The effect of pneumococcal conjugate vaccine and pneumococcal polysaccharide vaccine on nasopharyngeal colonisation following human infection challenge with serotype 3 and serotype 6B (PREVENTING PNEUMO 2): a double-masked, randomised, controlled, phase 4 trial

Background Although evidence suggests some direct protection from the 13-valent pneumococcal conjugate vaccine (PCV13) against Streptococcus pneumoniae serotype 3 (Spn3), Spn3 remains a frequent cause of pneumococcal disease in the UK, potentially due to lower vaccine effect on colonisation, shorter duration of protection, or the emergence of more successful Spn3 clades. To test these hypotheses, we compared PCV13 and 23-valent pneumococcal polysaccharide vaccine (PPV23) protection against prevalent Spn3 clades. Additionally, we assessed the long-term protection offered by pneumococcal vaccines against colonisation using S pneumoniae serotype 6B (Spn6B), a serotype PCV13 protects against in the short term. 

Methods This double-masked, randomised, controlled, phase 4 trial recruited healthy participants aged 18–50 years in Liverpool, UK, and assigned them (2:1:2) to PCV13, PPV23, or placebo (0·9% NaCl). Participants assigned to the PPV23 group were challenged with clade Iα, and participants in PCV13 and placebo groups were subsequently randomly assigned to receive clade Iα or II Spn3. Nasal challenge with Spn3 was at 1 month and with Spn6B in a subgroup at 6 months after vaccination. Selection for this subgroup was conducted on a first-come-first-served basis, with participants who enrolled earliest being offered participation in both challenges. Recruitment for the second challenge was discontinued once the target number of participants was reached. The primary outcome was the acquisition risk of the challenge strain as detected by nasal wash culture at 2 days, 7 days, 14 days, or 23 days in the vaccine versus the placebo groups. The analysis was performed in a modified intention-to-treat population, defined as all participants who received vaccination, underwent challenge, and had at least one nasal wash sample collected after the challenge. Randomisation used a computer-generated schedule that only the unmasked team could access. The unmasked team performed vaccinations and did not perform the nasal challenges or nasal washes. The laboratory staff and participants were masked to the vaccination status. This study was prospectively registered with the EU Drug Regulating Authorities Clinical Trials Database, 2019-004742-15, the International Standard Randomised Controlled Trial Number registry, ISRCTN15728847, and ClinicalTrials.gov , NCT04974294 , and is complete. 

Findings This trial was conducted between July 28, 2021, and Oct 3, 2023. The analysis included 407 participants challenged with Spn3 and 243 challenged with Spn6B. 1 month after vaccination, PCV13 was associated with a non-significant reduction (16%) in Spn3 colonisation acquisition when considering both clades combined(84 [56%] of 153 participants in the PCV13 group vs 101 [65%] of 155 in the placebo group; relative risk 0·84, 95% CI 0·70–1·01; p=0·068). PCV13 was moderately protective (29%) against clade II (0·71, 0·54–0·91; p=0·0090) but was not protective against clade Iα (1·01, 0·77–1·32; p=0·95). No evidence of protection from PPV23 vaccination was found against clade Iα (0·84, 0·63–1·11; p=0·22). At 6 months, PCV13 showed a 60% relative risk reduction against Spn6B (0·40, 0·22–0·69; p=0·0020) with no evidence of protection from PPV23 (0·90, 0·60–1·34; p=0.60). There were no severe or life-threatening adverse events. 

Interpretation Our findings indicate partial direct protection by PCV13 against Spn3 colonisation acquisition, with differential protection against the clades and no protection by PPV23 against clade Iα. By contrast, PCV13 protected against Spn6B colonisation for at least 6 months. These findings align with epidemiological evidence, indicating that, although PCV13 vaccination against Spn6B offers sustained direct and indirect protection, its effect on Spn3 colonisation and therefore indirect protection is limited. Direct vaccination of at-risk adults might therefore be more appropriate than relying solely on herd immunity from paediatric programmes. The development of next-generation pneumococcal vaccines and further immunological analysis are needed to optimise protection against Spn3.