Pediatric Norovirus Vaccination: Modeling the Influence of Schedule on Population Health

Introduction Noroviruses cause approximately 20 million cases of acute gastroenteritis (AGE) annually in the United States, with children under 5 years of age experiencing the highest incidence. With promising norovirus vaccines moving into pivotal trials in children, an important next step in norovirus vaccine evaluation is comparing benefits of various pediatric vaccination schedules.

We developed an age-structured deterministic compartmental model for norovirus transmission and fit it to norovirus case incidence data representative of the United States population. The model accounted for immunity accrued across multiple infections and potential maternal antibody interference with vaccine performance. Using this model, we simulated five pediatric vaccination schedules (at 0/2/4m, 2/4/6m, 6/12m, 12/24m, and 48m) with 70% and 90% vaccination coverage, with and without maternal antibody interference. We evaluated the impacts of vaccination on clinical outcomes, including acute gastroenteritis cases, outpatient visits, hospitalization, and death due to norovirus.

Vaccination impacts were primarily concentrated in the pediatric age group, with modest indirect effects to unvaccinated age groups. Comparing scenarios, the 2/4/6m schedule was more impactful, with a 43% (95% uncertainty interval (UI): 29 – 62%) reduction in pediatric AGE cases (<5 years old) and 19% (95% UI: 7 – 54%) reduction in total population cases (including pediatric cases) with 70% vaccination coverage and no maternal antibody interference. This scenario was estimated to avert 12,200 (95% US: 7,100 – 21,500) AGE cases, 2,100 (900 – 4,500) outpatient visits, and 50 (30 – 90) hospitalizations per 100,000 young children. In the total population, 3.72 million (95% UI: 2.06 – 7.07 million) AGE cases, 526,000 (24,800 – 1,092,000) outpatient visits, 18,000 (9,500 – 41,600) hospitalizations, and 152 (52-602) deaths were estimated to be averted across the population, with 38% of the overall impact conferred by indirect effects. While the 0/2/4m schedule had the greatest overall impact when assuming no interference from maternal antibody, the 2/4/6m schedule was less affected by interference from maternal antibodies. Assuming maternal antibody interference does compromise vaccine efficacy, the 2/4/6m schedule was comparable to the most impactful vaccination schedule with maternal antibody interference (6/12m schedule, 16% [95% UI: 7 – 29%] of pediatric cases and 6% [95% UI: 1 – 26%] of total cases averted, 2/4/6m schedule: 14% [95% UI: 7 – 25%] of pediatric cases and 6% [95% UI: 2 -21%] of total cases averted). Thus, while the total vaccination impact was highly sensitive to assumptions regarding maternal antibody interference, the 2/4/6m schedule impacts were robust across assumptions. Significance Pediatric norovirus vaccination scheduled at 2/4/6m and similar schedules have the potential to substantially reduce norovirus burden in high incidence age groups and avert healthcare utilization, likely with modest benefits to unvaccinated individuals. Competing Interest Statement BAL has served as a consultant for Epidemiological Research and Methods and Hillevax, LLC. Funding Statement NIH/NIAID grants T32AI138952, 5T32AI138952-05, and R01 GM124280, and Takeda Pharmaceuticals, who had no input into the study design, analysis, or interpretation. Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes Data Availability All data and code produced in the present study are available upon reasonable request to the authors.