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.
SECONDARY OUTCOMES: VT carriage prevalence among children 5-10 years old, among HIV
infected adults 18-40 years, add among children 9 months old. Others include prevalence
of multiple serotype carriage, and completeness of 3 doses PCV13.
POPULATION: Children who are aged 15-24 months, residents of Blantyre District, and who
have received PCV13 in either a 3+0 or a 2+1 schedule (recruited from households);
Children aged 5-10 years who have received PCV13 on a 3+0 schedule (recruited from
schools); children aged 9 months, who have received PCV13 in either a 3+0 or a 2+0
schedule (recruited from health centres at routine 9-month visit); HIV-infected adults
aged 18-40 years receiving ART and PCV13-unvaccinated (recruited from the Queen Elizabeth
Central Hospital (QECH) HIV/ART Clinic) EXPECTED FINDINGS: Data will inform NITAG
decisions on national vaccine policy, with implications at a national, regional and
global level. Results will be disseminated through peer-reviewed publications, scientific
conferences, and other relevant stakeholder and policymakers' meetings. This work will
strengthen collaboration between relevant government and academic institutions, provide
research training for MoH staff and early-career researchers.
