What Factors Protect Against Norovirus Infection and Gastroenteritis?

Sasirekha Ramani, Mary Estes and Robert Atmar, from Baylor College of Medicine, Houston, USA, discuss genetic factors and immune mechanisms that can protect from norovirus infections and disease, as featured in the PLOS Collection “The Global Burden of Norovirus & Prospects for Vaccine Development“.

In order to design effective vaccines or improve existing vaccines for a given pathogen, it is important to answer the question – what factors protect against infection and illness? The absence of clinical disease (evaluated by studies measuring clinical endpoints) is the most accurate approach to determine protection from infection or illness after vaccination. However, measuring clinical end points often involves large, expensive studies which eventually increase the cost of the vaccine. If a laboratory test can measure one or more immune factors that correlate with protection, this can be used to determine the proportion of vaccine recipients that are likely to be protected from infection or illness, in place of clinical endpoints. Such “correlates of protection” thus hold significant value for the development or improvement of vaccines as well as regulatory processes for vaccine introduction. For example, following poliovirus vaccination, the induction of a certain level of serum antibody that prevents poliovirus infection of cells in the laboratory indicates that a person will be resistant to illness and that the vaccine is protective.

In the PLOS Collection article titled Correlates of protection against norovirus infection and disease – where are we now, where do we go?, we summarize current findings on correlates of protection against human norovirus infection and disease, and discuss important challenges that need to be the focus of future studies. Understanding the correlates of protection to noroviruses is important because (a) norovirus causes significant burden of disease, so knowing what protects us from infection or illness is critical and (b) vaccines to norovirus are in development, with some such as virus-like particle (VLP) vaccines in clinical trials, and understanding mechanisms of protection will allow advancements in the field of norovirus vaccine development.

For human noroviruses, host genetics can be protective. A pattern of repeated resistance or susceptibility observed to the prototype strain, Norwalk virus laid the foundation for the discovery that cell surface glycans called histo-blood group antigens (HBGAs) play a role in norovirus susceptibility. Persons who do not express fucosylated HBGAs on the surface of epithelial cells and mucosal secretions, called non-secretors, are protected from infection with Norwalk virus. While many studies have confirmed the role of host genetics in protection from norovirus illness worldwide, it is important to recognize that there are more than 30 genotypes of human noroviruses and they show differences in their HBGA specificity, which means that it is likely that most of us will be susceptible to infection by at least one genotype of norovirus.

This leads to the question: which immune mechanisms protect from norovirus gastroenteritis? In human volunteers experimentally infected with Norwalk virus, persons with antibodies that block the binding of Norwalk VLPs to HBGAs prior to infection were more likely to be protected from gastroenteritis following infection. These findings were validated in clinical trials with VLP vaccines where “blocking antibodies” correlate with protection from both infection and illness following vaccination. However, this was not the only immune factor that was found to correlate with protection. Experimental infections studies show that other immune markers such as presence of salivary IgA and virus-specific IgG memory B-cells prior to infection also correlate with protection from illness. In addition, adaptive immune responses following infection, such as a rapid salivary IgA response or high titers of fecal IgA one week after infection also play protective roles.

These findings have lead us to think extensively about the mechanism(s) of protective immunity to noroviruses. What is the relative importance of the different correlates of protection that have been identified? Do all immune markers need to be evaluated in future studies to determine if a vaccine induces protection? What is the duration of protective immunity provided by each of these immune factors? Are there multiple correlates because some factors are important for short-term protection and others for long-term protection? Some of the immune factors identified correlate with one another; is this because these markers co-vary as part of human immune responses? Or are they reflective of other immune markers that directly mediate protection?

Finally, will immune markers identified through well-controlled clinical trials predict protection in the actual population where multiple norovirus strains circulate among people with different genetic susceptibility to the virus? Given that norovirus diversity is often likened to flu viruses with seasonal variations in prevalence of strains, one pertinent question for vaccine development is: will there be a need to include many different genotypes in vaccine formulations and frequently update them based on circulating strains? An exciting finding highlighted in this article is the discovery that with both infection and vaccination, norovirus immune responses appear to be heterotypic. This means that, at least in adults who likely have different histories of norovirus infections and are therefore a “primed” population, it is possible to achieve broadly cross-reactive immune responses to different norovirus strains. While this is promising for adults, what do these findings mean for the relatively “unprimed” population of children amongst whom norovirus causes a significant burden of disease? Will current vaccines work effectively in children and in the elderly or immunocompromised with waning immune responses? These are several important questions that need to be answered.

We stand at the threshold of exciting progress in the field of noroviruses, with greatest clarity thus far on disease burden worldwide. Current vaccines show great promise and other vaccines are in development. We have identified genetic and immune correlates of protection against human noroviruses and although most of the correlates of protection were identified from few, relatively small studies, they provide the rationale to evaluate these immune markers in future larger studies. The questions raised in this PLOS Collection provide directions for future studies on norovirus immunity.

Sasirekha Ramani is an Instructor in Virology & Microbiology at Baylor College of Medicine.

Mary Estes is a Professor of Virology & Microbiology at Baylor College of Medicine.

Robert Atmar, MD, is Professor and Interim Chief of Infectious Disease at Baylor College of Medicine.