31-Valent Pneumococcal Vaccine Meets Phase 3 Endpoints as VAX-31 Takes a Key Step Toward Broader Coverage

Expanding the protection offered by a pneumococcal vaccine requires more than increasing the number of serotypes covered; it also requires confirming whether immune responses can be maintained for each one. On October 5, Vaxcyte announced that its 31-valent vaccine candidate, VAX-31, met all prespecified primary endpoints in the Phase 3 OPUS-1 trial in adults, providing pivotal evidence for this vaccine, which has not yet been approved. However, behind the statement that “all endpoints were met,” the primary analysis and the results of comparisons with individual vaccines need to be understood separately.

OPUS-1 enrolled 4,047 participants, with the 20-valent Prevnar 20 and 21-valent Capvaxive serving as comparator vaccines. The trial primarily evaluated immune responses and safety following vaccination. The immune analysis used opsonophagocytic activity (OPA), which measures the ability of antibodies to help immune cells clear bacteria. This type of evidence can support vaccine development, but it does not directly demonstrate a reduction in cases of pneumonia or invasive infection among vaccine recipients.

According to the company’s announcement, adults aged 50 and older met the primary analysis’s noninferiority criteria for all 28 serotypes shared with at least one comparator vaccine. For serotypes covered by all three vaccines, the prespecified design allowed VAX-31 to meet the criteria relative to at least one comparator vaccine. This result therefore cannot be interpreted as showing that every serotype passed the same threshold against both vaccines. VAX-31 also met the primary analysis’s superiority criteria for its three unique serotypes and the cross-reactive serotype 20B.

Differences emerged in individual comparisons: VAX-31 passed the stricter noninferiority threshold for all 20 serotypes shared with Prevnar 20, while 17 of the 19 serotypes shared with Capvaxive passed. For the remaining serotypes, 3 and 12F, the lower bounds of the 95% confidence intervals for the geometric mean ratios of OPA responses exceeded the historically used threshold of 0.5, but did not exceed the stricter threshold of 0.667 used in this trial. The comparison using the less stringent threshold was already a prespecified secondary endpoint; it cannot replace the results of the stricter comparison, nor does it establish that the two serotypes provide no protection.

The immunobridging analysis between age groups also met its criteria: adults aged 18 to 49 met the noninferiority criteria relative to adults aged 50 to 64 in all 32 serotype comparisons. RTTNews’s report on the same day also confirmed the primary endpoint, immunobridging, and safety results. The company said VAX-31’s safety profile was similar to those of both comparator vaccines. However, the results released this time were summary results; assessments of how long immune responses persist and of less common adverse events still require support from the full data.

Next, development will extend to additional vaccination settings. Vaxcyte expects to announce results from OPUS-2 and OPUS-3 in the first half of 2027, examining coadministration with a seasonal influenza vaccine and adults previously vaccinated against pneumococcal disease, respectively. RTTNews also reported that the company plans to submit a U.S. Biologics License Application in the first half of 2028. These results advance the evidence base needed for the application, while the extent to which broader serotype coverage can translate into actual disease prevention remains a question that subsequent work must answer.