The magazine of the Institut national de la santé et de la recherche médicale (National Institute for Heath Care and Medical Research)
vaccines
Why
the fear?
N°24 l March-April 2015
©©François guénet/inserm
Although vaccines remain the most effective way of preventing
many infectious diseases, an increasing number of French people
are expressing doubts about their efficacy and, to an even greater
extent, their safety.
Nevertheless, in 2015, the successes of immunization cannot
be denied. Smallpox has been eradicated from the planet and
poliomyelitis has disappeared in many countries. Other diseases
like diphtheria and tetanus which used to cause massive morbidity and
mortality have been reduced and are on the way to eradication. And when
a new disease emerges (SARS, pandemic influenza, Ebola), the ideal way
of controlling its spread is to develop a vaccine.
So why the fear? Are vaccines associated with risks? As with any
medicinal product, their administration can induce adverse reactions
such as pain at the injection site, fever or malaise due to stimulation
of the immune system. And the fact that vaccines are supposedly
administered to prevent risks makes adverse reactions more difficult
to accept. This is why developing a vaccine involves testing on large
populations and then surveillance for a long time after launch in order
to detect rare adverse reactions that have not yet been observed.
Recommendations on immunization take into account a vaccine's
benefits at both the individual and collective levels as well as its potential
risks.
Finally, it is perhaps the very fact the these diseases have been
eradicated as a result of immunization that allows us to forget how
dangerous they used to be. And this may distort our perception of the
risks of immunization compared with those of the actual disease itself.
Leading to reduced vaccine coverage—not devoid of risk—as has recently
been seen with measles.
Odile Launay
Coordinator of Clinical Investigation Center 1417 Cochin-Pasteur,
and the National Network for the Clinical Investigation of Vaccines
(Réseau national d’investigation clinique en vaccinologie, I-REIVAC),
Université Paris-Descartes, Sorbonne Paris Cité, AP-HP
Vice-President of the Technical Immunization Committee
of the Supreme Public Health Council
N°24
mars - avril 2015
Abonnement gratuit, écrire à :
science-et-sante @ inserm.fr
Directeur de la publication
Yves Lévy
Directeur de la rédaction
Arnaud Benedetti
Rédacteur en chef
Yann Cornillier
Secrétaires de rédaction
Coralie Baud, Maryse Cournut
Chef de rubrique Julie Coquart
Assistante d’édition
Coralie Baud
Ont collaboré à ce numéro
Alexia Attali, Alice Bomboy,
Damien Coulomb, Françoise
Dupuy Maury, Jean Fauquet,
Alexandra Foissac, Tina Gereral,
Caroline Guignot, Étienne
Ledolley, Pascal Nguyên,
Julie Paysant, Hélène Perrin,
Simon Pierrefixe, Karl Pouillot,
Vincent Richeux, Nicolas Rigaud,
Bruno Scala
Conception graphique
et direction artistique
Ghislaine Salmon-Legagneur
Iconographie
Cécile Depot
Consultante projet
Françoise Harrois-Monin
Crédit de couverture
Illustration :
Miguel Porlan
Impression
Groupe Burlat
N° ISSN : 2119-9051
Dépôt légal : Mars 2015
March-April 2015 ● N° 24 ●
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© Jean Claude MOSCHETTI/REA
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➜
vaccines
Why
the fear?
The French resist immunization. Are they afraid of needles?
No, it is more their composition that causes worry, and their
supposed side effects. Whereas ten years ago, almost everyone
agreed with immunization, today nearly 40% have come to
mistrust vaccines. Now, at the moment of Immunization Week
from 20-25 April 2015, it is time for Science&Santé to give a
booster shot with a review of how vaccines work and the risks
and benefits of these distinct medicinal products which every year save millions
of lives throughout the world.
March-April 2015 ● N° 24 ●
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5
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➜
Edward Jenner,
an English physician,
immunizes a child
against smallpox with
pus taken from the
blister of someone
suffering from cowpox.
Louis
Pasteur,
chemist and
biologist,
vaccinates
against
rabies.
©©Institut Pasteur - Musée Pasteur
1796
1882
Robert Koch,
a German physician,
isolates the
bacillus that causes
tuberculosis
("Koch's bacillus")
6
● N° 24 ● March-April 2015
without delay activate
the immune system.
There are various ways
of eliciting this special
type of memory. Some
vaccines contain live
organisms of the
pathogen being immunized against. Their virulence is
attenuated by passage in culture in special conditions,
e.g. low temperature. Such vaccines are referred to as
attenuated live vaccines and they induce an infection
but one with no symptoms or only mild ones. This
group includes the famous BCG against tuberculosis,
the smallpox vaccine and MMR, the vaccine against
measles, mumps and rubella (German measles). Inactivated vaccines also contain whole organisms but these
are non-viable, having been killed by heat or chemical treatment, e.g. formaldehyde is used to kill the poliovirus in the vaccine against poliomyelitis. Another
group, sub-unit vaccines contain purified fragments of
the microbe. Because sometimes, not all a pathogen's antigens are needed to elicit a protective immune response,
explains Camille Locht. Today's vaccines against pneumococcus and meningococcus are based on fractions
purified from the bacterial capsules of the bacteria. Finally, sometimes it is not the microbe itself that causes
the disease but rather toxins that it releases inside the
body. In this case, detoxified toxin—or anatoxin—is
used as the antigen, e.g. in the vaccines against tetanus
and diphtheria.
1885
1890
Musée Pasteur
☛☛Camille Locht: Inserm Unit 1019/CNRS/
Université Lille 1/Institut Pasteur de
Lille – Université Lille 2 droit et santé,
Bacterial Infections of the Airways:
Pertussis and Tuberculosis team
Musée Pasteur
8 www.inserm.fr
©©Institut Pasteur -
See Ketty Schwartz' seminar
(2014): Immunization
(file and videos)
Looking at BCG
bacilli (green) under
a fluorescence
microscope
©©Institut Pasteur -
N
o doubt, regard for vaccines is on the decrease.
Whereas 90% of the French believed that they
were beneficial in 2005, only 61.5 did so in 2010
according to two comparable surveys conducted by the
National Institute for Prevention and Health Education
(Inpes, Institut national de prévention et d’éducation pour
la santé). Today, some confidence seems to have been
restored but not to the level of the early 2000's. What
is the problem? Some blame their lack of efficacy or
the risks associated with immunization, but many also
point to a serious lack of information. In 2004, another
Inpes survey revealed that 40% of those interviewed
did not know how vaccines work. And ignorance paves
the way for mistrust. A good reason to explain about
how vaccination works—the idea of immunization.
When someone with an infection recovers, they become
immunized, meaning that they are henceforth protected
against infection by the same pathogen, explains Camille
Locht *, microbiologist and Inserm Research Director at the Infection & Immunity Center in Lille. They
will not succumb to that infectious agent again, or only
develop a mild infection. It is this protective effect that
vaccination attempts to reproduce: to immunize the
vaccinated subject without making him ill. A vaccine
has to dupe the immune system to make it think that
it has an infection to deal with, the scientist goes on.
To do that, it must contain elements of the infectious
agent that can be recognized by the immune system,
so-called antigens. Once activated by antigens, the immune system can attack foreign agents. It is the innate
immune system that first gives battle. This indiscriminately targets most foreign bodies inside the body, including any agents derived from outside of the body.
Subsequently, the adaptive immune system takes the
baton with the activation of killer cells which finally
get rid of intruders (see the Figure on pages 08-09).
After the fight is over, most of these cells disappear but
a few of them survive and underlie what we refer to as
immunological memory. If the same antigens appear
in the body, these surviving cells recognize them and
Obligatory immunization
against smallpox in France
1902
Shitasaburo Kitasano, a Japanese
bacteriologist, and Emil von Behring,
a German physician, produce
diphtheria and tetanus anatoxins.
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1921
1923
Albert Calmette, physician
and bacteriologist,
and Camille Guérin,
veterinarian and biologist,
develop BCG which
immunizes against
tuberculosis.
Vaccine against
poliomyelitis
Vaccine against Around 4,000
cases before
tetanus
/ 0 afterwards
 Around 1,000
cases before
/ 20 afterwards*
1926
1952
1963
Vaccine against pertussis
 Around 550,000 cases
before / 1,000 afterwards*
Introduction of aluminum
salts as an adjuvant

☛☛Odile Launay: CIC 1417 Inserm/Cochin
Pasteur – Université Paris-Descartes
R. Thorstensson et al. PLoS One,
8 January 2014; 9 (1): e83449
©©CDC/ Dr Murphy

Vaccine against
diphtheria
Around 45,000
cases before / 0 afterwards
Although how vaccines work is now more or less understood, they nevertheless take a long time to develop,
as confirmed by Camille Locht. In practice, developing a vaccine takes a very long time. It takes at least ten
years from proof of concept to sale. Because extensive
research is necessary. Once a disease has been characterized and its etiologic agent identified, experiments
are conducted in animals to investigate the feasibility
of developing an effective vaccine. Then comes the preclinical development phase which includes pharmacological and toxicological tests. A comprehensive file on
the candidate vaccine is then submitted to the relevant
agencies, the European Medicines Agency (EMA) and
the French Drug Agency (Agence nationale de sécurité
du médicament et des produits de santé, ANSM). If the
application is approved, a long series of clinical studies
in humans is then begun. This is divided into different
phases. The first, Phase I involves studying the candidate
vaccine's safety and tolerance in dozens of volunteers who
are aware of the possible risks, explains the microbiologist. Last year, her team presented promising Phase I
results on a new attenuated live pertussis vaccine. This
is administered into the nose to directly immunize the
mucous membranes of the airways—exactly where the
pathogenic virus that causes whooping cough is found.
In Phase II, immune responses are analyzed in some
hundreds of patients and sometimes the ideal dosing
schedule is investigated. Finally, Phase III trials test the
vaccine in thousands or even tens of thousands 
©©Institut Pasteur
These various methods of immunization all have their
pros and cons. Attenuated live vaccines afford rapid,
long-lasting protection with just one or two injections
because they are almost as immunogenic—their ability
to elicit an immune response—as the virulent pathogen.
However, there is a risk—albeit small—of this type of vaccine causing an infection, says Odile Launay *, physician and Head of the Vaccine
Clinical Investigation Center “Attenuated live
at Cochin Hospital in Paris.
vaccines can—
They are therefore not recommended for immunodeficient rarely—cause
subjects, e.g. HIV-positive, infection„
leukemia, etc. Inactivated vaccines do not present this infectious risk and are highly
immunogenic. But some have side effects, e.g. the whole
pertussis vaccine against whooping cough rarely causes
encephalitis, inflammation of the brain. This vaccine is
no longer used in France and has been replaced by a
much safer sub-unit vaccine. Anatoxin-based vaccines
are also safe but, like sub-unit vaccines, they tend to
be less immunogenic. To enhance their immunizing
power, these vaccines contain adjuvants. Adjuvants
Years of work

Vaccine against mumps
Around 550,000 cases
before / < 30,000
afterwards*
1967
Vaccine against
measles
Around 50,000 cases
before / < 50,000
afterwards*
1977
The WHO
confirms the
eradication
of smallpox
1980
Last known
case of
smallpox
©©Institut Pasteur
©©Inserm/ Patrice Latron
potentiate the innate immune response, essentially by
activating lymphocytes, cells which are at the center of
the fight against pathogens and which underlie immunological memory, explains Camille Locht. Numerous
injections and booster shots are sometimes needed to
induce long-term immunity. Adjuvants can also be
used to cut down the quantity of antigen and number
of injections needed to obtain good protection with an
inactivated vaccine.
Vaccine against
papillomavirus
1981

2006
Vaccine against
Hepatitis B
Around 300,000
cases before / 28,000
afterwards*
*Number of cases
in 2000
March-April 2015 ● N° 24 ●
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7
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Immunization
How does
it work?
1
1 I ntroduction of the antigen
through vaccination or infection
2Phagocytosis of the antigen by a
macrophage which becomes an
antigen-presenting cell (APC).
2a T
he pathogen activates memory B
lymphocytes.
2bThe pathogen activates memory Tt
lymphocytes.
2c
The pathogen infects a cell.
3The antigen presented on the APC's
surface is recognized by helper T
lymphocytes (TH cells).
4aThe TH cells activate B cells.
4bThe TH cells activate killer T cells.
5a 3aActivated B cells proliferate and
differentiate, some to form plasma
cells and others memory cells.
5b 3bActivated Tt cells proliferate and
differentiate, some to form killer
cells and others memory cells.
3c T
he target cell presents antigens
at its surface.
6a 4aProduction of antibodies which
bind to free antigens as well as to
infected cells—which promotes
their phagocytosis.
6b 4b A
ctivated Tt lymphocytes bind to
the target cell.
7a 5aThe infected cell flagged by
antibodies is phagocytosed and
then destroyed.
7b 5b The infected cell is lysed.
8
● N° 24 ● March-April 2015
… and induce protection
against real infection
When a pathogen
bearing the same
antigens enters the
body, it is quickly
recognized by the
memory cells. The
memory T and B
lymphocytes then
directly transform
into killer and plasma
cells respectively.
The immune
system's response
is immediate and
intense. Plasma
cells quickly produce
large quantities of
powerful antibodies.
The infectious agent
is then brought
under control before
any symptom of the
disease can manifest.
Grand Angle
➜
Vaccinate
to immunize the subject…
response: a humoral
response mediated by
antibodies produced
by B lymphocytes,
and a cellmediated response
dependent on killer
T lymphocytes. A
small number of
the activated T cells
survive to support
immunological
memory.
©©figure: frédérique koulikoff/inserm
The inoculated
antigen is
phagocytosed by
macrophages. These
traffic the antigens to
their cell membranes
and become antigenpresenting cells
(APCs) that can
activate helper T
lymphocytes. This can
trigger two distinct
types of immune
March-April 2015 ● N° 24 ●
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9
Grand Angle
Clinical trials
are conducted
at the Cochin
immunization
center to test
preventive and
therapeutic
vaccines.
egressive
LRautism
A rare form of autism
that develops suddenly
in children whose
development had hitherto
seemed normal.
L. E. Markowitz et al. The Journal of
Infectious Diseases, 1 August 2013;
208 (3): 385-93
B. Baldur-Felskov et al. Journal of
the National Cancer Institute, 2014;
106 (3): djt460
N. M. Scheller et al. JAMA,
6 January 2015; 313 (1): 54-61
☛☛Patrick Zylberman: Inserm Unit 988
Inserm/Université Paris-Descartes/
CNRS - École des hautes études en santé
publique
☛☛Daniel Floret: President of the Technical
Immunization Committee of the Supreme
Public Health Council
10
©©Patrick ALLARD/REA
©©Patrick ALLARD/REA
➜
of subjects. This is very expensive. If the vaccine is shown to be
safe and effective, and its benefitto-risk ratio positive, it can be
granted Marketing Authorization
Production area for vaccines against the H1N1 virus
(MA). Manufacturing, started for
the clinical phases, can then be resumed and will take In 1994, ANSM launched an official pharmacovigilance
from six months to two years. Production involves two inquiry to monitor this vaccine and its side effects. No
main stages. The first is the biological stage in which the link could be established. At the same time, a big camactive substances—microbial antigens—are obtained. paign was being organized to immunize children and
This is followed by the pharmaceutical stage in which babies. In 1998, against the advice of the experts, the
the vaccine is formulated and packaged for distribu- Health Minister Bernard Kouchner then terminated it
tion and sale. A vaccine is not a medicinal product like in schoolchildren (but not in babies). This was a big misany other, explains Camille Locht. It is administered to take in terms of communication, in Patrick Zylberman's
healthy people, including children. Even more so than for opinion. Following this highly mediatized controversy,
other medicinal products, safety is primordial. At every vaccine coverage against HBV plummeted. A national
stage of production, stringent tests—accounting for commission regularly reviews data collected in France
nearly 70% of production time at some companies— and epidemiological data reported in the scientific litare carried out by either the company or a public-sector
erature. To date, no solid study
agency. And surveillance does not stop there. New vac- “Mistrust
has been able to establish any
cines are not only subject to a pharmacovigilance syscausal relationship between
of vaccines
tem, phase IV testing or Post-Marketing Surveillance
immunization against HBV
as for any drug, but also to a Risk Management Plan. is as old as
and the development of mulThis reinforced surveillance system is to look out for any immunization„ tiple sclerosis, assures Daniel
side effects that might not have been reported during
Floret *, President of the
clinical development. Most side effects are benign, such Technical Immunization Committee (Comité technique
as redness and mild inflammation at the injection site des vaccinations, CTV) of the Supreme Public Health
and sometimes, some rise in temperature.
Council (Haut Conseil de la santé publique, HCSP). This
episode nevertheless left traces in people's minds. HBV
Controversy
vaccine coverage has still not regained its ground.
So why, in the face of such minor side effects and strict At the same time on the other side of the Channel, it was
safety standards, is immunization so deeply mistrusted the MMR vaccine against measles, mumps and rubella
by some people? The very idea of introducing a for- that was in the spotlight, in this case for causing autism.
eign body into a healthy person is suspect. Mistrust A study published in 1998 in The Lancet reported a link
of vaccines is as old as vaccination, says Patrick Zyl- between this vaccine and the development of regressive
berman *, historian and Inserm researcher at the autism (L) and gastrointestinal problems. These findMedicine, Science, Mental Health & Society Research ings had a dramatic impact in the United Kingdom and
Center (Centre de recherche Médecine, sciences, santé, the United States. However, further research could not
santé mentale, société, Cermes 3) at Paris-Descartes Uni- confirm any link between the vaccine and autism. Other
versity. But it has recently reached an unprecedented surveys have demonstrated that the study published in
level in France. For some twenty years now, the contro- The Lancet was fundamentally fraudulent, based on false
versy has been gaining traction, confirms the historian. data, affirms Daniel Floret. Nevertheless, the journal
In 1993, a number of sufferers from multiple sclerosis did not retract the article in question until 2010.
(an autoimmune neurodegenerative disease) blamed More recently, the guns have been turned on the human
the Hepatitis B vaccine for having caused their disease. papilloma virus (HPV) vaccine. These vaccines are

● N° 24 ● March-April 2015
Grand Angle
➜
©©Peter Macdiarmid/Getty Images/AFP
The MMR
vaccine
has been
incorrectly
linked to cases
of autism.
Obligatory vaccination:
does it put people off?
A legacy from 20th Century public health policy, whether or not
immunization should be obligatory is often debated. In France, only
the DPT (diphtheria-poliomyelitis-tetanus) vaccine is still obligatory.
Only immunized children are allowed to attend collective institutions
like creches and school. Last year, one couple was summoned to
the criminal court in Auxerre because they had not had their two
young children immunized. Last January, their counsel appealed
to the Constitutional Court, challenging the constitutionality of
this obligation. The Court is due to give its ruling in March. This
casts doubt on the whole idea of obligatory immunization. Ending
obligatory vaccination is a perfectly legitimate question, judges Daniel
Floret. France is one of the last countries in Europe to maintain this
obligation and yet vaccine coverage is comparable elsewhere. Is it
time to turn the page? The HCSP recently proposed a major debate
on obligatory immunization.
Adjuvants in the
dock
The vaccine that
is supposed
to protect
against cervical
cancer is highly
controversial.
In parallel to these questions about the vaccines
themselves, there is the
issue of the safety of adjuvants based on aluminum salts. Such compounds have been in use
since 1920 to potentiate the immune response
to a variety of vaccines, they can directly cause
macrophagic myofasciitis (MMF). This complicated name describes tissue damage due to the
deposition of aluminum salts in the deltoid muscle
of the shoulder where vaccines are usually inoculated, explains Marc Pallardy *, toxicologist
and Head of an Inserm team at Paris-Sud University.
Could this local lesion which is recognized by the scientific community cause a rare syndrome characterized
by chronic fatigue, muscle pain and cognitive problems
in certain predisposed individuals. This is what Romain
Gherardi * believes, physician and Head of an Inserm team at the Mondor Institute for Biomedical Research at Créteil, who was the first to report this lesion
in an article published in 1998 in The Lancet. Hitherto,
it was thought that all the aluminum contained in vaccines was cleared via the urine within a few weeks, he
explains. However, experiment shows that such salts do
not completely dissolve in interstitial fluid (L) and that
in certain people some of the aluminum can persist for
years. Aluminum particles are quickly taken up by macrophages at the injection site, the scientist goes on. Our
recent experiments in wild-type and transgenic mice show
that a fraction of this aluminum migrates towards lymph
nodes and from there to the liver, spleen and brain. Buildup in the brain could induce neurological toxicity which
could account for some of the symptoms reported 
©©Boissonnet/BSIP
supposed to protect against cervical cancer and were
launched in 2006 and 2007. But they have attracted a
number of criticisms. First their price but also their
effectiveness and public health value. Both of the current vaccines only protect against two forms of human
papillomavirus, genotypes (L) 16 and 18. Although
these two forms account for 70% of all cases of cancer of
the cervix, immunization does not therefore completely
preclude the risk. Regular screening of cervical smears
is therefore still recommended. In addition, this vaccine
is aimed at young girls of 11-14 years of age. Whereas
cervical cancer develops much later in life, usually at
around 45-50. So it is difficult today to know whether
these vaccines will actually cut down the incidence of
cervical cancer. Nevertheless, a number of studies have
shown a reduction in the incidence of HPV infection
in immunized girls2. American scientists have analyzed
smears from more than 8,000 women, half collected
before introduction of the vaccine in 2006 and the other
half afterwards. After this date, the prevalence of HPV
infection halved in the immunized age group, i.e. girls of
between 14 and 19. This suggested that the prevalence
of HPV-induced damage would go down and, in consequence the incidence of cancer of the cervix. This was
confirmed in a recent study of more than 12,000 young
Danish women born between 1989 and 1999. Those
who had been immunized had significantly fewer (up to
80% less) high-grade precancerous cervical cells. However, it is the risk of side effects that raises the most fears.
The onset of multiple sclerosis has been seen in people
recently immunized against HPV. A number of complaints have been registered since 2013 but the scientific
literature does not show any increase in the incidence
of multiple sclerosis after HPV immunization. This is
confirmed in the most recent study published in the
Journal of American Medical Association which followed
nearly four million Scandinavian women.
LGenotype
All of a virus' genetic
characteristics
nterstitial
LIfluid
A substance that fills
the space between cells
and blood vessels that
supports the exchange
of nutrients and waste
products.
☛☛Marc Pallardy: Inserm Unit
996 – Université Paris-Sud 11,
Signaling in Immunotoxicology and
Immunopharmacology team
☛☛Romain Gherardi: Inserm Unit 955
– Université Paris-Est Créteil-Val-deMarne, IMRB, Cell Interactions in the
Neuromuscular System team
March-April 2015 ● N° 24 ●
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11
Grand Angle
©©Nicolas TAVERNIER/REA
➜
by
ystemic
LSmanifestation
A symptom or problem
that selectively involves
a whole, specific
anatomical system, e.g.
the nervous system or
the bones.
☛☛Béhazine Combadière: Inserm Unit
1135 - Université Pierre-et-Marie-Curie /
Immunology & Infectious Disease Center,
Vaccine Strategies & Immunity team
☛☛Yves Dauvilliers: Inserm Unit
1061 - Université Montpellier 1/
National Narcolepsy& Hypersomnia
Reference Center, Neuropsychiatry team:
Epidemiological & Clinical Research
patients seen at
The aluminum
contained in
the Mondor Institute.
vaccines causes
Some 640 such patients,
great controversy—
most of them women
as far as the Health
of between 45 and 50
Ministry.
years of age, blame their
problems on the aluminum in vaccines, especially that
against Hepatitis B. More recently, young women have
been coming after HPV immunization. Under pressure
from these patients, ANSM awarded a grant to Romain
Gherardi's team to investigate the impact of aluminum
salts in animals and humans. Final results will be available in 2016. But such work and in particular how to interpret its results is controversial. At this time, there is no
scientific consensus about the toxicity of vaccines containing aluminum, says Marc Pallardy. It may not be possible
to extrapolate results obtained in animals to humans.
Some of the transgenic mice used have an abnormal
blood-brain barrier that makes it permeable to molecules
that would not normally pass into the brain, stipulates
Daniel Floret. The Supreme Public Health Committee
(HCSP) was convened to discuss this question in 2013.
Their report of 11 July 2013 stipulates that "it is impossible to conclude from the scientific literature whether macrophagic
myofasciitis could be associated with
systemic manifestations (L)."
Influenza A(H1N1)
©©François GUENET/Divergence
But the episode which most undermined French confidence is the
pandemic of influenza A(H1N1) in
2009-2010. This crystallized fears and
raised many questions about vaccines.
Every aspect of the mass immunization campaign have been attacked,
often justly. First, the seriousness of the
Romain Gherardi studies the
impact of the aluminum salts
in vaccines.
12
● N° 24 ● March-April 2015
pandemic because, although the virus was contagious, it
was far less virulent than predicted. In April 2010, the
Health Monitoring Institute (Institut de veille sanitaire,
InVS) reviewed the 1,334 serious cases (involving admission into intensive care) due to the pandemic and
the 312 directly attributable deaths. Unlike seasonal
influenza, it is young adults who are most commonly
infected with the influenza A(H1N1) virus. Then the
efficacy and safety of the vaccines were questioned even
though their immunogenicity has been demonstrated
in many studies. Recently published work supervised
by Béhazine Combadière *, immunologist and Head
of an Inserm team at Pierre-et-Marie-Curie University
in Paris confirmed that the vaccine containing adjuvant induced a level of immunity comparable to that
induced by a moderate infection with the A(H1N1)
virus. The protection afforded therefore is equivalent to
that procured by moderate influenza. Similarly for the
adjuvant-free vaccines prescribed to some groups considered as particularly susceptible like pregnant women.
The PREFLUVA clinical study coordinated by Odile
Launay demonstrated that the influenza A(H1N1)
vaccine is immunogenic in pregnant women when
administered without any adjuvant. Immunization also
protects new-born babies up until the age of six months by
virtue of the passive transfer of maternal antibodies across
the placenta, she adds.
The fact that there are
“Administration
several vaccines, some
of the adjuvantwith adjuvant and some
free influenza
without, contributes
H1N1 vaccine
to the confusion. The
confers protection
adjuvant-free vaccine
is intended for at-risk
on babies through
populations like pregto the age of six
months by virtue of nant women, specifies
Odile Launay, because
the transplacental
they are most likely to
transfer of maternal suffer from complicaantibodies„
tions although they are
also more likely to experience side effects. The precautionary principle therefore takes first place. A recent review of the scientific
literature by Launay confirms the absence of side effects
in both mothers-to-be and their babies following immunization against influenza A(H1N1). Nevertheless,
the immunization campaign was not completely free
of adverse reactions. A number of cases of narcolepsy
have been reported since 2010 by different groups in
various countries, including Yves Dauvilliers *, Professor of Neurology and Inserm scientist at the National
Narcolepsy & Hypersomnia Center (Centre national
de référence Narcolepsie et hypersomnie, CNRNH) in
Montpellier. This sleeping disorder is characterized by
falling asleep suddenly and uncontrollably. It is sometimes associated with a sudden attack of muscle weakness, called cataplexy. A European study conducted at
multiple centers (VAESCO) confirmed a link between
Grand Angle
➜
©©Philippe MERLE/ AFP PHOTO
Queue to get
immunized against
influenza H1N1 in
Lyon in 2009.
immunization and narcolepsy in Swedish and Finnish
children and teenagers. In France, ANSM contributed
by funding the NarcoFlu case-control study coordinated by Antoine Pariente *, an Inserm clinical pharmacology researcher at Bordeaux–Segalen University,
working together with Yves Dauvilliers. This confirmed
the existence of an excess risk of narcolepsy in not only
children and teenagers but also in young adults. Incidence was increased by a factor of 6.5 in under-18
year-olds and 4.7 in adults. Approximately 60 people
in France have been affected out of 6 million vaccinees.
So the risk is small but it is important to understand the
mechanism underlying these cases of narcolepsy, emphasizes Daniel Floret. The adjuvant used in the vaccine, an
oil-in-water emulsion called squalene, could be guilty
but to date this is only a hypothesis.
Communication and debate
Above and beyond scientific arguments, there have
been criticisms of how the government handled the
pandemic. On the one hand, the agencies were heavily criticized for having excluded general practitioners
from the mass immunization campaign. And on the
other, the mass-purchasing of vaccines gave rise to suspicions of conflicts of interest with Big Pharma which
is itself much criticized for lack of transparency. Some
criticisms have even accused pharmaceutical companies of performing experiments on massive populations
by making an insufficiently tested vaccine available.
Although pandemic vaccines too are subject to strict
regulation. Nevertheless, certain procedures have been
relaxed in response to the urgency of the situation, concedes Daniel Floret. For H1N1, the products were based
on "prototype" vaccines against a possible pandemic of
avian influenza (H5N1) that had been under evaluation
and testing since 2005. Experience acquired with the
virus that causes seasonal influenza (see Box) made
it possible for pharmaceutical companies to develop a
new vaccine against H1N1 very quickly. The pandemic
story will nevertheless condition attitudes for a long
time to come, as is confirmed by the work of Patrick
Peretti-Watel *, sociologist and Inserm scientist at
Aix-Marseille University. The percentage of the French
population who are negative on the subject of immunization rose from 10% in 2005 up to nearly 40% by
2010. Of these, half spontaneously expressed negative
sentiments about the H1N1 vaccine.
Disease eradication?
Nonetheless, vaccines have helped—together with the
advent of antibiotics and improved living conditions—
to drastically reduce, and even bring about the 
☛☛Antoine Pariente: CIC Bordeaux 1401
Inserm - Université Bordeaux-Segalen,
Multidisciplinary module
☛☛Patrick Peretti-Watel: Inserm Unit 912/
IRD - Université Aix-Marseille
R. K. Gherardi et al. The Lancet,
1 August 1998; 352 (9125): 347-52
R. K. Gherardi et al. Brain,
1 September 2001; 124 (9): 1821-31
F.-J. Authier et al. Brain, 1 May 2001; 124
(5): 974-83
Z. Khan et al. BMC Medecine, 4 April 2013;
11: 99
O. Bonduelle et al. The Journal of
Clinical Investigation, 1 July 2014; 124
(7): 3129-36
V. Tsatsaris et al. Annals of Internal
Medicine, 6 December 2011; 155 (11):
733-41
P. Loubet et al. Expert Opinion on Drug
Safety, December 2014; 13 (12): 1709-20
Seaonal 'flu
The influenza vaccine is a special case. This is because the virus
is constantly changing to fool our immune system. These changes
affect proteins on the viral surface called hemaglutinin (H) and
neuraminidase (N). These are the molecules that give rise to the
naming system for different strains of the virus, e.g. H1N1, H3N2,
H5N1, etc. These mutations are closely monitored by the WHO which
tries to guess which strains will be the most likely to arrive the
following year. The composition of the vaccine is decided upon in February
so that the vaccine will be ready by October, explains Odile Launay.
However, the vaccine can prove to be ineffective if some other mutation
spreads between preparation of the vaccine and its distribution
for administration. That is what happened this year: the vaccine
targeted the H3N2 strain but the virus that arrived in the end was a
different strain. Nevertheless, the vaccine still affords some degree of
protection even if it does not target all strains.
March-April 2015 ● N° 24 ●
●
13
Grand Angle
➜
disappearance of, a number of serious infectious
diseases. Through immunization, smallpox had been
eradicated from the planet by 1978 and the incidence
of serious diseases like poliomyelitis, diphtheria and
tetanus has been reduced by 90-99% in the developed
world. The same is true for other diseases which are
considered benign—in some cases mistakenly—like
whooping cough and measles. The incidence of mumps
has massively decreased in France since mass immunization began in 1986. It had dropped from 859 cases per
100,000 in 1986 to just 9 per 100,000 by 2011 according to figures from the Sentinelles1 network of general
practitioners (partly funded by Inserm). The drop in
the prevalence of these diseases has led to a significant
increse in our life expectancy. The WHO estimated that
every year vaccines prevent some 2-3 million deaths.
However, there is another side to this coin. People are
not aware of these diseases any more and they don't understand the damage they can cause, says Daniel Floret.
Some like poliomyelitis are uncurable so immunization
is the only way of protecting against it. Of course, you
can question the justification for immunizing against a
disease that has practically disappeared, the pediatrician admits. But if we stop immunization, it will come
back. Sometimes with heavy repercussions on public
health. In recent years, a number of epidemics have
ravaged developed countries with thousands or even
tens of thousands of cases. Since 2011, whooping cough
has made a come-back in the United States, particularly
in California. German measles has been a problem in
Eastern Europe since 2012, especially in Poland and
Romania. Between 2008 and 2013, measles has come
back with a vengeance in Western Europe, especially
in France. According to InVS, 23,330 cases were confirmed during this period, with nearly 15,000 in 2011
alone. And measles is far from benign. Nearly 1,500
cases of severe pneumonia, 34 of neurological complications (encephalitis, myelitis, etc.) and 10 deaths have
been documented. Despite warnings, it took a massive
measles epidemic with all its devastating consequences to
see real mobilization on the part of the authorities, with
See S&S n° 21, Leader "Les
Sentinelles celebrate 30
years", p. 4-5
1 ☛☛Didier Torny: Risks, Work, Markets, State
(RiTME) unit, Inra
☛☛Pierre Verger: Inserm Unit 912/
IRD – Université Aix-Marseille,
Chronicisation of Health Risk, Health Care
Systems & Public Policy team
Y. Dauvilliers et al. Sleep,
1 November 2010; 33 (11): 1428-30
Y. Dauvilliers et al. Brain, 1 August 2013;
136 (8): 2486-96
P. Peretti-Watel et al. Eurosurveillance,
31 October 2013; 18 (44): 15-22
E. Coffinières et al. Vaccine,
19 November 2012; 30 (49): 7013-8
M. Schwarzinger et al. PLoS One,
16 April 2010; 5 (4): e10199
P. Peretti-Watel et al. Social Science &
Medicine, May 2014; 109: 10-8
P. Verger et al. PLoS One, 3 August 2012;
7 (8): e41837
©©npes

An Inpes poster aimed at GPs and the
general public
support from the media, points out Didier Torny *,
sociologist at the National Institute of Agronomic Research in Ivry-sur-Seine.
But Even if vaccine coverage is not perfect everywhere,
the situation is far from catastrophic, according to
Pierre Verger *, physician and epidemiologist at
the Marseille Laboratory of Social Science and Health,
and the Processing of Medical Information (Sciences
économiques et sociales de la santé et traitement de
l’information médicale, Sesstim). Poor coverage concerns the vaccines against papillomavirus (HPV), Hepatitis B and meningococcus C. And seasonal influenza
has been spreading since the notorious H1N1 episode.
A simplified immunization schedule
©©Inpes
Since 2013, a new immunization schedule has been available.
We wanted to make it clearer and easy to remember, explains Daniel
Floret, President of the HCSP Technical Immunization Committee.
Fewer shots are now recommended. Administering different
vaccines at the same time cuts down the number of appointments
needed, he adds. Finally, there are fewer booster shots and these
are administered at fixed ages (25, 45 and 65, and then every 10
years). This schedule has been well received by doctors, who
were consulted before its application. It can be accessed online at
mesvaccins.net. Enough to rebuild the image of vaccination?
14
8 www.mesvaccins.net
● N° 24 ● March-April 2015
Grand Angle
In contrast, measles coverage has been
slowly on the rise, especially since the
recent epidemic. But it remains at too
low a level to block circulation of the
virus, specifies Daniel Floret. In practice, immunization not only protects
the person vaccinated but also cuts
down transmission of the disease. So
immunization is also an altruistic act
that protects family and friends and
thereby the whole population, especially those who cannot be vaccinated,
e.g. babies and other people in whom
immunization is contra-indicated. So
how can popular confidence in vaccines be restored? First, we have to
understand how the mistrust of immunization arose. For that, the social
sciences represent a precious tool.
They help us understand the reasons
why people refuse immunization and thus contrib- information themselves ("healthism" concept), tending
ute to rational public health decisions. This is one of to distrust official sources and conventional medicine.
the objectives of Sesstim, which brings together doc- Nevertheless, it is most likely through physicians, and
tors, sociologists, economists and epidemiologists. general practitioners in particular, that the public opinBy means of surveys and statistical analyses, these ion battle will be won. Michaël Schwarzinger's survey
experts have investigated the failure of the mass im- showed that nearly 60% of those who consented to
munization campaign against H1N1 in
H1N1 immunization had been advised
France. Compliance varied enormously “The French have to do so by their doctor. Without a doctor's recommendation, only 12% wanted
between different countries, with 85%
confidence in
to get vaccinated. The general practitioof the Dutch, 65% of Swedes and 57% of
people from Québec getting immunized their GPs, so they
ner's role is central, believes Pierre Verger.
They are the linchpin of immunization
compared with just 8% of the French. The should be placed
authorities had been aiming for a target at the heart of the in France with some 80% of vaccines
administered by them. Around 60% of
of 50-75%. So what happened? An online immunization
general practitioners followed the offisurvey coordinated by Michaël Schwarz- system„
cial recommendations to get immunized
inger * just before the peak of the 2009
against influenza A(H1N1) according to
pandemic showed that public health announcements failed to convince the French public. The a telephone survey conducted by Pierre Verger, i.e. a far
official alarmist message was countered by personal higher proportion than in the general population. And,
experience. The disease was perceived as less serious the more vaccinated a care-provider, the more likely they
are to vaccinate their patients, affirms Odile Launay.
than the supposed risks of immunization.
Leaving general practitioners out of the immunization
Very different opponents
campaign without clear information massively contribHowever, the profiles of those who reject the idea of uted to the low adherence of the French to vaccinaimmunization are disparate. An analysis of Inpes data tion against H1N12. This is confirmed by Jean-Louis
recently published by Patrick Peretti-Watel and his Bensoussan *, general practitioner and Deputy
collaborators from Sesstim identifies two sociodemo- Secretary-General of the Syndicate of French General
graphic categories. On the one hand, low earners with Practitioners. He adds, The French have confidence in
less educational attainment who are ill-informed about their GPs, so they should be placed at the heart of the
the value of immunization: As a rule, older men in a immunization system."
vulnerable situation, comments Pierre Verger. And on Overall, modern vaccines are safe and effective but it
the other hand, well-informed people who want to be is perfectly legitimate to question immunization and its
free to choose: Relatively well-off, well-educated people possible side effects, believes Daniel Floret. So providwho make their own decision on the basis of analysis of ing reliable information with as much transparency as
the vaccine's risks and benefits, specifies the scientist. possible concerning links between the experts and the
Often younger women whose immunizations are up to pharmaceutical companies should restore the confidate. These educated, middle-class people pay great dence of the French people in vaccines and immunizaattention to their health and actively seek out medical tion. A word to the wise……n
Simon Pierrefixe
©©patrick allard/rea
➜
Getting immunized
also protects other
people.
8 www.sentiweb.fr
8 www.grippenet.fr
8 www.infovac.fr
See S&S n° 20, General
Medicine "Health crisis. The
general practitioner's
central role: proof from
H1N1", p. 35
2 ☛☛Michaël Schwarzinger: Inserm Unit 912
Inserm/IRD - Université Aix-Marseille,
Economic & Social Sciences in Health and
Medical Information Processing
☛☛Jean-Louis Bensoussan: general
practitioner in Castelmaurou (31),
Deputy Secretary-General of the Syndicate
of French General Practitioners, former
President of the Regional Influenza
Monitoring Groups (Groupes régionaux
d’observation de la grippe, GROG) network
March-April 2015 ● N° 24 ●
●
15
101, rue de Tolbiac
75654 Paris Cedex 13
www.inserm.fr
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