DIVERGENCE OF VP7 GENES OF G1 ROTAVIRUSES ISOLATED FROM INFANTS VACCINATED WITH REASSORTANT RHESUS ROTAVIRUSES

A large placebo-controlled efficacy trial of the rhesus tetravalent (R RV-TV) and serotype G1 monovalent (RRV-S1) rotavirus vaccines was cond ucted in 1991-1992 at 24 sites across the United States. Protection wa s 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 bo th vaccines, did not correlate with protection against subsequent illn ess with G1 strains. This result raised the possibility that in infant s who developed post-vaccination neutralizing antibody to Wa, breakthr ough (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 t he neutralizing antibodies elicited by vaccination. To test this hypot hesis, we initially compared post-vaccination neutralizing antibody ti ters of vaccinees against Wa and G1 breakthrough strains using sera fr om subjects who experienced breakthrough. Post-immunization neutralizi ng antibody titers to Wa elicited by vaccination were significantly (P <0.001) greater than to the breakthrough strains subsequently obtaine d from these subjects. This difference did not, however, correlate wit h lack of protection since similar differences in titer to Wa and brea kthrough strains were found using post-vaccination sera from vaccinees who either experienced asymptomatic rotavirus infections or no infect ions. To determine the genetic basis for these differences, we compare d the VP7 gene sequences of Wa with vaccine strain D, 12 G1 breakthrou gh strains, and 3 G1 control strains isolated during the same trial fr om placebo recipients. All breakthrough strains were distinct from Wa and D in antigenically important regions throughout the VP7 protein, b ut these differences were conserved between breakthrough and placebo s trains. Furthermore, a comparative analysis of the deduced amino seque nces from VP7 genes of G1 rotaviruses from 12 countries indicated that four distinct lineages have evolved. All breakthrough and control str ains from the U.S. vaccine trial were in a lineage different from stra in D, the serotype G1 vaccine strain. Although the overall results do not support our original hypothesis that immune selection of antigenic ally distinct escape mutants led to vaccine breakthrough in subjects w ith a neutralization response to Wa, it cannot be excluded that breakt hrough could be partially due to antigenic differences in the VP7 prot eins of currently circulating G1 strains.