Canada Communicable Disease Report
Volume 32 ACS-4
1 May 2006
An Advisory Committee Statement (ACS)
National Advisory Committee on Immunization (NACI)*†
Update on the recommendations for
the routine use of
Pneumococcal
conjugate vaccine for infants
PDF Version
7 Pages - 144 KB
Preamble
The National Advisory Committee on Immunization (NACI) provides
the Public Health Agency of Canada with ongoing and timely
medical, scientific, and public health advice relating to immunization.
The Public Health Agency of Canada acknowledges that the
advice and recommendations set out in this statement are based upon
the best current available scientific knowledge and is disseminating
this document for information purposes. People administering the
vaccine should also be aware of the contents of the relevant product
monograph(s). Recommendations for use and other information set
out herein may differ from that set out in the product monograph(s)
of the Canadian manufacturer(s) of the vaccine(s). Manufacturer(s)
have sought approval of the vaccine(s) and provided evidence as to its
safety and efficacy only when it is used in accordance with the product
monographs. NACI members and liaison members conduct themselves
within the context of the Public Health Agency of Canada's
Policy on Conflict of Interest, including yearly declaration of potential
conflict of interest.
Introduction
Since the initial publication of the NACI Statement on Recommended
Use of Pneumococcal Conjugate Vaccine(1) and the Supplementary
Statement on Pneumococcal Conjugate Vaccine2,
information has been published on immunization schedules that
differ from those recommended by NACI. To determine whether
the current recommendations should be revised, NACI has
reviewed the published and non-published reports of
immunogenicity and vaccine effectiveness with alternative
schedules.
The heptavalent pneumococcal conjugate vaccine (Pneu-C-7,
marketed as Prevnar®) is recommended for universal use for all
infants ≤ 23 months of age1. The recommended immunization
schedule for infants is four doses administered at 2, 4, 6, and 12
to 15 months of age. Infants can receive the immunization as
early as 6 weeks of age, and the recommended interval between
the subsequent two doses is 6 to 8 weeks1. Following review of
Prevnar’s® product monograph and the immunogenicity and
efficacy studies conducted before the vaccine’s approval for use in
Canada3-9, NACI ranked the level of evidence in support of a
four-dose schedule as Level I and the recommendation as Grade
A, see Table 1 10,11. For more detailed information regarding
Pneu-C-7, readers are referred to the original statement and
update or the Canadian Immunization Guide1,2,12.
Since the publication of these recommendations, additional
information has become available related to immunogenicity and
the effectiveness of Prevnar® in preventing invasive pneumococcal
disease when an abbreviated immunization schedule is
used13,14. An uncontrolled, multicentre study in Sweden,
involving 99 infants, assessed the immunogenicity of Pneu-C-7
using a vaccination schedule consisting of three doses (3, 5, and
12 months of age)13. Two doses evoked satisfactory antibody
responses, with the exception of serotypes 6B and 23F. Three
doses evoked strong responses for all serotypes, suggesting good
immunologic priming with the primary series of two doses. An
uncontrolled study of 92 infants in Italy assessed immunogenicity
of a three-dose schedule (3, 5, and 11 months of age) and had
comparable findings14. Both studies revealed that the immune
responses induced after the third dose of Pneu-C-7 using a
three-dose schedule were similar to those using a four-dose
schedule3,13,14. Preliminary data from a study conducted in the
United Kingdom using a nine-valent vaccine, PCV9, revealed
similar immunogenicity after two or three doses in early infancy,
and two doses given in early infancy primed for memory15.
In the United States (US), vaccine shortages that occurred during
the years 2001 to 2004 resulted in incomplete Pneu-C-7 administration,
and in 2004 the Centers for Disease Control and Prevention
(CDC) recommended temporarily discontinuing the fourth
dose of Pneu-C-7 for healthy children16. The effect of these
shortages on the incidence of invasive pneumococcal disease
among young children in the US has been assessed using
estimates of vaccine coverage and reported invasive pneumococcal
disease for that age group. A preliminary analysis of a casecontrol
study indicated that vaccine effectiveness with a threedose
series was 90% (95% confidence interval [CI] 74% to 96%)
compared with 96% (95% CI 68% to 100%) with four doses16.
This analysis did not consider the timing of the three doses.
Further analysis revealed vaccine effectiveness of 95% (95% CI 88% to 98%) for a three-dose series with all doses given before
7 months of age and 99% (95% CI 86% to 100%) for a three-dose
series consisting of two doses given before 7 months of age and
the third dose given at 12 to 16 months of age (Dr Cynthia
Whitney, CDC: personal communication, 2005). Post-licensure
surveillance data from California also revealed that the Pneu-C-7
was highly effective in reducing the burden of illness associated
with pneumococcal disease, despite only 24% of children < 2
years of age receiving four doses of the vaccine17.
Some jurisdictions are considering, or have already implemented,
a three-dose Pneu-C-7 schedule. Australia implemented a universal
pneumococcal conjugate vaccination program in January
2005, which consists of three doses of Pneu-C-7 given at 2, 4,
and 6 months of age18. Some regions in Italy have implemented a
three-dose schedule at 3, 5, and 11-12 months of age. The Province
of Quebec implemented a universal pneumococcal conjugate
vaccination program in January 2005 consisting of three doses
given at 2, 4, and 12 months. In February 2006, the United
Kingdom recommended a three-dose schedule at 2, 4, and 13
months; implementation will occur later this year.
It is also noteworthy that the impact of Pneu-C-7 on the prevention
of invasive pneumococcal disease has been greater than
expected from the results of the original clinical trials, which
were used for approval of the vaccine and to guide the initial
recommendations for the infant immunization schedule 3,17,19.
Disease rates have decreased in groups that did not receive the
vaccine, in particular among infants < 2 months of age, children
who were known not to have received the vaccine for medical
and other reasons, as well as the elderly 17, 19. The reduction in
carriage of vaccine serotypes is believed to be the basis for
indirect protection of non-vaccinated individuals, or herd immunity 19. Indirect protection has been observed during the
Pneu-C-7 vaccination program in the United States, even though
a number of children received incomplete schedules because of
vaccine shortages17.
The NACI recommendation for a four-dose schedule at 2, 4, 6,
and 12 to 15 months of age to protect against invasive and other
disease due to the pneumococcal serotypes included in the
vaccine is based on evidence from randomized controlled trials
(Level I, Grade A)10,11. The available data at this time do not
allow for a direct comparison of the efficacy of the three-dose and
the four-dose schedules. The available data indicate that the
short-term efficacy of the three-dose schedule after the third dose
is comparable. The level of evidence for the three-dose schedule
is considered II-2 for the following reasons: the immunogenicity
studies were relatively small and uncontrolled, and there were
statistically significant differences in the antibody levels of some
strains after the second dose for which the clinical correlation is
unclear. The long-term efficacy of a three-dose schedule has not
been determined, but this is generally not known for most vaccines
at the time of approval. The recommendation grade for the
three-dose schedule is thus considered at this time as “fair” or B.
As the studies evaluating a three-dose schedule were not conducted
among children at high risk of invasive pneumococcal
disease, NACI emphasizes that such children should continue to
receive the four-dose schedule. This group includes children at
high risk due to the following1, 20:
- sickle cell disease and other sickle cell hemoglobinopathies
- other types of functional or anatomic asplenia
- HIV infection
- immunocompromising conditions, such as primary immune
deficiencies, malignancies, receipt of immunosuppressive
therapy, solid organ transplant, long-term systemic
corticosteroids, or nephrotic syndrome
- chronic medical conditions, in particular chronic cardiac disease
and pulmonary disease such as bronchopulmonary
dysplasia, diabetes mellitus or cerebrospinal fluid leak
- children with cochlear implants or those receiving cochlear
implants
- Aboriginal children
In jurisdictions with a routine three-dose schedule, infants
should be evaluated at 6 months of age for these conditions
before administration of the third dose and a decision made at
that time as to whether the reduced-dose schedule would be
appropriate.
Table 1. Quality and strength of evidence
Level of evidence10,11
|
I |
Evidence obtained from at least one properly randomized, controlled trial.
|
II-1 |
Evidence obtained from well-designed, controlled trials without randomization.
|
II-2 |
Evidence obtained from well-designed cohort or case-control analytic studies, preferably
from more than one centre or research group (including immunogenicity
studies).
|
II-3 |
Evidence obtained from comparisons between times or places with or without the
intervention. Dramatic results in uncontrolled experiments (such as the results of
treatment with penicillin in the 1940s) could also be included in this category.
|
III |
Opinions of respected authorities, based on clinical experience, descriptive studies,
or reports of expert committees.
|
Strength of recommendations
|
A |
There is good evidence to recommend the clinical preventive action.
|
B |
There is fair evidence to recommend the clinical preventive action.
|
C |
The existing evidence is conflicting and does not allow to make a recommendation
for or against the clinical preventive action; however other factors may influence
decision-making
|
D |
There is fair evidence to recommend against the clinical preventive action.
|
E |
There is good evidence to recommend against the clinical preventive action.
|
I | There is insufficient evidence (in quantity or quality) to make a recommendation;
however other factorsmay influence decision-making.
|
References
- National Advisory Committee on Immunization (NACI). Statement
on recommended use of pneumococcal conjugate vaccine.
CCDR 2002;28(ACS-2):1-32.
- . National Advisory Committee on Immunization (NACI). Statement
on the recommended use of pneumococcal conjugate vaccine:
addendum. CCDR 2003;29(ACS-8):14-5.
- Black S, Shinefield H, Fireman B et al. Efficacy, safety and
immunogenicity of heptavalent pneumococcal conjugate vaccine in
children. Pediatr Infect Dis J 2000;19(3):187-95.
- Anttila M, Eskola J, Ahman H et al. Avidity of IgG for
type 6B and 23F polysaccharides in
infants primed with pneumococcal conjugates and boosted with
polysaccharide or conjugate vaccines. J Infect Dis
1998;177(6):1614-21.
- Anderson EL, Kennedy DJ, Geldmacher KM et al.
Immunogenicity of heptavalent pneumococcal conjugate vaccine in
infants. J Pediatr 1996;128(5 Pt 1):649-53.
- Blum MD, Dagan R, Mendelman PM et al. A comparison of multiple
regimens of pneumococcal polysaccharide-meningococcal
outer membrane protein complex conjugate vaccine and
pneumococcal polysaccharide vaccine in toddlers. Vaccine
2000;18(22):2359-67.
- Eskola J, Kilpi T, Palmu A et al. Efficacy of a pneumococcal conjugate
vaccine against acute otitis media. N Engl J Med
2001;344(6):403-9.
- 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):604-11.
- Shinefield HR, Black S, Ray P et al. Safety and immunogenicity of
heptavalent pneumococcal CRM197 conjugate vaccine in infants
and toddlers. Pediatr Infect Dis J 1999;18(9):757-63.
- Canadian Task Force on the Periodic Health Examination. New
grades for recommendations from the Canadian Task Force on Preventive
Health Care. Can Med Assoc J 2003;169(3):207-8.
- Canadian Task Force on the Periodic Health Examination. The
Canadian guide to clinical preventive health care. Ottawa: Minister
of Supply and Services Canada, 1994. Cat. no.
H21-117/1994E.
- National Advisory Committee on Immunization. Pneumococcal
vaccine. In: Canadian immunization guide. Ottawa: Health
Canada, 2002;177-84.
- Kayhty H, Ahman H, Ericksson K et al. Immunogenicity and
tolerability of a heptavalent pneumococcal conjugate vaccine
administered at 3, 5 and 12 months of age. Pediatr Infect Dis J
2005;24(2):108-14.
- Esposito S, Pugni L, Bosis S et al. Immunogenicity, safety and
tolerability of heptavalent pneumococcal conjugate vaccine administered
at 3, 5 and 11 months post-natally to pre- and full-term
infants. Vaccine 2004;23:1703-8.
- Goldblatt D, Ashton L, Southern J et al. Immunogenicity and
boosting following a reduced number of doses of a pneumococcal
conjugate vaccine in infants and toddlers. In: 4th International
Symposium of Pneumococci and Pneumococcal Disease 2004. May
9-13, 2004:206.
- Centers for Disease Control and Prevention. Notice to readers:
limited supply of pneumococcal conjugate vaccine: suspension of
recommendation for fourth dose. MMWR 2004;53(05):108-9.
- Black S, Shinefield H, Baxter R et al. Postlicensure surveillance for
pneumococcal invasive disease after use of heptavalent
pneumococcal conjugate vaccine in Northern California Kaiser
Permanente. Pediatr Infect Dis J 2004;23(6):484-9.
- National Health and Medical Research Council. Universal Childhood
Pneumococcal Vaccination Program. URL:
<http://www.immunise.health.gov.au/universal/public.htm>.
Accessed 29 July, 2005.
- O’Brien KL, Dagan R. The potential indirect effect of conjugate
pneumococcal vaccines. Vaccine 2003;21:1815-25.
- National Advisory Committee on Immunization (NACI). Immunization
recommendations for cochlear implant recipients. CCDR
2003;29(ACS2-3):1-4.
* Members:
Dr. M. Naus (Chair), Dr. S. Deeks (Executive Secretary), Dr. I.
Bowmer, Dr. S. Dobson, Dr. B. Duval, Dr. J. Embree, Ms. A. Hanrahan,
Dr. J. Langley, Dr. A. McGeer, Dr. K. Laupland, Dr. M.N. Primeau, Dr. B. Tan,
Dr. B.Warshawsky, Dr. S. McNeil.
Liaison Representatives:
S. Callery (CHICA), Dr. J. Carsley (CPHA), Dr. J. Smith
(CDC), Dr. D. Money (SOGC), A. Honish (CNCI), Dr. B. Larke (CCMOH),
Dr. B. Law (ACCA), Dr. M. Salvadori (AMMI Canada),
Dr. S. Rechner (CFPC), Dr. J. Salzman (CATMAT), Dr. L. Samson (CPS),
Dr. D. Scheifele (CAIRE).
Ex-Officio Representatives:
Dr. H. Rode (BGTD), Dr. M. Lem (FNIHB),
Dr. M. Tepper (DND).
† This statement was prepared by Dr. Joanne Embree, Dr. Shelley Deeks, and
Dr. Joanne Langley. It was approved by NACI and by the Public Health
Agency of Canada (PHAC).
[Canada Communicable Disease Report]
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