The duopoly of ten-valent and 13-valent pneumococcal conjugate vaccines: do they differ?
Authors: Shabir A Madhi, David Goldblatt
Journal: The Lancet Infectious Diseases (2019)

In The Lancet Infectious Diseases, Beth Temple and colleagues1Temple B Toan NT Dai VTT et al.Immunogenicity and reactogenicity of PCV10 versus PCV13 among infants in Ho Chi Minh City, Vietnam: a randomised controlled trial.Lancet Infect Dis. 2019; (published online April 8.)http://dx.doi.org/10.1016/S1473-3099(18)30734-5Summary Full Text Full Text PDF PubMed Scopus (23) Google Scholar report on a head-to-head comparison of the immunogenicity, in a low-income to middle-income setting (Vietnam), of the currently licenced ten-valent (PCV10) and 13-valent (PCV13) pneumococcal conjugate vaccines. The two vaccines were administered in a two-dose primary series (2 months and 4 months of age), with a booster dose at 9 months of age (a 2 + 1 schedule), with the primary comparison of immunogenicity between the vaccines being the proportion of recipients with serotype-specific antibody concentrations above the recommended composite putative threshold of protection developed for invasive pneumococcal disease (serotype-specific IgG concentration ≥0·35 μg/mL).2Jodar L Butler J Carlone G et al.Serological criteria for evaluation and licensure of new pneumococcal conjugate vaccine formulations for use in infants.Vaccine. 2003; 21: 3265-3272Crossref PubMed Scopus (301) Google Scholar By this measure, PCV10 and PCV13 did not differ in immunogenicity. This finding was supplemented by assessment of the prevalence of functional antibody (opsonophagocytic index ≥8) post-vaccination, which was also similar between groups. The similarity of PCV10 compared with PCV13 in the 2 + 1 dosing schedule was evident after both the primary series and the booster dose. The perceived benefit of PCV13 over that of PCV10 has been the superior coverage of PCV13 for three additional disease-causing serotypes (serotypes 3, 6A, and 19A). Evidence suggests that PCV13 has no effect on serotype 3 invasive pneumococcal disease,3Ladhani SN Collins S Djennad A et al.Rapid increase in non-vaccine serotypes causing invasive pneumococcal disease in England and Wales, 2000–17: a prospective national observational cohort study.Lancet Infect Dis. 2018; 18: 441-451Summary Full Text Full Text PDF PubMed Scopus (306) Google Scholar whereas evidence of a direct effect on serotypes 6A and 19A invasive pneumococcal disease in countries using PCV10 suggests some cross-protection.4Mrkvan T Pelton SI Ruiz-Guinazu J Palmu AA Borys D Effectiveness and impact of the 10-valent pneumococcal conjugate vaccine, PHiD-CV: review of clinical trials and post-marketing experience.Expert Rev Vaccines. 2018; 17: 797-818Crossref PubMed Scopus (14) Google Scholar Similarly to past studies, the data in this paper show cross-reactive IgG and functional antibodies to serotype 6A and 19A in 61–67% of PCV10 recipients after a booster dose; however, these percentages were lower than the percentage (>99%) of PCV13 recipients in whom functional antibodies to these serotypes were induced. Furthermore, the geometric mean opsonophagocytic indices were 15–77 times higher for serotypes 6A and 19A after the primary series, and 23–32 times higher after the booster dose in PCV13 recipients versus PCV10 recipients. The effect of these higher titres on direct protection is unclear. The lower cross-reactive responses to 19A might explain the reported failure of PCV10 to reduce 19A colonisation in children and provide indirect protection against 19A in unvaccinated individuals.5Isturiz R Sings HL Hilton B Arguedas A Reinert RR Jodar L Streptococcus pneumoniae serotype 19A: worldwide epidemiology.Expert Rev Vaccines. 2017; 16: 1007-1027Crossref PubMed Scopus (78) Google Scholar Another important observation by Temple and colleagues1Temple B Toan NT Dai VTT et al.Immunogenicity and reactogenicity of PCV10 versus PCV13 among infants in Ho Chi Minh City, Vietnam: a randomised controlled trial.Lancet Infect Dis. 2019; (published online April 8.)http://dx.doi.org/10.1016/S1473-3099(18)30734-5Summary Full Text Full Text PDF PubMed Scopus (23) Google Scholar was that the immunogenicity of a two-dose primary series of PCV13 was similar to a three-dose primary series of PCV10 (3 + 0). These data indicate the potential for using three doses of PCV13 in a 2 + 1 schedule rather than a 3 + 0 schedule. This schedule could potentially address the waning of protection against serotype 1, as reported in African efficacy trials of a nine-valent PCV (including serotype 1), which only immunised with a three-dose primary series.6Klugman KP Madhi SA Adegbola RA Cutts F Greenwood B Hausdorff WP Timing of serotype 1 pneumococcal disease suggests the need for evaluation of a booster dose.Vaccine. 2011; 29: 3372-3373Crossref PubMed Scopus (31) Google Scholar The interpretation of results from this and other similar immunogenicity studies, however, have limitations in extrapolating to overall direct vaccine effectiveness. These limitations include the likelihood of serotype-specific differences in thresholds of antibody associated with protection against invasive pneumococcal disease;7Andrews NJ Waight PA Burbidge P et al.Serotype-specific effectiveness and correlates of protection for the 13-valent pneumococcal conjugate vaccine: a postlicensure indirect cohort study.Lancet Infect Dis. 2014; 14: 839-846Summary Full Text Full Text PDF PubMed Scopus (342) Google Scholar the possibility that concentrations required for protection against invasive pneumococcal disease are not the same as those required for non-invasive pneumococcal disease syndromes, such as non-bacteraemic pneumococcal pneumonia, which constitutes the largest burden of severe pneumococcal disease;8Wahl B O'Brien KL Greenbaum A et al.Burden of Streptococcus pneumoniae and Haemophilus influenzae type b disease in children in the era of conjugate vaccines: global, regional, and national estimates for 2000–15.Lancet Glob Health. 2018; 6: e744-e757Summary Full Text Full Text PDF PubMed Scopus (480) Google Scholar and that concentrations of IgG required to protect against colonisation might be significantly higher than those required to protect against invasive pneumococcal disease.9Shiri T Datta S Madan J et al.Indirect effects of childhood pneumococcal conjugate vaccination on invasive pneumococcal disease: a systematic review and meta-analysis.Lancet Glob Health. 2017; 5: e51-e59Summary Full Text Full Text PDF PubMed Scopus (119) Google Scholar PCVs protect against the acquisition of nasopharyngeal colonisation,10Klugman KP Efficacy of pneumococcal conjugate vaccines and their effect on carriage and antimicrobial resistance.Lancet Infect Dis. 2001; 1: 85-91Summary Full Text Full Text PDF PubMed Scopus (111) Google Scholar and this protection is key to reducing the transmission of pneumococci and, thus, to the indirect protection from pneumococcal disease in unvaccinated individuals. A pooled analysis, which used seroincidence as a proxy of serotype-specific colonisation, suggested that serotype-specific antibody concentrations associated with reduced odds of nasopharyngeal colonisation range from 0·50 μg/mL (62% lower odds of imputed serotype 6B colonisation) to 2·54 μg/mL (87% reduced odds of imputed serotype 19F colonization).11Voysey M Fanshawe TR Kelly DF et al.Serotype-specific correlates of protection for pneumococcal carriage: an analysis of immunity in 19 countries.Clin Infect Dis. 2018; 66: 913-920Crossref PubMed Scopus (28) Google Scholar These estimates are approximately 3·1 times higher than the respective serotype-specific threshold estimated to confer 90% reduced risk of invasive pneumococcal disease for serotypes 6B (0·16 μg/mL), and 2·2 times higher than that for serotype 19F (1·17 μg/mL).7Andrews NJ Waight PA Burbidge P et al.Serotype-specific effectiveness and correlates of protection for the 13-valent pneumococcal conjugate vaccine: a postlicensure indirect cohort study.Lancet Infect Dis. 2014; 14: 839-846Summary Full Text Full Text PDF PubMed Scopus (342) Google Scholar, 11Voysey M Fanshawe TR Kelly DF et al.Serotype-specific correlates of protection for pneumococcal carriage: an analysis of immunity in 19 countries.Clin Infect Dis. 2018; 66: 913-920Crossref PubMed Scopus (28) Google Scholar In summary, Temple and colleagues' study showing non-inferiority of PCV10 versus PCV13 in terms of immunogenicity against invasive pneumococcal disease provides important endorsement of existing WHO advice on the use of PCVs for infant immunisation.12WHOPneumococcal vaccines WHO position paper—2012.Wkly Epidemiol Rec. 2012; 87: 129-144PubMed Google Scholar Furthermore, these data indicate that an individual country's decision on which vaccine to use in a 2 + 1 schedule to directly protect against vaccine-serotype invasive pneumococcal disease might well be influenced primarily by the cost of vaccine procurement. The effects of the differences between the vaccines in terms of absolute antibody concentrations are unclear, but might have implications for the effect of vaccines on non-invasive disease, carriage, and indirect protection for at least some serotypes. However, these questions require further study. SAM reports grants and personal fees from the Bill & Melinda Gates Foundation, and grants from GlaxoSmithKline, Pfizer, and Sanofi Pasteur outside of the submitted work. DG reports grants from GlaxoSmithKline outside of the submitted work. Immunogenicity and reactogenicity of ten-valent versus 13-valent pneumococcal conjugate vaccines among infants in Ho Chi Minh City, Vietnam: a randomised controlled trialPCV10 and PCV13 are similarly highly immunogenic when used in 2 + 1 schedule. The choice of vaccine might be influenced by factors such as the comparative magnitude of the antibody responses, price, and the relative importance of different serotypes in different settings. Full-Text PDF Open AccessEfficacy and effectiveness of ten-valent versus 13-valent pneumococcal conjugate vaccinesWe note some mischaracterisations in the Comment by Shabir A Mahdi and David Goldblatt1 on the Article by Beth Temple and colleagues.2 As an overarching framework, the data from Temple and colleagues cannot be used for predicting vaccine performance against most clinical outcomes, since the only accepted correlate of protection for pneumococcal conjugate vaccines (PCVs) is against invasive pneumococcal disease 1 month after three primary doses during infancy. For all other outcomes (carriage, mucosal disease), schedules, ages, and doses, no such association exists; thus the interpretation of immunogenicity data remains in doubt. Full-Text PDF Efficacy and effectiveness of ten-valent versus 13-valent pneumococcal conjugate vaccines – Authors' replyBradford D Gessner and colleagues argue that our Comment1 contains mischaracterisations regarding the relative merits of the PCV10 and PCV13 vaccines. Full-Text PDF