Disclosures: Burke, Giersing, Hall and Shane report no relevant financial disclosures. O’Ryan reports receiving funding for epidemiological studies and consultancy on diarrheal disease from Takeda vaccines.

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Norovirus vaccine development accelerates after success against rotavirus

Norovirus has become the leading cause of medically attended acute gastroenteritis in countries with national rotavirus vaccination programs, including the United States, and is a common cause of outbreaks worldwide. There is still no licensed vaccine against norovirus, but there are promising candidates in the pipeline, experts said, and researchers are working to define which genotypes and populations to target.

“Norovirus is estimated to cause one in every five cases of gastroenteritis. The latest — and really the first — WHO estimate was 685 million cases each year,” Aron J. Hall, DVM, MSPH, head of the norovirus epidemiology team in the CDC’s Division of Viral Diseases, told Infectious Disease News. “That burden is disproportionately affecting children under the age of 5 and people in developing countries. In terms of economic costs, [the burden is] $60 billion worldwide due to health care costs and lost productivity. So, it’s quite a tremendous impact in terms of morbidity, mortality and costs.”

Infectious Disease News spoke with Hall and other experts about the burden of norovirus, the vaccine candidates making their way through the pipeline and what can be done to prevent norovirus while vaccine trials are pending.

‘A democratic virus’

Of the nearly 700 million cases of norovirus that occur each year, approximately 200 million — including 50,000 deaths — are in children aged younger than 5 years, who live mostly in developing countries, according to the CDC. However, norovirus is a significant problem in both low- and high-income countries. Hall said it does not discriminate.

Rachel M. Burke, PhD, MPH, an epidemiologist in the CDC’s Viral Gastroenteritis Branch, said norovirus vaccines should target individuals in health care settings. Source: CDC (Credit: Natalie Duggan).

“It affects everyone across the age spectrum and different socioeconomic levels globally. We think of it as a democratic virus — affecting both developing and developed countries,” he said.

According to Hall, because young children are immunologically naive, they are more susceptible to the infection. Additionally, he said kids aged younger than 5 years have more contact with people, specifically other kids who likely have less effective hand hygiene habits than adults, giving them a higher chance of exposure.

Looking strictly at the burden in the U.S., norovirus causes between 19 million and 21 million cases of acute gastroenteritis and contributes to 56,000 to 71,000 hospitalizations and 570 to 800 deaths annually, according to the CDC. As with the worldwide burden, these cases and deaths occur mostly among young children and the elderly.

Additionally, norovirus is the leading cause of foodborne illness in the U.S., causing 58% of foodborne illnesses with known causes and costing about $2 billion in lost productivity and health care expenses.

The virus is highly contagious and typically spread through direct contact with an infected person, consuming contaminated food or water or after touching contaminated surfaces. Outbreaks are often reported in restaurants, schools and cruise ships but are most common in health care facilities, according to the CDC.

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In addition to the usual ways norovirus is spread, a recent study published in Clinical Infectious Diseases established vomiting as the main source of airborne norovirus outbreaks in health care facilities. Malin Alsved, MSc, a PhD student in the division of ergonomics and aerosol technology at Lund University in Sweden, and colleagues investigated associations between gastroenteritis symptoms and the presence of airborne norovirus, as well as the size of norovirus-carrying particles, an important marker of how long they can remain in the air and how easily they are inhaled.

According to the study, 24% of air samples from 10 of 26 patients tested positive for norovirus RNA, all of them collected during outbreaks, or before a succeeding outbreak. The researchers reported a strong association between airborne norovirus RNA and a shorter time period since the last vomiting episode (OR = 8.1; P = 0.04 within 3 hours since last episode), with the concentration of airborne norovirus ranging from 5 to 215 copies/m3, according to the study.

Vaccine development

Rotavirus has historically been the leading cause of pediatric diarrhea worldwide, which is why it was identified early on as a key target for vaccine development, Hall said. Following the development of effective vaccines, the burden of rotavirus has been reduced, demonstrating what may be possible with an effective norovirus vaccine.

Aron J. Hall

In a study published in 2018, Christopher Troeger, MPH, of the Institute for Health Metrics and Evaluation in Seattle, and colleagues estimated that, globally, rotavirus vaccination averted approximately 28,000 deaths in children aged younger than 5 years in 2016. They estimated that approximately 83,200 additional children could have been saved if full vaccine coverage had been achieved that year.

Another study by Casey L. McAtee, MD, from Baylor College of Medicine’s department of pediatrics, and colleagues examined the burden of norovirus and rotavirus in children after rotavirus vaccine introduction in Bolivia by analyzing the stool samples 206 children with acute gastroenteritis and 71 without the illness. Of 201 samples from children with acute gastroenteritis, 69 (34.3%) had positive results for norovirus, 38 (18.9%) for rotavirus and 9 (4.5%) for both. Among infants, norovirus was detected at nearly three times the rate of rotavirus, present in 34 (42.5%) and 12 (15%) samples, respectively, with three (3.8%) coinfections. The authors concluded that these findings highlight the importance of norovirus infections along with rotavirus infections in the developing world after rotavirus vaccination.

A study conducted in Quebec showed similar results in that norovirus became more prevalent than rotavirus in cases of pediatric gastroenteritis. According to Carolina Quach, MD, MSc, co-director of the Vaccine Study Centre at McGill University Health Centre, and colleagues, surveillance for acute gastroenteritis began among children aged 8 weeks to 3 years by testing stool samples for rotavirus, norovirus and sapovirus. Results showed that 20.4% (95% CI, 16.5%-24.3%) of patients tested positive for rotavirus, and 25.5% (95% CI, 21.3%-29.8%) had norovirus. From June 2012 to May 2013, soon after the introduction of a publicly funded rotavirus vaccination program in Quebec, rotavirus and norovirus prevalence were similar, but from June 2013 to May 2014, rotavirus prevalence was 21.4% (95% CI, 14.3%-28.5%) lower than norovirus. According to the researchers, the apparent reduction in prevalence of rotavirus-associated gastroenteritis was “not surprising, given the effectiveness of the Rotarix vaccine (GlaxoSmithKline) and the success of childhood rotavirus vaccination program.”

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Norovirus’ emergence as the next leading cause of pediatric diarrhea has led to an acceleration in vaccine development, experts indicated.

“Some pathogens are easier than others for developing a vaccine. We start with diseases that have a clear need and a relatively straightforward path to a vaccine,” Hall said.

According to Birgitte Giersing, PhD, technical officer in WHO’s Department of Immunization, Vaccines and Biologicals, there are some interesting norovirus vaccine candidates in the pipeline. She noted two in particular, the most advanced of which is being tested in clinical studies in several target populations, including infants and the elderly, although results have not yet been published. She added that if positive, these data could invigorate vaccine development efforts. The second candidate, which is in early development, is a combination vaccine against norovirus and rotavirus. Giersing explained that introducing combination vaccines is important for immunization schedules, although any norovirus vaccine at all would be beneficial in patients who could have recurring infections.

Birgitte Giersing

“People can be infected multiple times throughout their lives, so having a tool like a vaccine to prevent illness early in life when the outcome can be much more severe would be very helpful,” Hall said.

However, Giersing suggested that the business of vaccine development may be getting in the way of bringing a norovirus vaccine to market. She noted that in high-income countries, there is a greater perception of norovirus morbidity than mortality, and in low- and middle-income countries, there is less awareness and demand for a vaccine, even though this is where one is needed most.

“The clinical candidates in development tend to be geared toward the high-income country markets in the first instance, because these offer an opportunity for a quicker return on investment. Unfortunately, there is often a delay in vaccines becoming available for low-income countries, though there is a public health need for interest in both high- and low-income countries,” she said.

Last year, Miguel O’Ryan, MD, of the Millennium Institute of Immunology and Immunotherapy at the University of Chile, and colleagues published a paper outlining norovirus vaccine candidates in the pipeline. They explained that development of a norovirus vaccine has “faced many difficulties, including genetic/antigenic diversity, limited knowledge on norovirus immunology and viral cycle, lack of a permissive cell line for cultivation and lack of a widely available and successful animal model.”

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Miguel O’Ryan

“Vaccine development for norovirus — a virus that we cannot readily cultivate in the lab — relies on synthesis of antigenically relevant virus particles or subparticles,” O’Ryan told Infectious Disease News.

He said a vaccine candidate initially produced by a small biopharmaceutical company called LigoCyte Pharmaceuticals and purchased after preclinical and phase I studies by Takeda Vaccines is the most advanced candidate. The vaccine, which includes two synthesized virus-like particles of two genogroups, GI and GII, has advanced to phase 1-2 studies to evaluate the safety and optimal dosing schedules in adults (U.S. Army) and children (Panama and Colombia).

“A phase 2b study demonstrating efficacy in children should occur in 2020 and if successful should be followed by a large phase 3 study quite soon afterward,” O’Ryan said. “But the implementation of these studies, which is complex, depends on company strategic planning.”

Potential vaccine targets

A recent study by Rachel M. Burke, PhD, MPH, an epidemiologist in the CDC’s Viral Gastroenteritis Branch, and colleagues analyzed national surveillance data and identified the norovirus genotype GII.4 as an especially relevant target for vaccine candidates. Burke said data showed that vaccines also should target patients in health care facilities.

According to the CDC, three-quarters of norovirus outbreaks occur in long-term care facilities such as nursing homes.

“Few data have been available to show which outbreak characteristics — for example, host, virus or setting — may be associated with severe outcomes from norovirus disease,” Burke told Infectious Disease News.

In their study, Burke and colleagues analyzed data from two voluntary reporting sources — the National Outbreak Reporting System, which captures epidemiologic characteristics of norovirus cases such as age, outbreak setting and outcome, and CaliciNet, which captures laboratory data, including virus genotypes.

“By linking these two sources of information, we have a powerful dataset to examine what could lead to severe outcomes from norovirus illness,” Burke said.

The study confirmed that most outbreaks — 62.8% (n = 2,353) — were caused by the GII.4 genotype, and revealed that these outbreaks were associated with health care settings (OR = 3.94; 95% CI, 2.99-5.23), the months of November through April (OR = 1.55; 95% CI, 1.24-1.93) and older age, with at least 50% of patients aged 75 years or older.

GII.4 outbreaks also were more likely to result in severe outcomes (hospitalization rate ratio [RR] = 1.54; 95% CI, 1.23-1.96; mortality RR = 2.77; 95% CI, 1.04-5.78), Burke and colleagues reported.

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According to Burke, the results of the study suggest that for the best impact, any future norovirus vaccines should protect against GII.4 viruses and should target individuals in health care settings.

According to the CDC, GII.17 and GII.2 strains have replaced GII.4 strains as the most common norovirus strains in several Asian countries in recent years. These newly emerging strains, as well as emergent GII.4 strains, have contributed to the rise in norovirus outbreaks worldwide.

Although efforts are being made to determine what genotypes and groups would be primary targets for a norovirus vaccine, experts agree that any vaccine would have a positive impact on the burden of disease.

“Even a moderately effective vaccine could save thousands of lives, prevent millions of illnesses and save billions of dollars,” Hall said. “There’s tremendous potential for impact.”

In terms of clinical practice, Andi L. Shane, MD, MPH, MSc, associate professor of pediatrics and interim chief of the division of pediatric infectious disease at Emory University School of Medicine and Children’s Healthcare of Atlanta, said the impact of a norovirus vaccine on acute gastroenteritis would be similar to that of rotavirus vaccines, protecting not only those who are immunized but also unvaccinated patients through herd protection.

Andi L. Shane

“An effective vaccine with good uptake has the potential to greatly reduce or even eliminate the 50,000 childhood deaths that occur annually in resource-challenged settings and would have a notable impact on the 200 million pediatric infections and the 685 million infections experienced worldwide,” Shane said.

Giersing said key questions still need to be answered.

“I think we would all love to see a vaccine, particularly low-income countries,” Giersing said. “How it would be used is key — at the moment, injectable intramuscular delivery would mean giving a couple of doses. Other questions that need to be understood are what would the demand be? What is countries’ awareness of norovirus in the first place? Would they want to incorporate this into their programs, if available?”

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For now, prevention is key

According to the CDC, norovirus can be found in vomit or feces before the onset of symptoms and can remain in feces for 2 weeks or longer after symptoms cease. The CDC emphasizes proper hand hygiene, especially after using the bathroom or changing diapers, and always before eating, preparing or handling food. Alcohol-based hand sanitizers can be used in addition to hand-washing but sanitizers are not as effective as soap and water and should not be used independently for removing norovirus particles.

Additionally, the CDC recommends carefully washing fruits and vegetables before preparing and eating them, as well as cooking oysters and other shellfish thoroughly before consumption, making sure to clean and disinfect surfaces before and after. Any surfaces or laundry contaminated with vomit or feces should be immediately washed and disinfected to prevent the spread of norovirus.

“We have to emphasize what we can do now to prevent infection — we’re hopeful for a vaccine but in the meantime, people can focus on hand hygiene, staying home while sick and environmental cleaning and disinfection,” Hall said. “Norovirus is resistant and can persist in the environment, and these are things that should be kept in mind.” – by Caitlyn Stulpin

References:

Alsved M, et al. Clin Infect Dis. 2019;doi:10.1093/cid/ciz584.

Burke RM, et al. J Infect Dis. 2018;doi:10.1093/infdis/jiy569.

Doll MK, et al. Pediatr Infect Dis J. 2016;doi:10.1097/INF.0000000000001077.

Lucero Y, et al. Vaccine. 2018;doi:10.1016/j.vaccine.2017.06.043.

McAtee CL, et al. Am J Trop Med Hyg. 2016;doi:10.4269/ajtmh.15-0203.

Troeger C, et al. JAMA Pediatr. 2018;doi:10.1001/jamapediatrics.2018.1960.

For more information:

Rachel M. Burke, PhD, MPH, can be reached at rburke@cdc.gov.

can be reached at rburke@cdc.gov. Birgitte Giersing, PhD, can be reached at vaccineresearch@who.int.

can be reached at vaccineresearch@who.int. Aron Hall, DVM, MSPH, can be reached at media@cdc.gov.

can be reached at media@cdc.gov. Miguel O’Ryan, MD, can be reached at moryan@med.uchile.cl.

can be reached at moryan@med.uchile.cl. Andi L. Shane, MD, MPH, MSc, can be reached at ashane@emory.edu.

Disclosures: Burke, Giersing, Hall and Shane report no relevant financial disclosures. O’Ryan reports receiving funding for epidemiological studies and consultancy on diarrheal disease from Takeda vaccines.