ARCHIVED - Update on the Recommendations for the Routine Use of Pneumococcal Conjugate Vaccine for Infants

Canada Communicable Disease Report
Volume 32 • ACS-4 1 May 2006

An Advisory Committee Statement (ACS)

National Advisory Committee on Immunization (NACI)*†

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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 Canada^3-9, 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 Guide^1,2,12.

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 used^13,14. 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 schedule^3,13,14. 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 immunity¹⁹. 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 following^{1, 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

References

1. National Advisory Committee on Immunization (NACI). Statement on recommended use of pneumococcal conjugate vaccine. CCDR 2002;28(ACS-2):1-32.

2. . National Advisory Committee on Immunization (NACI). Statement on the recommended use of pneumococcal conjugate vaccine: addendum. CCDR 2003;29(ACS-8):14-5.

3. 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.

4. 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.

5. 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.

6. 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.

7. 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.

8. 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.

9. 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.

10. 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.

11. 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.

12. National Advisory Committee on Immunization. Pneumococcal vaccine. In: Canadian immunization guide. Ottawa: Health Canada, 2002;177-84.

13. 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.

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.

15. 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.

16. 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.

17. 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.

18. 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.

19. O’Brien KL, Dagan R. The potential indirect effect of conjugate pneumococcal vaccines. Vaccine 2003;21:1815-25.

20. 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).