Group A rotaviruses (RVs) are important pathogens that cause acute, dehydrating gastroenteritis in infants and young children. The burden of disease is severe, particularly in developing countries where RV infections lead to more than 500,000 deaths annually. RVs are non-enveloped, triple-layered icosahedral particles that enclose an eleven-segmented, double-stranded (ds) RNA genome. The genome encodes six structural proteins (VP1–VP4, VP6, and VP7) and five or six non-structural proteins (NSP1–NSP5, and sometimes NSP6). Individual RV strains have traditionally been classified into serotypes based on the antibody responses generated against the outermost structural proteins VP7 (G-serotypes) and VP4 (P-serotypes). Due to the ease of sequencing, RVs are now classified into G/P-genotypes based on the relatedness of the genes encoding VP7 and VP4.
Although the mechanism by which RV infection leads to immunological protection is not fully understood, G/P-type-specific neutralizing antibodies have been shown to play an important role. Strains with particular G/P-type combinations are the most prevalent causes of disease in humans worldwide, and these are the targets of the two currently licensed RV vaccines. RotaTeq (Merck) contains five live-attenuated, reassortant viruses with human VP7 genes in a predominantly bovine RV background. In contrast, Rotarix (GlaxoSmithKline) is a live-attenuated, human RV containing genotype 1 internal genes. Both vaccines have proven safe and effective at protecting against severe diarrheal disease in industrialized countries and Latin America. However, the efficacy of RotaTeq and Rotarix in developing countries is expected to be reduced, which may be related to viral serotype diversity among other factors. Additionally, the high monetary cost of these current vaccines may limit their availability in regions of the world where they are most needed. As a result, there is a global health initiative to develop new RV vaccines that can be manufactured on-site at a lower cost. Two vaccine candidates being considered are the live-attenuated human strains RV3 and 116E.
Complete genome sequence analysis of candidate human rotavirus vaccine strains RV3 and 116E. Virology. Jun 25 2010
Rotaviruses (RVs) cause severe gastroenteritis in infants and young children; yet, several strains have been isolated from newborns showing no signs of clinical illness. Two of these neonatal strains, RV3 (G3P) and 116E (G9P), are currently being developed as live-attenuated vaccines. In this study, we sequenced the eleven-segmented double-stranded RNA genomes of cell culture-adapted RV3 and 116E and compared their genes and protein products to those of other RVs. Using amino acid alignments and structural predictions, we identified residues of RV3 or 116E that may contribute to attenuation or influence vaccine efficacy. We also discovered residues of the VP4 attachment protein that correlate with the capacity of some P strains, including RV3, to infect newborns versus older infants. The results of this study enhance our understanding of the molecular determinants of RV3 and 116E attenuation and are expected to aid in the ongoing development of these vaccine candidates.