Are Norovirus Vaccines on the Horizon?

The hope that an effective norovirus vaccine may one day become reality was bolstered by early-phase data on two vaccine candidates presented during the IDWeek annual meeting.

The first, an investigational norovirus mRNA vaccine from Moderna (mRNA-1403), safely elicited strong antibody responses in adults against globally prevalent norovirus genotypes, according to interim results of a phase I/II clinical trial. The trivalent vaccine uses the same technology as the company’s COVID and RSV shots.

Separately, an oral tablet was found to be immunogenic, safe, and reduced both viral shedding and norovirus infection in a small phase II trial. Although the oral vaccine was not proven to reduce illness, exploratory analyses were promising.

The development of an effective, safe norovirus vaccine has been elusive, primarily because of the virus’ high genetic diversity and limited cross-genotype protection. One of the problems with developing an effective norovirus vaccine is that the virus has at least 48 genotypes.

“A multivalent mRNA vaccine could cover the most prevalent genotypes and would be amenable to composition updates to address changes in genotype prevalence,” explained Till Schoofs, MD, of Moderna in Cambridge, Massachusetts.

Norovirus is the leading cause of acute gastroenteritis globally with an estimated 685 million cases and 200,000 deaths annually, Schoofs said. In the U.S., the risk of severe outcomes from the disease is highest among young children and older adults.

mRNA Shot

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 younger and older adults across all dose levels, when compared with placebo, reported Schoofs.

He told IDWeek attendees that the vaccine contains three mRNAs that encode for the major capsid protein 1 (VP1) of three globally prevalent norovirus genotypes — GII.4, GI.3, and GII.3.

The shot was well tolerated across dose levels tested in both younger adults (up to age 59) and older adults (ages 60-80) and throughout phase I and phase II follow-up periods. Adverse reactions in both age groups were mostly grade 1/2 in severity, with few grade 3 and no grade 4 reactions.

Systemic reactions that occurred more frequently in the vaccine group when compared with the placebo group included headache, fatigue, and nausea. There were no serious adverse events or adverse events that led to study withdrawal throughout 8 months of follow-up during the phase I portion of the study and through 1 month of follow-up in phase II.

The phase I part of the trial enrolled 335 healthy younger (up to 49 years) and older (ages 60-80) adults. Investigators tested four vaccines against placebo. Most participants received two intramuscular injections, 1 month apart.

The phase II part of the trial, enrolling 616 participants, looked at three different dose levels in younger (up to 59 years) and older (ages 60-80) adults; participants here received only a single intramuscular vaccine injection.

Across both trial phases, 40% of trial participants were older adults, a population frequently excluded from clinical trials.

Based on results from this trial, a phase III trial has been initiated to evaluate the efficacy of a single dose of the mRNA-1403 vaccine to prevent moderate to severe norovirus acute gastroenteritis, Schoofs said. The trial aims to enroll about 20,000 adults worldwide.

How About a Pill?

Meanwhile, the novel oral vaccine VXA-G1.1-NN was associated with a 29% relative reduction in norovirus infection compared with placebo (P=0.003). However, it fell short of meeting its primary endpoint for preventing illness, with a non-significant 21% relative reduction (P=0.149), Sean Tucker, PhD, of developer Vaxart in South San Francisco, California, told attendees.

The vaccine is a stable, oral, enteric-coated tablet that dissolves in the small intestine.

“The key aspect of this technology is that we have a double-stranded RNA, non-replicating vector with a molecular adjuvant that creates an immune response against the antigen of choice, not the vector itself,” Tucker explained. He noted that because the vaccine doesn’t create anti-vector immunity like injected vectors, the technology can be reused.

In a post-hoc analysis, researchers found that vaccinated participants had twice the odds of having no acute gastroenteritis or a positive quantitative polymerase chain reaction (PCR) test for norovirus, when compared with placebo (34% vs 15%; OR 2.3, P=0.008).

The study enrolled 141 healthy adults ages 18 to 49. Participants were randomized to receive the vaccine candidate (n=76) or placebo (n=65). All participants were then given a large challenge dose of norovirus at day 29 after vaccination. Investigators measured norovirus infection and illness rates in the two groups between days 33 and 36. They also measured immune parameters to determine which ones were predictive of protection.

Post-challenge, vaccination resulted in a 35% relative reduction in the incidence of emesis as well as large reductions in viral shedding in vomitus and stool, Tucker said.

For immunogenicity endpoints, norovirus antibodies increased at 28 days after vaccination, including fecal IgA antibodies. In a machine learning analysis of the data, Tucker and colleagues determined that “functional fecal IgA is probably critical for protection against norovirus.”

Tucker’s presentation did not include safety or tolerability outcomes.