The development of norovirus vaccines has seen promising advancements with early-phase data from Moderna's mRNA vaccine candidate and Vaxart's oral tablet vaccine, presented at the IDWeek annual meeting. These developments offer hope for combating the highly contagious virus that causes widespread gastroenteritis.
Moderna's mRNA Vaccine Shows Promise
Moderna's investigational norovirus mRNA vaccine, mRNA-1403, has demonstrated the ability to safely elicit strong antibody responses in adults against globally prevalent norovirus genotypes. The trivalent vaccine leverages the same mRNA technology used in Moderna's COVID-19 and RSV vaccines. According to Dr. Till Schoofs of Moderna, a multivalent mRNA vaccine could effectively target the most prevalent genotypes and be updated to address shifts in genotype prevalence.
In a phase I/II clinical trial, a single injection of mRNA-1403 stimulated robust histo-blood group antigen-blocking antibodies and serum virus-like particle antibodies by day 29 against three virus genotypes in both younger and older adults across all dose levels, compared to placebo. The vaccine contains three mRNAs encoding for the major capsid protein 1 (VP1) of norovirus genotypes GII.4, GI.3, and GII.3.
The vaccine was well-tolerated across all tested dose levels in younger adults (up to age 59) and older adults (ages 60-80). Adverse reactions were primarily grade 1/2 in severity, with few grade 3 and no grade 4 reactions. Systemic reactions occurring more frequently in the vaccine group compared to placebo included headache, fatigue, and nausea. No serious adverse events or withdrawals occurred during the 8-month phase I follow-up and the 1-month phase II follow-up.
The phase I trial enrolled 335 healthy younger (up to 49 years) and older (ages 60-80) adults, testing four vaccine doses against placebo. Most participants received two intramuscular injections one month apart. The phase II trial involved 616 participants, examining three different dose levels in younger (up to 59 years) and older (ages 60-80) adults, who received a single intramuscular injection. Notably, 40% of trial participants across both phases were older adults.
A phase III trial has been initiated to assess the efficacy of a single dose of mRNA-1403 in preventing moderate to severe norovirus acute gastroenteritis. This trial aims to enroll approximately 20,000 adults worldwide.
Oral Tablet Vaccine Reduces Norovirus Infection
Vaxart's novel oral vaccine, VXA-G1.1-NN, was associated with a 29% relative reduction in norovirus infection compared to placebo (P = 0.003) in a phase II trial. While it did not meet its primary endpoint of preventing illness (21% relative reduction, P = 0.149), exploratory analyses showed promise. The vaccine is designed as a stable, oral, enteric-coated tablet that dissolves in the small intestine.
According to Dr. Sean Tucker of Vaxart, the vaccine utilizes a double-stranded RNA, non-replicating vector with a molecular adjuvant to create an immune response against the antigen. This technology can be reused because it does not create anti-vector immunity like injected vectors.
Post-hoc analysis revealed that vaccinated participants had twice the odds of having no acute gastroenteritis or a positive quantitative polymerase chain reaction (PCR) test for norovirus, compared to placebo (34% vs 15%; OR 2.3, P = 0.008).
The study enrolled 141 healthy adults aged 18 to 49, randomized to receive the vaccine candidate (n=76) or placebo (n=65). Participants were then given a challenge dose of norovirus 29 days post-vaccination. Norovirus infection and illness rates were measured between days 33 and 36, along with immune parameters to determine predictors of protection.
Vaccination resulted in a 35% relative reduction in the incidence of emesis and significant reductions in viral shedding in vomitus and stool post-challenge. Immunogenicity endpoints showed increased norovirus antibodies, including fecal IgA antibodies, 28 days after vaccination. Machine learning analysis suggested that functional fecal IgA is critical for protection against norovirus.
The Need for Norovirus Vaccines
Norovirus is the leading cause of acute gastroenteritis worldwide, responsible for an estimated 685 million cases and 200,000 deaths annually, according to Dr. Schoofs. In the U.S., young children and older adults face the highest risk of severe outcomes from the disease. The development of an effective norovirus vaccine has been challenging due to the virus's high genetic diversity, with at least 48 genotypes, and limited cross-genotype protection.
