The husbands
and wives of presidents are also engaged. For example, presidents’ wives initiated a campaign for neonatal
tetanus.
Prioritization of public health issues in Europe: Issues such as obesity and diabetes are prioritized as
having the highest burden of disease. Within vaccination, resources must go to both the introduction of new
vaccines and enforcing older ones, sometimes leading to the neglect of MMR.
Political leadership and commitment varies within Europe: Lower coverage is a bigger problem in
Western Europe than in the East. Progress has been strong in the former Soviet Union Republics and in
Central and Eastern Europe where political leadership for immunization has been influential.
The GAVI Alliance and Measles/Rubella Vaccine
The mission of the GAVI Alliance is to save children’s lives and protect peoples’ health
by increasing access to immunization in the poorest countries. To advance this mission,
in November 2011, GAVI decided to support the elimination of rubella using the combined
Measles Rubella (MR) vaccine.
Helen Evans, Deputy CEO of GAVI, said that fifty-one countries are eligible to apply
to participate in the new program. GAVI will fully fund the cost of catch-up vaccination
campaigns targeting children nine months to 14 years of age, covering both vaccine and
operational costs. To be eligible, countries will be required to pay the ongoing costs of routine
MR vaccination. By 2015, GAVI aims to have vaccinated 588 million children in 30 countries.
Evans noted that by basing their approach on the Measles Rubella vaccine, GAVI is
directly extending support for the measles elimination program. In addition, support for rubella
introduction—along with GAVI’s support for HPV vaccine—means the alliance is placing an
explicit focus on women’s reproductive health and on maternal and child health.
Rome, Italy, 8-10 February 2012
13
PANEL: Heterogeneous Roles of Pediatricians in the WHO/EURO
Immunization Programs
A second panel addressed the roles of pediatricians in Europe. Panel moderator, Dr. Andreas Konstantopoulos,
President, European Pediatric Association, set the stage, presenting both a regional and global context for MMR
immunization, and factors that affect variable rates of coverage. Globally, one factor underlying low vaccine coverage
rates is simply the ratio of pediatricians to patients. Two studies of European countries showed that pediatricians in the
region are typically responsible for 1,000 to 2,000 patients. In Nigeria, there is 1 pediatrician per 63,000 children (2008),
and in Malawi the number rises to 1 pediatrician per 90,700 children.
Another factor at work in the European region is substantial opposition to MMR vaccination among healthcare workers,
including opposition by:
•
•
•
25 percent of midwives in Germany (2008)
6 percent of doctors in France (2001)
22 percent of patients in Italy, who missed MMR vaccinations due to lack of appropriate information from
doctors (2001)
“That means we have to educate the healthcare workers,” Konstantopoulos said.
He pointed out huge differences among European countries in terms of both the gap in coverage with the second
dose, as well as the wide variation in vaccination schedules among countries. “In Europe, we don’t have a harmonized
schedule like you have in the United States. That’s a problem,” he said.
Measles in Europe, 2011
(36 of 53 Member States)
France
15076
Germany
1480
Italy
5090
UK
1030
Romania
2815
Switzerland
652
Spain
1914
Belgium
563
OVERALL 32154
As of January 1, 2012
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Progress Toward Rubella Elimination And CRS Prevention in Europe Proceedings
A Look at Six European Countries
Dr. Nicole Guérin, French Pediatric Society, described the critical role of French pediatricians in the country’s
measles control program. About 2,700 ambulatory pediatricians distributed throughout the country play a prominent role
in implementing the program. They are front-line vaccinators, and their coverage rates for both first and second doses
of vaccine are about 10 percent higher than that provided by general practitioners. Nonetheless, vaccination rates vary
geographically, with the lowest vaccination rates and the highest case rates in the southeast, where there are more than 30
cases per 100,000 population.
Guérin noted that many of the cases reported in 2011 occurred in people 15 years of age and above. Based on this,
“The pediatrician alone will not be able to solve the problem without the aid of politicians and other professionals, and
probably international help also,” Guérin said.
Georgia
Georgia’s vaccine program has dealt with significant political and resource hurdles hover the past 45 years. Dr. Nino
Kandelaki, Secretary General, Georgian Pediatric Association, described the vaccination journey of his country, a
former Soviet Republic. While a first dose of monovalent measles vaccine was introduced in 1966, use of a second dose
only began in 1985. Following independence from the Soviet Union in 1991, Georgia encountered substantial difficulties in
reaching coverage targets due to political, economic, and infrastructural changes. In 1994, a critical vaccine shortage led
to the suspension of the 2nd dose of measles vaccine. Only in 1997 did coverage with both doses resume.
In 2004-05, the gaps in coverage caught up with Georgia. In a major disease outbreak, 8,391 cases of measles and
5,151 cases of rubella were reported; 34 percent were in people over the age of 15. In 2004, the country also adopted the
combination vaccine MMR.
Within this difficult context, pediatricians have played a vital role in measles vaccination. The Georgia Pediatric
Association has supported a government vaccination campaign by supplying vaccines and cold boxes, and leading
a communication and social mobilization campaign with the slogan: “Timely immunization is your child’s bodyguard.”
UNICEF and the U.S. government also have supported vaccination since 2004, securing the non-interrupted provision of
vaccine and injection safety vaccines for the routine program.
As of 2011, there were a total of 63 confirmed measles cases, with an annualized incidence of 1.75 per 100,000
people. Going forward, the Government of Georgia will continue to strengthen routine childhood immunization with the goal
of more than 90 percent coverage among 1-and 5-year-olds.
Germany
A decentralized health care system serves Germany’s population of around 82 million, with responsibility for
vaccination falling to the country’s 16 federal states. Dr. Ole Wichmann, with the Robert Koch Institute, Germany,
reported that government-recommended vaccines--including two doses of measles vaccine--are free of charge and
voluntary. There is neither mandatory vaccination for school entry nor a central immunization register.
Pediatricians and other private physicians play a critical role in administering vaccine, and are reimbursed by the
health insurance system. In the absence of a mandated reporting system, it is the association of physicians that collects
case data and takes it to the media. Local public health offices are responsible for disease surveillance and outbreak
control, but are chronically understaffed, limiting the effectiveness of catch-up campaigns.
While overall two-dose routine measles vaccinations have been improving, serious gaps and troubling trends remain.
Geographically, coverage has been better in the Eastern region than Germany’s West. In 2011, measles resurged. Of
1,600 reported cases of measles, 520 were in the country’s Southwest, and 90 percent of all reported cases were in
unvaccinated individuals.
The median incidence by age has been increasing. Between 2003-05 and 2007-09, measles incidence among youth
under the age of 10 had decreased, while incidence among those ages 10 to 19 and 20 to 29 had increased. This finding
led to the recommendation of individual catch-up vaccinations in adolescents.
Rome, Italy, 8-10 February 2012
15
On the positive side, the Minister of Health has recently announced that measles elimination is a high priority, and
positive media coverage has increased. Major challenges include pockets of susceptible people, primarily unvaccinated
older children and adolescents. Migrants present a mixed picture—while some migrant groups have larger numbers of
unvaccinated, others have better coverage than native-born German children. Traveling communities like the Roma often
miss out on vaccination.
Vaccine skeptics include physicians and especially midwives. In 2011, several outbreaks occurred in hospitals.
Wichmann reported that a patient in an oncological ward died of measles after contracting it from unvaccinated nurses in
the ward. There is no regulation prohibiting unvaccinated staff from working in such settings.
Going forward, Germany is establishing a national verification committee for measles and rubella, with the secretariat
to be based at the Robert Koch Institute. The national action plan for measles and rubella is being updated, and in February
2012 the parliament decided to make rubella a notifiable disease for the first time.
According to Wichmann, two other measures are essential: national catch-up campaigns, especially in the country’s
Southwest, and companion communication campaigns. “If both of these measures are not put into place we will have
difficulties achieving the elimination goal by 2015,” he concluded.
“After school entry, we have no data actually that shows the success
of our recommendation for catch-up. We don’t have a clue if
young adults get the vaccine shot or not.”
Ole Wichmann, Robert Koch Institute, Germany
Italy
Italy, along with many other European countries, missed an initial goal of eliminating measles and congenital rubella
set for 2007. In 2011, the country approved a new elimination plan for measles, congenital rubella, rubella in pregnancy
and postnatal rubella. The target date is 2015, said Dr. Stefania Iannazzo, Ministry of Health, Italy.
The Italian Constitution guarantees health as a right, and the Ministry of Health sets national-level plans and defines
general principles and essential levels of assistance. It is up to the country’s 21 regions to autonomously set and implement
their health policies based on those guidelines. On a local level, Departments of Prevention are responsible for ensuring all
preventive activities.
Family pediatricians are integrated into the national health systems, but they do not directly provide vaccinations.
Iannazzo described their role as synergistic: providing diagnosis and treatment from birth to 16 years of age, and assisting
with disease prevention through promoting and monitoring vaccine use.
Coverage has increased in recent years, with outbreaks of waning strength. Measles Containing Vaccine (MCV)
coverage for the first dose in children under 2 years of age increased from 83.9 percent in 2003 to 90.6 percent in 2010.
A second dose of MMR at 5-6 years of age was introduced in all geographical regions in 2004, and supplementary
vaccination campaigns have been conducted for people born between 1991-97.
Nonetheless, Italy has experienced a slow accumulation of susceptible individuals, along with a trend toward an
increase in the age of infection.
In 2004, the Ministry of Health introduced a second dose of MMR, but its coverage is not recorded. Surveillance for
measles, rubella in pregnancy, and congenital rubella has been in place since 2005.
To eliminate measles and rubella by 2015, Iannazzo cited the need to strengthen surveillance systems, through
improving case investigations, laboratory confirmation of cases, molecular typing and seroreporting by each region.
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Progress Toward Rubella Elimination And CRS Prevention in Europe Proceedings
Russian Federation
Of all the countries that presented, measles vaccination coverage was strongest in the Russian Federation, where
97.2 percent of children six years of age had been vaccinated as of January 2010. With a morbidity rate of less than one
measles case per million people, Russia has met the WHO criteria for measles elimination since 2007, reported Dr. Leyla
Namazova, Scientific Center of Children’s Health RAMS, Russian Federation.
Namazova reported on the sometimes bumpy road to this achievement and the current challenge of imported
measles. Consistently high coverage rates were the norm prior to the fall of the Soviet Union. However, in the early 1990s,
coverage declined. Then, the new millennium brought renewed commitment, and the government gave responsibility to a
special company for vaccinating all people younger than 35 years.
In the last several years, however, the number of imported cases is increasing, including in Moscow and the Republic
of Chechnya. These cases come from a number of regions, including Western Europe and Central Asia. Other cases are
appearing in unvaccinated children and young adults.
In addition to the problem of importations, the mass media is increasingly presenting false information on vaccination,
contributing to anti-vaccine sentiment.
Public/Private Partnerships: New Opportunities
Excerpts from a talk by Dr. Louis Cooper, Past President of the American Academy
of Pediatrics
It seems on the surface very simple to vaccinate a child, but the truth is that immunization
and the immunization enterprise—because it depends on an enterprise—from the basic
science laboratory, to industry, clinical trials and broad expansion, to public health and private
clinicians in the community, and to the media, this is exceedingly complex.
We’ve set a remarkable standard for vaccine preventable disease that is unlike anything
else in health or medicine or in fact anything else in society. What else in society do you have
to get over a 90 percent bar to say that you’ve succeeded?
I hope all of you are as proud as I am to be part of this vaccine enterprise. It depends
upon a triad of sound science, of adequate and sustained resources, and finally of public will
and trust through social mobilization and advocacy. The roles of advocacy and education are
critical ones for pediatricians. As pediatricians we have unique responsibilities and assets
because people do trust us. How we better use those unique assets is critical to getting us
across, what we call in my country, the “goal line” of protecting all our children.
Pediatricians really do share a commitment to the inherent worth of every child. We
know immunization saves lives. The challenge is that immunization programs require a
collaborative enterprise.
The presentations this afternoon made the case that there’s no two nations that are alike,
and how you do this in each country has to vary depending on the characteristics and the
culture of the country. By bringing together the constellation of people we have here today—
which includes public health people, government officials and also heavy representation from
the pediatricians of Europe—we are building partnerships that can move forward.
Rome, Italy, 8-10 February 2012
17
Closing Comments
In his closing comments, Dr. Samuel Katz, noted that in the first 11 months of 2011, Europe had experienced more
than 30,000 cases of measles, “which just shouldn’t be occurring in developed nations.”
He emphasized the point that “measles and rubella are inextricably woven together in our prevention programs,”
and that the day’s discussions provide a framework for the upcoming two days of discussion around rubella. “Whatever
happens with rubella is going to happen because it’s conjoined with measles,” he said, noting that monovalent rubella
vaccine is no longer used. Instead, vaccines contain some combination of measles, rubella, mumps, and varicella.
Also of note in the day’s session was that, “In the 2011 measles outbreaks in Europe, nearly 50 percent of the cases
occurred in individuals over the age of 15 years—not 15 months but 15 years.”
Katz pointed out that the fight against measles and rubella will be assisted by the unpleasant fact that measles is
almost a 100 percent visible disease. This is similar to smallpox, whose visibility made eradication much easier. It is not
the case for polio, nor for rubella, which can exist and be transmitted sub-clinically.
Katz concluded by echoing Cooper’s words, calling on pediatricians to lead the fight in implementing immunization
against measles and rubella.
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Progress Toward Rubella Elimination And CRS Prevention in Europe Proceedings
SESSION II:
Background Information
Virus
Dr. Joseph Icenogle, US Centers for Disease Control and Prevention
“We have in rubella a two-faced little virus that causes almost no disease in children and has a devastating effect
on pregnant women and their developing fetuses,” Icenogle began. He then gave an overview of the history, structure,
genome and life cycle of the virus.
Described in the 18th century, rubella was recognized as a disease independent of measles in 1881. Until 1941 it was
considered a mild childhood rash illness, and little thought was given to it. Then, in 1941, N. McAlister Gregg made the
seminal observation that congenital cataracts are associated with German measles (as it was then called).This discovery
debunked the prevalent opinion that all birth defects were genetic in origin. Much work followed, ultimately establishing
Congenital Rubella Syndrome as a prevalent and serious disease. In 1962, the virus was first detected in tissue culture.
A devastating rubella epidemic swept the world between 1962 and 1965, launching the era of rubella control and
elimination, emphasizing the urgent need for a vaccine to prevent rubella and CRS.
Rubella Virus-A Class in Itself
Rubella is an enveloped single-stranded RNA virus, belonging to the class of Rubivirus, of which it is the sole member.
Unlike related alphaviruses, rubella has no animal host, but relies entirely on human to human transmission. Icenogle
described its structure partly by analogy to the related alphavirus Sindbis about which more is known.
The outer layer of the virus is composed of E1 and E2 proteins, both of which elicit neutralizing antibodies against
rubella. While both proteins play a major role in long lasting protective immunity, E1 is particularly immunogenic.
Below this surface is a bilayer lipid membrane, and below that the nucleocapsid. However, unlike related viruses, the
outside of the rubella nucleocapsid is embedded in the lipid membrane. Therefore, disassembly of the virus nucleocapsid
involves the disassembly of the membrane itself.
The deep interior of the virus contains the nucleic acid. The RNA genome contains both highly conserved areas, and
regions of great heterogeneity. In terms of variability, the genome of the circulating viruses will change on a time scale
of months to years – making it less variable than rapidly changing polioviruses, and more variable than measles viruses,
which changes on a timescale of years to decades.
Based on genome sequencing, the rubella virus is divided into 13 genotypes, each belonging to one of two clades.
Within tissue culture, the virus grows in about three days, and can make persistent infections—a hallmark of Congenital
Rubella Syndrome (CRS). Little is currently known about pathogenicity of the rubella virus on a molecular level.
“We have in rubella virus a two-faced little virus that causes
almost no disease in children and has a devastating effect
on pregnant women and their developing fetuses.”
Joseph Icenogle, U.S. Centers for Disease Control and Prevention
Rome, Italy, 8-10 February 2012
19
Clinical and Follow-up
Dr. Louis Cooper, Past President of the American Academy of Pediatrics
Dr. Cooper shared lessons from The Rubella Project, based on work with 1,000 patients and parents from 1962 to 1998
at New York University and Columbia University, conducted by a team of four dozen people. This work was prompted by
an epidemic of babies born with purpuric spots, jaundice and low birth weight. He noted that full-fledged rubella epidemics
can affect 1 percent of pregnancies. In fact, it was the US epidemic in the 1960s, with its legions of mentally and physically
impaired babies, that led to the passage of the first Federal early childhood education program statutes in the U.S.
Cooper described the findings of this work in terms of the clinical manifestations of rubella, which vary greatly. The
disease can be as devastating as severe measles with a high fever, and it can be absolutely subclinical. Rubella acquired
in utero becomes a chronic infection, with a quite different pattern of antibody responses and viral excretion. “However,
many newborns who are infected may appear normal at birth, so if your detection system is dependent upon the newborn
nursery and neonatologist, forget about it. They’re going to miss most of them,” Cooper said.
When rubella occurs in the first weeks of pregnancy, the likelihood of infection and of damage is high. Virus can be
found in virtually every organ in the developing fetus, and every organ can be damaged in a baby born with CRS. Rubella
at this early stage of pregnancy, before organogenesis is complete, can cause eye cataracts and heart disease. Rubella
after the first eight weeks in utero tends to attack the developing brain, and hearing.
Hearing loss is the most common defect. “In countries like the U.S., where we’ve eliminated congenital rubella, we’ve
been able to close schools of the deaf,” he said. Another common manifestation is transient bone lesions that disappear
completely by age two months in most kids. CRS can result in retinopathy, or, more rarely, glaucoma.
There is a shotgun effect on the central nervous system. It may cause mental retardation or autism. In fact, “Congenital
Rubella Syndrome is the only known and therefore preventable cause of autism,” Cooper said. Adolescents with CRS may
experience endocrine disorders, particularly insulin-dependent diabetes mellitus. Rubella virus antigen has been found in
children with thyroid disease. The condition also depresses cell mediated immune responses.
Many children born with CRS require a lifetime of total care. In New York, the financial costs for those in supported
housing are about US$175,000 per person per year. “It is a tremendous burden,” Cooper said. “Obviously, the human
costs are immeasurable.”
“I have spent roughly half a century with a life that has been
rearranged and in many ways made rewarding and meaningful
and in other ways made sad while tracking this virus.”
Dr. Louis Cooper, Past President of the American Academy of Pediatrics
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Progress Toward Rubella Elimination And CRS Prevention in Europe Proceedings
Incidence per 10,000 of Congenital Defects/Diseases
40
30
30
20
12
11
10
6
5
2
1
0
Hearing Loss
Cleft Lip
or Palate
Down Syndrome
Limb Defects
Spina Bifida
Sickle Cell
Anemia
PKU
Pathogenesis
Dr. Jenny Best, Kings College London
Although the pathogenesis of rubella is not fully understood, Dr. Jenny Best described what is now known about the
virus. It is spread by droplets from the upper respiratory tract, and excreted from seven days before to seven-to-ten days
after the onset of rash. Within that time period the patient is probably infectious for a total of about ten days. The virus can
be detected in the blood, stool and urine, with samples from the nasopharynx being the best source for isolation of the virus.
The incubation period for rubella is typically about 14 days. Virus replication takes place in the buccal mucosa and
lymphoid tissue. It is spread through the lymphatic system which leads to viremia and systemic infection. Rash usually
starts on the face and then spreads down the body and onto the limbs.
Fever can occur, and joint problems sometimes develop as the rash disappears. Joint symptoms such as arthritis
are most common in post-pubertal females and can last anywhere from a few days to a month. The presence of rubella
antibodies in synovial fluid suggests that immune complexes may be responsible for such joint problems. Hormonal factors
may also play a role, and there is an association with the menstrual cycle. There is no convincing evidence that rubella or
rubella vaccination is associated with chronic joint disease.
Rubella antibodies can be detected by hemagglutination inhibition a day or two after the onset of the rash. More
commonly, ELISA techniques are used to detect antibodies by about six to seven days after onset of rash. Both rubella
IgM and IgG are important for diagnostic purposes. Cell mediated immune responses have also been detected, but little is
known about this.
In congenital rubella, most damage is done early in pregnancy during organogenesis. However, the persistence of
rubella virus means that there may be delayed manifestations of congenital rubella, in late infancy or even beyond. It is
easy to detect virus in the lens of the eye, especially in lenses removed in the first year of life, but the virus has also been
detected in the lens in children up to the age of three, and in the thyroid up to age five .
Best noted that there is a lot that is still not understood about rubella, including how it causes ongoing damage in
infants and young children. Studies in cell cultures show that rubella inhibits cell division and can induce programmed cell
death. Rubella also disturbs signaling pathways that control cell differentiation, proliferation and survival. On the other hand,
interferon may limit rubella virus replication.
Rome, Italy, 8-10 February 2012
21
Insulin-dependent diabetes mellitus may develop in the second decade of life in CRS children, possibly the result of
an autoimmune reaction or direct damage caused by persisting virus. Scientists have found virus-induced damage to islet
cells in the pancreas.
Best urged that more funding be made available to understand the mechanisms by which rubella virus interferes with
normal cell growth, as well as the mechanisms that cause fetal damage.
Some Common Manifestations
of Congenital Rubella
Permanent
Transient
• Cataract
• Low birth weight
• Retinopathy
• Hepatosplenomegaly
• Sensorineural deafness
• Meningoencephalitis
• Heart defects
• Thrombocytopenic purpura
• Microphthalmia
• Bone lesions
• Microcephaly
Vaccine
Dr. Stanley Plotkin, University of Pennsylvania, United States
Globally, nine different manufacturers currently make rubella vaccines, and most use the RA27/3 virus strain. Dr.
Plotkin described how he had developed the first vaccine based on that strain. In 1964, when rubella was still common
during pregnancy, Plotkin’s lab isolated rubella virus from one of the many aborted fetuses it received for study. He grew the
virus in WI-38 human fetal fibroblast cell strains developed at The Wistar Institute, and attenuated it.
The vaccine ultimately proved to be immunogenic whether delivered via subcutaneous, intramuscular, intranasal or by
aerosol routes, and has been in use since the 1960s. Today it is most commonly administered as part of combined
vaccines against measles (MR), measles and mumps (MMR), or measles, mumps and varicella (MMRV). A first dose is
usually given between 9 and 15 months of age.
Over the years, numerous studies have been conducted to assess the long-term persistence of rubella antibodies after
vaccination with the RA27/3 strain. Results ranged from 63 percent to 100 percent persistence over up to 22 years.
Studies of efficacy against rubella disease during outbreaks have found protective efficacy of from 90 percent to 100
percent. One efficacy study was done in a Toyota factory in Japan, and within two weeks after vaccination, the only rubella
cases were in unvaccinated boys. The vaccine induces neutralizing antibodies to rubella, those initially seronegative
become seropositive.
Target groups for vaccination include infants as part of routine vaccination; older unvaccinated children and
adolescents in catch-up campaigns; college students if they haven’t been previously vaccinated; childcare personnel;
healthcare workers; military personnel; adult women before pregnancy; adult seronegative women after pregnancy; and
adult men in contact with pregnant women.
“Essentially, congenital disease no longer exists in the U.S., thanks to
the general vaccination program. In the entire Western hemisphere,
rubella essentially has been eliminated except for importation.”
Stanley Plotkin, University of Pennsylvania
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Progress Toward Rubella Elimination And CRS Prevention in Europe Proceedings
Vaccine reactions in children are few: one study of twins showed fever present in between 1 and 3 percent of
vaccinated twins; generalized rash in 1.6 percent more of the vaccines than the controls; and joint symptoms in 0.7 percent
more of the vaccines. Adult women may have transient joint symptoms after vaccination.
An important concern has been whether or not the vaccine would harm the fetus of a woman who is inadvertently
vaccinated during pregnancy. Of 2,931 seronegative women followed in 11 studies in 11 different countries, not one of the
children born had abnormalities associated with CRS. “This does not mean that one should vaccinate during pregnancy,
but it does mean that the fear of causing an abnormality is not justified,” Plotkin said. This clears the way for the vaccine to
be used in mass vaccination campaigns.
Plotkin noted that each potential obstacle to rubella elimination can be overcome. The cost is low, at $0.25-0.50 per
dose. While there is some sub-clinical inapparent rubella, rash is present in 60 percent to 70 percent of cases. While
surveillance of CRS can be difficult, a screen for neonatal cataracts yields a close estimate of the extent of the condition.
A final concern is the paradoxical enhancement of susceptibility of pregnant women. This can be a problem when vaccine
coverage is low. Then women can grow up without being naturally infected and without getting vaccinated. This leads them
to be susceptible to the virus. High coverage—of at least 80 percent--eliminates this perverse effect, Plotkin explained.
Thus far, the vaccine has been used to eliminate rubella in Scandinavia, the U.S., Canada, the Caribbean and Latin
America. Elimination has been set as a goal in the European Region.
“Essentially, congenital disease no longer exists in the U.S., thanks to the general vaccination program. In the entire
Western hemisphere, rubella essentially has been eliminated except for importation,” Plotkin said. He gave two people
special credit for this achievement. “ One is Ciro de Quadros, who led the effort in the Western hemisphere to eliminate
rubella, and the other is Susan Reef, who has worked tirelessly to promote rubella vaccination throughout the world.”
Impact of Rubella Control and Elimination Strategies,
The Americas, 1990 – 2007*
Nb. Rubella Cases (in thousands)
150
Accelerated
Rubella Control
Strengthening of
Measles Elimination
Reduction: 98.5%
(1998 to 2006**)
100
Rubella
Elimination
50
Strengthening of Febrile
Rash Illness Surveillance
0
1990
1992
1994
1996
1998
2000
2002
2004
2006
* Includes rubella cases reported to PAHO as of Epidemiological Week 19/2007.
** Provisional data.
Source: Country Reports to Immunization Unit, PAHO
Discussion
One topic of discussion was whether infected infants need to be isolated to prevent transmission of rubella.
“Newborns with congenital rubella are contagious, period,” Cooper said. This was clear when personnel working in a
hospital nursery were infected. Although the level of contagion declines fairly quickly, and CRS babies can be taken home
without having transmission to other susceptible children, there are risks to doing so.
Plotkin reiterated that a fetus infected with rubella is infected in every organ, which explains why excretion of virus
occurring after birth can continue for long periods of time.
Rome, Italy, 8-10 February 2012
23
SESSION III:
Diagnostics
Rubella in Pregnancy
Dr. Maria Grazia Revello, Fondazione IRCCS Policlinico San Matteo, Italy
Dr. Revello urged screening of women of childbearing age—before they become pregnant—to identify those who lack
rubella antibody acquired either as the result of either vaccination or natural infection. These seronegative women are at
risk of contracting rubella during pregnancy.
“Unfortunately, in Italy the vast majority of rubella screening is performed during pregnancy and not before,” she said.
Revello recounted the case of a 33-year-old woman counseled in her lab in 2008. After having trouble conceiving, the
woman used assisted procreation. While she eventually became pregnant with twins, nobody along the way had checked
her status for rubella, Revello recounted. The woman became infected with rubella when she was 15 weeks pregnant, and
testing showed that both fetuses were infected as well. The woman and her husband decided to terminate the pregnancy.
That year, Revello’s center diagnosed and counseled another 21 pregnant women infected with rubella. They came
from all over Italy, indicating that very few regions of the country had been spared of rubella that year. “Termination of
pregnancy was the most frequent consequence of the rubella diagnosis,” Revello said
During pregnancy, both amniotic fluid and fetal blood can be used in diagnosis. Yet, diagnosis can be complicated
by factors such as the time interval between maternal infection and the diagnostic procedure, as well as the quality of
the clinical samples that are examined and the techniques used. Today, only four to five laboratories worldwide have
experience in prenatal diagnosis of congenital rubella.
Revello also urged the implementation of postpartum vaccinations. “I’ve very ashamed to tell you that in Pavia as well
as many Italian hospitals, seronegative women are not vaccinated when they have delivered. They are discharged not with
the vaccination, but with the recommendation of getting the vaccination. That’s, of course, not enough.”
“Termination of pregnancy was the most frequent
consequence of the rubella diagnosis.”
Maria Grazia Revello, Fondazione IRCCS Policlinico San Matteo, Italy
Molecular Diagnostics
Dr. Joe Icenogle, U.S. Centers for Disease Control and Prevention
Dr. Icenogle gave a broad and detailed description of the tools involved in molecular diagnosis, their advantages and
challenges. Importantly, molecular tools make diagnosis possible earlier in the course of infection than do serologic tools.
This is because rubella RNA can often be detected in oral fluid before rubella-specific IgM antibody materializes in the
blood sometime after rash onset.
Where in the past, RNA was identified after being grown in viral culture, today’s molecular methods such as RT-PCR
can make such detection fast and easy.
However, timing matters. If RNA specimens are collected early on in infection, molecular methods work well. In the
first three days of rash onset, RT-PCR would confirm more cases than IgM in blood. However, molecular methods are not
particularly useful if specimens are collected a week after rash onset, as the amount of virus has already declined.
Ease of use is a factor, as specimens for RNA detection can be collected by non-invasive means, including through a
simple swab to obtain oral fluid.
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Progress Toward Rubella Elimination And CRS Prevention in Europe Proceedings
In general though, “two specimens are better than one,” and it is better yet if both molecular and serologic methods are
used to confirm rubella, Icenogle said.
He described the three molecular tools used by the CDC for detection and characterization of rubella RNA. They are:
•
•
•
Conventional RT-PCR diagnostic assay that uses three primers to accommodate sequence variability;
Real time assay that uses thermal cycling to amplify rubella RNA, and fluorescence to identify its presence.
It can detect down to less than 250 copies of rubella RNA in the specimen, making it highly sensitive;
An assay that uses two rounds of PCR to amplify the RNA product for sequencing and genotyping the viruses.
These techniques overcome the difficulty of low copy numbers in typical rubella virus specimens. The sequencing
and genotyping method has allowed scientists to identify the source of imported virus. In order to use the technique for
surveillance, standardized reagents must be made available to laboratories—and they can be prepared in relatively simple
kits, Icenogle said. The Kits have now been used for training in laboratories in five WHO regions.
In addition to these methods, another method used to detect individual cases uses dried blood spots and serum
collected within two days of rash onset for some molecular testing. “Molecular diagnostic methods for detection of
Congenital Rubella Syndrome still must be improved”, Icenogle said. For example, it would be valuable to know how long
viral RNA can be detected in CRS cases..
Serology and International Units
Dr. Liliane Grangeot-Keros, of the National Reference Laboratory for Rubella, Clamart, France
There are a multitude of different serologic assays manufactured by dozens of diagnostic companies around the world.
Ideally, the results from a patient would be comparable, regardless of the laboratory or methods used. This is not the case.
Dr. Grangeot-Keros described a number of the challenges involved with the diagnostic tests for rubella. Serologic
techniques aim to measure the amount of rubella-specific IgG antibody in the blood. The test is particularly important
for women who are pregnant or who want to become pregnant, as IgG concentrations above a certain threshold indicate
immunity to the virus, while those below that threshold indicate susceptibility to infection and the need for immunization.
In the mid-1960s, Hemagglutination Inhibition assay (HAI) was used to measure antibody, but the method was
cumbersome and neither specific nor very sensitive. Beginning in the early 1980s, enzyme and chemiluminescent assays
replaced HAI. These newer methods report results based on International Units of IgG per milliliter ((IU/mL). However,
every test works differently, leading to widely divergent conclusions, Grangeot-Keros explained.
“There can be a ten-fold difference in results depending on the assay used,” she said. “This range is so large that,
depending on the assay, a subject can be considered either immune or non-immune.”
This range of results is partly caused by the use of different IU cutoffs, ranging from 10 IU/mL to 15 IU mL, which
represents a potentially significant difference. Different assays also detect different rubella antigens, presenting another
confounding factor.
Grangeot-Keros said that the situation raises several questions: is it sound to report results in “International Units”;
should all assays use the same cut-off; can a “protective” cut-off be determined; should equivocal results be interpreted
in the same way; how dependent are these issues on the situation, i.e., rubella antibody screening during pregnancy or
epidemiological (seroprevalence) studies.
“There can be a ten-fold difference in results depending on the assay
used. This range is so large that depending on the assay, a subject can
be considered either immune or non-immune.”
Dr. Lilane Grangeot-Keros, Clamart, France
Rome, Italy, 8-10 February 2012
25
Roundtable with Diagnostic Companies and WHO
These and related questions were discussed in a roundtable with diagnostic companies. Icenogle noted that the U.S.
CDC set its immunity level at 10 IU/mL based not only on scientific studies, but also on the information gained from public
health service activities, which indicated that this level of immunity did not result in any significant breakthrough disease.
He also pointed out that establishing immunity thresholds based on a single serologic test is inherently incomplete
because it does not assay all components of the immune system, or account for variability in immune responses from
person to person.
Representatives of the companies Abbott, bioMériex, Diasorin, and Roche spoke to complexities of diagnostic assays
and possible actions needed.
Abbott’s Gregory Maine suggested that rather than thinking about different cutoffs for different assays, a reference
measurement system should be developed for rubella IgG, and approved by the Joint Committee of Traceability in
Laboratory Medicine. Commercial assays would then have to map to that measurement standard.
“It would be hard to do, but you have to make a decision. At some point in the world, someone said ‘This is a meter,
we’re all going to call this a meter, and the same must be done now,” he said.
On the other hand, Antonio Boniolo from DiaSorin made the case that rubella IgG assays cannot genuinely be
deemed quantitative, given that they reflect unknown combinations of concentration and binding capacity of the antigens
being measured. In addition, different assays use different automation strategies to speed up results, and this might
affect reaction kinetics, potentially leading to different antibody selection/recognition. He proposed that diagnostics “stop
pretending too much from antibody quantitation,” and agree on ‘consensus’ proficiency panels (of 20 or more samples)
from individual patients that could validate the accuracy of assays. He suggested that the panels could be made available
by an independent manufacturer’s organization. Ultimately, a qualitative or semi-quantitative analytical environment would
evaluate an assay as reactive, not reactive, low reactive, or some other useful categories.
Ralf Bollhagen of Roche Diagnostics elaborated on some of the problems in the standardization of rubella IgG assays.
These include working with a heterogeneous analyte (polyclonal human IgG of different subclasses, different maturation,
directed to different antigens and epitopes); different assay principles (sometimes including different secondary antibodies);
and different buffers.
bioMériex was the only company which expressed overall satisfaction with the current situation. The company
representative compared two of their assays. One was developed in 1997 for the European Reference, has a positive cutoff of 15 IU/mL, and is calibrated with the second preparation of the WHO International Standard. The other has a positive
cut-off of 10 IU/mL for the US Reference, and is calibrated with the third preparation of the WHO International Rubella
Standard. Both have worked well, and of thousands of tests administered since 2004, there have been only two customer
complaints for correlation issues.
David Featherstone from WHO briefly outlined the WHO international standards. WHO’s Third International Standard
was developed in 1995 and was assessed by 11 laboratories in seven countries using a range of methods including HI and
ELISA. New generation assays used today were not part of that original assessment. Furthermore, the sample it used was
an immunoglobulin, not a serum sample. “It was a purified serum…which is not confused by some of the other factors that
we find in patient serum. I think that is one of the reasons we’re getting some variability in the tests,” he said.
Plotkin noted that using an assay against E1, which is the major inducer of neutralizing antibody, provides information
that is biologically close to what is needed. He suggested that the situation is similar to Lyme disease, in that ELISA is used
for screening, and a Western blot test is used to confirm infection. “The way forward is to develop better tests using E1 as
the antigen…and to get away from what is essentially binding antibody measurements,” he said.
26
Progress Toward Rubella Elimination And CRS Prevention in Europe Proceedings
During discussion, Icenogle suggested that a next step could be to hold an unofficial meeting including commercial
and public health sectors to better define the issues. Later in the Symposium, Icenogle clarified the context of this issue,
noting that, in general, today’s commonly used assays work well in determining immunity in more than 90 percent of cases.
“The discussion is about incremental improvements in IgG testing, specifically in two areas,” he said. “One is improving the
ability to detect immunity in that small percentage of individuals who we think are immune, but for which the tests do not
confirm immunity. The second is potential improvements in the long standing and effective standardization procedures for
these tests.”
“Seroprevalence in the United States using standard assays is above
90 percent, which is what you would expect for a population which is
essentially all vaccinated or naturally immune… So, the discussion is not
about the overall performance of these tests, it is about the incremental
improvements that might be applied to them.”
Joseph Icenogle, U.S. Center for Disease Control and Prevention
Rome, Italy, 8-10 February 2012
27
SESSION IV:
Global Epidemiology
Dr. Susan Reef, U.S. Centers for Disease Control and Prevention
The presentation on the global use of rubella vaccines was based on research conducted by Dr. Reef along with Drs.
Peter Strebel and Marta Gacic-Dobo from the World Health Organization (WHO). The presentation covered the uptake of
rubella-containing vaccines (RCVs) and the impact of the GAVI Alliance funding window for rubella.
In 1996, the first global survey on the use of rubella vaccines found that 83 countries were administering an RCV. By
2010, that number had reached 130. Over the same time span, the Americas went from 60% of countries using the vaccine
to 100%. In Europe, 74% of countries had introduced an RCV by 1996; by 2010 this reached 100%. The Western Pacific
Region more than doubled the number of countries using the vaccine, from 37% in 1996 to 78% in 2010. The Eastern
Mediterranean Region increased its use from 43% to 67% of countries over that period. In Africa, only two small island
countries were using the vaccine in 1996, increasing to only three countries by 2010.
Rubella Vaccine Use by WHO Region
1996 vs. 2010
1996
No. of countries (%)
2010
No. of countries (%)
AFR
2 (4%)
3 (7%)
AMR
21 (60%)
35 (100%)
EMR
9 (43%)
14 (67%)
EUR
39 (74%)
53 (100%)
SEAR
2 (20%)
4 (36%)
WPR
10 (37%)
21 (78%)
Global
83 (43%)
130 (67%)
Region
Today, 41% of the birth cohort around the world have access to an RCV – most commonly the RA273 rubella vaccine
virus, which has 95% effectiveness after one dose. Eighty-nine percent of countries administer the measles-mumpsrubella (MMR) vaccine; only 8% give the measles-rubella (MR) jab and 2% give the measles-mumps-rubella-varicella
(MMRV) vaccine. Last year, the WHO rubella position paper was updated. “Importantly,” said Reef, “SAGE recommended
that countries should seize the opportunity of the two-dose measles vaccine strategy to use the MR or MMR vaccines,
integrating measles and rubella prevention.”
In November 2011, GAVI opened a funding window to help countries introduce RCV into their national programs.
GAVI will be supporting the MR vaccine and part of the operational costs for a campaign targeting children 9 months to
14 years and 11 months in addition to a vaccine introduction grant. meet the operational costs of introducing an RCV. The
application guidelines are currently under development, but it is hoped that countries will be able to apply by mid-year. GAVI
anticipates introducing the MR vaccine to 30 countries by the end of 2015.
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Progress Toward Rubella Elimination And CRS Prevention in Europe Proceedings
Africa has 34 GAVI-eligible countries and the Americas have three, all of which have introduced an RCV. In the
Eastern Mediterranean, there are seven GAVI-eligible countries, none of which have introduced the vaccine. None of the
six eligible countries in Southeast Asia currently immunize against rubella; the same is true for five of the six GAVI countries
in the Western Pacific. Laos conducted the MR campaign in November 2011.
Africa and Southeast Asia, which are home to countries with the lowest rate of introduction of rubella-containing
vaccine and which lack rubella control goals, understandably have the highest CRS disease burden.
Globally, 124 non-GAVI countries have introduced an RCV and only 13 have not. Only seven of the 58 GAVI-eligible
countries have introduced the vaccine. Three regions have rubella goals and two have elimination goals. “Opening the
GAVI funding window to these regions gives them the opportunity to introduce rubella control to their poorest countries –
and to those with the highest burden of disease,” Reef said.
The Global CRS Burden
Dr. Emily Vynnycky, Health Protection Agency, Centre for Infections, United Kingdom
Dr. Vynnycky presented new research estimating the annual burden of CRS during 2000-2008, for the 193 WHO
member states, six WHO regions and globally. The study also revised the previous CRS estimate of 110,000 global
cases of CRS in 1996 to include countries which had already initiated rubella vaccination. In 1996, 126 countries had not
introduced an RCV, whereas by 2008, this number had fallen to 67.
The research by Vynnycky, Elizabeth Adams and other colleagues utilized a huge volume and range of data. They
searched 16 databases, finding 31 datasets available for countries that had not introduced a rubella vaccine by the year
2000. Twenty countries were covered by that data, including 14 in Africa. There were eight datasets from India and two
from Pakistan and Yemen. The quality of the data was extremely variable.
The study used a catalytic model to estimate the force of infection—the rate at which susceptible people are infected—
which is critical to determining the burden of CRS. The model categorized people as ‘susceptibles’, who then shift into the
‘immune’ category at a constant rate. Typically, the catalytic model yielded datasets spanning five or six age groups.
“To work out the CRS incidence per 100 ,000 live births, we took the proportions of susceptible women in a given age
range and multiplied them by the risk of infection during the first three months of pregnancy, when a mother infected with
rubella has a 65 percent likelihood of bearing a child with CRS,” said Vynnycky. For countries without any datasets, the
CRS incidence was taken to be the regional value. Multiplying this value by the number of live births produced an estimate
of the number of CRS cases.
In Benin, there were roughly 200 CRS incidences per 100,000 live births, compared with about 20 per 100,000 live
births for Ethiopia. The incidence of CRS was likewise quite variable for the Eastern Mediterranean and Southeast Asia.
There were a few limitations to the study: only about one-third of the serological datasets are from the period 1990 to
2008. The year of study is unknown for about one-third of the datasets and so the data were not entirely reliable. Data were
available for only 20 of the 67 countries under study.
To estimate the disease burden for countries that had introduced an RCV, Dr Vynnycky and colleagues used a
different model that estimates the transmission of rubella among males and females. It stratifies people into ‘susceptibles’,
‘pre-infectious’, ‘infectious’ and ‘immunes’ for every age group, starting with newborns. Because the model incorporates the
actual vaccination coverage over time, it explicitly describes how the force of infection changes over time. Putting together the estimates of both countries that had introduced vaccination and those that had not, the incidence
of CRS per 100,000 births is less than 50 in the Americas and Europe. Mongolia has more than 150 CRS cases per
100,000 births, while the case rate is between 100 and 150 in much of Africa.
In Europe, there was a large drop in the number of CRS cases between 2000 and 2008 and the confidence on those
estimates improved.
Rome, Italy, 8-10 February 2012
29
Looking at the actual numbers of babies being born with CRS, Europe and the Americas have a low burden, Africa and
India have a high and growing burden. Roughly 30,000 babies were born with CRS in Africa in 2000, and population growth
increases that number by 2008. Population growth also accounts for the increased numbers of babies born with CRS in
Southeast Asia. Meanwhile, there are significant decreases in the Americas and Europe, in countries that have introduced
adequate vaccination programs.
In the end, Vynnycky found that the average global burden of CRS has remained fairly stable since 2000, with roughly
112,000 cases each year, and only a small decrease since 1996, but very wide confidence limits on those estimates due to
lack of data quality.
Better serological studies are needed to improve the reliability of the estimates and to see whether GAVI’s funding of
RCV results in changes in the burden of CRS, Vynnycky concluded.
Discussion
Vaccination in China
The discussion concerned vaccination activities in China. Susan Reef explained that the vaccine has been available
throughout China since 2008. Initial problems with vaccine availability were resolved in 2010. The birth cohort now has
more than 95% coverage. But there is variability, particularly on the east coast.
CRS incidence window
A participant questioned whether Dr. Vynnycky’s choice of the window of 16 weeks and a risk of 65 percent might be
underestimating CRS burden. A window of 10 weeks, for example, would raise the risk to 90%. While acknowledging that
65 percent could indeed underestimate the burden, Vynnycky explained that she chose it in order to be able to compare
results against the 1996 estimates.
Total CRS burden
One participant noted that while the CRS burden is substantially reduced by vaccination, it is also necessary to look
at miscarriages and terminations carried out as a consequence of rubella. The availability of data varies from country to
country. Nevertheless, it is important to consider the total impact of rubella in pregnancy.
Measuring the impact of vaccination
The discussion turned to baseline data on the incidence of congenital rubella or seropositivity prior to vaccination
campaigns as well as follow-up data after vaccine introduction. Respondents noted WHO has already worked with some
countries, including Nepal, to assess seroprevalence and incidence of CRS, and intends to work with others prior to
introduction of an RCV. In addition, countries will be required to monitor the impact of introducing the rubella vaccine.
Reef stressed that countries need to integrate their measles and rubella surveillance.
30
Progress Toward Rubella Elimination And CRS Prevention in Europe Proceedings
SESSION V:
Burden of Rubella and CRS in Europe
Rubella and CRS overview for WHO Europe
Dr. Dragan Jankovic, World Health Organization Regional Office for Europe
In 2010, the European Region set a goal of eliminating measles and rubella and preventing CRS by 2015. Toward this
end, WHO is working with member state to implement four strategies:
•
•
•
•
Reach at least 95 percent coverage of the population with two doses of measles-containing vaccine and one
dose of rubella-containing vaccine (RCV);
Use mass campaigns and other supplementary vaccination activities to provide “catch-up” vaccination and
reach everyone who is susceptible;
Establish case-based surveillance with strong laboratory involvement component; and
Make evidence-based information on immunization’s benefits and risks available to experts and the public.
Rubella containing vaccines are included in the routine immunization programme of all 53 Memebr States. In addition,
from 2000 to 2010, about 30 million people in Europe were immunized against rubella trough supplemental immunization
activities – SIAs (mostly mass immunization campaigns). National immunization coverage is overall high across the
region, especially for MCV1 (95 percent coverage in 2010) But most SIA’s took place in the Newly Independent States,
supported by WHO and other international partners. Existing data indicates that the regional incidence of rubella decreased
significantly: from 800,000 cases in 1999 to 10,000 in 2010.
But the data is incomplete. “For many countries, we don’t know the percentage of the population covered by
immunization, especially with second dose of vaccine,” said Jankovic. “Some highly populated countries in Western
Europe do not provide us with any data or the data is incomplete. Others don’t have proper surveillance systems in place.”
As of beginning of 2012, WHO received reports about 737 rubella cases from 25 member states in 2011; only 213 of
mentioned were confirmed by a laboratory. Most of the confirmed cases concerned adolescents in the age range of 15-19
years, indicating the need for an immunization strategy targeting this age group. For five hundred of the 737 reported cases
information about immunization status was not available.
The situation with congenital rubella syndrome is also unclear: in 2010, only two cases of CRS were reported by
Russia and Poland. In the period from 1990 to 2010, there were only 467 cases of CRS reported in total. “This figure is very
low, given the overall incidence of rubella reported in Europe, indicating that we need better surveillance,” Jankovic said.
Jankovic reported that coverage is often low or non-existent for the second RCV dose. This has resulted in many
susceptible adolescents and adults. In addition, there are pockets of population with generally low coverage (with all
vaccines), especially among marginalized populations, and immunization refusal is on the rise.
The situation varies greatly around the region and the solutions must be country-specific. Historically, European
countries have employed very different rubella strategies, from only immunizing women of childbearing age, to just
targeting children. Some countries employed a one-dose routine and others used two doses. “It wasn’t until 2009 that
the last country in the region introduced routine immunization and we are aware that some countries have only had
immunization for five years.”
“By improving surveillance of measles and rubella,
we want to improve surveillance for all vaccine-preventable diseases.”
Dragan Jankovic, World Health Organization Regional Office for Europe
Rome, Italy, 8-10 February 2012
31
WHO’s immunization activities are a core part of its ‘Health 2020’ policy, which aims to provide equal access to health
for all Europeans. It is strengthening partnerships and providing technical support to strengthen national immunization and
surveillance systems, and not only for measles and rubella. “By improving surveillance of measles and rubella, we want to
improve surveillance for all vaccine-preventable diseases,” said Jankovic.
Rubella Cases Reported by Year,
WHO/Europe and Globally, 1999 - 2010
1000000
900000
804,567
800000
700000
600000
500000
400000
300000
200000
10,448
100000
0
1999
2000
2001
2002
2003
2004
EUR
2005
2006
2007
2008
2009
2010
World
Progress Toward Elimination: Successes and Remaining Challenges
Dr. Laura Zimmerman, U.S. Centers for Disease Control and Prevention
Between 2001 and 2010, the WHO Europe region had a 99 percent decline in reported cases of rubella. Zimmerman
reported that major advances took place in the Central and Eastern Region, and the Newly Independent States.
Nonetheless, outbreaks continue, and some countries, including Azerbaijan and Kazakhstan, have coverage of less
than 80 percent. “You can probably rest assured that there are actually a lot of pockets of susceptibles for measles and
potentially rubella as well,” Zimmerman said.
Furthermore, “When we look at Western European countries there again remain questions of what needs to happen in
terms of supplemental immunization activities and those nagging pockets of susceptibles.”
The best way to answer those questions is through analyzing data, and the WHO regional office evaluates the
reliability of surveillance. In particular, it looks at completeness of reporting and timeliness of reporting, with a goal of 80
percent for both for rubella. The region falls seriously short on both accounts.
Zimmerman summarized a 2009 survey of national rubella surveillance programs sent to all 53 member states.
Forty-five replied, and 41 of these had some sort of national surveillance program. In total, 73 percent of countries had a
confirmed surveillance programs, “which is a bit unnerving in terms of trying to reach the elimination goal by 2015,” she said.
“In 2005, less than 0.1% of reported cases were confirmed,” Zimmerman
said. “By 2010 that figure had reached 22% – but this is still far too low.”
Laura Zimmerman, U.S. Centers for Disease Control and Prevention
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Progress Toward Rubella Elimination And CRS Prevention in Europe Proceedings
Of the 41 countries with a program, 36 linked epidemiologic and laboratory data – an important development. “One
issue has been that some countries have used two different reporting systems, one through their lab and one through their
epidemiologic and surveillance unit,” Zimmerman said. “And many times, these numbers did not match.”
Thirty eight of the surveyed countries said that they report their data to WHO or to the European Union’s surveillance
repository, EUVAC.net, on a monthly basis. However, they noted barriers to reporting, including lack of human resources,
limited funds, large numbers of rubella cases and the lack of mandatory reporting requirements.
When outbreaks occur, they reflect the history of the vaccination programs in the respective countries. In Poland, for
example, the majority of new cases appear to be adolescent and adult males, reflecting the country’s long history of only
vaccinating girls. In general, however, insufficient information about the age of new cases makes it difficult to definitively
analyze or document rubella outbreaks.
The laboratory confirmation rate is also a problem for many countries. “In 2005, less than 0.1% of reported cases were
confirmed,” Zimmerman said. “By 2010 that figure had reached 22% – but this is still far too low.”
Countries can request an elimination assessment to gain information on demographics, surveillance and reporting,
vaccination status, and the actions needed to achieve rubella elimination. This provides useful feedback for both countries
and WHO.
Surveillance Systems:
Rubella Surveillance Practices in the European Region
National Rubella Surveillancea
Yes (n=41)b
Case-based
data (n=31)c
Aggregate data
(n=10)
Belarus
Kazakhstan
Lithuania
Poland
Romania
Russian Federation
Serbia
FYRMd
Turkemenistan
Ukraine
Case-based data available
at sub-national level (n=5)
Belarus
Kazakhstan
Lithuania
Poland
FYRMd
Rome, Italy, 8-10 February 2012
No (n=4)
Belgium
Denmark
France
Germany
= ~18% of the Regional
population
No response (n=8)
Andorra
Bosnia and Herzegovine
Israel
Luxembourg
Monaco
Montenegro
San Marino
Turkey
No case-based data at
sub-national level (n=5)
Romania
Russian Federation,
Serbia
Turkmenistan
Ukraine
33
Sub-Regional Overview: Central Eastern Europe
Dr. Vytautas Usonis, Vilnius University, Lithuania
The 12 countries of the region—from Estonia in the north to Turkey in the south—work together through the Central
European Vaccination Advisory Group. A number of the member countries participated in clinical trials for an MMR
vaccine known today as Priorix. The trials were conducted in Lithuania and the Czech Republic on different parameters
of that vaccine. A 1999 paper published in The Pediatric Infectious Diseases Journal showed high immunogenicity when
measuring sero-conversion rates. “This is historical data,” said Usonis, “but it does tell us that we now have two vaccines of
excellent quality here in the region and we should be using them.”
Lithuania introduced rubella vaccination in 1990, “on the day of re-establishing our national independence,” Usonis
said. Early vaccines used were mono- or bivalent, and by 1992 first dose coverage stood at 40 percent. MMR was
introduced in 1996, with very good results. Then, a 1997 Swedish study showed that a risk group strategy of vaccinating
only girls is not effective enough. “The introduction of universal vaccination is the only way to achieve significant results for
rubella, and other diseases as well,” said Usonis.
Vaccine coverage for the sub-region has reached 90%. In most Central Eastern European countries, the first MMR
vaccination is now given at the age of 11–13 months; however, there is a large disparity in the timing of the second dose.
A recent study by the Central European Vaccine Advisory Group found major declines in the number of reported cases
between 2000 and 2008.
All countries have rubella surveillance systems and reporting is mandatory. All but one country (Croatia) has CRS
surveillance systems. However, not all cases are laboratory tested, and many that are discarded. “Clinical diagnosis is not
reliable,” Usonis said. Clinicians operate off of different case definitions and, “at least ten diseases might be clinically similar
to rubella and that means clinically suspected cases need to be confirmed by laboratory testing.”
In Bulgaria, over 44 samples were tested for rubella in 2009, none of which were found to be positive. An outbreak
in Poland in 2009 prompted reports of 6,693 cases of rubella—only four were laboratory confirmed. A similar failure to
confirm results in other countries indicates that clinical diagnoses in the region are not reliable.
“Despite the success of vaccination programs, rubella is still present in Europe. This is partly due to a lack of
awareness among medical professionals and the limited availability of laboratory services,” said Usonis. “This needs to
change if elimination goals are going to be met.”
For more information, see the website of the Central European Vaccination Advisory Group http://www.cevag.org.
“Despite the success of vaccination programs, rubella is still present
in Europe. This is partly due to a lack of awareness among medical
professionals and the limited availability of laboratory services. This
needs to change if elimination goals are going to be met.”
Vytautas Usonis, Vilnius University, Lithuania
Discussion
Supplementing disease surveillance
Respondents discussed the value of supplementing disease surveillance with the surveillance of other indicators as
a means of gauging progress toward elimination. These could include factors such as areas with suboptimal coverage,
the proportion of pregnant women who have been screened, or the proportion of susceptibles who have been vaccinated
postpartum. Jankovic noted that countries will have to document absence of endemic viruses in presence of strong
surveillance system by providing variety of relevant information prior to the WHO’s verification of diseases elimination in
the European Region. The regional verification commission, should help countries to go beyond the classical public health
approach to meeting this challenge.
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Progress Toward Rubella Elimination And CRS Prevention in Europe Proceedings
Meeting elimination goals by 2015
A participant questioned whether catch-up vaccination in Western Europe is realistic when there are major countries
that do not even carry out surveillance. Respondents noted that achieving the goal of eliminating rubella in Europe by 2015
will require increasing popular demand for vaccines by working closely with governments and the media, and bringing in a
range of health professionals, especially obstetricians and general practitioners. Mass immunization campaigns will not be
enough.
There is a strong demand from Eastern European countries for the region to move towards elimination. That will
require a strong commitment from Western Europe, particularly the large countries that are, so far, not much involved.
Kari Johansen noted that the ECDC is starting an EU-wide project on CRS surveillance. And for measles, every EU country
is submitting case-based reports for 2011 and 2012. EUVAC.NET was transferred to ECDC in September 2011 and that
has enabled monthly reports on measles to be published on the ECDC web site. In a few months, ECDC will start to
produce quarterly reports on rubella.
A participant clarified the meaning of providing a “second opportunity” for immunization, as this term has caused some
confusion: if after the recommended two doses of RCV coverage is still not high enough, supplementary immunization
activities are needed, and these have been referred to as the “second opportunity” for immunizing susceptibles. However,
the use of that term is now dated, and upcoming plans will use other wording.
Lessons from polio eradication
Participants observed that when Europe began verification for polio eradication, uniform requirements for verifying
elimination were applied to all member states. When not all could meet the requirements, the indicators were modified to
accommodate surveillance limitations in some countries. Participants debated whether such flexibility would be necessary
or appropriate in the case of measles and rubella. It was noted that it is unlikely that the regional verification committee will
accept any exceptional approach to verification in Western Europe, as happened with polio. If it does, other countries that
are working with very limited resources to establish and improve surveillance systems are likely to object.
The first regional commission on verification of elimination was held in January in Copenhagen, and some national
committees are expected to begin functioning this year, Jankovic said. These will be important issues for the committees.
Routine rubella antibody testing of pregnant women
Asked how many countries routinely check the immune status of pregnant women through rubella antibody testing,
Jankovic replied that such testing is not a routine diseases surveillance issue, and so it is not collected by surveillance
programs. It is more likely to be collected by laboratories, and could be important supplementary information on immunity
in adults.
When PAHO decided to make progress on rubella immunization and the elimination of CRS, they looked at how many
obstetricians used rubella antibody screening in pregnancy to prompt postpartum vaccination; very few did. Sero-surveys
are useful but very expensive; but pregnancy antibody testing at least provides a proxy for the level of immunity in that age
group. Andrus said that in Latin America, TORCH titer screening at the first prenatal visit has become standard practice.
De Quadros called out the need for awareness campaigns to invite women of childbearing age to get tested before
pregnancy, when they can still do something to prevent congenital rubella.
Rome, Italy, 8-10 February 2012
35
SESSION VI:
Country Experiences
W
hen it comes to disease control in Europe “the rubber hits the road” at the country level. During this session,
representatives from five European countries reported on their experiences. The countries were chosen to represent a
range of epidemiologies and responses to rubella.
Italy
Dr. Stefania Salmaso, Director of the National Centre for Epidemiology Surveillance and Health Promotion
(CNESPS) in Rome, reported on the evolution of Italy’s vaccination plan and its impact on disease.
Rubella has been a statutory notifiable disease in Italy since 1970. At that time, vaccination for measles, rubella
and mumps were recommended, but were neither mandatory nor free. Therefore, many parents opted out. This situation
changed in the 1990s, when vaccination for measles and rubella was offered free of charge to all newborns. It changed
even more dramatically in 2002, following a disastrous national epidemic of measles, with 40,000 cases in one region and
the deaths of eight children. The first national Measles and Congenital Rubella Elimination Plan was approved in 2003,
however sub-optimal vaccine coverage precluded success by the target date of 2007. Congenital rubella has been a
statutory notifiable disease since 2005.
As of 2010, mean national coverage was 90.6 percent, and only one of Italy’s regions had achieved 95 percent
coverage of first dose MMR-MMRV in two-year old children.
As vaccination coverage has improved, cases have fallen dramatically. But Salmaso said that a worrisome change is
taking place in the age of those infected. During the epidemic of 2008, about 70 percent of notified rubella cases occurred
in individuals aged 15 or older. This is a big change from the pre-vaccination period, when the average age of rubella and
measles infection was five years. Today, as vaccination coverage of newborns improves, the largest group of susceptible
individuals is adolescents and young adults. This raises concerns about a possible increase in children born with CRS,
because of the higher risk of reaching adulthood without having been exposed to either natural infection or immunization as
a child.
Italy passed a new National Measles and Rubella Elimination and CRS Prevention Plan in 2011, with specific
strategies for vaccinating women of childbearing age. It aims to eliminate endemic transmission of measles and rubella by
2015, and reduce the incidence of congenital rubella to less than 1 case per 100,000 live births.
MMR vaccinations follow WHO recommendations of the first dose in the first month of the second year of life, and the
second dose at preschool age. Strategies for preventing congenital rubella in the national plan include:
Use evidence-based interventions to improve coverage, with the goal of reaching 95 percent childhood coverage for two
doses of MMR vaccine
•
•
•
•
•
•
36
Use any opportunity to vaccinate susceptible women of childbearing age, including postpartum (and postabortion) vaccination of susceptible women
Promote awareness of CRS and its prevention among women
Improve awareness of clinicians and cooperation between clinicians, epidemiologists and labs
Vaccinate healthcare workers and school personnel
Vaccinate foreign-born women at their first encounter with the Italian healthcare system
Strengthen surveillance systems
Progress Toward Rubella Elimination And CRS Prevention in Europe Proceedings
Russian Federation
Dr. Olgav Tsvirkun, from the National Scientific Methodical Center for Measles and Rubella Surveillance, said that
rubella cases have been reported in the Russian Federation since 1976. Rubella vaccine was introduced in the national
vaccination schedule in 1997, and a high coverage level was reached by 2002. During the last 14 years, the vaccination
schedule was revised several times.
In 2006-07, an immunization campaign carried out as part of the National Project Health vaccinated 17 million children
under 14 years old and women aged 17-25 years.
During the last five years, approximately 26 million children, teenagers and adults up to 25 years of age were
vaccinated against rubella. Coverage levels for first and second doses of MR combination vaccines have reached 95
percent. Between 2009 and 2011, the proportion of laboratory confirmed rubella cases increased from 18.4 percent to 89.2
percent.
There have been dramatic and sustained declines in the number of cases of rubella and of CRS reported. In 2000,
there was notification of 11 children born with CRS. In 2011, only a single case of CRS was registered, although Tsvirkun
acknowledged the possibility that some cases were not detected.
As in Italy, the age of infection in the Russian Federation is changing. In 2002, 82.5 percent of cases were in children.
In 2011, 88.6 percent of cases were in adults.
Russian Federation goals for achieving measles and rubella elimination by 2015 include:
•
•
•
•
•
Sustain high measles and rubella vaccination coverage (no less than 90-95 percent) with first and second
doses in target groups in all territories of the Russian federation;
Introduce case-based registration of rubella cases in the information system used for measles registration;
Ensure no less than 90 percent of compulsory laboratory confirmation for rubella cases;
Carry out targeted activities to inform the population about the importance of prevention;
Regularly train and re-train specialists in issues of diagnostics, clinical picture, epidemiology and prevention
of measles, rubella and CRS.
Finland
Dr. Irja Davidkin, from the National Institute for Health and Welfare, Finland, reported that vaccinations against
measles and rubella started in 1975, as monocomponent vaccines. Rubella vaccine was given to girls from 11 to 13
years old and to seronegative mothers. Vaccination with combination vaccines began in 1982, with the goal of eliminating
measles, mumps and rubella. Catch-up campaigns targeted children 1.5 to six years of age, as well as special groups,
including nurses, students, and the military.
Finland reached high coverage by the end of the 1980s,, and by the mid-1990s, vaccination programs had interrupted
endemic circulation of rubella virus nationally.
Along with the vaccination campaign, Finland put increased emphasis on surveillance. Enhanced surveillance of MMR
diseases began in 1982, and has improved steadily. Since 1995, it has been mandatory for diagnostic laboratories and
clinicians to send reports to the National Infectious Disease Register.
All confirmed measles and rubella cases between 1996-2011 were imported, with no secondary cases. In 2011, there
was one confirmed case of CRS—the first since 1986—born to a mother who had emigrated from Asia.
From 1975-1994, pregnant mothers were screened for rubella immunity, and seronegative mothers were offered the
vaccine postpartum. A 25-year follow-up study of antibody persistence, based on vaccine-induced immunity, has shown
100 percent persistence of seropositivity, although about 20 percent were under 10 IU/mL for antibody levels.
Rome, Italy, 8-10 February 2012
37
Other studies have shown high rubella seropositivity across the population. One study of population immunity was
based on 1,500 samples from individuals 1- to over 60- years-old. It showed high rubella seropositivity across age groups,
including both vaccinated and naturally infected individuals.
Another study measured antibody levels against rubella in pregnant women, with sera that was collected in 1983, 2002
and 2007. It found that antibody levels were significantly lower in sera collected in the MMR vaccination era compared to
before vaccinations. This suggests that vaccine-induced antibodies against rubella wane significantly over time, Davidkin
said. Nonetheless, since 1996, only imported cases of rubella have been confirmed.
Future challenges include:
•
•
•
•
•
Sustaining the high level of vaccine coverage, and maintaining Finland’s rubella-free status
Identifying and coping with isolated importations of rubella and measles
Sustaining surveillance, with adequate samples for laboratory investigations
Maintaining awareness about measles and rubella among health care personnel
Following immunity against measles and rubella regularly across the population
Poland
Dr. Włodzimierz Gut, Virology Department, National Institute of Public Health, Poland
While there have been significant vaccination successes in Poland, “With rubella, our success is doubtful, if any,” Gut
began.
He contrasted the situation with measles and rubella control. Control of measles began in 1975, with the introduction
of monovalent vaccine. The country’s political situation at the time favored projects that were “something big, model
and correct politically,” Gut said. Measles vaccination fit this model: the vaccine came from Russia, and government
participation was secured from the beginning.
A monovalent rubella vaccine was introduced for vaccination of 13 year old girls in 1988. Widespread coverage for
rubella in both boys and girls began only in 2003, when MMR replaced a first dose of monovalent vaccine. At that time,
a second dose of monovalent rubella vaccine was given to 13-year-old girls. Beginning in 2005, a two dose schedule of
MMR was adopted with the second dose administered to all 10-year-old children.
Poland’s case registration systems also differ considerably between measles and rubella. For measles, only
confirmed cases are registered. For rubella, only suspected cases are registered.
Although rubella elimination has been a goal since 2003, “Our program for rubella came much later than for measles,
about 30 years, and now we have a situation for rubella like that of 30 years ago for measles,” Gut said. For example, in
2010 there were 14 cases of measles registered, and 4,197 cases of rubella. In addition, financial problems have limited
the strategy for elimination of congenital rubella.
France
Dr. Isabelle Parent du Châtelet, French Institute for Public Health, reported that France has committed to rubella
elimination and prevention of CRS by 2015. Current vaccine coverage is high: MMR1 coverage at 24 months of age is
89 percent, and it is estimated that 93 percent of the 6-to 49-year old population is protected against rubella. This positive
situation evolved over several decades. Rubella vaccination was introduced in France in 1970, with selective vaccination
of preadolescent girls. National lab-based surveillance of rubella infection during pregnancy was initiated in 1976. However,
to this day, there is no post-natal rubella surveillance in France.
MR vaccine entered the routine immunization program in 1983 (MMR in 1986), with a second dose introduced in
1996. In 1992, mandatory antenatal rubella IgG testing was put in place to determine susceptibility and to offer post-partum
vaccination.
38
Progress Toward Rubella Elimination And CRS Prevention in Europe Proceedings
A National Plan for Elimination for Measles and Congenital Rubella was adopted in 2005. It includes:
•
•
MMR at 12 months of age, MMR2 before 24 months of age
Catch up: two doses for anyone born in 1980 or later
– Women born before 1980 not vaccinated against rubella: 1 dose MMR
– Use any opportunity to vaccinate women of childbearing age
Based on data from insurance beneficiaries (sample including about 500,000 people), 2008 coverage for the first
dose of MMR was estimated to be close to 90 percent at 24 months of age. For the second dose it was around 52 percent.
Since then, the use of catch-up vaccinations in older ages at nursery schools, primary and middle schools (in fifth and ninth
grade) has improved France’s coverage of MM1 and MMR2 at 11 years to 97% and 85% respectively in 2008.
Surveillance is carried out by about 300 public and private laboratories across France. Twice a year the laboratories
are asked to notify the French Institute for Public Health of any positive diagnosis in pregnant women, fetuses, and in the
products of pregnancy termination or at birth. The Institute classifies the case as maternal primary infection or reinfection,
and in the case of newborns or stillborns or pregnancy terminations as either CRI or CRS.
Coverage variability between men and women persist, as do geographic differences. A seroprevalence study in 20092010 found that the proportion of susceptible women at the age of 20-29 was 4 percent -- significantly lower than in males
of the same age (13 percent susceptible). Other studies have shown that the lowest immunization coverage is in the south
of France.
While enormous progress has been made nationally, Parent du Châtelet pointed out that localized outbreaks could
occur in specific populations. In addition, improvements are needed in surveillance. The current system, which lacks casebased data in the general population, will not allow for certification of rubella elimination. Currently, a mandatory notification
system is being considered.
Proportion of Susceptible Population by Gender and
Age Group in France Mainland, 2009-2010 (n=5,000)
14%
M
% Susceptibles
12%
F
10%
8%
6%
**
4%
2%
0%
6-9
**: p<0.05
10-19
20-29
30-39
40-49
Age Groups (years)
Source: InVS
Rome, Italy, 8-10 February 2012
39
Discussion
Panelists and participants addressed a wide range of questions, from the role of adult vaccination campaigns to efforts
to vaccinate internal migrants.
Given that rubella is increasingly affecting older populations, and that the childbearing age in Italy has increased to an
average of about 30 years of age, Italy’s Dr. Salmosa discussed the potential of adult immunization campaigns. The major
difficulty with such campaigns is that they fall outside of well-established immunization program settings, she noted. She
emphasized the need to reinforce all opportunities for catch-up vaccinations, especially with women. This could be done,
for example, in medical centers for assisted procreation. One limitation is that the tools for monitoring progress in such
areas do not exist, “so we can launch everything but then we do not have the way of knowing how it’s going.”
When asked about the challenge of stopping the spread of rubella through internal migration, Russia’s Dr. Tsvirkun
replied that the best way to address unvaccinated people migrating from the South to the North of the Federation would
be through achieving a very high immunization coverage across all regions. Italy’s Dr. Salmosa said that there is no direct
vaccination outreach to illegal immigrants, although if they show up at a clinic they can be vaccinated. However most
pregnant immigrants only use the health system at the time of delivery.
Regarding the challenge of ensuring the vaccination of young men, one speaker noted that with declining military
forces in many countries, large male populations do not receive the vaccinations they would have received upon entering
the military. France’s Dr. du Châtelet noted that there was increased vaccination of adolescents and adults in response
to the recent measles epidemic, and that preliminary data shows that this is lowering the percentage of susceptible
young men.
When asked whether data from birth defect registries or hearing loss have been used for surveillance, Dr. Salmosa
noted that, in Italy, such registries are not comprehensive enough to yield useful information.
40
Progress Toward Rubella Elimination And CRS Prevention in Europe Proceedings
SESSION VII:
Strategies, Policy Implementation and
Documentation of Rubella/CRS
T
his session on strategies, policy, implementation and documentation of rubella and CRS heard presentations from a
global perspective, the regional perspective of PAHO and the experience of the European region.
WHO Position: Vaccine Strategies and Country Experience Outside of Europe
Dr. Peter Strebel, WHO, summarized the WHO’s position paper on rubella vaccines, published in July 2011, and provided
examples of WHO country experiences.
The goal of rubella vaccination is to prevent the occurrence of congenital rubella, and the WHO paper outlines two
basic vaccination strategies. One focuses on reduction of CRS by only immunizing adolescent girls and/or women of
childbearing age. However, this leaves circulation of rubella virus intact. Therefore, for this strategy to work, there must be
100 percent vaccination coverage of all women of childbearing age—something extremely difficult to achieve.
WHO’s recommended strategy aims at interrupting transmission and eliminating rubella as well as CRS, Strebel said.
To accomplish this, WHO suggests that countries:
•
•
•
•
Begin with a wide age range ( 9 months to 14 years) catch-up campaign with either MR or MMR;
Introduce that vaccine into the routine childhood programme;
Use the same combination vaccine for all subsequent follow-up campaigns;
Immunize adolescent girls or women of childbearing age, either through routine services or mass campaigns.
The strategy recognizes the opportunity provided by measles elimination and delivery strategies for advancing
rubella and CRS elimination. “All countries now are providing two doses of measles vaccine using either routine and/or
supplementary activities and these can be used as a platform for introduction of rubella-containing vaccines,” Strebel said.
Field and laboratory surveillance should also be fully integrated with measles in a single surveillance system.
WHO recommends achieving and maintaining at least 80 percent immunization coverage with at least one dose of
rubella-containing vaccine. This level is necessary if pregnant women are to be adequately protected from rubella. Lower
levels of coverage can result in the “paradoxical effect” of increased susceptibility to rubella among young women.
Strebel emphasized that introduction of rubella-containing vaccine implies a long-term commitment to achieving
and maintaining sufficient immunization coverage to ensure a sustained reduction in CRS. “This is not a vaccine that you
introduce and then stop using. This is a long-term change from natural immunity to a vaccine-induced immunity. And to
ensure that this happens, strong political commitment as well as sustainable financing is important.”
Strebel summarized several country examples from the Eastern Mediterranean Region.
The case of Tunisia illustrated the limitation of a strategy targeting adolescent girls and women of childbearing age
only, and leaving virus circulation intact. Tunisia implemented MR for 12 year old girls in 2005, with a catch-up campaign
for girls 13-18 years old the same year. Both attained 90 percent coverage. They initiated postpartum vaccination as well,
but with only 19 percent coverage. In the following years, IgM confirmed rubella cases rose, with a large outbreak in 2011
(over 1,700 confirmed cases). 55 percent of cases were in children under 12; 21 percent of cases were in 12-20 year olds
(88 percent male). To date there have been 50 hospitalizations, three deaths and four cases of CRS.
Oman’s experience with a comprehensive vaccination approach presents a strong contrast. In 1994, Oman introduced
rubella vaccine with a catch-up campaign targeting 15month to 18 year olds (achieving 94 percent coverage) accompanied
by introduction of rubella-containing vaccine in the routine program (achieving 95 percent coverage). They subsequently
introduced post-partum vaccination. The number of reported rubella cases dropped rapidly and dramatically over just
several years. In the last five years, the country had just 1 reported case of CRS.
Rome, Italy, 8-10 February 2012
41
The cases underscore the need for a strategy that combines a mass catch-up campaign with introduction of the
vaccine into the routine schedule to ensure immunity for all subsequent birth cohorts, both boys and girls.
“WHO recommends that countries take the opportunity offered by
accelerated measles control elimination to introduce rubella vaccine. The
only real requirement is the ability of a country to achieve a coverage of
80 percent or higher through routine or mass vaccination activities.”
Peter Streble, WHO
Rubella and CRS Elimination in the Americas
Dr. Jon Kim Andrus, Deputy Director, Pan American Health Organization described the road to the elimination of
Rubella and CRS in the Americas and the steps ahead.
The first challenge is to convince policymakers that there was a problem, Andrus said. The second was to convince
them that, when introducing the vaccine, there is no turning back, and that close monitoring of coverage and a stronger
surveillance infrastructure would be needed.
Studies of disease burden, the impact of elimination, plus “putting a face on the disease” helped make the case and
secure the political commitment of Ministers and national leaders. Evidence included a PAHO study which showed that
without control interventions, there were 20,000 cases of CRS per year in Latin America and the Caribbean. Another PAHO
study estimated that rubella elimination in the region would prevent 112,500 CRS cases over 15 years. Retrospective
studies in individual countries showed the burden of CRS.
Within the Americas, English-speaking Caribbean countries took the lead. In 1998, they passed a resolution to
eliminate rubella and CRS in their region. Information on costs saved through avoiding the life-long treatment of babies
born with CRS helped to make the case. PAHO used similar information as it talked to Presidents and Health Ministers
across the region. Its calculations showed that, given the cost of an MR vaccination at US$1.10, benefit-cost ratio was 10:1
– 12:1.
PAHO developed a strategy that went from:
•
•
•
1997 Control: Introduction of the rubella vaccine, to
1999 Accelerated control: Mass MR vaccination campaigns in women only or all adults
2003 Elimination: Mass MR vaccination campaign in all adults
“It’s challenging, but the beauty is that if done well, your campaign can stop transmission,” Andrus said.
In 2003, The Directing Counsel of health ministers adopted a rubella elimination initiative targeting a 2010 elimination
date. In 2006, the Counsel reinforced the campaign by committing to improved surveillance and data collection.
PAHO defined elimination as the “Interruption of endemic rubella virus transmission in all countries of the Americas for
at least 12 months without the occurrence of CRS cases associated with endemic transmission, in the presence of highquality surveillance.”
“The point was zero cases, zero cases was very important,” Andrus said.
“We believe that over a 15 year period, we will be able to save 120,000
children from CRS, and that we will save countries some US$3 billion.”
Jon Kim Andrus, Pan American Health Organization
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Progress Toward Rubella Elimination And CRS Prevention in Europe Proceedings
In addition to routine vaccination and a “catch-up” campaign, countries implemented “speed-up” campaigns in
adolescents and adults, with each country identifying the groups to vaccinate. In 1998 through 2005, Chile, Brazil,
Costa Rica, Honduras, Ecuador, El Salvador all carried out speed-up campaigns, with another 18 countries following in
subsequent years. The speed-up campaigns had a huge impact on measles as well, and are credited with preventing the
re-establishment of endemic measles virus transmission in the region.
Campaigns were typically launched by the country’s president or health minister, who remained involved throughout,
galvanizing attention and action. Campaign characteristics included the vaccination of nontraditional groups, especially
adolescents and adults, both men and women; and vaccination of 40 percent-70 percent of the total population. All was
implemented within a short, intense six week time period.
A stable supply of vaccine was ensured by the Serum Institute of India, to whom PAHO later extended a special award.
Meanwhile, surveillance integrated measles and rubella, and CRS surveillance was initiated. Laboratory activities
included serological diagnosis and viral detection. “We had routine testing of every rash and fever suspect case with the
measles IgM and rubella IgM,” Andrus said.
An extensive reporting network included 30,000 reporting sites (a target of at least one per 100,000 population
integrated for measles and rubella surveillance); 148 sub-national, national and regional laboratories; 14 PAHO field
epidemiologists in priority countries; and case-based community surveillance with data sent to the Regional office. Health
workers in primary care were educated to monitor CRS, looking for alerts through hearing screening, eye cataracts and
similar signs.
“The results speak for themselves. Our last endemic case was in February of 2009, ten months before the target,”
Andrus said.
Today the region continues to deal with imported cases of rubella, and to maintain its high level of routine coverage in
order to ensure the ongoing elimination of rubella in the Americas.
Rubella Elimination in The Americas, 1982 – 2011
>36 months with no endemic rubella
cases in the Region.
Speed-up campaigns
100
60,000
40,000
Last rubella case (2B)
EW 5/2009
80,000
80
Follow-up campaigns
1G transmission
finalized
100,000
Beginning in 2001, over
a 15 year period the
rubella and CRS initiative
will have saved an
estimated US $3 B
by preventing more than
112,500 CRS cases in
LatinAmerica and the
Caribbean.
1G transmission
finalized
120,000
60
40
20
20,000
0
Routine Vaccination Coverage (%)
Confirmed Rubella Cases
140,000
0
82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 00 01 02 03 04 05 06 07 08 09 10 11
Cases
Routine Coverage
Source: Country reports to PAHO/WHO.
Rome, Italy, 8-10 February 2012
43
Progress Toward Rubella Elimination and CRS Prevention in Europe
Dr. Dragan Jankovic, Vaccine Preventable Diseases & Immunization, WHO-EURO, placed Europe’s rubella elimination
efforts in the context of a new regional policy, Health 2020. It is based on recognition of the universal right to health and
health care, to equality and equity in health. “Everyone in this region has the same equal rights to health, and all health
services have to be equally available,” Jankovic said. It is especially relevant for the immunization program, which cuts
across many areas, including health system reform, mother and child health, and primary health care.
The WHO European Region has three programmatic goals regarding immunization: systems strengthening;
accelerated disease control, with a focus on diseases targeted for eradication and elimination; and enhanced surveillance
and monitoring. Communications and advocacy is an important part of all three goals, especially given increased vaccine
refusal among the public.
Main challenges include: decreasing commitment, health competing priorities, economic crisis, and frequent changes
in leadership; health system reform as some countries struggle to replace old or dysfunctional systems; and unrecognized
pickets of unimmunized in marginalized and vulnerable groups, which include migrants, legal, illegal and temporary
workers.
A growing challenge of particular concern is vaccine refusal. This is due to a combination of complacency in the
absence of disease, trust issues, the anti-vaccination movement, and opposition based on religious and philosophical
beliefs. Some parents, particularly among the more affluent, consider that the risk of vaccines and adverse events are
much higher than the risk of disease.
Today, a major challenge is to sustain the progress of the recent past. Jankovic noted that polio was eliminated in the
European Region in 2002. Then, in 2010, four countries were affected by imported polio cases. Likewise, the number of
measles and rubella cases was greatly reduced by 2007-09, but more recently a number of big outbreaks have threatened
this progress.
Fortunately, in September 2010, the momentum toward political commitment for immunization stepped up. Fifty-three
representatives of Ministries of Health meeting at the WHO Regional Committee for Europe renewed their commitment to
eliminate measles and rubella, and prevent CRS, by 2015.
Four key strategies guide this work: routine immunization; additional opportunities for immunization; improved
surveillance; and the availability and use of high-quality information that can ultimately provide evidence of no endemic
viruses causing diseases. Within this framework, the WHO regional office has a number of main activities: partnerships
and resource mobilization; immunization policy; economics of elimination; monitoring and surveillance; national
immunization and technical advisory groups in every country; the establishment of verification processes; and operational
research.
Six components are needed to verify elimination. These include documentation of the epidemiology of both measles,
rubella and CRS for a three-year period with surveillance data (both case-based and laboratory data) and any other
relevant information that confirms a country has been free of endemic disease. Other elements of verification include:
demonstration of population immunity against measles and rubella; molecular epidemiology of measles and rubella viruses;
performance of surveillance; sustainability of the National Immunization Programme; and public acceptance of measles/
rubella immunization and elimination.
Regarding public acceptance of immunization, Jankovic urged the development of effective advocacy and information,
especially for reaching vaccine opponents “belonging to the very top level of societies in many countries.” He noted, “We
have families of medical health workers who are refusing immunization of their kids because they don’t consider that as
important. It’s a very complex situation.” He noted that currently local newspapers that sensationalize purported dangers
and “deadly vaccines” are much more influential than the public health system.
WHO is developing toolkits to help countries formulate research and best communication practices, and is urging
countries to share their information.
44
Progress Toward Rubella Elimination And CRS Prevention in Europe Proceedings
In summary, Jankovic reiterated the commitment of WHO Europe to eliminate both measles and rubella by 2015 and
to work with countries to frame their immunization activities to reach this goal.
“Everyone in this region has the same equal rights to health, and all
health services have to be equally available.”
Dragan Jankovic, WHO Europe
Discussion
Much of the discussion focused on the role of campaigns, whether catch-up campaigns or campaigns targeting adults.
Participants addressed the challenges to such campaigns in Europe, steps needed to meet the challenges, and lessons
from other regions.
Campaigns in Adults: The discussion was kicked off by Plotkin when he commented that it does not look as if
campaigns in adults are likely to happen in Europe. Jankovic concurred that it is unlikely that all 53 member states will
implement mass campaigns, given different capacities and resources. “With current circumstances, advocacy and social
mobilization is probably the only possible approach in some of the countries, but it will take time,” he said.
de Quadros commented that he is always surprised to hear in Europe that campaigns cannot be conducted here. “I
think that’s considered a defeat before even trying,” he said. Speaking of the experience in the Americas, he said, “In the
Americas we had the same thing, ‘Here we cannot vaccinate adults,’ ‘Here we cannot vaccinate males.’ And when we tried,
it was possible.” de Quadros encouraged the European Region and leaders in the health field to try, and to be prepared to
be surprised when they succeed.
Jankovic agreed that for the WHO Europe region, supplemental immunization activities with mass immunization
campaigns of susceptible populations are critical to reaching the 2015 elimination target.
Andrus underscored the point about sticking to proven strategies. “When embarking on elimination, it requires a
different mental approach because if you target a certain year it requires engagement, commitment to deliver, and it’s
different than saying control.”
Wichmann from Germany said that he is convinced that mass vaccination campaigns are needed by Germany to
reach the 2015 elimination goal. He suggested that the subject needs to be taken to a higher level of political debate,
perhaps by the ECDC or WHO-EURO bringing it to the EU commission to debate the need for mass vaccination in
European countries. He said that such a discussion on the European level could help cement political commitments from
countries.
Campaigns planned in Europe: Representatives from several European countries spoke to the mass campaigns
they currently have planned.
•
•
Beginning 1 March 2012, Denmark will offer free of charge immunization with MMR for all people born after
1974 who were not yet completely immunized;
Ireland will be conducting a catch-up campaign in primary and secondary schools with MMR vaccination
Learnings from the U.S. experience: O’Flannagan from Ireland, suggested that mass campaigns in Europe might
look different from those in Latin America and Caribbean, where vaccinators sometimes went from house to house, and
may instead more closely resemble campaigns in the U.S. and Canada. This gave rise to discussion of additional lessons
from those countries.
Rome, Italy, 8-10 February 2012
45
Among the points made:
•
•
•
School-based requirements that every child have a documented vaccination history contributed substantially
to interrupting endemic transmission for both measles and rubella;
A large resurgence of measles in the mid-1990s mobilized the country to address immunization as a top
priority, with a commitment from the President to do so;
The measles epidemic also led to passage of a law requiring the federal government to pay for vaccines for
all poor children in the US
Other topics discussed included making use of outbreaks to advance immunization, including through highlighting
the health and economic costs of outbreaks. “Make sure that people know that failure to prevent outbreaks actually also
implies cost,” one participant said. A number of people commented on the role of the media and ways to shift the public
debate. Some urged getting practitioners out in front of the media, and Best pointed out that it was only after the U.K. set
up a science media center that the tide began to turn on popular perception of the relationship between vaccines and
autism. Regarding equity, a participant pointed out the need for funding campaigns targeted at reaching “pockets” of the
unimmunized. “We speak a lot about equity, but we do not address that. We speak about vaccination as a health right, but
we do not follow that,” she said. A participant from Israel pointed out that “pockets” of the under- and unimmunized may be
as small as 5 percent, or, “It’s 20 percent in one district and zero in another… so you cannot rely on average immunization
coverage.”
“If I were a politician in Europe, I would want to be able to say, ‘Look,
here’s something we’re really fixing,’ rather than kicking the can down
the road by borrowing more money.”
Louis Cooper, Past President American Academy of Pediatrics
46
Progress Toward Rubella Elimination And CRS Prevention in Europe Proceedings
SESSION VIII:
Surveillance Strategies
Rubella Surveillance in the European Region of the World Health
Organization
Dr. Dragan Jankovic, World Health Organization Regional Office for Europe
The reason for surveillance is simple: “If I don’t know the dimension of the problem, I cannot fight against it, I cannot
advocate to prevent it,” Jankovic said.
One of WHO’s key measles and rubella elimination strategies is the strengthening of surveillance, and the best way to
accomplish this is through rigorous investigation and laboratory confirmation of suspected sporadic cases and outbreaks.
Jankovic said that case-based systems are essential to validate elimination of disease. A good surveillance system
is one that can collect, collate and analyze complete data in a timely manner, and create operational information and
feedback for implementing response measures.
A surveillance system must be able to detect, investigate and characterize sporadic cases and clusters. This
involves determining contacts, identifying cause (e.g. importation, failure to vaccinate, or vaccine failure); assessing the
sustainability of transmission; identifying populations at risk; and ensuring a public health response. The system’s second
objective is to monitor disease incidence and circulation of the virus. This provides vital information for preventive programs
and control measures; enables the assessment and documentation of progress toward elimination; identifies changes in
risk groups and disease epidemiology; and identifies the virus genotypes in circulation.
To effectively contribute to disease elimination, surveillance systems need to be:
•
•
•
•
Standardized;
Comprehensive and countrywide;
Sensitive—able to detect all clinical cases of measles and rubella; and
Specific—able to confirm diagnosis.
Jankovic stressed that every single suspected case has to be connected inside the health system with a unique
identification number, or EPID number. This protects personal privacy and avoids potential legal issues, while making all
relevant data available to the triad of cooperating experts who need it: clinicians, epidemiologists and laboratory specialists.
Despite the importance of case-based surveillance reporting, in 2011 in the WHO European Region, only 28 countries
provided it; 10 provided aggregate data and 15 provided no data.
Other areas needing improvement are the timeliness and completeness of data and surveillance for CRS. In many
countries, surveillance for CRS must also be significantly improved. CRS surveillance systems should allow detection
of infants with clinically apparent manifestations of CRS; use standardized reporting; and provide laboratory testing of
potential CRS cases. A related goal is the establishment of sentinel site surveillance that captures the majority of infants
with suspected CRS.
WHO makes all of the surveillance data submitted from throughout the region available on its website, providing
feedback to national systems and to the public. WHO provided a range of support to member countries. From the
development of case-based reporting tools to support for national reference laboratories and their integration into the
Regional Reference Laboratory network.
“If I don’t know the dimension of the problem, I cannot fight against it, I
cannot advocate to prevent it.”
Dragan Jankovic, World Health Organization Regional Office for Europe
Rome, Italy, 8-10 February 2012
47
Going forward, Jankovic said that all 53 member states are expected to report measles case-based data by 2012
and rubella case-based data by 2013, provide immunization coverage once a year, and start reporting discarded cases.
Ongoing monitoring and evaluation of the performance of surveillance systems is also essential. Ultimately, only high
quality and timely data will enable the verification of measles and rubella elimination.
Challenge of Timeliness and Completeness
100%
%Completeness
90%
80%
70%
Measles
TARGET
60%
50%
%Timeliness
40%
30%
20%
2009
2010
Oct
Jul
Aug
Sep
Jun
Apr
May
Mar
Jan
Feb
Dec
Oct
Nov
Sep
Jul
Aug
Jun
Apr
May
Mar
Jan
Feb
Dec
Oct
Nov
Sep
Jul
Aug
Jun
Apr
May
Mar
Jan
0%
Feb
10%
2011
100%
90%
80%
TARGET
70%
Rubella
%Completeness
60%
50%
40%
30%
20%
10%
2009
2010
Oct
Aug
Sep
Jul
Jun
May
Apr
Mar
Feb
Jan
Dec
Nov
Oct
Sep
Aug
Jul
Jun
May
Apr
Mar
Feb
Jan
Dec
Nov
Oct
Sep
Aug
Jul
Jun
May
Apr
Mar
Jan
%Timeliness
Feb
0%
2011
Surveillance performance indicators
•
Timeliness
•
Completeness
•
Lab Confirmation rate
•
Chains of transmission/outbreaks
with genotype dates
48
•
Source/origin of infection
•
Adequacy of investigation
Progress Toward Rubella Elimination And CRS Prevention in Europe Proceedings
Congenital Rubella Surveillance
Dr. Pat Tookey, National Congenital Rubella Surveillance Programme, Institute of Child Health, UK
Data presented by Pat Tookey demonstrated the powerful impact of vaccination on decreasing the number of children
born with CRS and the number of pregnancies terminated because of rubella infection.
In the United Kingdom, immediately prior to the introduction of MMR there were 30 CRS births and 75 pregnancy
terminations a year due to rubella. Following MMR introduction in 1988 there was an immediate reduction in reported births
and terminations. In the 2000s, there has been an average of 1 or 2 CR births reported each year.
“In the early ‘70s we were seeing 800 to 1,000 pregnancy terminations a year for congenital rubella disease. Now we
have fewer than ten a year,” Tookey said.
Despite these successes, fifteen years of inadequate MMR uptake still leaves pregnant women vulnerable. In 2011,
2nd dose coverage in England had reached 85 percent by age 5, a significant improvement over years past but below what
is required for elimination of both measles and rubella.
Tookey explained the UK’s surveillance system for rubella and CR, which involves four major agencies, and has
offered antenatal screening of rubella susceptibility for the past 40 years. Tookey’s own organization, the National
Congenital Rubella Surveillance Programme which was established in 1971, is currently unfunded. “The financial cuts and
the fact that there is hardly any congenital rubella about means that this is no longer seen as a priority, so we are literally
running this on nothing at the moment,” she said.
The British Pediatric Surveillance Unit (BPSU) has run an active surveillance system for rare conditions of childhood
since 1986, and congenital rubella has been included in this system since 1990. It sends a monthly form out to about
3,000 pediatricians across the country. On the form, pediatricians tick off any cases they have seen of CRS or other rare
conditions of childhood. The BPSU thus provides comprehensive national coverage and is highly sensitive to changes in
birth prevalence of congenital rubella, Tookey said. The International Network of Pediatric Surveillance Units, INoPSU, is
similar to BPSU, and has units in many European countries.
Across the country, some 95 percent of pregnant women are routinely tested for rubella, and about 4 percent fall below
the screening cut-off and require postpartum vaccination; but delivery of postpartum vaccine is very variable, Tookey said
A recent study set out to identify who the vulnerable women are. A review of clinical samples from 19,000 infants born
to an ethnically diverse population of women in London found that about 2.7 percent of women were likely seronegative.
Women from sub-Saharan Africa were four times as likely to be seronegative than women born in the U.K, and South Asian
women were five times more likely. Women under 20 were significantly more likely to be negative than women in their early
thirties.
Surveillance has confirmed that within the UK, rubella susceptibility is especially high in first generation immigrants,
and that areas of low vaccine uptake tend to coincide with ethnically mixed areas. The threat of imported cases of infection
is ongoing, particularly given the frequency of travel between the UK and immigrants’ countries of origin. Most congenital
rubella births in the UK are unexpected, Tookey reported: most diagnosed reported CR infants have typical severe signs,
and CRI or non-specific signs (including isolated hearing loss) are unlikely to be diagnosed and reported.
Challenges to CRS surveillance include maintaining high quality active surveillance when cases are rare; maintaining
awareness of rubella, CR, and importation of infection among health care staff; and lack of agreement on what typical
defects associated with CRS should be monitored in situations which rely on sentinel surveillance.
Other surveillance challenges lie in detecting the impact of miscarriage, intrauterine death, survival of pre-term or low
birth weight infants and termination of pregnancy, the latter being the most common result of rubella infections in early
pregnancy.
For more information on the International Network of Paediatric Surveillance Units see http://www.inopsu.com.
Rome, Italy, 8-10 February 2012
49
Surveillance Strategies: Molecular Epidemiology
Dr. David Featherstone, Global Measles Laboratory Network and WHO Geneva
According to Featherstone, molecular epidemiology can help fill the large gaps in rubella surveillance, playing a role in
monitoring progress with rubella control and in verifying elimination.
Molecular epidemiology combines genetic sequence data from the laboratory with information from the epidemiologist
about case contacts, travel, patient age, vaccination history, location and more.
“Marrying this epidemiological data with the sequence information allows us to map transmission pathways, identify
possible sources of virus, and assist with the confirmation of true positives.”
Oral fluid samples collected for IgM detection to confirm disease can also yield whole virus and virus RNA. Along with
serum, oral fluid samples are an important resource for molecular epidemiology.
Featherstone emphasized the need to collect baseline genomic data before any acceleration in control that could
quickly remove indigenous virus from circulation. This baseline data enables molecular epidemiologists to assess whether
outbreaks are from imported or indigenous virus, a determination that informs control strategies and is crucial to verification
of elimination. About five to ten samples are needed from every new chain of transmission.
The Global Measles Laboratory Network has about 690 labs, with at least one in nearly every country. “There’s a
lab near you,” Featherstone said. Together, these labs tested more than 200,000 IgM serum samples in 2011. Today, the
rubella database has 1,100 rubella viruses; the measles database has 12,000.
Rubella’s 13 genotypes are grouped into two clades. The sequencing work focuses on a discrete section of
the genome—the 739 nucleotides of the E1 gene—making the data comparable. The sequence variation of strains
within genotypes can vary by 3-4 percent. There are also some clues as to whether a virus is indigenous or imported,
Featherstone explained. For example, small outbreaks in low incidence countries with multiple different sequences are
likely to be due to importation. A large number of cases with little sequence variability over more than one year are likely to
be an endemic strain.
To ensure that labs are proficient, the Laboratory Network uses standardized procedures, validated assays and
reagents and has a comprehensive training program with regular refresher course. Each year, every national lab gets a
proficiency test that consists of 20 samples, and “the pass rate is phenomenal, it’s way over 98 percent,” Featherstone said.
Rubella virus surveillance can be challenging. Highlighting the gaps, Featherstone pointed out that, “In the last two years in
the European region, we have four countries that have reported genotypes for rubella. Thirty-three countries have reported
rubella cases but no sequence information.”
More data is needed, the tools and laboratory capacity exists to gather it, and the data is accumulating, Featherstone
says. Now, the job is to share it. “No use just getting this data, we need to share the data.”
“The lab can do a lot but we can’t tell you everything. We need to get
epidemiological information about the case as well.”
David Featherstone, Global Measles Laboratory Network
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Progress Toward Rubella Elimination And CRS Prevention in Europe Proceedings
Surveillance of Rubella and CRS in Catalonia
Dr. Angela Domínguez, Department of Health, Catalonia, Spain
Catalonia is an autonomous region of Spain, with a population of 7.92 million as of July 2011, 16% of whom are
immigrants. Domínguez reported on the role of the surveillance system in the region’s largely successful, 10-year program
to eliminate rubella and CRS.
Catalonia initiated a one-dose rubella vaccine for 11-year-old girls in 1978, a two-dose strategy for girls in 1981, and a
two-dose strategy for boys in 1988. By 2002, a seroepidemiological survey showed that 98.9% of males and females were
seropositive, demonstrating immunity to rubella. That same year, the Catalonian government decided to take advantage of
this positive landscape and the measles elimination program (begun in 1998), to launch a rubella elimination program. Its
goal was to eliminate postnatal and congenital rubella by December 31, 2005.
The surveillance program’s main activities in this effort included urgent reporting (within 24 hours) of suspected cases
by the Epidemiological Surveillance Units of the Department of Health. This allowed follow up of the case and its contacts
and collection of clinical samples between 5-21 days after rash. Susceptible contacts of a confirmed case were vaccinated.
The Statutory Disease Reporting System required all public and private physicians to report suspected cases of
postnatal rubella and congenital rubella based on a standard case definition. The Measles Elimination Program also
screened suspect viruses. Meanwhile, the Microbiological Reporting System, encompassing 44 Catalan hospitals covering
more than 80 percent of hospital beds reported positive results for rubella IgM antibodies to the Department of Health.
From 2002 to 2008, first dose MMR coverage was above 95 percent, dipping just below that in 2010. Second dose
coverage reached 95 percent in 2006, then dropped in the following years (although still remaining above 90 percent.
The program identified 98 suspected cases of postnatal rubella between 2002 and 2011. This is a low number that
suggest some cases may not have been identified, Domínguez said. Of these 98 suspected cases, 39 were confirmed
positive. The program closed a large initial gap between the number of suspected and laboratory tested cases, and
by 2011, all notified cases were laboratory tested. Four cases of CRS were confirmed over the same time period. This
included one case reported in 2008, which was the first indigenous CRS case since 1990. The other three CRS cases were
related to temporary stays of the mothers in Morocco and Poland during pregnancy.
The two sources providing the largest number of confirmed cases were Urgent Notification, which provided 33 percent
of confirmed cases, and the Microbiological Reporting System, which provided 23 percent of confirmed cases. Of the 39
confirmed cases, 21 were imported cases of known origin, all in unvaccinated individuals. Only 50 percent of confirmed
cases had received one dose of vaccine and 49 percent of cases were imported or related to an imported case. The age
group with the highest incidence was 25-44 years of age.
Domínguez noted that surveillance quality is generally high, with just two areas needing improvement: the timeliness
of reporting and identification of origin. “In conclusion, in the ten years of the program, the elimination of indigenous
congenital rubella was maintained,” Domínguez said.
Discussion
Participants discussed the need for cultivatable strains of the virus—something not permitted by PCR techniques—in
order to determine whether the vaccine strain is protecting against circulating virus (an issue with mumps vaccine).
Icenogle replied that while there’s not a huge collection of rubella viruses, there are representative viruses. Some 20
strains from different genotypes have all been tested, and the vaccine remains effective against all of them.
Cooper raised a concern about the use of IgM screening in pregnancy because some individuals maintain persistent
rubella specific IgM for a long period of time, well past the time of infection. “I’ve been concerned about pregnancy
terminations on the basis of positive IgM when they may not have been warranted.” Domínguez suggested the need to
distinguish between countries with high prevalence and with low prevalence. She gave the example of Catalonia (Spain),
where only a few cases of potential rubella are identified during pregnancy, and where IgM screening is not recommended
on a routine basis for pregnant women.
Rome, Italy, 8-10 February 2012
51
SESSION IX:
Issues to be Addressed
UNICEF Vaccine Procurement Overview
Ms. Selenge Lkhagva, UNICEF
Ms. Lkhagva described the UN agency’s vaccine procurement from the points of view of supply and demand, globally,
regionally and for Middle Income Countries, focusing on vaccines for measles and rubella.
UNICEF’s centralized procurement operation is based in Copenhagen, Denmark, and its supply division secured
US$955 million worth of vaccines in 2011 – some 2.47 billion doses. These included traditional and new vaccines, among
them vaccines for measles and rubella. The value of UNICEF vaccine procurement began a steep rise in 2001, mainly due
to global programs such as polio eradication and measles and tetanus elimination. In addition, UNICEF has been procuring
vaccines for GAVI funded vaccine introductions, from pentavalent to the new vaccines such as rotavirus. The total of
vaccines procured by UNICEF dropped slightly in 2010, the combined result of some price decreases and India switching
to self-procurement.
UNICEF plays a minor and supplementary role in vaccine procurement for the European Region, where most of the
region buys its own vaccines. “This region is one of the most demanding regions in terms of registration and legal issues, a
lot of legal issues, a lot of strict regulations… and very specific preferences on country of origin,” Lkhagva said. Generally
speaking, UNICEF successfully complies with these issues.
Going forward, UNICEF expects demand to increase as GAVI opens a new support window for countries. “We expect
our procurement of MR and MMR—mostly MR—to reach up to 300 million doses of vaccine in 2015,” Lkhagva said. After
GAVI-eligible countries carry out catch-up campaigns with MR vaccines, demand for these vaccines is likely to stabilize.
As for the supply market, Lkhagva noted that there is a limited global supply for this MR vaccine, given that currently
there is only one manufacturer producing pre-qualified vaccine. On the other hand, there is growing global demand, not
just from UNICEF, but also from self-procuring countries. “It’s inevitable that UNICEF is in competition with higher margin
markets for production capacity because of the limited supply base,” she said. Since 2000, price per dose for UNICEFprocured MR vaccine has increased from a bit over US$0.30 per dose to a bit over US$0.50 in 2011.
There are four manufacturers that produce WHO prequalified MMR vaccine. While demand through UNICEF in the
past has been low, there is growth potential as more countries tackle rubella. The weight average price of MMR is relatively
higher than that for MR, and the scale of procurement has a big impact. In 2011, the average price a single dose was above
US$3.50, while for a 5-dose purchase it was just under US$1.00 per dose.
In 2011, UNICEF procured vaccine for 56 middle income countries, representing 45 percent of the total vaccine value
compared to 2007, when this procurement represented 8 percent of total value. This shift occurred as a result of economic
growth by a number of the countries served by UNICEF, and subsequent change in their income classification for countries
by the World Bank.
“Vaccine Security is the underlining principle of procurement at UNICEF.
For this, I would like to highlight the importance of accurate forecasting.
In the situation of global competition for a limited supply base, it
becomes even more crucial.”
Selenge Lkhagva, UNICEF
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Progress Toward Rubella Elimination And CRS Prevention in Europe Proceedings
This requires efforts on vaccine pricing to ensure financial sustainability. UNICEF is refining its strategy and
strengthening its engagement in MICs procurement to reduce inequity in new vaccine introduction, using mechanisms such
as “temporary” pooled procurement that supports introduction without replacing existing markets and their transition to selfprocurement.
Lkhagva stressed the need for accurate demand forecasting, to ensure a sustained and uninterrupted supply of
affordable vaccines in support of the objectives of the Global Measles and Rubella Elimination Programme.
UNICEF Procurement of Measles Containing Vaccines
for CEE/CIS Countries in 2000 – 2011
30,000,000
25,000,000
Doses
20,000,000
15,000,000
10,000,000
5,000,000
0
2000
2001
2002
2003
MEA
2004
2005
MMR
2006
MR
2007
2008
2009
2010
2011
RUBELLA
Safety of Rubella and MMR Vaccines
Dr. Jan Bonhoeffer, Brighton Collaboration
Dr. Bonhoeffer reviewed what is actually known about MMR safety, and contrasted this to public concerns, particularly
among parents. He urged the public health community to not only anticipate upcoming issues, but also to be prepared to
address them with confidence, backed by robust evidence, and data aggregated across regions as helpful.
Looking at data reporting Adverse Events Following Immunization (AEFI), Bonhoeffer noted that fever -- the most
commonly reported adverse event – is typically a good thing. “When patients come to my immunization clinics, and they
have a question about fever, I congratulate them on the immune system of their kids. Fever is something we expect.” In
essence, it shows the vaccine is working. Febrile convulsions, while far less common, are also an expected adverse event
for a minority of vaccines.
Yet fear of fever is not what keeps parents from vaccinating their children. Vaccine skeptics are more likely to fear
consequences that have no evidence of a causal association with MMR vaccines, including autism.
Rome, Italy, 8-10 February 2012
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Bonhoeffer reported on new work by Heidi Larson which categorized coverage of MMR in European media from May
2011 to February 2012 based on issues of concern. Nearly 70 reports were concerned with autism, fewer than three each
related to either rash/fever or seizures.
“There’s a clear sort of disparity between what the public is concerned about and what the professionals are
concerned about,” Bonhoeffer said. “That just goes to show that if we’re not listening to the public, we’ll miss the point and
face a headwind for this campaign. We really need to listen closely here.”
Bonhoeffer cautioned that what might look like a rare event in routine reporting may suddenly pop up during
campaigns as a population level effect. In particular, he pointed out the need for more data on vaccine exposure during
pregnancy. He highlighted the need to think ahead regarding catch-up campaigns among adult populations. “It makes
sense to prepare for a catch-up campaign in terms of safety, and while there may not be a real concern, it would be very
wise for us to have the right data available if public concern arises.”
Today, major drivers of vaccine skepticism include: parents’ lack of experience of disease and its complications;
continued exposure to second-hand information about autism, creating a kind of “societal theory of risk”; fear of making a
wrong decision related to vaccination; and distrust in policy and manufacturers.
“What derails immunization programs is not only concern about the vaccine’s safety—most of the issues are actually
concerned with the policy changes,” Bonhoeffer said.
Disease elimination programs and vaccination campaigns raise two big issues: they represent a change in policy,
and a change in recommendation. Therefore, the very launch of a mass campaign can nearly generate a public headwind
against it.
He argued for engaging the opinionated in discussion, noting that timing is everything. Drawing on experience with
measles outbreaks in Switzerland, where vaccine skeptics tend to be members of anthroposophic groups and traditional
farmers, Bonhoeffer said, “Particularly with the opinionated people, outbreaks help a lot.” He pointed out that the immediacy
of having your own, or a neighbor’s daughter, infected with measles can have a strong effect on people’s theoretical ideas
about life.
Bonhoeffer said that it is critical to know the main drivers of public trust—and they are healthcare providers, particularly
general practitioners. He noted that, “By bringing together public health authorities with pediatric societies, this conference
is absolutely right on target. Increasing collaborations and making sure that the message goes out through those who
provide pediatric primary care in their respective communities is exactly where we should put our attention.”
An important message to convey is to “build confidence in being a good parent with MMR by giving it,” Bonhoeffer said.
He summarized main lessons learned thus far from MMR vaccine implementation: Anticipate public concerns;
understand the dynamics of “threshold events” to prevent the derailment of programs by public concerns; recognize that
communication alone will not stop public mistrust and provide strong evidence to speak with confidence; be ready for
rapid, reliable investigation of concerns; and replace small-scale fragmented research with international collaboration and
data sharing.
“By bringing together public health authorities with pediatric societies,
this conference is absolutely right on target. Increasing collaborations
and making sure that the message goes out through those
who provide pediatric primary care in their respective communities
is exactly where we should put our attention.”
Jan Bonhoeffer. Brighton Collaboration
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Progress Toward Rubella Elimination And CRS Prevention in Europe Proceedings
Monitoring and assessing vaccine safety – an EU perspective
Dr. Kari Johansen, European Centre for Disease Prevention and Control (ECDC)
Dr. Johansen described the ECDC and its initiative, the Vaccine Adverse Events Surveillance and Communication
(VAESCO) Program, launched by the ECDC in 2008.
ECDC’s role is to “Identify, asses and communicate current and emerging health threats to human health from
communicable diseases.” It carries our EU-level disease surveillance, provides scientific opinions and conducts studies on
vaccine effectiveness and safety. Its early warning and response system goes out confidentially to all Ministries of Health in
the European Union and other close collaborators. Technical assistance, training, epidemic intelligence, and scientific and
public communication are all part of its remit.
Its partners include Member States, the European Medicines Agency and the European Commission which has
responsibility for risk assessment and management.
VAESCO was started in 2008 to improve the EU’s ability to rapidly assess vaccine safety signals. Already in place
was a strong signal detection system based on national regulatory agencies that report to the European Medicines Agency.
The EMA feeds data into its Eudravigilance database.
However, weaknesses in the EU’s readiness to validate and assess vaccine safety signals became apparent
18 months ago with the emergence of a very strong signal on narcolepsy, potentially related to pandemic influenza
vaccination. While national immunization registries and clinical outcome databases offer critical data, but they are not
sufficient to rapidly assess potential safety signals.
VAESCO began as a small network, whose development was accelerated due to the use of new pandemic vaccines.
Combining the data of its members, VAESCO has access to information of a pan-European source population of 50 million
individuals representing up to 250 million person years.
Johansen summarized some of VAESCO’s accomplishments thus far. It has provided proof of concept that data can
be linked and shared across country borders. One initial study pooled data from Denmark and the UK using the MMR
vaccine and the known adverse event of thrombocytopenic purpura. The project used a special software program to extract
relevant data from diverse medical data bases, but the process was cumbersome.
Other work has compiled background rates of Guillain-Barré Syndrome, as a baseline to look for possible correlations
between GBS incidence and the use of various vaccines in campaigns to protect against pandemic influenza.
Johansen summarized the value of EU-wide studies in understanding the potential impacts of the range of different
types of vaccines used in the EU, both adjuvant and non-adjuvant; in understanding differences among subpopulations,
such as age groups, pregnant women and others; and in understanding possible risk factors outside of the vaccines
themselves, such as genetics or concurrent infections. For all of these, only very large sample sizes will have the statistical
power to shed light on rare events.
Going forward, challenges include linking vaccination registries in more countries, creating infrastructure for
epidemiological studies, and securing funding. Johansen noted that the studies are costly, prohibitively so for some
countries. Funding is needed as well to improve capacity building.
VAESCO will be holding training workshops both with partner countries and non-partner countries, bringing 15 EU
member states to Stockholm to share experiences acquired thus far on the project.
“We need to link vaccination registries in more countries. We need
to create infrastructure for all kinds of epidemiological studies of any
vaccine, and we need sustainable models of funding.”
Kari Johansen, European Centre for Disease Prevention and Control (ECDC)
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Manufacturers Roundtable
The roundtable brought together representatives from four vaccine manufacturers: Dr. Suresh Jadhav from the Serum
Institute of India, Jonas Vezbergas from GlaxoSmithKline, Barbara Kuter from Merck, and Alla Lobastova from Russia’s
Microgen, each of which made brief remarks.
The value and purpose of partnerships with manufacturers emerged as a major topic. From the Serum Institutes point
of view, “Normally manufacturers are considered as little untouchables in these types of meetings, but as Ciro de Quadros
has said… unless you have the ammunition you cannot be in the war.”
GlaxoSmithKline highlighted the necessity to partner in the planning phase of mass campaigns, pointing out that only
if manufacturers know what is coming can they plan vaccine production to meet upcoming needs. “The worst thing is when
a country is coming to us and saying we need the vaccine next week,” Vezbergas said. Merck suggested that vaccine
manufacturers could be partners in three regards: planning partners to ensure the availability of vaccine when and where
it’s needed; research partners to identify and address outstanding questions regarding vaccines; and communications
partners, whether in training the media or putting together educational programs for broadcast.
Company representatives also highlighted aspects of their company’s vaccine manufacturing:
•
•
•
•
The Serum Institute of India manufactures about 900 million vaccine doses a year, supplying them to various
countries including India. It supplies about 70-75% of the DPT and MMR vaccines needed by UNICEF and
PAHO, and supplied more than 85% of the vaccine that was used for the elimination of measles and rubella in
the PAHO region.
GlaxoSmithKline distributes about 80% of its production to developing countries. It has longstanding contracts
with UNICEF for polio vaccine, and has a commitment to rotavirus and pneumococcal vaccination. It also
produces and supplies MMR vaccine.
Merck brought the first MMR vaccine to licensure.
Microgen, a Russian state-run company, has developed and licensed its own vaccine against rubella, having
recently produced about 4.5 million doses for the national immunization schedule. Microgen produces more
than 300 medicines, 70% of them vaccines. It has 14 manufacturing plants and a workforce of over 6,000
specialists. Other vaccines produced include DTP, hepatitis, BCG, and influenza.
Discussion
Much discussion centered on the need for accurate forecasts in order for industry to reliably meet demand; on
questions of supply and demand; and on issues of communication.
The Serum Institute is the world’s only supplier of MR vaccine, and de Quadros asked about its manufacturing
capacity for this vaccine. Jadhav reported that its annual capacity is now between 150 to 200 million doses of MR.
However, demand for MR is expected to increase, as 30 countries may be adding MR to their schedule. At the same time,
demand of measles vaccine will go down. The Serum Institute produces 400 million doses a year of measles vaccine, and
has been for the last five to six years.
Kim Thompson voiced concern about strategies for product development which drive inventories down. “How do you
foresee a negotiation around creating excess stockpiles playing out in the upper levels with pressure in inventory and your
annual reporting?” he asked. Vezbergas reiterated that the most essential issue is one of communication around accurate
forecasting. “If we are getting good information from our customers or our partners on what is the future demand, then we
can increase our inventory as well,” he said. Kuter suggested that either European countries or the ECDC should have
standard vaccine stockpiles, as a safeguard, as the CDC does.
Cooper raised the issue of communications and perceptions of industry, noting that many vaccine opponents
allege that the real purpose behind vaccination campaigns is for companies to sell more vaccines. “How we define our
relationships in ways that demonstrate the integrity of our relationships will be one of our challenges, especially in some of
the countries in this region who clearly could use more aggressive immunization programs.”
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Progress Toward Rubella Elimination And CRS Prevention in Europe Proceedings
Thompson asked what industry needs from its public health partners, especially regarding issues of communication.
“When issues of communication come up, everybody expects you to defend yourselves, but also questions your integrity
because you have financial stakes,” he said.
Kuter suggested that a rapid response team be put together as a joint forum for manufacturers, the ECDC, CDC, WHO
and regulatory agencies to be able to coordinate when urgent issues come up.
Concluding Remarks
Speaking on behalf of WHO, Dr. Peter Strebel thanked all the member states of the European Region for “being so
frank and open… sharing with us the successes you’ve had with measles and rubella elimination, but also sharing the
problems…. Just acknowledging the problems is the start of success,” he said.
Dr. Strebel extended a warm thanks on behalf of WHO-EURO to the organizers: Ciro de Quadros, the Sabin Vaccine
Institute and their partners. He spoke of the inspiration of being in the room with the “giants of measles and rubella
vaccination,” people like Sam Katz, Stanley Plotkin, Lou Cooper, Jenny Best, Pat Tookey, and Lilianne Grangeot-Keros.
Noting it is just three and a half years before the target date of rubella elimination in the region, “I think we can do it,” he
said. “So let’s try.”
Dr. Ciro de Quadros thanked his colleagues in the Organizing Committee, among them Maria Grazia Revello, who
was the inspiration for the meeting. He congratulated the participants for their commitment. Addressing all in attendance,
he said, “A few years from now, I hope not too many years, when Europe is completely free of measles and rubella, all of
your names will be in the history of that. When Europe eliminates measles and rubella, it’s no doubt that it’s because of
you. You are the ones that will make the change.”
Rome, Italy, 8-10 February 2012
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Speakers
Jon Andrus
Pan American Health Organization
United States
Jenny Best
Kings College London
United Kingdom
Jan Bonhoeffer
Brighton Collaboration Foundation
Switzerland
Louis Cooper
Columbia University
United States
Irja Davidkin
Ministry of Health
Finland
Ciro de Quadros
Sabin Vaccine Institute
United States
Angela Dominguez
University of Barcelona
Spain
Isabelle du Chatelet
Institut de Veille Sanitaire
France
Nedret Emiroglu World Health Organization
Denmark
Helen Evans
GAVI Alliance
Swizerland
David Featherstone World Health Organization
Swizerland
Liliane Grangeot-Keros
National Reference Laboratory for Rubella
France
Nicole Guérin
Pédiatrie tropicale France
Wlodzimierz Gut Ministry of Health Poland
Joe Icenogle
Centers for Disease Control and Prevention
United States
Dragan Jankovic
World Health Organization
Denmark
Kari Johansen
Swedish Institute for Infectious Disease Control
Sweden
Samuel Katz
Duke University
United States
Andreas Konstantopoulos
European Pediatric Association Greece
58
Barbara Kuter
Merck
United States
Selenge Lkhagva
UNICEF
Mongolia
Alla Lobastova
Microgen
Russian Federation
Pierluigi Lopalco
ECDC
Sweden
Leyla Namazova
Scientific Center of Children‘s Health
Russian Federation
Stanley Plotkin
Univerity of Pennsylvania
United States
Maria Grazia
Pompa Ministy of Health
Italy
Susan Reef
Centers for Disease Control and Prevention
United States
Maria Grazia
Revello Ministry of Health
Italy
Stefania Salmaso
Ministy of Health
Italy
Peter Strebel
World Health Organization
Switzerland
Jadhav Suresh
Serum Institute of India Ltd.
India
Pat Tookey
University College London
United Kingdom
Olga Tsvirkun
Ministry of Health Russian Federation
Vytautas Usonis
Vilnius University Centre of Paediatrics
Lithuania
Jonas Vezbergas
GlaxoSmithKline
Belgium
Emilia Vynnycky
Health Protection Agency
United Kingdom
Laura Zimmermann
Centers for Disease Control and Prevention
United States
Progress Toward Rubella Elimination And CRS Prevention in Europe Proceedings
Delegates
Annalisa Agangi
Italy
Ashot Davidyants
Armenia
Joldosh Kalilov
Kyrgyzstan
Juan Picazo
Spain
Maral Aksakova
Turkmenistan
Eleonora De Ponti
Italy
Nino Kandelaki
Georgia
Giulia Piccirilli
Italy
Luisa Almeida Santos
Italy
Silvia Declich
Leva Kantsone
Latvia
Ivan Pristas
Croatia
Michael Katz
United States
Roman Prymula
Czech Republic
Richard Keros
France
Oystein Riise
Norway
Terhi Kilpi
Finland
Maria Cristina Rota
Italy
Tiziana Lazzarotto
Italy
Angela Santoni
Italy
Aurora Limia
Spain
Evelyne Sauty
France
Goranka Loncarevic
Serbia
Guido Scalia
Italy
Marianne Louis-Tisserand
Belgium
Wilhem Sedlak
Austria
Alessandra Macari
Italy
Brian C. Shaw
United States
Fabio Magurano
Italy
Veranika Shymanovich Belarus
Gregory Maine
United States
Kai Soop
Estonia
Kazi Mamun
Bangladesh
Emma Spranzi
Italy
Annette Mankertz
Germany
Theodora Stavrou
Greece
Stéphane Martin
Belgium
Chen Stein-Zamir
Israel
Dorothea Matysiak-Klose
Germany
Leszek Szenborn Poland
Joseph Meyongo Okala
Cameroon
Shahina Tabassum
Bangladesh
Jan Mikas
Slovakia
Hariram Thacker Naveenkumar
India
Lidia Mladenova Georgieva
Bulgaria
Kimberly Thompson
United States
Susanne Modrow Germany
Alberto Eugenio Tozzi
Italy
Emanuele Montomoli
Italy
Francesco Trotta
Italy
Mick Mulders
Denmark
Veronika Ucakar
Slovenia
Darina O’Flanagan Brown
Ireland
Ingrid Urbancikova
Slovakia
Elisabetta Pandolfi
Italy
Kirsti Vainio
Norway
Jonathan Pearman
Switzerland
Paula Valente
Portugal
Catherine Peckham
United Kingdom
Christelle Vauloup-Fellous
France
Marcello Pellegrino
Italy
Ole Wichmann Germany
Elena Pfaffenrot
Switzerland
Robyn Wood
France
Peter Anderson
Denmark
Andrey Demin
Russian Federation
Lucie Deprez
France
Tamar Dolakidze
Georgia
Valentina Anró
Italy
Tiiu Aro
Estonia
Melissa Baggeri
Italy
Diana Bastinac
Bosnia and Herzegovina
Daniela Bernasconi
Italy
Sivia Bino
Albania
Arianna Boiani
Italy
Ralf Bollhagen
Germany
Antonio Boniolo
Italy
Marie - Claude Bonnet
France
Blenda Böttiger
Denmark
Victoria Bucov
Republic of Moldova
Wilma Buffolano
Italy
Antoneata Bukasa
United Kingdom
Margaret Burgess
Australia
Sergio Cabral
Brazil
Etelvina Calé
Portugal
Ana Flavia Carvalho
United States
Flaminia Cassiani
Italy
Jitka Castkova
Czech Republic
Stella Cerri
Italy
Maka Chachanidze
Georgia
Todor Chernev
Bulgaria
Daniela Chialant
Italy
Alya Dabbagh
Switzerland
Paola Falconieri
Italy
Berit Feiring
Norway
Patrizia Felicetti
Italy
Teresa Fernandes
Portugal
Laura Ferrara
Italy
Antonietta Filia
Italy
Radosveta Filipova Ivanova
Bulgaria
Marianne Forsgren
Sweden
Claudia Fortuna
Italy
Jean-Francois Fougere
Switzerland
Barbara Francis
Australia
Graça Freitas
Portugal
Milena Furione
Italy
Claudio Galli
Italy
Cristina Giambi
Italy
Georgia Gioula
Greece
Steffen Glismann
Belgium
Simone Graf
Switzerland
Adnike Grange
Nigeria
Rami Grifat Israel
Fabienne Heskia
France
Didier Hue
Belgium
Stefania Iannazzo
Italy
Lia Jabidze Georgia
Rome, Italy, 8-10 February 2012
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