Background

The full extent to which childhood pneumococcal conjugate vaccines (PCV) can indirectly reduce illness in unvaccinated populations is not known. We aimed to estimate the magnitude and timing of indirect effects of PCVs on invasive pneumococcal disease.

Methods

In this systematic review and meta-analysis, we searched bibliographic databases for non-randomised quasi-experimental or observational studies reporting invasive pneumococcal disease changes following PCV introduction in unvaccinated populations (studies published Sept 1, 2010, to Jan 6, 2016), updating the previous systematic review of the same topic (studies published Jan 1, 1994, to Sept 30, 2010). Two reviewers extracted summary data by consensus. We used a Bayesian mixed-effects model to account for between-study heterogeneity to estimate temporal indirect effects by pooling of invasive pneumococcal disease changes by serotype and serogroup.

Findings

Data were extracted from 70 studies included in the previous review and 172 additional studies, covering 27 high-income and seven middle-income countries. The predicted mean times to attaining a 90% reduction in invasive pneumococcal disease were 8·9 years (95% credible interval [CrI] 7·8–10·3) for grouped serotypes contained in the seven-valent PCV (PCV7), and 9·5 years (6·1–16·6) for the grouped six additional serotypes contained in the 13-valent PCV (PCV13) but not in PCV7. Disease due to grouped serotypes contained in the 23-valent pneumococcal polysaccharide vaccine (PPV23) decreased at similar rates per year in adults aged 19–64 years (relative risk [RR] 0·85, 95% CrI 0·75–0·95) and 65 years and older (0·87, 0·84–0·90). However, we noted no changes in either group in invasive pneumococcal disease caused by the additional 11 serotypes covered by PPV23 but not PCV13.

Interpretation

Population 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.

Funding

Policy Research Programme of the Department of Health, England.

Invasive pneumococcal disease due to Streptococcus pneumoniae infection is a major source of ill health worldwide, especially in children under 5 years, older people, and individuals with risk factors (ie, splenic dysfunction, heart disease, or immunodeficiency). ^{1 , 2 , 3 and 4} Childhood vaccination is recommended by WHO and is increasingly implemented across the world. ⁵ The first pneumococcal conjugate vaccine (PCV) was seven-valent (PCV7), was licensed in 2000, and has since been replaced by ten-valent (PCV10) or 13-valent (PCV13) versions. In some countries, mostly high-income countries, the 23-valent pneumococcal polysaccharide vaccine (PPV23) was introduced in adults earlier than childhood PCVs. ^{6 , 7 , 8 and 9}

Routine use of childhood PCVs has substantially changed the epidemiology of pneumococcal disease. In vaccinated young children, disease due to serotypes included in the vaccines has been reduced to negligible levels. ¹⁰ Decreases in both disease and carriage have also been observed in unvaccinated groups in different countries. ^{11 , 12 , 13 and 14} However, in unvaccinated population age groups, especially older adults, substantial residual disease and deaths due to serotypes covered by both childhood and adult vaccines remain. ^{15 and 16} Also, in some settings, disease due to serotypes not covered by these vaccines has increased. ^{17 , 18 , 19 , 20 and 21}

In addition to childhood PCVs and adult PPV23 programmes, the use of conjugate vaccines in healthy and immunocompromised adults is effective. A randomised placebo-controlled trial ^{15 and 22} of PCV13 use conducted during 2008–13 in the Netherlands among 85 000 adults 65 years and older showed an efficacy of 75·0% (95% CI 41·4–90·8) against vaccine-type invasive pneumococcal disease, 45·6% (21·8–62·5) against all vaccine-type pneumonia, and 45·0% (14·2–65·3) against vaccine-type non-bacteraemic pneumonia. Previously, PCV7 showed an efficacy of 75% (29–92) for prevention of invasive pneumococcal disease in HIV-infected adults in Malawi. ²³ In view of the efficacy of PCV13 in adults, ^{15 and 22} some countries such as the USA introduced this vaccine into their adult immunisation programme, in addition to PPV23, with authorities in the USA due to review the programme in 2018. By contrast, several developed countries have not introduced PCV13 into their adult immunisation programmes. ¹⁶

Research in context

Evidence before this study

Strong evidence shows that there are direct and herd immunity effects of pneumococcal conjugate vaccines (PCVs). However, the protective effect of existing vaccination programmes have not been systematically quantified. A previous systematic review focused on the seven-valent pneumococcal vaccine (PCV7) only, which has since been replaced by the 13-valent pneumococcal vaccine (PCV13) in most countries. Since 2010, many more countries have introduced the PCV13 vaccine. Data from individual studies have become available from different countries, with a wide range of programme maturity, vaccination schedules, and coverage.

Added value of this study

We have used data for disease changes due to serotypes covered by conjugate vaccines to provide quantitative estimates of the expected rate of development of herd immunity. Countries with mature PCV7 programmes allowed the evaluation of the long-term effects. We showed that similar early effects on disease due to the additional six serotypes in PCV13 suggest that long-term effects will follow a similar course—ie, a 90% reduction in disease burden due to the covered serotypes among adults through herd immunity can be achieved within a decade of establishing a sustained childhood programme. Disease burden reduction is more rapid with higher vaccine coverage but variations in schedule are less important.

Implications of all the available evidence

The large indirect protection of childhood vaccinations programmes should be considered when assessing vaccination of older age groups, an issue that is pertinent in high-income countries, as well as informing priorities in the childhood programme. The evidence gap is substantial for low-income countries on the impact of childhood pneumococcal vaccination on disease in age groups not eligible to be vaccinated. Because these countries are increasingly undertaking childhood vaccination programmes, research to assess the indirect effects in these settings is particularly relevant.

In this systematic review and meta-analysis, we aim to assess the extent to which childhood pneumococcal vaccination affects disease incidence in adult populations and the time course of this effect when childhood vaccination programmes are introduced. This work is motivated by both the need to improve understanding of the full effects of childhood programmes and the need to inform policy decisions on the use of PCVs or PPV23 in adult populations that have an effective childhood PCV13 programme. The findings should inform the existing immunisation policy discussions around the cost-effectiveness of introducing PCVs into adult immunisation programmes to speed up elimination of residual disease due to vaccine serotypes. ^{24 and 25}