Gastroenterologist Stephanie D. Pointer, MD, has seen a noticeable increase in patients presenting with acute gastrointestinal illness this winter. Many have tested positive for norovirus on stool testing.

Like many other physicians, she would love to have a norovirus vaccine at her disposal to protect her patients from illness.

“I have been encouraged to see the growing number of norovirus vaccine candidates currently in development,” said Pointer, co-owner and managing partner of Digestive and Liver Health Specialists, in Nashville, Tennessee.

Norovirus is the leading cause of acute gastroenteritis— characterized by vomiting and diarrhea — across all age groups in the US. According to the CDC, about 2,500 norovirus outbreaks are reported annually, although its prevalence rises during the winter months.

Anywhere from 19 to 21 million people get sick each year, leading to roughly 109,000 hospitalizations and about 465,000 emergency department visits. It’s also responsible for approximately 900 deaths annually, mostly among adults aged 65 years or older.

Outbreaks are particularly challenging to control because transmission can occur with an extremely small infectious dose, said Pointer. “Although many cases are self-limited, norovirus can cause severe disease in vulnerable populations, including older adults, infants under 12 months of age, and immunocompromised individuals,” she added.

Vulnerable patients can develop chronic diarrhea lasting months, sometimes resulting in malnutrition and failure to thrive. “For these reasons, the development of a safe and effective vaccine is essential to reducing the global burden of disease,” said Pointer.

The diversity of vaccine platforms being explored is exciting, especially those designed to address limited efficacy in pediatric populations and the critical need for robust mucosal immunity, she added.

Vaxart’s oral replication deficient adenovirus vector vaccine is one of the more advanced alternative platforms under investigation, said Pointer. The tablet-based vaccine “uses a nonreplicating adenovirus vector to deliver the norovirus VP1 [viral protein] directly to the small intestine, with the goal of stimulating mucosal immune responses at the primary site of infection,” she summarized.

Despite these promising developments, vaccine candidates face some challenges with respect to their efficacy in certain populations, as well as potential hurdles on the policy side.

Virus Presents as Multiple Mutations

The virus itself is a difficult infection to pin down and control, according to infectious disease specialists.

Norovirus is a hearty specimen. It can survive on surfaces, making transmission easy through minimal contact. It takes only a small dose to make people sick, said William Schaffner, MD, a professor of infectious diseases at the Vanderbilt University Medical Center, Nashville, Tennessee.

Although vaccine development is underway, it has been delayed due to the difficulty in growing the virus in laboratories, said Schaffner.

Norovirus exhibits substantial genetic diversity and ongoing evolution. “Its diversity is driven by frequent mutations and recombination events that promote antigenic variation, allowing the virus to partially evade preexisting population immunity,” said Stephen Goldberg, MD, chief medical officer of HealthTrackRx, which specializes in outpatient infectious disease diagnostics.

Noroviruses are classified into at least 10 genogroups (GI-GX), with more than 48 recognized genotypes. Of these, genogroups GI and GII are responsible for the vast majority of human disease.

Within GII, the GII.4 lineage has historically been associated with most large outbreaks, severe cases, and hospitalizations in the US and globally, Goldberg noted. He is a family medicine physician who also practices urgent care and primary care at UofL Health, affiliated with the University of Louisville School of Medicine in Louisville, Kentucky.

What developers of a vaccine would like to do is provide one that protects against the whole array of these different genotypes, so they wouldn’t have to keep changing the vaccine, said Schaffner.

Second Generation Oral Vaccine Boosts Immunity

Several norovirus vaccine candidates are in various stages of clinical development. Vaxart’s oral tablet vaccine candidate has generated encouraging early-phase data, Goldberg noted.

In a phase 2b randomized, placebo-controlled human norovirus challenge trial, a first generation iteration of oral GI.1 (VXA-G1.1-NN) reduced acute gastroenteritis by 30% relative to participants who took the placebo, and also reduced viral shedding. The vaccine triggered strong antibody responses in the blood and at mucosal sites such as the nose, saliva, and stool.

“We saw a strong mucosal immunity, particularly fecal IgA [immunoglobulin A] as well as serum functional antibodies. The phase 2b study demonstrated those were really the most important immune responses elicited by our vaccine that protected individuals from a norovirus challenge,” said Becca Flitter, PhD, one of the lead authors of the phase 2b trial and director of immunology for Vaxart.

The company has since developed a second-generation vaccine, which improved antigen expression and ease of manufacturing. In an ongoing follow-up trial that compared the first- and second-generation vaccines, the latter showed significant improvements, with a 141% increase in serum functional responses and a 25-fold increase in fecal IgA responses compared with the first generation, said Flitter.

Michael Bass, MD, a gastroenterologist and hepatologist and founding director of Oshi Health, is intrigued about the oral platform — specifically its ability to target immunity right where the virus enters. “That’s a meaningful advantage over an injectable approach that mainly drives serum antibodies and may not generate the same local intestinal defense,” he said.

In other developments, Moderna is in the second phase of trialing its investigational messenger RNA (mRNA)-based norovirus vaccine candidate, mRNA-1403, to evaluate safety, immunogenicity, and potential efficacy in preventing symptomatic norovirus gastroenteritis. The mRNA platform enables relatively rapid redesign if circulating strains shift and supports multivalent formulations that target more than one genotype — an important consideration given norovirus genetic diversity, Goldberg noted.

Meanwhile, HilleVax has advanced a virus-like particle (VLP)-based vaccine candidate, HIL-214. This approach uses recombinant VP1 capsid proteins that self-assemble into noninfectious VLPs. Similar VLP technology is used in licensed vaccines such as those for hepatitis B and human papillomavirus. Because VLPs structurally resemble the native virus but contain no genetic material, they can stimulate robust immune responses without the risk for replication, Goldberg explained.

The development of vaccines is not a straight line, so you can’t always anticipate how things will work out, noted Schaffner. “It’s wonderful that there are several different approaches that are currently underway. One or perhaps more of them will eventually provide an effective vaccine.”

Moderna and HilleVax did not provide comments by press time.

Protection, Efficacy Matters

For physicians, two key questions stand out. First, how effective is the vaccine — how much does it reduce risk? And second, how long does protection last? Will it work for 2, 5, or even 10 years? The longer the protection, the more appealing the vaccine becomes. If frequent boosters are required, that could affect acceptance, said Schaffner.

Early human challenge studies suggest that immunity following norovirus infection — and potentially vaccination — may be relatively short-lived, with protection against homologous strains measured in months to a few years. However, more recent modeling analyses of population-level data estimate that protective immunity after natural infection may persist longer, potentially averaging 4-8 years, though this protection may be incomplete and strain-specific, Goldberg noted.

“Any vaccine will face the challenge of substantial genetic and antigenic diversity,” he said. “Because norovirus evolves over time — particularly within dominant lineages such as GII.4 — vaccine formulations may need periodic updating, similar in concept to influenza vaccines, although the optimal strategy remains under study.”

Most individuals experience multiple norovirus infections over their lifetime. These repeated exposures create complex and heterogeneous patterns of preexisting immunity across populations, which could influence vaccine responsiveness and overall effectiveness in ways that are still being defined, Goldberg added.

Flitter anticipates that Vaxart will be distributed annually. “We will look at continuously monitoring current epidemiology and viral evolution patterns to make sure our vaccine provides immunity to cover the most important circulating norovirus genotypes” such as the GI.1, GII.4, and GII.17 strains, she said.

Duration of protection and extent of efficacy are other important factors. “If you reduce the risk by 50%, people are not going to be as enthusiastic as if the result were 85%,” said Schaffner.

Everyone will be looking very carefully at the populations of these phase 3 studies, Schaffner continued. “Are they really being done in high-risk patients? Are they going to study this vaccine in nursing home patients or are they going to do it only in healthy adults who live in the community?” he said.

For meaningful physician adoption, a norovirus vaccine would need to demonstrate at least a 50% reduction in infection rates, although higher efficacy would be ideal, said Pointer.

Ease of administration and broad accessibility are also critical. “While most vaccines are delivered via injection and this is both familiar and expected in clinical practice, an oral vaccine could be particularly appealing to patients and may enhance uptake, especially if it offers comparable efficacy,” she said.

Vaxart’s pill is shelf-stable and can be stored at room temperature — features that could significantly expand access by enabling self-administration, said Flitter. Initially, the vaccine would likely be administered in traditional healthcare settings, such as primary care clinics or pharmacies, she said. When patients are offered a vaccine in these settings, the option of taking an oral dose rather than receiving an injection may make vaccination more appealing to many individuals, said Flitter.

A long-term goal is to allow the vaccine to be delivered directly to individuals’ homes, similar to receiving a prescription by mail from a pharmacy, she added.

Another potential global benefit: “You can send a lot of pills easily in the mail to underdeveloped areas, whereas needles and cold chain make it really difficult to get the vaccine to those areas where norovirus really can be a problem,” she said.

Vaccine Priorities May Differ Among Physicians

Pointer believes that most doctors would strongly welcome the availability of a norovirus vaccine, given the virus’s ability to cause both endemic disease and widespread outbreaks.

“As gastroenterologists, we routinely manage patients with acute and chronic diarrheal illnesses and reducing the incidence of norovirus infection would meaningfully decrease morbidity across vulnerable populations,” she said.

The continued development of safe and effective vaccines represents one of the most powerful tools to lessen disease burden, protect vulnerable populations, and strengthen global health, Pointer emphasized.

In immunocompromised patients — transplant recipients, people on biologics, patients getting chemotherapy — norovirus can become chronic and genuinely dangerous, agreed Bass, who sees these cases in his practice.

“This is a massive unmet need. Norovirus causes roughly 685 million infections a year globally, and there’s still no approved vaccine,” he said.

Priorities may vary in the medical community, however, depending on the specialty and populations they care for.

From a public health perspective, norovirus is clearly significant. Outbreaks continue to occur in settings where people live close together, particularly nursing homes. “I work closely with my state health department, and every year they deal with norovirus outbreaks in these facilities — outbreaks that can be life-threatening for very fragile individuals,” said Schaffner.

Pediatricians, who saw the immediate benefits of a rotavirus vaccine, are likely to be very receptive to a norovirus vaccine. Internists, who see infrequent cases of norovirus, may need convincing of the vaccine’s importance. “Norovirus tends to appear as sudden outbreaks rather than a steady, ongoing problem,” said Schaffner.

From an individual clinician’s perspective, there will be need to education — much as there was with Respiratory Syncytial Virus (RSV) vaccines. “Those of us with a public health lens already recognize how important this is, but clinicians who primarily treat older adults will need more convincing,” he said.

More Work Ahead in Trialing Vaccines

Norovirus vaccine development continues to face several scientific and regulatory challenges. Vaxart’s oral tablet platform offers potential practical advantages, including needle-free administration, ease of distribution, and the possibility of self-administration — factors that could improve uptake across age groups, including pediatric and older adult populations, Goldberg noted.

“However, significant hurdles remain,” he added. “These include achieving broad, cross-genotype protection in the setting of substantial viral diversity, as well as defining reliable immunologic correlates of protection. At present, there is no universally accepted immune marker that definitively predicts protection against norovirus disease.”

Fecal IgA and functional blocking antibodies need to hold up in field trials with natural exposure, not just controlled inoculation with a single strain, agreed Bass.

But the trajectory is encouraging, he added. An oral pill vaccine with no cold chain requirement that generates mucosal immunity against a gut pathogen with no current vaccine is a compelling story if the efficacy data holds, Bass said.

Flitter is hoping that Vaxart’s strong safety profile record will help move the platform along, so it can be licensed and provided to patients. “We hope to first roll out the vaccine to older adults and to populations in high-risk settings like the military,” she said. In the meantime, a study Flitter and colleagues conducted in South Africa demonstrated how the bivalent first generation oral vaccine induced breast milk IgA in postpartum mothers, which was transferred to infants.

“We do have a little way to go,” with the Vaxart candidate, she acknowledged. The next step is to seek partners for larger trials to move the second-generation bivalent vaccine into phase 2 and 3 studies, she said.

For Moderna’s investigational norovirus vaccine program, large-scale clinical development has included both enrollment and safety considerations typical of late-stage vaccine trials. The FDA placed a temporary clinical hold on the phase 3 study following a reported case of Guillain-Barré syndrome to allow additional safety review. Such holds are precautionary and are intended to assess potential causality before a trial proceeds, said Goldberg.

Medscape Medical News reached out to FDA, but federal law restricts the agency from discussing pending biologics license applications.

Because norovirus incidence fluctuates by season and geography, trial sites have also been adjusted to regions with higher expected viral circulation to ensure adequate case accrual for efficacy analysis, Goldberg noted. Conducting field efficacy trials for pathogens with unpredictable seasonal activity can pose logistical challenges.

Similarly, HilleVax’s VLP-based candidate demonstrated protection against moderate-to-severe norovirus gastroenteritis in adult challenge studies. However, demonstrating consistent protection in pediatric populations — particularly infants — has been more difficult, Goldberg continued. Young children have distinct immune responses, higher exposure risk, and limited prior immunity, all of which complicate vaccine performance in this age group, he said.

Recent changes to the Advisory Committee on Immunization Practices (ACIP) could also affect vaccine progression.

Members of the previous ACIP took companies to task for not testing their vaccines in the very populations at higher risk, Schaffner noted. “But we now have a new ACIP, and they have a very different view of vaccines. They have not yet been presented with a new vaccine for any population. And it remains to be seen how receptive they are to making recommendations for new vaccines.”

Concerns about insurance coverage and reimbursement are always prevailing obstacles to implementing a future norovirus vaccine, said Goldberg.

Economic modeling studies suggest that norovirus vaccination could be cost-effective — and in some scenarios potentially cost-saving — particularly when targeted to higher-burden groups such as young children and older adults he said. However, these projections are highly sensitive to assumptions about vaccine efficacy, duration of protection, genotype coverage, vaccine price, and disease incidence. “Small changes in those inputs can materially shift the cost-effectiveness threshold,” Goldberg said.

Reimbursement and coverage considerations will likely influence adoption of any future norovirus vaccine, Goldberg noted. As with other adult and pediatric vaccines, coverage decisions would depend on recommendations from ACIP, demonstrated clinical benefit, population burden of disease, and overall budget impact assessments by public and private payers, he added.

That said, medical societies and other organizations are promoting their own vaccine recommendations to balance or counterbalance the recommendations that are coming from this newly constituted ACIP, Schaffner said.

Flitter is immunology director and shareholder of Vaxart Inc. Goldberg is chief medical officer at HealthTrackRx. Bass is the founding medical director at Oshi Health and global medical director at Viome Diagnostics. Schaffner and Pointer had no disclosures.

Jennifer Lubell is a freelance medical writer in the Metropolitan Washington Area.