Rotavirus vaccine efficacy: current status and areas for improvement

Carvalho, Miguel F.; Gill, Davinder

It is estimated that worldwide, approximately 500,000 children under 5 years of age die annually as a consequence of diarrhea. Rotavirus gastroenteritis (RGE) is the leading cause of diarrheal death with a total estimate of 200,000 for all ages (146,000 among under 5 years old 11 ). Rotaviruses were first identified by electron microscopy in intestinal biopsies of children diagnosed with acute gastroenteritis. 12 These viruses consist of non-enveloped, icosahedral particles comprising 11 segments of dsRNA encoding 6 structural (VP1-4, 6, 7) and 6 non-structural proteins (NSP1-6 13 ). Cleavage of VP4 leads to VP5* involved in cell penetration, and VP8*, the head of the VP4 spike required for attachment and infection of intestinal cells. 14, 15 Infection with naturally-occurring Rotavirus strains does not confer immunity but prevents strong diarrhea upon reinfection. Post reinfection, serotypic response is normally broader. Antibody responses are not limited to outer capsid proteins but include also VP2, VP6, NSP2, NSP4. 16 Neutralizing IgA specific to VP4 and VP7 prevents adsorption, uncoating and penetration, while VP6-specific IgA prevents intracellular viral replication during transcytosis across enterocytes. 13, 14 Outer capsid proteins VP4 and VP7 are used in P (VP4 protease) and G (VP7 glycoprotein) serotyping and genotyping. Epidemiological studies indicate that Rotavirus diversity changes over the years within and between countries by point mutations (genetic drift) leading to antigenic changes, reassortment within and between animal strains, infections of other species as well as genetic rearrangements. 16 A review of the prevalence of Rotavirus strains in 100 reporting nations from 1996 to 2007 noted that strain diversity was associated with accumulation of point mutations driving antigenic drift, genome reassortment and zoonotic transmission. Five genotypes (G1-4, G9) accounted for 88.2% of all strains, with G1 declining from 2000 onwards and G3 re-appearing. Concurrently G9, G12 emerged and G8 strains increased in Africa, while G3-4 decreased. 17 It is interesting to note that in Africa, P [6] strains comprise 25% of VP4 genotypes while in Europe and North America these account for less than 4%. 18 Rotavirus infection takes place via the apical tip of villi within the small intestine, with replication occurring primarily in differentiated epithelial cells, ultimately leading to cell death. This in turn leads to limited food digestion and release of fluids causing diarrhea. 13 Interaction with glycans is critical for early stages of Rotavirus infection. Histo-blood group antigens (HBGAs) expressed at the surface of red blood and epithelial cells can serve as non-sialylated glycan binding partners for Rotavirus entry via the VP8* protein within which a narrow cleft's wideness determines binding of cellsurface glycans. HBGA expression is genetically determined by the addition of monosaccharide to precursor disaccharides through the activity of ABH genes, FUT2 (secretor gene) and FUT3/4 (Lewis gene). Loss of function mutations in FUT2 and FUT3 lead to secretor-and Lewis-negative phenotype individuals which can determine Rotavirus specificity (e.g. VP8* of strain HAL1166 P [14] has a narrower cleft allowing binding to A-type HBGA) and A-type binding is also seen in P [9] and P [25] strains. Furthermore, P [11] strain is associated with high rates of infection in newborns from India with strain N155 recognizing type I, II precursor