No 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.

Human rotaviruses from the states of Rio de Janeiro, São Paulo and Pará of Brazil were analysed by RNA electrophoresis. At least some bands characteristic of rotavirus double-stranded RNA were detected in 138 (86.8%) of 159 faecal samples in which the presence of rotavirus had been demonstrated by enzyme immunoassay. Of the RNA-positive samples, 18 (13.0%) were classified as subgroup 1, 94 (68.1%) as subgroup 2, and 26 (18.8%) could not be classified due to absence of visible bands 10 and 11. Subgroup 2 was more frequent in the three states. All strains of subgroup 1 detected in Rio de Janeiro were associated with a single short-lived school outbreak. All strains of subgroup 1 resembled each other in electrophoretic pattern, irrespective of geographical origin, although minor differences could be detected by co-electrophoresis. Subgroup 2, on the other hand, showed a great degree of electrophoretic heterogeneity and could be divided into several sub-categories.

From December 1982 to March 1986 a group of 80 children between 0 and 3 years old who lived in the peripheral area of Belém, Brazil, were followed up for episodes of diarrhoea. A total of 441 diarrhoeal episodes were recorded and 36 (8.2%) were associated with rotavirus. This agent was the only pathogen in 50% of rotavirus-related episodes of acute diarrhoea, and strains were characterized by analysis of RNA in polyacrylamide gels. Forty-one belonged to subgroup II (long pattern) and five to subgroup I. Reinfections by rotavirus were noted in 12 children involving either the same or different subgroups. Ten distinct electrophoretypes were detected in the study period and the predominant one had the '1N2L' profile. The cumulative age-specific attack rate for diarrhoea reached 2.8 by the end of the first year of life; a frequency of 2.3 episodes of diarrhoea per child per year was observed throughout the complete investigation. In comparing the age-specific attack rates for diarrhoea between breast-fed and bottle-fed children, a peak at 6 months of age was noted in the former, and at 1 month in the latter. A comparison by Fischer's exact test (P = 0.21) provided no evidence for protection against clinical rotavirus disease by maternal milk. By the same test, however (P = 0.021), we found significant evidence that early rotavirus infections were more likely to be asymptomatic and that infections after 4 months were more likely to be symptomatic. The clinical picture in children with rotavirus-related diarrhoea was more severe than in those suffering from acute diarrhoea due to another agent.