Vaxart’s second-generation oral norovirus constructs drove a 25-fold increase in GII.4 fecal IgA and a 10-fold increase in GI.1 after a single high-dose tablet, with 8-fold and 7-fold increases, respectively, at a lower dose. In the same Phase 1 head-to-head study, the first-generation constructs at the high dose achieved 13-fold (GII.4) and 6-fold (GI.1) increases. Previously reported in June, the second-generation constructs also produced higher norovirus blocking antibodies versus first-generation (GI.1 up 141% and GII.4 up 94%). Fecal IgA and blocking antibodies were correlates of protection in Vaxart’s earlier Phase 2b challenge study, where first-generation constructs achieved a 30% relative reduction in infection versus placebo.
The company disclosed the new Phase 1 readout at the International Calicivirus Conference and positioned the data as the basis for moving into a Phase 2b safety and immunogenicity trial, contingent upon securing a partner or other financing. The plan anticipates an End-of-Phase 2 FDA meeting following the Phase 2b readout and the potential to initiate Phase 3 in 2026. The program remains unpartnered, and there is no approved vaccine for norovirus.
Strategically, Vaxart is leaning into a mucosal immunity thesis to differentiate in a category that has struggled to translate systemic antibody responses into robust, consistent field efficacy. The head-to-head, single-study comparison to first-generation constructs is an efficient way to show platform iteration, and the oral tablet format simplifies administration, site workflows, and distribution. If improvements in fecal IgA and blocking antibody levels reliably track with protection, the program could prioritize faster, smaller studies centered on validated immune endpoints rather than large, seasonally constrained efficacy trials.
The tension is that correlation is not approval. Phase 1 was not powered for superiority claims, and regulators have not endorsed fecal IgA as a surrogate endpoint for licensure in norovirus. Challenge models inform mechanisms but can underrepresent exposure heterogeneity, strain diversity, and real-world disease severity endpoints. GII.4 evolution and regional variability complicate antigen selection and durability expectations, and any Phase 3 will face attack-rate volatility and endpoint adjudication issues that have derailed prior efforts in this space.
For sites and CROs, a mucosal-immunity-centric path shifts operational burden to stool collection, processing, and assay standardization, with implications for lab networks and logistics. The oral pill should streamline pharmacy and nursing time, reducing cold-chain needs and potentially widening site participation, enabling broader geographic dispersion. However, if Vaxart pursues a challenge component, capacity at specialized units becomes a gating factor. On the sponsor side, assay qualification and cross-study bridging of IgA and blocking antibody readouts will be critical to maintain regulatory credibility and comparability across cohorts.
Near term, watch for construct selection and dose confirmation for a bivalent regimen, the exact Phase 2b design and readout cadence, and whether the FDA provides early alignment on acceptable intermediate endpoints at the End of Phase 2. Funding remains the primary execution risk; without a partner, the proposed 2025 start and 2026 Phase 3 timeline are likely to slip. The pivotal question is whether Vaxart can convert stronger mucosal signals into reproducible, clinically meaningful protection in heterogeneous, community-acquired disease—preferably with a clear path to an approvable endpoint and a manufacturing plan that scales the tablet format without compromising consistency.
Jon Napitupulu is Director of Media Relations at The Clinical Trial Vanguard. Jon, a computer data scientist, focuses on the latest clinical trial industry news and trends.
