Text sizing:
Pediatric Infectious Disease Journal:
doi: 10.1097/INF.0b013e318199f5f2


Dagan, Ron MD*; Frasch, Carl MD†

Free Access
Article Outline
Collapse Box

Author Information

From the *Pediatric Infectious Disease Unit, Soroka University Medical Center, Beer-Sheva, Israel; and †Frasch Biologics Consulting, Martinsburg, VA, USA.

In the past 12 months, Ron Dagan has received grants/research support from Berna/Crucell, Binax, GlaxoSmithKline, MedImmune, Merck & Co., Inc., Novartis and Wyeth. He has received consultant fees from Berna/Crucell, GlaxoSmithKline, MedImmune, Merck & Co., Inc., Novartis and Wyeth and speaker fees from Berna/Crucell, GlaxoSmithKline and Wyeth. Carl Frasch has no conflicts of interest to declare.

Address for correspondence: Ron Dagan, MD, Pediatric Infectious Disease Unit, Soroka University Medical Center, P.O. Box 151, Beer-Sheva 84101, Israel. E-mail: rdagan@bgu.ac.il.

The development of effective conjugate vaccines targeting Streptococcus pneumoniae represents a significant advance in improving the health of children. In this edition, results are presented for 5 clinical trials that evaluated the new 10-valent pneumococcal non-typeable Haemophilus influenzae (NTHi) protein D–conjugate vaccine candidate (PHiD-CV, GlaxoSmithKline Biologicals) containing polysaccharides from pneumococcal serotypes 1, 4, 5, 6B, 7F, 9V, 14, 18C, 19F, and 23F. PHiD-CV uses a recombinant version of protein D, a nonlipidated form of a highly conserved cell-surface lipoprotein of non-typeable H. influenzae, as carrier protein for 8 of the 10 vaccine serotypes. For the other 2 serotypes, diphtheria toxoid and tetanus toxoid are the carrier proteins. PHiD-CV is the first new pneumococcal conjugate vaccine candidate since the appearance of the 7-valent (7vCRM, Prevenar™/Prevnar™) and 9-valent (9vCRM) pneumococcal conjugate vaccines, and represents the first of the next generation of pneumococcal conjugate vaccines with global serotype coverage. Several previous vaccine candidates1–3 by different manufacturers were unable to proceed past clinical trial stage due to insufficient immunogenicity and/or immune interference issues. However, at least one other vaccine (13-valent) is in advanced clinical trials.4

Anticapsular antibodies are known to mediate protection against IPD.5,6 Since licensure of 7vCRM in the United States in February 2000,7 the scientific community has therefore sought to identify a serological antibody threshold by which new vaccines may be immunologically compared with 7vCRM, thus avoiding the need to conduct large efficacy studies in populations where 7vCRM is already licensed for use. Initial concerns were that comparing geometric mean antibody concentrations (GMCs) might eliminate effective vaccines because previous experience with Hib and MenC conjugate vaccines showed that differences in antibody concentrations do not necessarily result in similar differences in protective efficacy. The World Health Organization (WHO) reviewed the efficacy data of 7vCRM and the experimental 9vCRM and determined anti-pneumococcal antibody concentrations between 0.2 and 1.0 μg/mL were associated with population-level protection against invasive disease, with the lower estimate observed in North American infants and higher estimates observed in Native American Indian and South African infants.8 Finally, a serum anti-pneumococcal IgG antibody concentration of 0.35 μg/mL (using the original non-22F-reference ELISA) was established as the reference level to be used in noninferiority comparison. This reference antibody concentration was shown to equate to 0.2 μg/mL when measured by the 22F-inhibition ELISA performed at the GlaxoSmithKline Biologicals Laboratories.9 Post-primary immunogenicity comparisons of PHiD-CV with the licensed 7vCRM in terms of the percentage of vaccinees reaching the reference ELISA IgG antibody concentration was the basis by which immunogenicity of the new vaccine was assessed.5 This single antibody threshold represents a compromise, because serotypes differ in their immunogenicity and clinical disease potential. Further, the threshold is assumed to apply to non-7vCRM serotypes for which vaccine efficacy against invasive disease has never been demonstrated.

In view of the limitations of the antibody threshold approach, demonstration of the induction of functional antibody activity by new vaccines was recognized as essential by the WHO experts.5 Opsonophagocytic activity (OPA) is the functional correlate of protection against invasive pneumococcal disease,6,10 because it allows one to determine the presence and quantity of killing antibodies ex vivo, although there are currently no generally accepted criteria defined by which to compare vaccines. In the 5 clinical trials reported in this issue, opsonophagocytic activity was examined with a minimum dilution titer of 8, which was shown to correlate with an antibody concentration between 0.2 and 0.35 μg/mL (using the non-22F ELISA) in pooled efficacy studies of 7vCRM.5 Furthermore, an opsonic titer of 8 was shown to confer protection against invasive disease in a mouse model and to correlate with protection in infants vaccinated with pneumococcal conjugate vaccines.10

In each of the 5 clinical studies presented in this edition, the immune response and safety profile of PHiD-CV was compared with 7vCRM. In the key study by Vesikari et al,11 anti-pneumococcal antibody GMCs were observed to be lower for most serotypes after PHiD-CV compared with 7vCRM. Using the WHO licensure criteria, noninferiority of the PHiD-CV vaccine compared with 7vCRM was established for 8 out of 10 serotypes (5 of the 7 common serotypes and all new serotypes). For serotypes 6B and 23F the ELISA antibody response noninferiority criteria were not met, but high postvaccination OPA titers were observed for both serotypes, with only small differences between PHiD-CV and 7vCRM in the percentage of subjects with OPA titers ≥8.5

The number of concomitantly administered vaccines and the prospect of immune interference makes it vital to carefully examine the immunogenicity of any new vaccine within different schedules and alongside different pediatric vaccines. In the study by Wysocki et al,12 the immune responses to PHiD-CV and 7vCRM (primary and booster) were compared when given at the same time as other currently available conjugate vaccines: ie, Hib conjugate vaccine and meningococcal serogroup C conjugate vaccines using either tetanus toxoid or CRM as the carrier, for which evidence of interference with other coadministered conjugate vaccines exists.13 The study indicated that coadministration of PHiD-CV with other conjugate vaccines tested in the study was possible.

In addition, immunogenicity after 2 primary doses of PHiD-CV12 was shown to be similar to 2 primary doses of 7vCRM. For PHiD-CV and 7vCRM, a lower percentage of subjects achieved the ELISA antibody threshold for serotypes 6B and 23F compared with 3 doses, whereas the percentage of subjects reaching the threshold for other serotypes were high. Antibody GMCs overall were lower after 2 vaccine doses, and 3 doses were needed to optimize OPA titers for some serotypes. Following an update of the 7vCRM summary of product characteristics recently approved by the European regulatory authorities, a 2-dose priming schedule followed by an early booster dose can be considered for 7vCRM, with the caveat that some post-primary immune responses may be inferior to 3 doses and that protection against mucosal infections remains for the moment to be proven.14

A comparison of the immune response to PHiD-CV and 7vCRM when given with a pentavalent whole cell pertussis-based combination vaccine and poliovirus vaccines according to 2 different immunization schedules was evaluated in the study by Bermal et al.15 In the Philippines, immune responses were within the same range for PHiD-CV and 7vCRM vaccines for all shared serotypes, with significantly higher responses compared with studies performed in Europe,11,12 despite the challenging 6-, 10-, and 14-week schedule. Interestingly, the European arm of this study using a 2-, 4-, 6-month schedule, showed immune responses in line with other European studies where DTPa-combined vaccines were coadministered.11,12

Knuf et al16 examined the antibody responses to the pediatric vaccines coadministered with PHiD-CV and 7vCRM in each of the 5 primary and booster clinical trials. A limitation of these studies was the absence of a control group that did not receive either of the 2 pneumococcal conjugates. However, in routine practice, the 7vCRM vaccine is commonly coadministered with other pediatric vaccines. No differences between the coadministered vaccine immune responses were observed when given concomitantly with PHiD-CV or with 7vCRM, indicating that immunogenicity of the vaccines coadministered with PHiD-CV was in line with that obtained with the current routine practice.

The final paper by Chevallier et al17 reviewed the safety data collected in all 5 studies. The reactogenicity and safety profile of the PHiD-CV vaccine was acceptable and did not indicate any clinically relevant differences compared with that of 7vCRM.

The 5 studies demonstrate that the immunogenicity profiles of PHiD-CV and 7vCRM vaccines differ on a serotype-specific basis, and whether one uses ELISA or OPA as the basis of comparison. Translating these immunologic data to the public health arena is problematical. It is difficult to directly predict the public health impact of each vaccine formulation on IPD unless one is able to also factor in serotype-specific efficacy or effectiveness information: on one hand it is unlikely that any serotype conjugate is truly 100% effective, and on the other hand, there may be cross-protection against vaccine-related types. Despite the difficulties in translating serologic results to effectiveness, it seems likely that the overall IPD prevention from the 7 shared serotypes is within the same order of magnitude for PHiD-CV and 7vCRM, with PHiD-CV providing additional value in countries with significant serotype 1, 5, or 7F diseases. Indeed, results of an attempt to estimate the impact of these 2 vaccines on overall IPD, using serotype-specific vaccine effectiveness data for 7vCRM, combined with head-to-head immunogenicity data presented in this supplement, were in line with this assumption.18

Head-to-head comparisons of antibody responses11,12,15 are however unable to predict effects on nasopharyngeal carriage of S. pneumoniae and thus herd immunity, for which high antibody levels are likely to be needed. Neither do these comparisons predict efficacy against AOM and pneumonia. However, results from an efficacy study with a previous vaccine formulation showed significant protection against pneumococcal AOM, and suggested that H. influenzae AOM was also partially prevented (POET19).

It is estimated that the 10-valent PHiD-CV could cover more than two-thirds of all invasive isolates from children <5 years in virtually all countries studied and ≥80% of isolates in North America, Western Europe, and parts of South America. And that the 13-valent vaccine will bring IPD coverage in young children to ≥80% in many other parts of the world as well.20 Lack of head-to-head immunogenicity comparisons with 13vCRM using a common assay, plus evidence of cross-protection against serotype 6A by PHiD-CV, make it difficult to predict the relative impact of this next vaccine vis a vis PHiD-CV. Serotypes 1, 5, and 7F, included in both candidate vaccines, are necessary for a global vaccine formulation. It is noted, however, that only 13vCRM contains serotype 19A,4 a serotype of increasing importance in some countries. Availability of PHiD-CV and soon, 13vCRM, represent significant progress in prevention of pneumococcal disease in children. Both vaccines will each protect against the bulk of pneumococcal disease. A potential added benefit of PHiD-CV is its suggested ability to protect against NTHi, an important second pathogen in respiratory infections.19

There is now considerable evidence that all conjugate vaccines require a booster dose after priming in infancy to achieve effective and long-term immunity. Immunity was shown to wane after primary vaccination without booster for Hib conjugate vaccines in the United Kingdom.21 Missing the recommended booster dose was associated with an increase in H. influenzae type b (Hib) disease in Germany,22 with a reduction in the prevention of Hib colonization23 and with an increase in invasive Hib disease in the United Kingdom once the herd effect of the mass catch-up immunization campaign had waned.24,25 After introduction of routine meningococcal serogroup C-conjugate vaccination in the United Kingdom, surveillance data showed waning vaccine effectiveness in infants after a year out from primary vaccination.26 In both studies of PHiD-CV that evaluated pneumococcal antibody and OPA persistence into the second year of life,11,12 there was a fall in antibody and OPA titers in PHiD-CV and 7vCRM recipients between primary and booster immunization, suggesting a booster dose in late infancy or during the second year of life is necessary for long term protection. Compared with other serotypes, post-primary and persisting OPA titers after PHiD-CV were lower for serotype 1, but rose substantially after the booster dose. A booster dose may therefore be particularly important for protection against serotype 1 disease in view of previous studies using other candidate vaccines without a booster dose that failed to convincingly demonstrate protection against serotype 1 after vaccination, and because serotype 1 may cause more disease in older children.27

After a PHiD-CV booster dose, robust antibody responses were observed for all serotypes, including the less immunogenic 6B and 23F serotypes. Importantly, from a public health perspective, the PHiD-CV vaccine given during the second year of life effectively boosted the immune response against serotypes for which children were primed, using either 7vCRM or PHiD-CV.

More data are needed to understand whether 3 priming doses are necessary or if 2 would suffice, although initial data suggest similar immune responses after 2 doses of PHiD-CV compared with those observed after the 2-dose 7vCRM schedule.

In conclusion, these 5 studies provide a comprehensive evaluation of the new PHiD-CV vaccine in a range of populations and schedules, including administration of a booster dose. Differences in immunogenicity profiles between both vaccines are observed, but they seem to be acceptable and unlikely to result in major differences in IPD protection. Post-licensure surveillance in countries where PHiD-CV is used at a larger scale will provide valuable additional information to better understand the public health impact of this new vaccine.

Back to Top | Article Outline


1. Buttery JP, Riddell A, McVernon J, et al. Immunogenicity and safety of a combination pneumococcal-meningococcal vaccine in infants: a randomized controlled trial. JAMA. 2005;293:1751–1758.

2. Dagan R, Goldblatt D, Maleckar JR, et al. Reduction of antibody response to an 11-valent pneumococcal vaccine coadministered with a vaccine containing acellular pertussis components. Infect Immun. 2004;72:5383–5391.

3. Zangwill KM, Greenberg DP, Chiu CY, et al. Safety and immunogenicity of a heptavalent pneumococcal conjugate vaccine in infants. Vaccine. 2003;21:1894–1900.

4. Kieninger DM, Kueper K, Steul K, et al. Safety and Immunologic Non-inferiority of 13-valent pneumococcal conjugate vaccine compared to 7-valent pneumococcal conjugate vaccine given as a 4-dose series with routine vaccines in healthy infants and toddlers [abstract]. Paper presented at 48th Annual ICAAC; October 25–28, 2008; Washington DC.

5. World Health Organization. Pneumococcal conjugate vaccines. Recommendations for production and control of pneumococcal conjugate vaccines. WHO Tech Rep Ser. 2005;927(annex 2):64–98.

6. Jodar L, Butler J, Carlone G, et al. Serological criteria for evaluations and licensure of new pneumococcal conjugate vaccine formulations for use in infants. Vaccine. 2003;21:3265–3272.

7. Centers for Disease Control and Prevention. 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.

8. Siber GR, Chang I, Baker S, et al. Estimating the protective concentration of anti-pneumococcal capsular polysaccharide antibodies. Vaccine. 2007;25:3816–3826.

9. Henckaerts I, Goldblatt D, Ashton L, et al. Critical differences between pneumococcal polysaccharide enzyme-linked immunosorbent assays with or without 22F inhibition at low antibody concentrations in pediatric sera. Clin Vaccine Immunol. 2006;13:356–360.

10. Romero-Steiner S, Frasch CE, Carlone G, et al. Use of opsonophagocytosis for serological evaluation of pneumococcal vaccines. Clin Vaccine Immunol. 2006;13:165–169.

11. Vesikari T, Wysocki J, Chevallier B, et al. Immunogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae Protein D Conjugate Vaccine (PHiD-CV) compared to the licensed 7vCRM vaccine. Pediatr Infect Dis J. 2009;28:S66–S76.

12. Wysocki J, Tejedor JC, Grunert D, et al. Immunogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae Protein D Conjugate Vaccine (PHiD-CV) when coadministered with different Neisseria meningitidis serogroup C conjugate vaccines. Pediatr Infect Dis J. 2009;28:S77–S88.

13. Dagan R, Poolman JT, Zepp F. Combination vaccines containing DTPa-Hib: impact of IPV and coadministration of CRM197 conjugates. Expert Rev Vaccines. 2008;7:97–115.

14. Prevenar® summary of product characteristics. Available at: http://www.emea.europa.eu/humandocs/Humans/EPAR/prevenar/prevenar.htm.

15. Bermal N, Szenborn L, Chrobot A, et al. The 10-valent pneumococcal non-typeable Haemophilus influenzae Protein D conjugate vaccine (PHiD-CV) coadministered with DTPw-HBV/Hib and poliovirus vaccines: assessment of immunogenicity. Pediatr Infect Dis J. 2009;28:S89–S96.

16. Knuf M, Szenborn L, Moro M, et al. Immunogenicity of routinely used childhood vaccines when coadministered with the 10-valent pneumococcal non-typeable Haemophilus influenzae Protein D conjugate vaccine (PHiD-CV). Pediatr Infect Dis J. 2009;28:S97–S108.

17. Chevallier B, Vesikari T, Brzostek J, et al. Safety and reactogenicity of the 10-valent pneumococcal non-typeable Haemophilus influenzae Protein D Conjugate Vaccine (PHiD-CV) when coadministered with routine childhood vaccines. Pediatr Infect Dis J. 2009;28:S109–S118.

18. Hausdorff W, Beckers F, Dagan R, et al. Estimation of the direct impact of a 10-valent pneumococcal non-typeable Haemophilus influenzae protein D-conjugate vaccine (PHiD-CV) candidate against invasive pneumococcal disease (IPD). [abstract]. Paper presented at 6th International Symposium on Pneumococci & Pneumococcal dieases (ISPPD); June 8–12, 2008; Reykjavik, Iceland. Abstract Book p. 402.

19. Prymula R, Peeters P, Chrobok V, et al. Pneumococcal capsular polysaccharides conjugated to protein D for prevention of acute otitis media caused by both Streptococcus pneumoniae and non-typable Haemophilus influenzae: a randomised double-blind efficacy study. Lancet. 2006;367:740–748.

20. Hausdorff WP, Brueggemann AB, Hackell J, et al. “Pneumococcal Serotype Epidemiology” In: Siber G, Klugman K, Makela H, eds. Pneumococcal Conjugate Vaccines. Washington, DC: ASM Press; 2008.

21. Ramsay M, McVernon J, Andrews NJ, et al. Estimating Haemophilus influenzae type b vaccine effectiveness in England and Wales by use of the screening method. J Infect Dis. 2003;188:481–485.

22. Von Kries R, Bohm O, Windfuhr A. Haemophilus influenzae b-vaccination: the urgency for timely vaccination. Eur J Pediatr. 1997;156:282–287.

23. Kayhty H. Difficulties in establishing a serological correlate of protection after immunisation with Haemophilus influenzae conjugate vaccines. Biologicals. 1994;22:397–402.

24. Ladhani S, Slack MP, Heys M, et al. Fall in Haemophilus influenzae serotype b (Hib) disease following implementation of a booster campaign. Arch Dis Child. 2008;93:665–669.

25. Goldblatt D. Bacteria, polysaccharides, vaccines and boosting: measuring and maintaining population immunity. Arch Dis Child. 2008;93:646–647.

26. Trotter CL, Andrews NJ, Kaczmarski EB, et al. Effectiveness of meningococcal serogroup C conjugate vaccine 4 years after introduction. Lancet. 2004;364:365–367.

27. Hausdorff WP, Dagan R. Serotypes and pathogens in paediatric pneumonia. Vaccine. 2008;26(suppl 2):B19–B23.

© 2009 Lippincott Williams & Wilkins, Inc.