Oral norovirus vaccine candidate successfully tested in human challenge

 Norovirus is a leading cause of epidemic and endemic gastroenteritis worldwide, presenting with symptoms including vomiting, diarrhea, and abdominal pain. Transmission occurs primarily through contaminated food, water, and surfaces, as well as person-to-person contact.

Extensive research efforts are underway, though no vaccines have yet been approved to prevent norovirus infection. Progress in advancing vaccine candidates to late-stage trials has been slowed by the absence of markers that reliably indicate protection against infection without requiring exposure to the pathogen.

Traditional drug trials assess efficacy against existing treatments or a placebo in patients already experiencing a condition. Vaccines are administered to healthy individuals to prevent infection, typically rendering such comparative studies unethical and impractical as it would require intentionally introducing the pathogen.

Rather than waiting for participants to encounter the virus naturally, Vaxart Inc. researchers pursued a controlled human challenge, in which participants are deliberately exposed to a known pathogen under clinical supervision. The approach allows for direct measurement of infection incidence while simultaneously evaluating immune markers that may indicate protection against infection.

In the study, "An oral norovirus vaccine generates mucosal immunity and reduces viral shedding in a phase 2 placebo-controlled challenge study," published in Science Translational Medicine, researchers evaluated the efficacy, immunogenicity, and safety of the VXA-G1.1-NN oral tablet vaccine.

A total of 165 participants meeting inclusion criteria were enrolled in the study. Participants were randomly assigned in a 1:1 ratio to receive either the VXA-G1.1-NN oral tablet vaccine (n = 86) or a placebo (n = 79). Immunogenicity and viral shedding were assessed through nasal lining fluid, saliva, and fecal samples at multiple intervals.

Day 28 testing and immune response analysis

Twenty-eight days after receiving the vaccine, assessments indicated substantial increases in GI.1-specific antibodies, including immunoglobulin A (IgA) and immunoglobulin G (IgG).

IgA is primarily found in mucosal tissues such as the intestines and respiratory tract, where it plays a key role in preventing viral infections at barrier surfaces. IgG, the most abundant antibody in blood circulation, is critical for neutralizing pathogens and providing systemic immune protection.

Serum IgA concentrations in the VXA-G1.1-NN group were 8.76-fold higher and serum IgG concentrations were 5.68-fold higher compared to the placebo group.

Mucosal IgA concentrations were 4.25-fold higher in fecal samples, 4.32-fold higher in nasal lining fluid, and 3.29-fold higher in saliva samples compared to placebo.

The challenge

On the same day as the testing, the 28th after vaccination, brave volunteers took a controlled challenge dose of GI.1 norovirus. Participants were then monitored for the development of norovirus gastroenteritis, defined as persistent vomiting, diarrhea, or abdominal pain.

Post-challenge results

Incidence of norovirus infection was 57.1% among VXA-G1.1-NN recipients and 81.5% among placebo recipients, reflecting a 23.6% absolute reduction and a 30% relative risk reduction in infection incidence.

Gastroenteritis occurred in 44.7% of VXA-G1.1-NN recipients and 56.9% of placebo recipients, reflecting a 12.2% absolute reduction and a 21% relative reduction in gastroenteritis incidence, which did not reach statistical significance.

No serious vaccine-related adverse events occurred among study participants. Reported adverse events were predominantly mild and included malaise, fatigue, and headache, affecting 58.1% of VXA-G1.1-NN recipients and 45.6% of placebo recipients.

Diarrhea was reported in 19.4% of participants, with higher incidence in the VXA-G1.1-NN group (23.3%) than in the placebo group (15.2%). Severe adverse events were not observed in either group.

Significant increases in serum and mucosal antibodies and a reduction in viral shedding position the VXA-G1.1-NN oral vaccine as a promising candidate for norovirus prevention, particularly in high-risk environments where transmission control is critical.

Vaxart Inc.'s controlled human challenge model successfully identified immunological markers predictive of vaccine efficacy, a development that may expedite clinical progress and inform regulatory decision-making. Yet, intentional pathogen exposure involves an ethically complex balance of informed consent, risk mitigation, and potential harm.

Such studies must remain tightly controlled, rigorously regulated, and exceedingly rare given the repeated historical risks of ethical violations in pharmaceutical research.

More information: Becca A. Flitter et al, An oral norovirus vaccine generates mucosal immunity and reduces viral shedding in a phase 2 placebo-controlled challenge study, Science Translational Medicine (2025). DOI: 10.1126/scitranslmed.adh9906

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