Human noroviruses (NoV) are a leading cause of sporadic and epidemic gastroenteritis across all age groups and are associated with nearly one-fifth of all cases of acute gastroenteritis worldwide (Ahmed et al., 2014). A systematic review of global data showed that NoVs were detected in approximately 24% of acute gastroenteritis cases in the community, 20% of cases in outpatient settings and 17% among inpatients. In the United States, NoV infections result in 19–21 million total illnesses annually, leading to 1.7–1.9 million outpatient visits, 400,000 emergency department visits, 56,000–71,000 hospitalizations and 570–800 deaths (Hall et al., 2013). The economic burden of NoV disease is also high with NoV hospitalizations costing an estimated $500 million annually in the US while foodborne NoV infections result in $2 billion in healthcare and loss of productivity costs (Bartsch et al., 2012). While NoV infections occur in individuals of all age groups, severe outcomes are seen in the elderly and in immunocompromised populations (Bok and Green, 2012; Trivedi et al., 2013). NoVs are also important pediatric pathogens, accounting for nearly 12% of diarrheal hospitalizations in children under 5 years of age (Ramani et al., 2014). In countries where rotavirus vaccines are effective, NoVs are rapidly replacing rotavirus as the most common cause of viral gastroenteritis in this age group (Koo et al., 2013; Payne et al., 2013). The high clinical and economic impact of NoV disease warrants the need for safe and effective vaccines. While there are currently no licensed NoV vaccines, many candidate vaccines are under development or are in clinical trials.

A correlate of protection (CoP) can be defined as an immune marker that statistically correlates with protection from infection or illness, be it induced by natural infection or in response to vaccination. Specifically in the case of vaccines, the CoP marker correlates with vaccine efficacy or protection from disease after vaccination. (Plotkin and Gilbert, 2012). The identification of such a marker (or markers) is often based on studies of immune responses to natural infection with the pathogen. Seroprevalence studies in many populations indicate that most adults have high levels of antibodies to NoVs (Greenberg et al., 1979; O’Ryan et al., 1998; Menon et al., 2013). However, the absence of a fully permissive cell culture system or a small animal models for human NoVs has limited the study of immunity to NoVs. In particular, this poses a problem for performing virus neutralization assays to assess protective immunity.

In the absence of efficient cell culture systems to grow human NoVs, the possibility of developing live-attenuated or killed NoV vaccines is limited. However, a number of vaccine candidate for NoVs have been evaluated (Table 3.6.2). The expression of NoV capsid proteins in vitro results in self-assembly of virus-like particles (VLPs) that are morphologically and antigenically identical to particles of the infectious virus (Jiang et al., 1992; Green et al., 1993). The production of VLPs was first demonstrated when the NV capsid was produced by expressing the second and third open reading frames of the viral genome in insect cells infected with a recombinant baculovirus (Jiang et al., 1992). VLPs contain 180 copies of the VP1 capsid protein, and their particulate nature may enhance immune activation and uptake by antigen presenting cells in the Peyer’s patches of the gastrointestinal tract. NoV VLPs have been proposed as candidate vaccines since their first description. Preclinical studies evaluated the immunogenicity of VLPs in mice, rabbits, gnotobiotic pigs and chimpanzees using various routes of administration (Table 3.6.3). The effect of different adjuvants on immune response was also tested in several studies.

Following preclinical studies that demonstrated the immunogenicity of VLPs, clinical studies were initiated to assess the safety, immunogenicity and efficacy of VLP vaccines in humans (Table 3.6.4). The earliest phase I clinical studies evaluated the safety and immunogenicity of oral immunization with increasing doses of rNV VLPs in healthy adults. In one study, two doses of 100  or 250 μg of the rNV VLP vaccine were administered without adjuvant and a dose-dependent increase in serum IgG responses to rNV VLPs was observed (Ball et al., 1999). All vaccinees who received 250ug of rNV VLPs had a > fourfold increase in serum IgG titers, although most responses were seen after the first dose of vaccine. The vaccine was well tolerated, and no serious adverse events were reported. In another study, healthy adult volunteers received increasing doses of rNV VLP vaccines ranging from 250 to 2000 μg and humoral, mucosal and cellular immune responses were assessed (Tacket et al., 2003). The vaccine was well tolerated, and no volunteer experienced fever, diarrhea or vomiting in the 3 days following vaccination. Three vaccinees reported mild cramps while one person each in the vaccine and placebo arms experienced nausea. Headache and malaise were reported more commonly in the placebo arm of the study. Serum antibody responses were observed in 90% of vaccinees who received two doses of 250 μg of VLPs administered three weeks apart, and there was no further increase in response in the higher dosage groups. All vaccinees developed significant rises in IgA ASCs. Mucosal IgA responses were seen in less than 50% of vaccinees while transient lymphoproliferative and interferon gamma (IFNγ) responses were observed in the two lower dosage groups. Immune responses were also measured in persons who consumed transgenic potatoes expressing the NV capsid protein (Tacket et al., 2000). Although IgG and IgA antibody responses were modest, 95% of vaccinees had a significant increase in virus-specific IgA-ASCs.