The Norwalk GI.1 virus Lot 001-09NV may be a useful challenge strain for future norovirus vaccine development, according to a study published in the Journal of Infectious Diseases.
Human noroviruses (HuNoV) are the leading cause of acute gastroenteritis; infections result in approximately 200,000 deaths per year in mostly young children and older adults. Most HuNoV disease is caused by strains in 2 genogroups (G): GI and GII. Individuals who do not have a functional secretor enzyme are genetically resistant to GI.1 infection, but GII.2 infection is dependent of a different secretor type. However, the effect of genetic susceptibility on immunity and vaccine response is not well understood.
The use of controlled human infection models to evaluate vaccine candidates has increased, requiring methods to isolate and purify noncultivatable/recalcitrant viruses. Studies on vaccine efficacy that use a human challenge design require large quantities of well-characterized virus stocks that meet United States Food and Drug Administration standards for purity and sterility for use in humans. Therefore, this study developed a methodologic pipeline to manufacture high-quality stocks of HuNoV for controlled human infection models to improve the understanding the mechanisms of HuNoV susceptibility, immunity, and vaccine efficacy (ClinicalTrials.gov identifier: NCT03721549).
In total, 16 genetically susceptible participants who were secretor positive were included. Initially, 8 participants were assigned to the low-dose challenge (3.6 x 105 GC of Norwalk virus) and once the assessments for that cohort were complete, 8 participants were assigned to the higher-dose challenge (1 x 106 GC of Norwalk virus). After an overnight fast, participants in each group received 100 mL of bicarbonate buffer solution to neutralize stomach acid and then were administered the Norwalk virus inoculum suspended in 100 mL of distilled water 1 minute later. Over the following 48 hours, participants were assessed for symptoms and signs of gastroenteritis every 2 hours while awake, then every 8 hours from day 3 to day 5. Fecal and emesis samples were collected, weighed, graded, and processed for Norwalk virus infection; saliva and blood samples were collected and evaluated for H type-1 antigens secretor status; and peripheral blood mononuclear cells were obtained for the detection of immunoglobulin (Ig)A and IgG antibody secreting cells. Participants were assessed for anticipated subjective symptoms of Norwalk virus illness, which included diarrhea, vomiting, headache, nausea, fever, abdominal cramps or pain, abdominal burgling or bloating, and myalgia. Acute gastroenteritis was defined according to the criteria of Bernstein.
Results suggest that Lot 001-09NV is similar to previous passages of Norwalk virus strain 8FIIa because it has a similar time to disease onset, duration of illness, and safety profile in challenged participants. There were no statistically significant differences in outcome between the 2 treatment groups. In total, Lot 001-09NV induced gastroenteritis in 9 (56%) participants and infection in 11 (69%) participants. In the low-dose group, 5 (63%) participants met the criteria for acute gastroenteritis and were positive for Norwalk virus.
In the high-dose group, 6 (75%) participants were positive for Norwalk virus, but only 4 participants met the criteria for acute gastroenteritis. Participants in the high-dose group who were positive for Norwalk virus with acute gastroenteritis had more severe illness compared with those in the low-dose group, as measured by diarrheal stool output and vomiting. Additionally, the onset of illness was shorter and the duration of illness was longer in the high-dose group. A strong immune response to GI.1 developed in all infected participants, with a 161-fold increase in in GI.1-specific IgG titers and a 30-fold increase in blocking titers. In peripheral blood, GI.1-specific cellular responses were observed 9 days after the challenge, with an average of 1227 IgG and 3253 IgA antibody secreting cells per million peripheral blood mononuclear cells.
Overall, the study authors concluded that, “The safety profile, attack rate, and duration of illness make GI.1 Lot 001-09NV a useful challenge strain for future vaccine studies aimed at establishing immune correlates.”
Mateo R, Lindesmith MC, Garg SJ, et al. Production and clinical evaluation of Norwalk GI.1 virus lot 001-09NV in norovirus vaccine development [published online October, 20, 2019]. J Infect Dis. doi:10.1093/infdis/jiz540