The effect of Pneumococcal Conjugate Vaccine and Pneumococcal Polysaccharide Vaccine on nasopharyngeal colonisation following human infection challenge with serotype 3 and serotype 6B: a randomised controlled trial

Background
Although evidence suggests some direct protection from the 13-valent pneumococcal conjugate vaccine (PCV13) against pneumococcus 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 longer-term protection offered by pneumococcal vaccines against colonisation using Spn6B, a serotype PCV13 protects against in the short term.
Methods
This trial was conducted between the 28 July 2021 and 3 October 2023. Healthy participants aged 18-50 were recruited in a double-masked, randomised, controlled trial in Liverpool, UK, and assigned (2:1:2) to PCV13, PPV23, or placebo (0.9%NaCl). Participants assigned to the PPV23 arm were challenged with clade Iα, while participants in PCV13 and placebo arms were subsequently randomised to receive clade Iα or II Spn3. Nasal challenge with Spn3 was at 1-month and serotype 6B (Spn6B) in a sub-group at 6-months post-vaccination. Selection for this sub-group 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 objective was to compare the acquisition risk of the challenge strain as detected by nasal wash (NW) culture at 2, 7 or 23 days in the vaccine vs. placebo arms. The analysis was performed on a modified intention-to-treat population, defined as all participants who received vaccination, underwent challenge, and had at least one NW sample collected after the challenge. Randomisation was via a computer-generated schedule that only the unmasked team could access. The unmasked team performed vaccinations and did not perform the nasal challenge or NWs. The lab staff and participants were masked to the vaccination status. The completed study was prospectively registered (EudraCT:2019-004742-15; ISRCTN15728847; ClinicalTrials.gov:NCT04974294).
Findings
The analysis included 407 and 243 participants challenged with Spn3 and Spn6B, respectively. At 1-month post-vaccination, PCV13 was associated with a non-significant reduction (16%) in Spn3 colonisation acquisition (both clades combined: PCV13 84/153[56%] vs placebo 101/155[65%], RR 0.84[0.70-1.01], p=0.068). PCV13 was moderately protective (29%) against clade II (RR 0.71[0.54-0.91], p=0.0090) but not protective against clade Iα (RR 1.01[0.77-1.32], p=0.95). No evidence of protection from PPV23 vaccination was found against clade Iα (RR 0.84, 95%CI 0.63–1.11, p=0.22). At 6 months, PCV13 showed a 60% relative risk reduction against Spn6B (RR 0.40, 95%CI 0.22-0.69, p=0.0020) with no evidence of protection from PPV23 (RR 0.90, 95%CI 0.60-1.34, p=0.60). There were no severe or life-threatening adverse events.
Interpretation
Our findings indicate limited direct protection by PCV13 against Spn3 colonisation acquisition, with differential protection against the clades and no protection by PPV23 against clade Iα. In contrast, PCV13 protected against Spn6B colonisation for at least 6 months. These findings align with current epidemiological evidence, indicating that whilst 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 may 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.
Funding
Collaboration between the Liverpool School of Tropical Medicine (sponsor) and Pfizer (funder).