BACKGROUND:Pneumococcal conjugate vaccines (PCVs) have substantially reduced vaccine-type pneumococcal disease, yet a considerable burden of adult pneumococcal disease remains due to persistent serotype diversity and replacement. This study aimed to evaluate the safety, tolerability, and immunogenicity of VAX-31, a 31-valent PCV candidate designed to provide broad serotype coverage and higher immunogenicity.
METHODS:This phase 1/2, double-blinded, active-controlled, parallel-group, dose-finding randomised clinical trial enrolled healthy, pneumococcal-naive adults aged 50 years or older from 25 clinical sites in the USA. Participants were block randomised (1:1:1:1) using a web-based randomisation and trial management system to receive a dose of intramuscular low-dose, mid-dose, or high-dose VAX-31, or 20-valent PCV (PCV20). VAX-31 doses were defined by polysaccharide content: 1·1 μg (low), 2·2 μg (mid), or 3·3 μg (high) for all serotypes except 1, 5, and 22F, which were dosed at 1·65 μg (low), 3·3 μg (mid), and 4·4 μg (high). Investigators, participants, and trial personnel were masked to treatment assignment. Participants were followed up for 6 months, with blood samples collected at baseline and 1 month. Primary safety outcomes, assessed in the safety population (all vaccinated participants with safety data), included solicited local and systemic adverse events within 7 days after vaccination, unsolicited adverse events within 1 month, and serious adverse events, medically attended adverse events, and new-onset chronic illnesses up to 6 months. Safety was evaluated overall and across prespecified age groups. Secondary immunogenicity outcomes were assessed in the immunogenicity-evaluable population (no major protocol deviations affecting immunogenicity and with evaluable serum samples) and included serotype-specific opsonophagocytic activity (OPA) geometric mean titres (GMTs) and IgG geometric mean concentrations at 1 month. Although no formal hypothesis testing was performed, the lower bound of the two-sided 95% CIs for OPA GMT ratios (VAX-31 to PCV20) was compared using precedent PCV licensure criteria: non-inferiority of at least 0·5 for serotypes shared with PCV20 and superiority of at least 2·0 for novel serotypes. This study is registered at ClinicalTrials.gov (NCT06151288).
FINDINGS:Between Nov 8, 2023, and Jan 10, 2024, 1015 participants were enrolled and randomly assigned; 255 participants were vaccinated with low-dose VAX-31, 254 participants were given mid-dose VAX-31, 253 participants were given high-dose VAX-31, and 253 participants were given PCV20. In 1015 total participants, the mean age was 59·8 years (SD 6·7), 609 (60%) were female, and 406 (40%) were male. Solicited adverse events were reported in 192 (76% [95% CI 70-81]) of 253 participants given low-dose VAX-31, 197 (78% [72-83]) of 254 participants given mid-dose VAX-31, 210 (83% [78-87]) of 253 participants given high-dose VAX-31, and 180 (71% [65-77]) of 252 participants given PCV20; most events were mild or moderate. Serious adverse events occurred in two (1% [0-5]) of 255 participants given low-dose VAX-31, three (1% [0-3]) of 254 participants given mid-dose VAX-31, five (2% [1-5]) of 253 participants given high-dose VAX-31, and three (1% [0-3]) of 253 participants given PCV20; none were considered related to study vaccine, and no deaths occurred. The VAX-31 mid-dose and high-dose groups met or exceeded the precedent OPA non-inferiority criterion for all 20 serotypes shared with PCV20, while the low-dose group met the criterion for 18 of 20 serotypes. All 11 serotypes unique to VAX-31 met the precedent OPA superiority criterion at all doses.
INTERPRETATION:Across all doses, VAX-31 was well tolerated, had a safety profile similar to PCV20, and elicited robust OPA responses across all 31 serotypes. These data further validate the potential for VAX-31 to provide broad-spectrum coverage with high immunogenicity to protect against circulating and historically prevalent serotypes and, if confirmed in phase 3 studies, to have important public health and vaccination policy implications.