Julius Goepp, James Geyer, Paul Cox

Enteric diseases causing severe diarrhea threaten survival of children and are a source of considerable morbidity in low- and middle-income countries (LMIC)1. Human Noroviruses (HuNoVs), a group of single-stranded RNA, non-enveloped viruses in the family Caliciviridae, are the predominant viral pathogens associated with acute gastroenteritis in humans2,3. HuNoVs are common etiopathogens in travelers’ diarrhea (TD), affecting children and adults traveling from industrialized nations to LMIC, as well as military and diplomatic personnel stationed in endemic regions4,5. HuNoV is also a common agent of outbreaks in long-term care facilities, contributing to excess morbidity and mortality among older adults6.

Figure: Life cycle of Human Norovirus, beginning with adhesion of the viral capsid P domain to HBGA moieties on duodenal and jejunal cells7.

Importantly, chronic HuNoV infections can cause gastroenteritis and intestinal barrier dysfunction in both primary and acquired immunodeficiency  states, which include patients undergoing immunosuppressive therapies related to hematopoietic stem cell and solid organ transplants, those with human immunodeficiency virus infection, and those with cancer or undergoing cancer treatment8. Although the overall incidence of HuNoV disease in hospital and community settings remains unclear, studies in hematopoietic stem cell transplant recipients suggest an 18% infection rate over one year, and a two-year survey of kidney transplant recipients reported a 17% chronic HuNoV infection rate8-11.

To establish infection, HuNoV must first adhere to mucosal epithelial cells in the duodenum or upper jejunum12,13, as shown in the Figure7. Protruding (P) domains of the viral capsid mediate HuNoV binding to histo-blood group antigens (HBGAs), resulting in cellular invasion and virus replication, and inducing the physical symptoms associated with acute gastroenteritis14,15. Efforts to develop vaccines focus overwhelmingly on preventing or interrupting adhesion of the P-domain to HBGA receptors16. Hence, viral capsid domains have been targets of HuNoV vaccine candidates3. However, diversity among HuNoV variants, including mutations within viral capsid domains, and the emergence of newer genotypes in genogroups I and II (GI and GII, respectively) has complicated vaccine development2,17. Currently, no licensed vaccine against HuNoV is available, though several are in early-stage clinical trials2,17.

Citations

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