Pneumococcal Conjugate Vaccine 13 (PCV13) Schedule Change From 3+0 to 2+1 to Accelerate Reduction in Pneumococcal Vaccine Serotype Carriage in Blantyre, Malawi: an Effectiveness Study

STUDY TYPE: Pragmatic health center-based evaluation to compare effectiveness of a MoH-mandated structured PCV13 schedule change from 3+0 to 2+1 dosing in a high disease burden setting in Malawi PROBLEM: Streptococcus pneumoniae is a leading cause of childhood pneumonia, meningitis, and bacteremia in sub-Saharan Africa. Pneumococcal conjugate vaccines (PCV) the commonest pneumococcal serotypes have been shown to be effective against pneumococcal meningitis and sepsis, so-called invasive pneumococcal disease (IPD), pneumonia, and all-cause mortality among young children when introduced into infant expanded programs on immunization (EPI). Colonization of the nasopharynx by Streptococcus pneumoniae is a necessary prerequisite to pneumococcal disease. Critically important to the population impact of PCV is therefore reducing vaccine serotype (VT) carriage prevalence, and therefore reducing both disease and onward transmission to vulnerable individuals. Thus, as well as protecting the vaccinated individual (direct protection), PCV confers indirect protection (herd immunity) to unvaccinated populations and to vaccinated individuals who have insufficient protective immunity.

While the ability of PCVs to induce herd immunity has been strong enough to control pneumococcal carriage and disease in industrialized countries, such benefits have not been as marked in low-income countries. In Malawi, the introduction of the PCV13 achieved an approximate 70% reduction in IPD among vaccinated children, and an estimated 35% fall in all-cause mortality among vaccinated children. However, carriage surveillance 4 to 7 years post-vaccine implementation shows persistent VT carriage. Data suggests that most of the vaccine's direct benefit occurs in the first 12 months of life, further suggesting that vaccine-induced protection against pneumococcal disease and colonization wanes rapidly under the current 3+0 schedule. With the exception of South Africa, most sub-Saharan African countries, including Malawi, have introduced PCV using a 3+0 schedule (doses at 6, 10, and 14 weeks of age). Whether the 2+1 schedule (6, 10 weeks and 9 months of age) will maximize vaccine-induced protection has been identified as a research gap by the WHO. There is a dearth of head-to-head studies directly comparing these two schedules. In this context, the Malawian Ministry of Health (MoH) and the National Immunizations Technical Advisory Committee (NITAG) are seeking evidence of adequate superiority of a 2+1 schedule to inform a change to the current Malawi EPI schedule.

HYPOTHESIS: Prolonging the period of vaccine-induced protection with a booster vaccine dose at 9 months will extend the period of low VT carriage, hence providing longer direct vaccine-induced protection as well as boosting the indirect herd immunity effect.

METHOD: The MoH will implement a 2+1 PCV13 vaccine schedule change in Blantyre District. A comparison with the ongoing 3+0 schedule will use a pragmatic health centre-based randomization protocol, with 10 centres continuing with the current 3+0 and 10 implementing the WHO-approved 2+1 schedule. This change will be implemented within the scope of the EPI, subjected to EPI standard procedures for delivery, monitoring, and assessment. This MoH-led change will be evaluated as part of a longstanding partnership with the Malawi Liverpool Wellcome Trust Clinical Research Programme. Researchers will undertake two population based pneumococcal carriage surveys in these 20 health centre catchment areas, at 15 and 33 months after the introduction of the 2+1 schedule.

PRIMARY OUTCOME: VT carriage prevalence among children 15-24 months of age 36 months after schedule change.