The indirect effect of pneumococcal conjugate vaccine
Authors: David Goldblatt
Journal: The Lancet Global Health (2016)

Bacterial glycoconjugate vaccines contain capsule-derived bacterial polysaccharides chemically conjugated to carrier proteins and are highly immunogenic in the infant population for whom they were originally designed. This class of vaccine has shown a profound impact on the incidence of both invasive disease, such as septicaemia and meningitis, as well as mucosal infections including pneumonia and otitis media, in individuals who receive the vaccine. Unlike purified polysaccharide vaccines, glycoconjugates have also shown a profound indirect impact, reducing the incidence of disease in the unvaccinated population of all ages. This indirect or herd effect is the result of the reduced spread of bacteria from those vaccinated, a consequence of vaccine-induced prevention of bacterial colonisation of the upper respiratory tract. The glycoconjugate vaccines that have shown the most profound indirect effect and which have been best studied are the pneumococcal conjugate vaccines (PCV) first licensed in 2000. The indirect effect of PCV is particularly relevant because the pneumococcus is an important cause of disease in older people and in adults with comorbidities. Most data for the indirect effect of PCV are from developed countries with mature surveillance systems where PCV was introduced into the infant immunisation programme relatively soon after licensure. Surveillance in these countries has revealed not only the reduction of invasive pneumococcal disease in older people but also a reduction in disease rates in adults with underlying comorbidities in whom direct protection might be suboptimal.1Cabaj JL Nettel-Aguirre A MacDonald J Vanderkooi OG Kellner JD Influence of Childhood Pneumococcal Conjugate Vaccines on Invasive Pneumococcal Disease in Adults With Underlying Comorbidities in Calgary, Alberta (2000–2013).Clin Infect Dis. 2016; 62: 1521-1526Crossref PubMed Scopus (26) Google Scholar In The Lancet Global Health, Tinevimbo Shiri and colleagues2Shiri T Datta S Madan J et al.Indirect effect of childhood pneumococcal conjugate vaccination on invasive pneumococcal disease: a systematic review and meta-analysis.Lancet Glob Health. 2016; 5: e51-e59Summary Full Text Full Text PDF Scopus (119) Google Scholar present a meta-analysis of the indirect effect of PCV, using data from 34 different countries and assessing the reduction in invasive pneumococcal disease and the mean time to maximal impact. Analysis of the impact of the first licensed PCV, which was seven-valent (PCV7), confirmed the near-elimination of invasive pneumococcal disease due to serotypes in the vaccine in the unvaccinated in settings with a mature childhood PCV7 programme. A second-generation vaccine containing 13 serotypes (PCV13) was licensed and introduced in 2010. Shiri and colleagues' meta-analysis predicts that the residual invasive pneumococcal disease due to the additional six serotypes contained in PCV13 will be halved after an average period of 3·3 years (95% credible interval [CrI] 2·1–6·8) and nearly eradicated after about 9 years following the introduction of PCV13 (5·7–19·7). The predicted mean time to attaining the maximal indirect impact is relevant when considering adult vaccination with PCV. Most developed countries do not recommend PCV in adults, believing that with the high coverage in the infant programme, adult disease will (eventually) decline. The US vaccine decision-making body, the Advisory Committee on Immunization Practices, recommended PCV13 vaccination in adults despite high coverage of PCV13 in the infant programme.3Tomczyk S Bennett NM Stoecker C et al.Use of 13-valent pneumococcal conjugate vaccine and 23-valent pneumococcal polysaccharide vaccine among adults aged ≥65 years: recommendations of the Advisory Committee on Immunization Practices (ACIP).MMWR Morb Mortal Wkly Rep. 2014; 63: 822-825PubMed Google Scholar However, in recognition of the probable changing epidemiology of adult disease, the recommendation built in a review of the evidence, scheduled for 2018, to re-evaluate the decision. Questions remain over whether the indirect impact on invasive pneumococcal disease is mirrored by the same reduction in pneumonia. A US study4Sherwin RL Gray S Alexander R et al.Distribution of 13-valent pneumococcal conjugate vaccine Streptococcus pneumoniae serotypes in US adults aged ≥50 years with community-acquired pneumonia.J Infect Dis. 2013; 208: 1813-1820Crossref PubMed Scopus (75) Google Scholar of adults admitted to hospital with community-acquired pneumonia suggested a persistent burden of disease due to serotypes contained in PCV13; however, UK5Rodrigo C Bewick T Sheppard C et al.Impact of infant 13-valent pneumococcal conjugate vaccine on serotypes in adult pneumonia.Eur Respir J. 2014; 45: 1632-1641Crossref Scopus (98) Google Scholar and Dutch studies6van Werkhoven CH Hollingsworth RC Huijts SM et al.Pneumococcal conjugate vaccine herd effects on non-invasive pneumococcal pneumonia in elderly.Vaccine. 2016; 34: 3275-3282Crossref PubMed Scopus (26) Google Scholar suggest the magnitude of the decline in non-invasive pneumococcal pneumonia in adults mirrors the reduction seen in invasive pneumococcal disease. Important questions regarding the indirect effect of PCV for the global pneumococcal community remain. These questions include the impact of different vaccines and schedules, particularly the presence or absence of a dose in older infants or toddlers after priming in infancy (a booster dose) as well as the applicability of the findings in developed countries to developing countries. Shiri and colleagues' analysis showed no impact of schedule; however, most studies described the use of a 2 + 1 or 3 + 1 schedule and the number of data points was too low to analyse the impact of a booster dose. Similarly, the low number of studies of PCV10 prevented a comparison of vaccine formulation. No data from low-income countries have been published and data from only four lower middle-income countries were available for analysis. A pooled analysis of the indirect effect in these four countries (South Africa, Morocco, Brazil, and Uruguay) showed a trend in invasive pneumococcal disease reduction similar to that seen in developed countries, although data were sparse. The relevance of the latter finding to low-income countries with high rates of pneumococcal carriage and vaccine schedules that do not include a booster dose of PCV needs to be interpreted with caution and should be a priority for further study. Replacement disease by serotypes not in the vaccine has reduced the overall impact of PCV. Data from this meta-analysis have shown an overall reduction of invasive pneumococcal disease in all unvaccinated age groups of just 1%. Although the magnitude of replacement disease described in individual studies has varied geographically, this analysis suggests an overall trend towards significant impact on invasive pneumococcal disease. New extended-valency vaccines will be required to halt this erosion of PCV impact. Vaccines are in development that do not rely on capsule-specific responses but widely expressed non-capsular antigens instead and might provide a permanent solution. I report grants and personal fees from GSK, Merck, Sharpe, and Dohme, and a publication with Pfizer, outside the submitted work. Indirect effects of childhood pneumococcal conjugate vaccination on invasive pneumococcal disease: a systematic review and meta-analysisPopulation childhood PCV programmes will lead, on average, to substantial protection across the whole population within a decade. This large indirect protection should be considered when assessing vaccination of older age groups. Full-Text PDF Open Access