BACKGROUND: In Malawi, the national 13-valent pneumococcal conjugate vaccine (PCV13) demonstrated less herd immunity than in the United States, likely due to higher natural pneumococcal carriage rates. We assessed PCV13 efficacy against experimental pneumococcal carriage in healthy Malawian adults. We explored how natural carriage (pneumococcal carriage of any serotype apart from 6B) influenced experimental carriage rates and vaccine efficacy. METHODS: Healthy adults aged 18 to 40 years were randomly assigned to PCV13 (n = 98) or saline (n = 106), followed by intranasal SPN 6B inoculation at 20 000 (n = 40), 80 000 (n = 74), or 160 000 (n = 90) colony-forming units/100 µL at 28 days postvaccination. We evaluated natural and experimental pneumococcal carriage before and after vaccination on days 2, 7, and 14 postinoculation using culture and multiplex quantitative polymerase chain reaction (qPCR) targeting the lytA/cpsA genes, and we compared carriage rates by vaccination status. RESULTS: Of 204 participants, 19.6% (n = 40) exhibited experimental carriage detected by culture and 25.5% (n = 52) by qPCR. Vaccinated individuals had lower experimental carriage rates (10.2%, n = 10/98) than the placebo group (28.3%, 30/106). This difference in vaccine efficacy was more pronounced in participants without natural carriage (PCV13, 8%, 6/75
placebo, 25.9%, 21/81) vs those with natural carriage (PCV13, 14.8%, 4/27
placebo, 26.5%, 9/34). According to a log-binomial model, vaccine effectiveness (VE) was 62%, whether assessed by culture or qPCR. Natural carriers had lower VE (52%) vs participants with no natural carriage (69%). CONCLUSIONS: We have shown that the PCV13 VE estimate (62%) is robust whether carriage is assessed by culture or qPCR. PCV13 had lower VE in natural carriers when compared with those without natural carriage at the inoculation visit.