Norovirus is the leading cause^[1] of acute gastroenteritis outbreaks worldwide. It’s responsible for roughly one in every five cases^[2] of gastro annually.

Sometimes dubbed the “winter vomiting bug” or the “cruise ship virus”, norovirus – which causes vomiting and diarrhoea^[3] – is highly transmissible. It spreads via contact with an infected person or contaminated surfaces. Food can also be contaminated with norovirus.

While anyone can be infected, groups such as young children, older adults and people who are immunocompromised are more vulnerable^[4] to getting very sick with the virus. Norovirus infections lead to about 220,000 deaths^[5] globally each year.

Norovirus outbreaks also lead to massive economic burdens^[6] and substantial health-care costs.

Although norovirus was first identified more than 50 years ago^[7], there are no approved vaccines or antiviral treatments for this virus. Current treatment is usually limited to rehydration, either by giving fluids orally^[8] or through an intravenous drip^[9].

So if we’ve got vaccines for so many other viruses – including COVID, which emerged only a few years ago – why don’t we have one for norovirus?

An evolving virus

One of the primary barriers to developing effective vaccines lies in the highly dynamic nature of norovirus evolution. Much like influenza viruses, norovirus shows continuous genetic shifts, which result in changes to the surface of the virus particle^[10].

In this way, our immune system can struggle to recognise and respond when we’re exposed to norovirus, even if we’ve had it before.

Compounding this issue, there are at least 49 different norovirus genotypes^[11].

Both genetic diversity and changes in the virus’ surface mean the immune response to norovirus is unusually complex. An infection will typically only give someone immunity to that specific strain and for a short time – usually between six months and two years^[12].

All of this poses challenges for vaccine design. Ideally, potential vaccines must not only induce strong, long-lasting immunity, but also maintain efficacy across the vast genetic diversity of circulating noroviruses.

Recent progress

Progress in norovirus vaccinology^[13] has accelerated over the past couple of decades. While researchers are considering multiple strategies to formulate and deliver vaccines, a technology called VLP-based vaccines is at the forefront.

VLP stands for virus-like particles^[14]. These synthetic particles, which scientists developed using a key component of the norovirus (called the major caspid protein), are almost indistinguishable from the natural structure of the virus.

When given as a vaccine, these particles elicit an immune response resembling that generated by a natural infection with norovirus – but without the debilitating symptoms of gastro.

What’s in the pipeline?

One bivalent VLP vaccine^[15] (“bivalent” meaning it targets two different norovirus genotypes) has progressed through multiple clinical trials. This vaccine showed some protection^[16] against moderate to severe gastroenteritis in healthy adults.

However, its development recently suffered a significant setback. A phase two clinical trial in infants failed to show it effectively protected against moderate or severe acute gastroenteritis^[17]. The efficacy of the vaccine in this trial was only 5%.

In another recent phase two trial, an oral norovirus vaccine^[18] did meet its goals^[19]. Participants who took this pill were 30% less likely to develop norovirus compared to those who received a placebo.

This oral vaccine uses a modified adenovirus^[20] to deliver the norovirus VLP gene sequence to the intestine to stimulate the immune system.

With the success of mRNA vaccines during the COVID pandemic, scientists are also exploring this platform for norovirus.

Messenger ribonucleic acid (mRNA) is a type of genetic material that gives our cells instructions to make proteins^[21] associated with specific viruses. The idea is that if we subsequently encounter the relevant virus, our immune system will be ready to respond.

Moderna, for example, is developing an mRNA vaccine^[22] which primes the body with norovirus VLPs.

The theoretical advantage of mRNA-based vaccines lies in their rapid adaptability. They will potentially allow annual updates to match circulating strains.

Researchers have also developed alternative vaccine approaches using just the norovirus “spikes” located on the virus particle^[23]. These spikes contain crucial structural features, allowing the virus to infect our cells, and should elicit an immune response similar to VLPs. Although still in early development, this is another promising strategy.

Separate to vaccines, my colleagues and I have also discovered a number of natural compounds that could have antiviral properties against norovirus. These include simple lemon juice^[24] and human milk oligosaccharides^[25] (complex sugars found in breast milk).

Although still in the early stages, such “inhibitors” could one day be developed into a pill to prevent norovirus from causing an infection.

Where to from here?

Despite recent developments, we’re still probably at least three years away from any norovirus vaccine hitting the market.

Several key challenges remain before we get to this point. Notably, any successful vaccine must offer broad cross-protection against genetically diverse and rapidly evolving strains. And we’ll need large, long-term studies to determine the durability of protection and whether boosters might be required.

Norovirus is often dismissed as only a mild nuisance, but it can be debilitating – and for the most vulnerable, deadly. Developing a safe and effective norovirus vaccine is one of the most pressing and under-addressed needs in infectious disease prevention.

A licensed norovirus vaccine could drastically reduce workplace and school absenteeism, hospitalisations and deaths. It could also bolster our preparedness against future outbreaks of gastrointestinal pathogens.

References

1. ^{^} the leading cause (www.cdc.gov)
2. ^{^} one in every five cases (journals.plos.org)
3. ^{^} vomiting and diarrhoea (www.cdc.gov)
4. ^{^} more vulnerable (www.cdc.gov)
5. ^{^} 220,000 deaths (journals.plos.org)
6. ^{^} economic burdens (journals.plos.org)
7. ^{^} 50 years ago (journals.asm.org)
8. ^{^} fluids orally (www.health.nsw.gov.au)
9. ^{^} an intravenous drip (www.ncbi.nlm.nih.gov)
10. ^{^} surface of the virus particle (journals.asm.org)
11. ^{^} 49 different norovirus genotypes (www.microbiologyresearch.org)
12. ^{^} six months and two years (wwwnc.cdc.gov)
13. ^{^} norovirus vaccinology (pmc.ncbi.nlm.nih.gov)
14. ^{^} virus-like particles (journals.asm.org)
15. ^{^} bivalent VLP vaccine (academic.oup.com)
16. ^{^} some protection (www.sciencedirect.com)
17. ^{^} against moderate or severe acute gastroenteritis (ir.hillevax.com)
18. ^{^} oral norovirus vaccine (www.science.org)
19. ^{^} meet its goals (investors.vaxart.com)
20. ^{^} a modified adenovirus (insight.jci.org)
21. ^{^} instructions to make proteins (cepi.net)
22. ^{^} mRNA vaccine (www.nature.com)
23. ^{^} located on the virus particle (journals.asm.org)
24. ^{^} lemon juice (www.sciencedirect.com)
25. ^{^} human milk oligosaccharides (journals.asm.org)