VAX-31 Advances to Pivotal Phase 3 Trial: Vaxcyte Targets Broader Pneumococcal Coverage in Adults

The race to develop next-generation pneumococcal vaccines just entered a critical phase. Vaxcyte announced that enrollment has commenced in the OPUS trial, a Phase 3 noninferiority study evaluating VAX-31—a 31-valent pneumococcal conjugate vaccine (PCV)—for preventing invasive pneumococcal disease (IPD) and pneumonia in adults. This milestone marks the transition from early-stage validation to large-scale clinical evaluation, with approximately 4,000 participants expected to be enrolled across roughly 50 U.S. sites.

Why VAX-31 Matters: Closing the Coverage Gap

Current standard-of-care vaccines like Prevnar 20 (PCV20) and Capvaxive (PCV21) have significantly improved adult protection against pneumococcal disease. However, they don’t capture the full spectrum of disease-causing serotypes circulating today. VAX-31 is engineered to address this limitation directly.

The vaccine is designed to provide coverage for approximately 95% of invasive pneumococcal disease and roughly 88% of pneumococcal pneumonia in U.S. adults aged 50 and older. More impressively, this translates to an incremental gain of 14–34% broader IPD coverage and 19–31% broader pneumonia coverage compared to existing vaccines. The approach maintains pressure on both currently prevalent serotypes and historically established strains that remain controlled through ongoing vaccination efforts.

The OPUS Trial: Head-to-Head Comparisons

Unlike previous studies, the OPUS trial adopts a rigorous design that directly compares VAX-31 against both PCV21 and PCV20 in adults aged 50+, with a separate cohort of adults aged 18–49. Participants will be randomized to receive a single dose and monitored for six months to assess safety, tolerability, and immune responses.

The trial’s primary immunogenicity objectives focus on two key criteria:

Noninferiority Demonstration: For the 28 serotypes shared between VAX-31 and existing comparators, the vaccine must show that the lower bound of the 95% confidence interval for opsonophagocytic activity (OPA) geometric mean ratio exceeds 0.667.

Superiority Demonstration: For the three serotypes unique to VAX-31 (serotypes 2, 7C, and 20C) plus serotype 20B, the vaccine must achieve an OPA geometric mean ratio lower bound exceeding 2.0—a substantially higher threshold reflecting the potential for enhanced protection.

Strong Foundation: Phase 1/2 Data

Vaxcyte isn’t entering this Phase 3 trial blind. The company’s earlier Phase 1/2 adult study delivered encouraging results. The VAX-31 High Dose formulation demonstrated robust OPA immune responses across all 31 serotypes, with all 11 incremental serotypes unique to VAX-31 meeting superiority criteria. When compared to PCV20, VAX-31 generated greater average OPA responses for 18 of 20 common serotypes, with seven achieving statistically significantly higher immune responses. The safety profile remained comparable to PCV20, supporting advancement to this larger trial.

Timeline to Licensure

Vaxcyte has outlined an ambitious development timeline aligned with regulatory expectations. Topline safety, tolerability, and immunogenicity data from the OPUS trial are anticipated in the fourth quarter of 2026. Additional Phase 3 studies will be initiated in 2026 with readouts expected in 2027. These results are intended to form the cornerstone of a Biologics License Application (BLA) submission, keeping the company on track for potential U.S. market launch.

Parallel to the adult program, VAX-31 is also advancing in pediatric indications. The Phase 2 infant dose-finding study is expected to yield topline data—including results from both the primary immunization series and booster dose—by mid-2027.

The Broader Context: Why This Matters

Pneumococcal disease remains a significant public health threat. In the United States alone, pneumococcal pneumonia drives over 150,000 hospitalizations annually. The causative bacterium, Streptococcus pneumoniae, is listed by the CDC as a “serious threat” due to antibiotic resistance and ranks among the World Health Organization’s top priority pathogens for urgent intervention. Among young children globally, Streptococcus pneumoniae is the leading cause of vaccine-preventable deaths.

The emergence of serotypes not covered by current vaccines underscores the clinical need for broader-spectrum protection. VAX-31’s design—leveraging Vaxcyte’s proprietary carrier-sparing, site-specific conjugation technology—aims to deliver exactly that: a vaccine that maintains immune pressure on both circulating and established disease-causing strains while optimizing overall immunological response.

What’s at Stake

If OPUS delivers positive results, VAX-31 could reshape the adult pneumococcal vaccine landscape by establishing a new standard for breadth of coverage and durability of protection. The trial results will be scrutinized not only for immunogenicity metrics but also for safety signals and tolerability—factors that directly influence clinical adoption in a competitive vaccine market.

The FDA’s May 2025 Breakthrough Therapy designation for VAX-31—expanded to include pneumonia prevention in addition to IPD prevention—signals regulatory confidence in the program’s potential. This designates VAX-31 development as a priority pathway, potentially streamlining the review process if pivotal trial data support approval.

For Vaxcyte, the OPUS trial represents a defining moment. Success could validate the company’s carrier-sparing platform technology and position VAX-31 as a best-in-class vaccine candidate against pneumococcal disease in both adult and pediatric populations.