Immune Responses to Rotavirus Infection and Vaccination and Associated Correlates of Protection

Group A rotavirus (RV) strains are a major cause of acute gastroenteritis (AGE) in infants and young children worldwide 1. RV disease accounts for more than one-third of all diarrhea-related hospitalizations and 500, 000–600, 000 deaths per year 2–4; most deaths occur in sub-Saharan Africa and Asia 3, 4. Direct medical and indirect annual costs associated with RV disease are estimated to be €400 million in Europe 5–7 and to exceed US 1 billion in the United States 8. RV strains form a genus of the Reoviridae family and possess a genome of 11 segments of double-stranded (ds) RNA, encoding 6 structural viral proteins (VPs) and 6 nonstructural proteins (NSPs). The infectious particle (ie, virion) consists of 3 layers: the inner layer (core) contains the viral genome, the viral RNA-dependent RNA polymerase (RdRp, VP1), the capping enzyme (VP3), and the scaffolding protein (VP2) ; the core is surrounded by a middle layer (VP6), and the outer layer consists of VP7 and VP4 9. RV infects mature enterocytes in the small intestine. Viral replication leads to increased intracellular Ca2+ level (effected by NSP4), increased Cl- secretion, and shut-off of host cell protein synthesis (effected by NSP3), resulting in acute osmotic and secretory diarrhea (described in 9). Various RV genes have been implicated in the pathogenesis of AGE 10. After RV infection, a viremic stage of, at present, unclear significance has been identified in humans and experimental animals 11–13. The RV-encoded NSP1 blocks interferon (IFN) production by various pathways 14–17. RV infection down-regulates the IFN- and pro-inflammatory cytokine–associated pathways in calves 18. RV strains have a high genomic and antigenic diversity and are classified into at least 7 different groups (A–G), distinguished by different VP6. Most human RV infections are caused by group A RV strains, which are further subdivided into at least 2 subgroups (I, II), 23 G types (determined by VP7, a glycoprotein), and 31 P types (determined by VP4, a protease-sensitive protein) 9, 19–21. RV strains with different G and P types cocirculate and change in geographical regions over time 22–25. In temperate climate regions, most cocirculating RV strains are types G1–G4 and G9 (typically G1P1A8, G2P1B4, G3P1A8, G4P1A8, and G9P1A8), but other G types (G5, G8, G10, and G12), in combination with various P types, may be most prevalent in tropical areas 21, 23, 24. Nonspecific (innate) and acquired virus-specific humoral and cellular immune responses are elicited by RV infection 26, 27 or RV vaccination 28–33. Although currently licensed vaccines are highly efficacious in protecting children from severe RV AGE, the molecular mechanisms of protection are not fully understood. This article considers the immune responses to natural RV infection and RV vaccination in both experimental animals and humans as potential correlates of protection.