Abstract
Noroviruses (NoV; previously know as Norwalk-like Caliciviruses) are a common cause of gastroenteritis in humans of all ages. In the Netherlands an estimated 500.000 infection occur each year, including a unknown number of (large-scale) foodborne infections.
Their very high incidence leading to a high burden of illness in institutions such as
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nursing homes and hospitals, the increased risk for diarrheal mortality in such groups, the ageing of the population which will further increase these risks, the high risk of foodborne transmission, and the epidemic potential of these viruses have led to the push for development of vaccines. This effort was aided by the observed self-assembly virus-like particles (VLPs) following the expression of the capsid protein.
Based on experimental infection studies in human volunteers, short-term protection against infection can occur after homologous infection, but not after infection with another NoV type. However, current evidence indicates that patients with pre-existing antibodies may be more susceptible to a more fulminant disease course. It is suspected that enhancing antibodies may play a role in this syndrome. Also, recent evidence suggest that a genetic component may be involved in susceptibility to NoV infection. A relationship between the presence of bloodgroup antigens and infection with a certain NoV type was observed.
Thus the immuneresponse and prophylactic vaccine candidates (i.e. VLPs) must first be evaluated in a suitable animal model for safety and efficacy. At present the only available model for enteric calicivirus are chimpanzees, which seroconverted and shed virus in stool.
Several primate species will be tested for use as a NoV infection model. In addition the development of an immune response after natural NoV infections in humans will be studies. Finally, the relationship between blood group antigens and susceptibility to NoV infections will be investigated.
For the development of a suitable animal-model for NoV, a clinical surveillance program was started with several primate species, designed to identify naturally occurring NoV infections. In addition , 4 different primate species have been experimentally infected with NoV, extracted from human feces. Only one Rhesus macaque was found to be infected, developing a virus specific immune respons and shedding virus for 19 days.
The NoV specific immune response in humans was investigated in several cohorts. A high seroprevalence for NoV was found in children at 1 year of age. Cross-reacting antibodies were found in both children and adults but may not correlate with protective immunity. Therefore, assays were developed for detection of virus type-specific antibodies. These studies show that people who are infected with a NoV, produce antibodies which block the binding of the NoV to its receptor. This is an important development: blocking of receptor binding is likely to be the equivalent of detection of neutralizing antibodies, which are generally thought to confer protection against virus infection. Since NoV are noncultivatable , neutralization test are not available. The blocking antibodies only inhibited binding of the virus for which they were produced and therefore virus type-specific in contrast to the normal (cross-reactive) antibody responses. This means that a NoV vaccine should include antigens from multiple NoV types.
Research into the genetic susceptibility to NoV infections shows that humans expressing blood group B antigens seem less sensitive to infection with NoV strains belonging to genogroup I but not to NoV belonging to genogroup II.
In conclusion, Rhesus macaques are possible candidates as a model for NoV infection. Both virus type specific and cross-reactive antibodies are produced after primary NoV infection in young children. In addition, virus receptor-binding-blocking antibodies are produced which may confer protection against NoV infection. Blood group antigens are a second component in susceptibility to NoV infection.
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