Jin Q, Ward R L, Knowlton D R, Gabbay Y B, Linhares A C, Rappaport R, Woods P A, Glass R I, Gentsch J R
Viral Gastroenteritis Section, Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
Arch Virol. 1996;141(11):2057-76. doi: 10.1007/BF01718215.
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.
1991年至1992年期间，在美国24个地点进行了一项关于恒河猴四价（RRV-TV）和G1血清型单价（RRV-S1）轮状病毒疫苗的大型安慰剂对照疗效试验。两种疫苗针对所有腹泻的保护率分别为49%和54%，但针对非常严重的肠胃炎的保护率分别为80%和69%。接种疫苗后，针对G1 Wa株的中和抗体滴度与两种疫苗中所含轮状病毒D株的VP7蛋白几乎相同，与针对随后G1株疾病的保护作用无关。这一结果增加了一种可能性，即在接种疫苗后产生针对Wa的中和抗体的婴儿中，突破性感染（即疫苗接种失败——免疫后发生轮状病毒腹泻）可能是由于感染了与疫苗株抗原性足够不同的G1株，从而逃避了疫苗接种所引发的中和抗体。为了验证这一假设，我们最初使用经历突破性感染的受试者的血清，比较了疫苗接种者针对Wa和G1突破性毒株的接种后中和抗体滴度。接种疫苗后针对Wa产生的免疫中和抗体滴度显著（P < 0.001）高于随后从这些受试者获得的突破性毒株。然而，这种差异与缺乏保护作用并无关联，因为在经历无症状轮状病毒感染或未感染的疫苗接种者的接种后血清中，针对Wa和突破性毒株的滴度也存在类似差异。为了确定这些差异的遗传基础，我们将Wa的VP7基因序列与疫苗株D、12株G1突破性毒株以及在同一试验中从安慰剂接受者分离出的3株G1对照毒株进行了比较。所有突破性毒株在整个VP7蛋白的抗原重要区域都与Wa和D不同，但这些差异在突破性毒株和安慰剂毒株之间是保守的。此外，对来自12个国家的G1轮状病毒VP7基因推导氨基酸序列的比较分析表明，已经进化出了四个不同的谱系。美国疫苗试验中的所有突破性毒株和对照毒株都属于与血清型G1疫苗株D不同的谱系。虽然总体结果不支持我们最初的假设，即对抗原性不同的逃逸突变体的免疫选择导致了对Wa有中和反应的受试者出现疫苗突破性感染，但不能排除突破性感染可能部分归因于当前流行的G1株VP7蛋白的抗原差异。
