Response to: Hausdorff WP, Hoet B, Schuerman L: Do pneumococcal conjugate vaccines provide any cross-protection against serotype 19A? BMC Pediatr 2010, 10:4.
Peter Paradiso, Pfizer Vaccines
21 April 2010
Dear Sir or Madam:
The article by Hausdorff et al. [1] is a compilation of available published data on cross-protection for serotype 19A afforded by serotype 19F in pneumococcal conjugate vaccine formulations. As pointed out by the authors, when 7-valent pneumococcal conjugate vaccine (PCV7; Prevenar; Pfizer Inc) was developed, it was hoped that the protective anticapsular antibody induced by the 19F and 6B conjugates would provide cross-protection for serotype 19A and 6A disease, respectively. While some cross-protection has been observed against serotype 6A disease, from a practical perspective, regardless of the “suggestions” from the literature, there has been no impact on 19A disease in countries where PCV7 has been used [2-7]. As pointed out by the authors, serotype 19A is on the rise in well-immunized populations.
Hausdorff et al. state that other pneumococcal conjugate vaccines may have different immunological properties, implying that outcomes might be different for the recently licensed 10-valent pneumococcal conjugate vaccine (PCV10) in which the 19F polysaccharide is conjugated to diphtheria toxoid [8]. While the authors cite functional antibody assessed by opsonophagocytic activity (OPA) assay data in terms of the percentage of subjects achieving titers >/=1:8, this assessment can be misleading since no correlate of protection exists based on OPA assay titers. A titer of 1:8 is merely the first measurable titer above background in these assays.
While no OPA correlate exists, comparisons of the geometric mean antibody titer (GMT) responses with conjugate vaccines are informative. Two recently published pivotal studies compared PCV7 with either the PCV10 referenced above or the recently licensed 13-valent pneumococcal conjugate vaccine (PCV13) that contains a 19A component conjugated to CRM carrier [8,9]. Both studies were conducted in Europe using a primary immunization schedule administered at 2, 3, and 4 months of age with a booster dose in the second year of life.
In both studies, the OPA titers to serotype 19A in the PCV7 cohorts were very low with geometric mean titers (GMTs) after the three dose primary series of only 4.5 and 6.7 in the Kieninger and Vesikari studies, respectively, after the primary series and 11.1 and 59 after the booster dose. This lack of significant functional activity reflects the lack of effectiveness against serotype 19A disease with the PCV7 vaccine. Similarly, the response to PCV10, which also does not contain a 19A conjugate, a had similar low OPA GMT of 8.6 after the primary series and 29.2 after the booster dose.
In contrast, the cohort that received PCV13 in the Kieninger study had an OPA GMT of 442 after the primary series and a GMT of 1349 after the booster dose. It is clear that neither PCV7 nor PCV10 induce a significant level of functional antibody against serotype 19A, either after the primary series or after the booster dose in absolute terms but especially when viewed in comparison to PCV13, which contains a 19A conjugate.
On the other hand, an OPA response to serotype 6A is seen after PCV7 vaccination in these same studies [8,9], though it is approximately 5- to 10-fold lower than the response seen following PCV13, which contains a 6A conjugate [9]. The 6A response to PCV10 is approximately a third to half that elicited by PCV7 [8] and the clinical relevance of that lower response remains to be determined.
It is clear that dependence on cross-protection within a serogroup is not the best strategy for pneumococcal conjugate formulations. In particular, with the emergence of serotype 19A globally, inclusion of a 19A component in conjugate formulations is critical.
Peter R. Paradiso, PhD Pfizer Vaccines Specialty Care Division 500 Arcola Road Collegeville, PA 19426 Telephone: 484-865-2047 Email: peter.paradiso@pfizer.com
References
1. Hausdorff WP, Hoet B, Schuerman L: Do pneumococcal conjugate vaccines provide any cross-protection against serotype 19A?BMC Pediatr 2010, 10:4.
2. Whitney CG, Pilishvili T, Farley MM, Schaffner W, Craig AS, Lynfield R, et al.: Effectiveness of seven-valent pneumococcal conjugate vaccine against invasive pneumococcal disease: a matched case-control study.Lancet 2006, 368:1495-1502.
3. Pai R, Moore MR, Pilishvili T, Gertz RE, Whitney CG, Beall B; Active Bacterial Core Surveillance Team: Postvaccine genetic structure of Streptococcus pneumoniae serotype 19A from children in the United States.J Infect Dis 2005, 192:1988-1995.
4. Moore MR, Gertz RE Jr, Woodbury RL, Barkocy-Gallagher GA, Schaffner W, Lexau C, et al.: Population snapshot of emergent Streptococcus pneumoniae serotype 19A in the United States, 2005.J Infect Dis 2008, 197:1016-1027.
5. Kaplan SL, Barson WJ, Lin PL, Stovall SH, Bradley JS, Tan TQ, et al.: Serotype 19A is the most common serotype causing invasive infections in children.Pediatrics 2010, 125:429-436.
6. Bettinger JA, Scheifele DW, Kellner JD, Halperin SA, Vaudry W, Law B, et al.: The effect of routine vaccination on invasive pneumococcal infections in Canadian children, Immunization Monitoring Program, Active 2000-2007.Vaccine 2010, 28:2130-2136.
7. Mahjoub-Messai F, Doit C, Koeck JL, Billard T, Evrard B, Bidet P, et al.: Population snapshot of Streptococcus pneumoniae serotype 19A isolates before and after introduction of seven-valent pneumococcal vaccination for French children.J Clin Microbiol 2009, 47:837-840.
8. Vesikari T, Wysocki J, Chevallier B, Karvonen A, Czajka H, Arsene JP, 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.
9. Kieninger DM, Kueper K, Steul K, Juergens C, Ahlers N, Baker S, 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. Presented at: 48th Interscience Conference on Antimicrobial Agents & Chemotherapy (ICAAC); Washington DC, USA; 2008. Abstract 2638.
Competing interests
Dr. Paradiso is employed by Pfizer Inc, the manufacturer of the 7-valent and 13-valent pneumococcal conjugate vaccines.
Response to: Hausdorff WP, Hoet B, Schuerman L: Do pneumococcal conjugate vaccines provide any cross-protection against serotype 19A? BMC Pediatr 2010, 10:4.
21 April 2010
Dear Sir or Madam:
The article by Hausdorff et al. [1] is a compilation of available published data on cross-protection for serotype 19A afforded by serotype 19F in pneumococcal conjugate vaccine formulations. As pointed out by the authors, when 7-valent pneumococcal conjugate vaccine (PCV7; Prevenar; Pfizer Inc) was developed, it was hoped that the protective anticapsular antibody induced by the 19F and 6B conjugates would provide cross-protection for serotype 19A and 6A disease, respectively. While some cross-protection has been observed against serotype 6A disease, from a practical perspective, regardless of the “suggestions” from the literature, there has been no impact on 19A disease in countries where PCV7 has been used [2-7]. As pointed out by the authors, serotype 19A is on the rise in well-immunized populations.
Hausdorff et al. state that other pneumococcal conjugate vaccines may have different immunological properties, implying that outcomes might be different for the recently licensed 10-valent pneumococcal conjugate vaccine (PCV10) in which the 19F polysaccharide is conjugated to diphtheria toxoid [8]. While the authors cite functional antibody assessed by opsonophagocytic activity (OPA) assay data in terms of the percentage of subjects achieving titers >/=1:8, this assessment can be misleading since no correlate of protection exists based on OPA assay titers. A titer of 1:8 is merely the first measurable titer above background in these assays.
While no OPA correlate exists, comparisons of the geometric mean antibody titer (GMT) responses with conjugate vaccines are informative. Two recently published pivotal studies compared PCV7 with either the PCV10 referenced above or the recently licensed 13-valent pneumococcal conjugate vaccine (PCV13) that contains a 19A component conjugated to CRM carrier [8,9]. Both studies were conducted in Europe using a primary immunization schedule administered at 2, 3, and 4 months of age with a booster dose in the second year of life.
In both studies, the OPA titers to serotype 19A in the PCV7 cohorts were very low with geometric mean titers (GMTs) after the three dose primary series of only 4.5 and 6.7 in the Kieninger and Vesikari studies, respectively, after the primary series and 11.1 and 59 after the booster dose. This lack of significant functional activity reflects the lack of effectiveness against serotype 19A disease with the PCV7 vaccine. Similarly, the response to PCV10, which also does not contain a 19A conjugate, a had similar low OPA GMT of 8.6 after the primary series and 29.2 after the booster dose.
In contrast, the cohort that received PCV13 in the Kieninger study had an OPA GMT of 442 after the primary series and a GMT of 1349 after the booster dose. It is clear that neither PCV7 nor PCV10 induce a significant level of functional antibody against serotype 19A, either after the primary series or after the booster dose in absolute terms but especially when viewed in comparison to PCV13, which contains a 19A conjugate.
On the other hand, an OPA response to serotype 6A is seen after PCV7 vaccination in these same studies [8,9], though it is approximately 5- to 10-fold lower than the response seen following PCV13, which contains a 6A conjugate [9]. The 6A response to PCV10 is approximately a third to half that elicited by PCV7 [8] and the clinical relevance of that lower response remains to be determined.
It is clear that dependence on cross-protection within a serogroup is not the best strategy for pneumococcal conjugate formulations. In particular, with the emergence of serotype 19A globally, inclusion of a 19A component in conjugate formulations is critical.
Peter R. Paradiso, PhD
Pfizer Vaccines
Specialty Care Division
500 Arcola Road
Collegeville, PA 19426
Telephone: 484-865-2047
Email: peter.paradiso@pfizer.com
References
1. Hausdorff WP, Hoet B, Schuerman L: Do pneumococcal conjugate vaccines provide any cross-protection against serotype 19A? BMC Pediatr 2010, 10:4.
2. Whitney CG, Pilishvili T, Farley MM, Schaffner W, Craig AS, Lynfield R, et al.: Effectiveness of seven-valent pneumococcal conjugate vaccine against invasive pneumococcal disease: a matched case-control study. Lancet 2006, 368:1495-1502.
3. Pai R, Moore MR, Pilishvili T, Gertz RE, Whitney CG, Beall B; Active Bacterial Core Surveillance Team: Postvaccine genetic structure of Streptococcus pneumoniae serotype 19A from children in the United States. J Infect Dis 2005, 192:1988-1995.
4. Moore MR, Gertz RE Jr, Woodbury RL, Barkocy-Gallagher GA, Schaffner W, Lexau C, et al.: Population snapshot of emergent Streptococcus pneumoniae serotype 19A in the United States, 2005. J Infect Dis 2008, 197:1016-1027.
5. Kaplan SL, Barson WJ, Lin PL, Stovall SH, Bradley JS, Tan TQ, et al.: Serotype 19A is the most common serotype causing invasive infections in children. Pediatrics 2010, 125:429-436.
6. Bettinger JA, Scheifele DW, Kellner JD, Halperin SA, Vaudry W, Law B, et al.: The effect of routine vaccination on invasive pneumococcal infections in Canadian children, Immunization Monitoring Program, Active 2000-2007. Vaccine 2010, 28:2130-2136.
7. Mahjoub-Messai F, Doit C, Koeck JL, Billard T, Evrard B, Bidet P, et al.: Population snapshot of Streptococcus pneumoniae serotype 19A isolates before and after introduction of seven-valent pneumococcal vaccination for French children. J Clin Microbiol 2009, 47:837-840.
8. Vesikari T, Wysocki J, Chevallier B, Karvonen A, Czajka H, Arsene JP, 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.
9. Kieninger DM, Kueper K, Steul K, Juergens C, Ahlers N, Baker S, 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. Presented at: 48th Interscience Conference on Antimicrobial Agents & Chemotherapy (ICAAC); Washington DC, USA; 2008. Abstract 2638.
Competing interests
Dr. Paradiso is employed by Pfizer Inc, the manufacturer of the 7-valent and 13-valent pneumococcal conjugate vaccines.