Evaluation of the effect of serotype on pneumococcal conjugate vaccine-induced immunity: an exploratory analysis of the PREVENTING PNEUMO 2 trial.

Abstract

Although evidence suggests some direct protection against Streptococcus pneumoniae serotype 3 (Spn3) from the 13-valent pneumococcal conjugate vaccine (PCV13), Spn3 remains a common cause of pneumococcal disease. We aimed to assess whether serotype-specific humoral immune responses to capsule polysaccharide (CPS) 3 and CPS6B after vaccination were associated with protection from experimental pneumococcal carriage. We undertook a prospective cohort study nested within the PREVENTING PNEUMO 2 double-masked, randomised, phase 4 human pneumococcal challenge trial conducted at the Liverpool School of Tropical Medicine, UK. Healthy adults aged 18-50 years who had received PCV13, 23-valent pneumococcal polysaccharide vaccine (PPV23), or placebo in the parent trial were included in assay-specific analyses according to sample availability and protocol-defined exclusions. Participants were intranasally challenged with Spn3 1 month after vaccination, and a subgroup was additionally challenged with S pneumoniae serotype 6B (Spn6B) 6 months after vaccination. We measured CPS-specific serum IgG, serum opsonophagocytic activity, nasal CPS3-specific and CPS6B-specific IgG and IgM, and circulating CPS3-specific and CPS6B-specific memory B cells. The trial is registered with EudraCT (2019-004742-15), the International Standard Randomised Controlled Trial Number registry (ISRCTN15728847), and ClinicalTrials.gov (NCT04974294). Between July 28, 2021, and Oct 3, 2023, 407 participants were included in the Spn3 challenge analyses and 243 in the Spn6B challenge analyses. Vaccination with PCV13 significantly increased CPS3-specific (1 month vs baseline [p<0·0001]) and CPS6B-specific IgG serum levels (1 month vs baseline [p<0·0001]), but only CPS6B-specific IgG was detectable in the nasal wash samples (1 month vs baseline [p<0·0001]). More than a two-fold increase in CPS3-specific IgG concentration was seen in 93 (67%) of 139 participants who received PCV13 vaccination and 46 (51%) of 91 participants who received PPV23 vaccination; similarly, that in CPS6B-specific IgG concentrations was seen in 103 (96%) of 107 participants who received PCV13 vaccination and 58 (79%) of 73 participants who received PPV23 vaccination. Nasal CPS3-specific IgG was detected only after Spn3 challenge in participants with pneumococcal carriage. CPS3- and CPS6B-specific serum opsonophagocytic activity increased after PCV13 and PPV23 vaccination with opsonophagocytic titres higher in carriage-negative participants after challenge with Spn6B but not Spn3. PCV13-induced CPS3-specific memory B cells were associated with protection from Spn3 carriage acquisition but their frequency rapidly declined. CPS6B-specific memory B-cell frequencies were higher and associated with protection from Spn6B carriage acquisition. PCV13 vaccination induced systemic humoral immune responses to both serotypes but they differed in magnitude, duration, and tissue distribution. The low mucosal immunity to Spn3 might contribute to reduced protection against Spn3 carriage acquisition. Pfizer.