Divergence of VP7 genes of G1 rotaviruses isolated from infants vaccinated with reassortant rhesus rotaviruses

Abstract

A large placebo-controlled efficacy trial of the rhesus tetravalent (RRV-TV) and serotype G1 monovalent (RRV-S1) rotavirus vaccines was conducted in 1991-1992 at 24 sites across the United States. Protection was 49% and 54% against all diarrhea but 80% and 69% against very severe gastroenteritis for the two vaccines, respectively. Post-vaccination neutralizing antibody titers to the G1 Wa strain, whose VP7 protein is nearly identical to that of the D strain of rotavirus contained in both vaccines, did not correlate with protection against subsequent illness with G1 strains. This result raised the possibility that in infants who developed post-vaccination neutralizing antibody to Wa, breakthrough (i.e., vaccine failure-the occurrence of rotavirus diarrhea after immunization) may have been due to infection by G1 strains that were sufficiently antigenically distinct from the vaccine strain to evade the neutralizing antibodies elicited by vaccination. To test this hypothesis, we initially compared post-vaccination neutralizing antibody titers of vaccinees against Wa and G1 breakthrough strains using sera from subjects who experienced breakthrough. Post-immunization neutralizing antibody titers to Wa elicited by vaccination were significantly (P< 0.001) greater than to the breakthrough strains subsequently obtained from these subjects. This difference did not, however, correlate with lack of protection since similar differences in titer to Wa and breakthrough strains were found using post-vaccination sera from vaccinees who either experienced asymptomatic rotavirus infections or no infections. To determine the genetic basis for these differences, we compared the VP7 gene sequences of Wa with vaccine strain D, 12 G1 breakthrough strains, and 3 G1 control strains isolated during the same trial from placebo recipients. All breakthrough strains were distinct from Wa and D in antigenically important regions throughout the VP7 protein, but these differences were conserved between breakthrough and placebo strains. Furthermore, a comparative analysis of the deduced amino sequences form VP7 genes of G1 rotaviruses from 12 countries indicated that four distinct lineages have evolved. All breakthrough and control strains from the U.S. vaccine trial were in a lineage different from strain D, the serotype G1 vaccine strain. Although the overall results do not support our original hypothesis that immune selection of antigenically distinct escape mutants led to vaccine breakthrough in subjects with a neutralization response to Wa, it cannot be excluded that breakthrough could be partially due to antigenic differences in the VP7 proteins of currently circulating G1 strains.

Genetic and antigenic variation of capsid protein VP7 of serotype G1 human rotavirus isolates.

“…Similar results were obtained by Maunula & von Bonsdorff (1998). These studies indicated that there was no geographical clustering within the lineages ; however, samples of Australian origin were classified into only one lineage [lineage II according to the classification of Jin et al (1996)]. Utilizing complete VP7 deduced amino acid sequences derived from strains representative of each of these lineages, the 12 samples investigated in this study [10 sequences determined here and two from 1990 and 1991 determined by Palombo et al (1993)] were phylogenetically analysed.…”

“…A number of studies of VP7 of rotavirus clinical isolates belonging to the major serotypes (G-types) known to infect humans have indicated the existence of discrete genetic lineages of this protein (Jin et al, 1996 ;Wen et al, 1997 ;Maunula & von Bonsdorff, 1998 ;Piec & Palombo, 1999). Over the last decade, serotype G1 has represented the most common serotype responsible for the hospitalization of children worldwide (Gentsch et al, 1996).…”

“…Over the last decade, serotype G1 has represented the most common serotype responsible for the hospitalization of children worldwide (Gentsch et al, 1996). Phylogenetic analysis has determined that at least four major global lineages of serotype G1 VP7 occurred within rotaviruses collected from diverse geographical locations (Jin et al, 1996 ;Maunula & von Bonsdorff, 1998).…”

“…The scale bar is proportional to genetic distance. Lineages I, II, III and IV indicate sequences (derived from strains Jpn-417, Oh-64, Wa and Kor-54, respectively) that represent the phylogenetic lineages defined by Jin et al (1996). (Page, 1996) using genetic distances generated by the neighbour-joining method of Saitou & Nei (1987) with ClustalW analysis (Wisconsin package, version 8.1 UNIX, 1995).…”

“…According to Jin et al (1996), VP7 of serotype G1 rotavirus isolates can be classified into four distinct lineages based on amino acid sequences. Similar results were obtained by Maunula & von Bonsdorff (1998).…”