Duration of Immunity to Norovirus Gastroenteritis

Kirsten Simmons, Manoj Gambhir, Juan Leon, and Ben Lopman

Author affiliations: Rollins School of Public Health, Emory University, Atlanta, Georgia, USA (K. Simmons, J. Leon, B. Lopman); Centers for Disease Control and Prevention, Atlanta (K. Simmons, B. Lopman); Imperial College London, London, UK (M. Gambhir)

Abstract

The duration of immunity to norovirus (NoV) gastroenteritis has been believed to be from 6 months to 2 years. However, several observations are inconsistent with this short period. To gain better estimates of the duration of immunity to NoV, we developed a mathematical model of community NoV transmission. The model was parameterized from the literature and also fit to age-specific incidence data from England and Wales by using maximum likelihood. We developed several scenarios to determine the effect of unknowns regarding transmission and immunity on estimates of the duration of immunity. In the various models, duration of immunity to NoV gastroenteritis was estimated at 4.1 (95% CI 3.2–5.1) to 8.7 (95% CI 6.8–11.3) years. Moreover, we calculated that children (< 5 years) are much more infectious than older children and adults. If a vaccine can achieve protection for duration of natural immunity indicated by our results, its potential health and economic benefits could be substantial.
Noroviruses (NoVs) are the most common cause of acute gastroenteritis (AGE) in industrialized countries. In the United States, NoV causes an estimated 21 million cases of AGE (1), 1.7 million outpatient visits (2), 400,000 emergency care visits, 70,000 hospitalizations (3), and 800 deaths annually across all age groups (4). Although the highest rates of disease are in young children, infection and disease occur throughout life (5), despite an antibody seroprevalence > 50%, and infection rates approach 100% in older adults (6,7).
Frequently cited estimates of the duration of immunity to NoV are based on human challenge studies conducted in the 1970s. In the first, Parrino et al. challenged volunteers with Norwalk virus (the prototype NoV strain) inoculum multiple times. Results suggested that the immunity to Norwalk AGE lasts from ≈2 months to 2 years (8). A subsequent study with a shorter challenge interval suggested that immunity to Norwalk virus lasts for at least 6 months (9). In addition, the collection of volunteer studies together demonstrate that antibodies against NoV may not confer protection and that protection from infection (serologic response or viral shedding) is harder to achieve than protection from disease (defined as AGE symptoms) (10–14). That said, most recent studies have reported some protection from illness and infection in association with antibodies that block binding of virus-like particles to histo-blood group antigen (HBGA) (13,14). Other studies have also associated genetic resistance to NoV infections with mutations in the 1,2-fucosyltransferase (FUT2) gene (or “secretor” gene) (15). Persons with a nonsecretor gene (FUT2−/−) represent as much as 20% of the European population. Challenge studies have also shown that recently infected volunteers are susceptible to heterologous strains sooner than to homotypic challenge, indicating limited cross-protection (11).
One of many concerns with all classic challenge studies is that the virus dose given to volunteers was several thousand–fold greater than the small amount of virus capable of causing human illness (estimated as 18–1,000 virus particles) (16). Thus, immunity to a lower challenge dose, similar to what might be encountered in the community, might be more robust and broadly protective than the protection against artificial doses encountered in these volunteer studies. Indeed, Teunis et al. have clearly demonstrated a dose-response relationship whereby persons challenged with a higher NoV dose have substantially greater illness risk (16).
Furthermore, in contrast with results of early challenge studies, several observations can be made that, when taken together, are inconsistent with a duration of immunity on the scale of months. First, the incidence of NoV in the general population has been estimated in several countries as ≈5% per year, with substantially higher rates in children (5). Second, Norwalk virus (GI.1) volunteer studies conducted over 3 decades, indicate that approximately one third of genetically susceptible persons (i.e., secretor-positive persons with a functional FUT2 gene) are immune (Table 1) (18,20,22). The point prevalence of immunity in the population (i.e., population immunity) can be approximated by the incidence of infection (or exposure) multiplied by the duration of immunity. If duration of immunity is truly < 1 year and incidence is 5%, < 5% of the population should have acquired immunity at any given time. However, challenge studies show population immunity levels on the order of 30%–45%, suggesting that our understanding of the duration of immunity is incomplete (8,11,17,18). HBGA–mediated lack of susceptibility may play a key role, but given the high seroprevalence of NoV antibodies and broad diversity of human HBGAs and NoV, HBGA–mediated lack of susceptibility cannot solely explain the discrepancy between estimates of duration of immunity and observed NoV incidence. Moreover, population immunity levels may be driven through the acquisition of immunity of fully susceptible persons or through boosting of immunity among those previously exposed.
In this study, we aimed to gain better estimates of the duration of immunity to NoV by developing a community-based transmission model that represents the transmission process and natural history of NoV, including the waning of immunity. The model distinguishes between persons susceptible to disease and those susceptible to infection but not disease. We fit the model to age-specific incidence data from a community cohort study. However, several factors related to NoV transmission remain unknown (e.g., the role asymptomatic persons who shed virus play in transmission). Therefore, we constructed and fit a series of 6 models to represent the variety of possible infection processes to gain a more robust estimate of the duration of immunity. This approach does not consider multiple strains or the emergence of new variants, so we are effectively estimating minimum duration of immunity in the absence of major strain changes.