As Covid-19 exited the spotlight, it made way for other seasonal viruses like norovirus. Despite limited monitoring for this virus, cases have still been surging compared to previous years.

The U.K. noted a 66 percent increase in cases compared to the average caseload at this time of year. 

The U.S. has also recorded a similar trend with 17 percent of norovirus tests in the country coming back positive, higher than last season’s average. 

Meanwhile, Korea has also experienced an uptick in cases averaging 166 cases per week approximately in December which rose to a weekly average of 248 cases in January and February.

Norovirus was first reported in Korea in 2003. It usually spreads through touching surfaces or ingesting food and water contaminated with fecal matter. It causes inflammation of the stomach and intestines in humans, with vomiting and diarrhea symptoms which last approximately one to three days. However, in rare cases, it can be more harmful to those with weakened immune systems like older adults and children.

Most viruses do not reproduce at low temperatures, but norovirus is rather active at low temperatures and consequently, is the leading cause of food poisoning in winter from November to April. 

Outbreaks are particularly associated with oysters, commonly eaten raw, along with other shellfish such as clams, mussels, and scallops.

Why is there a rotavirus vaccine but no norovirus vaccine?

Still, anyone who has had the virus can attest to the unpleasant nature of the virus. Rotavirus was once the most common cause of severe food-borne illness but since rotavirus vaccines emerged, norovirus has now taken its place as the most common cause of acute gastroenteritis. Since 2016, the WHO has recognized the development of a norovirus vaccine as a high priority. Then, why is there still no vaccine?

Wyeth’s Rotashield was the first developed rotavirus vaccine in 1998 but was withdrawn one year later as it was linked with causing intussusception, a type of bowel obstruction. This spurred the development of other rotavirus vaccines and there are currently, four WHO-prequalified vaccines for rotavirus from GSK, Merck, Bharat, and the Serum Institute. So why was rotavirus prioritized?

According to the World Health Organization, five rotavirus strains cause the bulk of human rotavirus disease. Additionally, adults who've had rotavirus as children typically develop lifelong immunity to the virus. However, an individual can get infected repeatedly with norovirus. Therefore, it is harder for the body to build up immunity against norovirus as it is much more prone to mutating.

On top of this, the International Vaccine Institute’s (IVI) Program Director of New Initiatives, Dr. Jean Louis Excler said the development of a broadly effective norovirus vaccine remains difficult, owing to the wide genetic and antigenic diversity of noroviruses with multiple co-circulated variants of various genotypes. 

“The absence of a robust cell culture system, an efficient animal model, and reliable immune markers of norovirus protection for vaccine evaluation further hinders the developmental process,” he said.

Further elaborating on this, CHA Vaccine Institute CEO and Director Yum Jung-sun explained that building an appropriate animal model that can show the immunogenicity of pathogens and induce an immune response similar to that of the human body is essential.

“Since the 1980s, rotavirus can be cultured through monkey kidney cells regardless of stool or serum. In addition, there are various animal models such as mice, rabbits, and rhesus monkeys to evaluate the protective effect against viral infection after vaccination,” said Yum. “As norovirus has no methods for animal models and virus culture, norovirus vaccines and therapeutics are currently still in the development stage.”

Issues with norovirus surveillance

Moreover, the global disease burden is difficult to assess which poses problems in justifying the need for a vaccine. In Korea, data is collected from 208 hospitals, while in the U.S., only 14 states track the virus. Still, the CDC estimates that there are about 685 million annual cases worldwide but the biggest norovirus disease burden occurs in low- and middle-income settings.

It claims over 200,000 lives per annum with $4.2 billion in direct health system costs and $60.3 billion in social economic loss, according to Dr. Excler.

Although overall mortality risks of norovirus are generally much lower in high-income settings, high disease incidence appears universal. A recent study showed that in high- and middle-income countries with successful rotavirus vaccination programs, norovirus was the most common cause of pediatric gastroenteritis. Accordingly, vaccination through children seems like the most effective way to stop virus transmission.

At the same time, real-time quantitative reverse-transcription PCR (RT-qPCR) remains the most sensitive diagnostic for noroviruses, but these tests are often limited to middle- and high-income countries.

What is needed to develop a norovirus vaccine?

Five vaccines have reached clinical development and Takeda’s virus-like particle (VLP) norovirus vaccine is currently the most advanced after completing phase 2b trials. 

According to Fierce Biotech, a 2018 study of 4,712 patients including elderly, adults, and children, failed to demonstrate sufficient cases of the homotypic norovirus genotype and thus could not fully evaluate the primary endpoint. 

However, when the data were analyzed for other norovirus genotypes, the vaccine showed significant efficacy against any moderate to severe norovirus acute gastroenteritis, encouraging researchers to continue evaluating the candidate through a long-term immunogenicity study. 

In July 2021, Takeda spinout, Hillevax, took over the development of the investigational vaccine, HIL-214.

As of December 2022, Hillevax confirmed positive immunogenicity results in 5-month-old infants. The company is scheduled to announce the full NEST-IN1 topline safety and efficacy data by the second half of 2023.

Dr. Excler also noted some other preclinical candidates utilizing platforms like the recombinant adenovirus, plant-based virus-like particles, and combinations with enterovirus 71 (EV71).

In Korea, there have not been many companies stepping forward to make a norovirus vaccine as it is not very profitable, said a domestic vaccine manufacturer.

CHA Vaccine Institute is developing a norovirus vaccine but it is in the preclinical stage.

“Norovirus mutates widely but we are currently conducting research to develop a vaccine that can respond to future variants,” said CEO Yum.

Yum said strengthening national response capacity to national catastrophic outbreaks caused by the emergence of new variants of the virus has become an important policy issue after Covid-19. 

However, developing a vaccine against new virus variants is very time-consuming and expensive, making it a heavy burden for private companies to carry out independently, she said.

She added the development of new vaccines for viral infectious diseases for which there is no existing vaccine must not only prove its effectiveness but also safety for various age groups.

Accordingly, Yum called for direct and indirect support using public infrastructure for establishing animal infection models to verify efficacy and greater national R&D support.