COMMENTARY
Pneumococcal Conjugate Vaccine: Are 3 Doses Equal
to 4 Doses?
AUTHORS: Emmanuel B. Walter, MD, MPH and Dennis A.
Clements, MD, PhD, MPH
Duke Clinical Vaccine Unit, Department of Pediatrics, Duke
University School of Medicine, Durham, North Carolina
KEY WORDS
vaccine, pneumococcal conjugate vaccine, cost-effectiveness,
schedule, dosing
ABBREVIATIONS
IPD—invasive pneumococcal disease
PCV—pneumococcal conjugate vaccine
PCV-7—7-valent pneumococcal conjugate vaccine
Opinions expressed in these commentaries are those of the
author and not necessarily those of the American Academy of
Pediatrics or its Committees.
Dr Walter drafted the initial manuscript; Dr Clements reviewed
and revised the manuscript; and both authors approved the
final manuscript as submitted.
www.pediatrics.org/cgi/doi/10.1542/peds.2013-1573
doi:10.1542/peds.2013-1573
Accepted for publication May 20, 2013
Address correspondence to Emmanuel B. Walter, MD, MPH, Duke
Children’s Primary Care, 4020 North Roxboro St, Durham,
NC 27704. E-mail: [email protected]
PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).
Copyright © 2013 by the American Academy of Pediatrics
FINANCIAL DISCLOSURE: Dr Walter has received funding from
Pfizer to conduct clinical research studies. Dr Clements has no
financial relationships relevant to this article to disclose.
FUNDING: No external funding.
COMPANION PAPER: A companion to this article can be found on
page XXX, and online at www.pediatrics.org/cgi/doi/10.1542/
peds.2012-3350.
After the introduction of routine infant immunization with 7-valent
pneumococcal conjugate vaccine (PCV-7), the United States has witnessed a 74% decline in the number of children ,5 years of age
diagnosed with invasive pneumococcal disease (IPD) and a 30% decline among all age groups.1 Likewise, rates of pneumonia- and otitis
media-related medical visits among children, hospitalizations for
pneumonia among children and young adults, and procedures for
insertion of tympanostomy tubes also decreased.2 Because of increases in IPD owing to pneumococcal serotypes not included in the
vaccine, 13-valent pneumococcal conjugate vaccine replaced PCV-7 10
years later.3,4 Although a major public health accomplishment, the
current 4-dose 13-valent pneumococcal conjugate vaccine series administered at 2, 4, 6, and 12 to 15 months of age is now the most
expensive vaccine series in the routinely recommended immunization
schedule for persons 0 through 18 years of age.5
In this issue, Stoecker et al describe the cost savings if the United
States adopted a reduced 3-dose pneumococcal conjugate vaccine
(PCV) (2 1 1) schedule, as is recommended in many other countries.6
They suggest that possible increases in observed morbidity and
mortality resulting from adoption of a reduced schedule could be
mitigated by increasing vaccine coverage. Another option for a reduced schedule is 3 1 0; this regimen gives greater early protection
but without the benefit of a booster dose (although the booster dose
greatly enhances antibody response, there are no clinical differences
documented to date). The 3 1 0 vaccine schedule is found in a few
countries where vaccination after 9 months becomes less reliable.7
There have been 2 recent reviews of reduced immunization schedules
for PCV. Both reviews note the variation by serotype in the immune
response after the first 2 versus the first 3 doses.8,9 For most serotypes there are only modest reductions in the immune response after
2 doses; however, for serotypes 6B and 23F the diminution in immune
responses is more significant. The World Health Organization estimated that an antibody concentration of 0.35 mg/mL for all PCVassociated serotypes correlates with clinical efficacy against IPDs
related to that specific vaccine serotype.10 Although believed true for
IPD, the antibody concentration correlating to protection from pneumonia or otitis media remains unknown. Interestingly, in a prelicensure immunogenicity study for PCV-7, responses to serotypes
6B and 23F did not achieve the 0.35 mg/mL concentration after 2
doses but did after 3, thus providing the rationale for the 4-dose
series.11 These data further suggest that children receiving only 2
primary doses would remain vulnerable to infection owing to these
serotypes and hence would need to rely on herd immunity for protection until receiving a boosting dose at 12 months of age.
PEDIATRICS Volume 132, Number 2, August 2013
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1
Despite somewhat reduced immunogenicity, in observational studies reduceddose regimens have been shown to be
effective at preventing otitis media,
pneumonia, and IPD.12–14 However, in
1 study examining effectiveness of a
reduced-dose regimen at preventing
lower respiratory tract infections,
there was some suggestion that a
reduced-dose regimen may confer
less protection during the first year
of life.13 Furthermore, in the study
assessing effectiveness of vaccine at
preventing IPD, there were 2 cases of
IPD reported after 2 doses, whereas
there were none reported after 2 doses
plus a booster.14 Additional randomized
controlled trials comparing the effectiveness of the 3- versus 4-dose regimens are lacking.
In looking back, the driving force behind
the 2000 recommendation for PCV-7 was
its remarkable efficacy at preventing
IPD and devastating sequelae such as
meningitis, neurologic complications
after meningitis, and death.16,17 Efficacy
estimates with respect to the prevention of less serious infections such
as pneumonia and otitis media were
realized to be more modest. Ironically,
as the authors point out, the majority of
cost savings for PCV are related to
reductions in costs for treating very
frequently occurring infections, such as
otitis media, rather than less commonly occurring but more serious lifethreatening IPD. Before contemplating
a switch to a 3-dose series, it is important to remember the most serious
diseases that PCV prevents and assure
that the dosing schedule ultimately
chosen is up to the challenge of preventing these infections.
of 13-valent pneumococcal conjugate vaccine.
Pediatrics. 2013; 132(2):XXX–XXX
Scott P, Rutjes AW, Bermetz L, et al. Comparing pneumococcal conjugate vaccine
schedules based on 3 and 2 primary doses:
systematic review and meta-analysis. Vaccine. 2011;29(52):9711–9721
Jackowska T, Pluta J. Routine infant immunization with the 7- and 13-valent
pneumococcal conjugate vaccines: current
perspective on reduced-dosage regimens.
Arch Med Sci. 2012;8(3):542–548
Rückinger S, Dagan R, Albers L, Schönberger
K, von Kries R. Immunogenicity of pneumococcal conjugate vaccines in infants
after two or three primary vaccinations:
a systematic review and meta-analysis.
Vaccine. 2011;29(52):9600–9606
World Health Organization. Recommendations for the production and control
of pneumococcal conjugate vaccines. WHO
Technical Report Series 64-98, No 927; 2005
Rennels MB, Edwards KM, Keyserling HL,
et al. Safety and immunogenicity of heptavalent pneumococcal vaccine conjugated to
CRM197 in United States infants. Pediatrics.
1998;101(4 pt 1):604–611
Stoecker C, Hampton LM, Moore MR. 7-Valent
pneumococcal conjugate vaccine and otitis
media: effectiveness of a 2-dose versus
3-dose primary series. Vaccine. 2012;30
(44):6256–6262
Pelton SI, Weycker D, Klein JO, Strutton D,
Ciuryla V, Oster G. 7-Valent pneumococcal
conjugate vaccine and lower respiratory
tract infections: effectiveness of a 2-dose
versus 3-dose primary series. Vaccine.
2010;28(6):1575–1582
Deceuninck G, De Wals P, Boulianne N, De
Serres G. Effectiveness of pneumococcal
conjugate vaccine using a 211 infant
schedule in Quebec, Canada. Pediatr Infect
Dis J. 2010;29(6):546–549
Centers for Disease Control and Prevention. National, state, and local area
vaccination coverage among children aged
19-35 months—United States, 2011. MMWR
Morb Mortal Wkly Rep. 2012;61:689–696
Advisory Committee on Immunization
Practices. Preventing pneumococcal disease among infants and young children.
Recommendations of the Advisory Committee on Immunization Practices (ACIP).
MMWR Recomm Rep. 2000;49(RR-9):1–35
Black S, Shinefield H, Fireman B, et al;
Northern California Kaiser Permanente
Vaccine Study Center Group. Efficacy, safety
and immunogenicity of heptavalent pneumococcal conjugate vaccine in children.
Pediatr Infect Dis J. 2000;19(3):187–195
Lastly, Stoecker et al argue that modest
increases in vaccine coverage could
prevent the potential increase in the
number of disease cases. Although true,
achieving these increases may be difficult. Whereas coverage for 4 or more
doses of PCV for children aged 19 to 35
months increased during the period
between 2007 and 2011, the 84.4% coverage reported for 2011 is now comparable to the 4-dose coverage level for
diphtheria, tetanus, and acellular pertussis vaccine. Diphtheria, tetanus, and
acellular pertussis vaccine coverage
remained stable during the same time
period, suggesting that improving coverage rates for PCV may be a challenge.15
REFERENCES
1. Atkinson W, Wolfe S, Hamborsky J, eds.
Epidemiology and Prevention of VaccinePreventable Diseases. Centers for Disease
Control and Prevention. 12th ed, second
printing. Washington DC: Public Health
Foundation; 2012
2. Grijalva CG, Griffin MR. Population-based
impact of routine infant immunization
with pneumococcal conjugate vaccine in
the USA. Expert Rev Vaccines. 2008;7(1):
83–95
3. Sucher AJ, Chahine EB, Nelson M, Sucher
BJ. Prevnar 13, the new 13-valent pneumococcal conjugate vaccine. Ann Pharmacother. 2011;45(12):1516–1524
4. Centers for Disease Control and Prevention.
Licensure of a 13-valent pneumococcal
conjugate vaccine (PCV13) and recommendations for use among children - Advisory
Committee on Immunization Practices (ACIP),
2010. MMWR Morb Mortal Wkly Rep. 2010;
59(9):258–261
5. Centers for Disease Control and Prevention. Vaccines for Children Program (VFC).
Available at: www.cdc.gov/vaccines/programs/
vfc/awardees/vaccine-management/pricelist/index.html. Accessed May 12, 2013
6. Stoecker C, Hampton LM, Link-Gelles R,
Messonnier ML, Zhou F, Moore MR. Costeffectiveness of using 2 vs 3 primary doses
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WALTER and CLEMENTS
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Pneumococcal Conjugate Vaccine: Are 3 Doses Equal to 4 Doses?
Emmanuel B. Walter and Dennis A. Clements
Pediatrics; originally published online July 1, 2013;
DOI: 10.1542/peds.2013-1573
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PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned, published,
and trademarked by the American Academy of Pediatrics, 141 Northwest Point Boulevard, Elk
Grove Village, Illinois, 60007. Copyright © 2013 by the American Academy of Pediatrics. All
rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Downloaded from by guest on June 16, 2017
Pneumococcal Conjugate Vaccine: Are 3 Doses Equal to 4 Doses?
Emmanuel B. Walter and Dennis A. Clements
Pediatrics; originally published online July 1, 2013;
DOI: 10.1542/peds.2013-1573
The online version of this article, along with updated information and services, is
located on the World Wide Web at:
/content/early/2013/06/26/peds.2013-1573.citation
PEDIATRICS is the official journal of the American Academy of Pediatrics. A monthly
publication, it has been published continuously since 1948. PEDIATRICS is owned,
published, and trademarked by the American Academy of Pediatrics, 141 Northwest Point
Boulevard, Elk Grove Village, Illinois, 60007. Copyright © 2013 by the American Academy
of Pediatrics. All rights reserved. Print ISSN: 0031-4005. Online ISSN: 1098-4275.
Downloaded from by guest on June 16, 2017