Kotaki Tomohiro, Kanai Yuta, Ogden Kristen M, Onishi Megumi, Kumthip Kattareeya, Khamrin Pattara, Boonyos Patcharaporn, Phoosangwalthong Pornkamol, Singchai Phakapun, Luechakham Tipsuda, Minami Shohei, Chen Zelin, Hirai Katsuhisa, Tacharoenmuang Ratana, Mizushima Hiroto, Ushijima Hiroshi, Maneekarn Niwat, Kobayashi Takeshi
Department of Virology, Research Institute for Microbial Diseases, The University of Osaka, Osaka, Japan.
Department of Pediatrics, Vanderbilt University Medical Center, Nashville, Tennessee, USA.
mBio. 2025 Jul 9;16(7):e0089725. doi: 10.1128/mbio.00897-25. Epub 2025 May 30.
Rotavirus infections remain a significant cause of morbidity and mortality in infants. The viral surface proteins VP4 and VP7 are each classified into multiple genotypes (P[1]-P[58] for VP4 and G1-G42 for VP7), which differ in their susceptibility to neutralizing antibodies; however, detailed analyses of these differences remain limited. This study investigates the susceptibility of diverse VP4 and VP7 genotypes to neutralizing antibodies induced by vaccination or natural infection. A reverse genetics system based on the human rotavirus Odelia strain (G4P[8]) was used to create monoreassortant viruses by replacing the VP4 or VP7 genes with those from clinical isolates (obtained in Thailand) or prototype strains. We generated 11 VP4 and 19 VP7 reassortants, covering 7 and 17 genotypes, respectively. Neutralization tests using the monoreassortant viruses, immune sera, and MA104 cells indicate that the VP7 genotype, rather than the VP4 genotype, primarily influences susceptibility to neutralization. Furthermore, genotypes G2, bat-like G3, G11, G12, G25, and G33 were significantly less susceptible to sera from naturally infected Thai individuals, highlighting the importance of monitoring these genotypes. To identify the protein region responsible for susceptibility to neutralization, we generated chimeric viruses by exchanging the domains of high- and low-susceptibility VP7 genotypes and found that Domain I appears to play a substantial role in determining susceptibility. Thus, we identified multiple rotavirus genotypes with reduced susceptibility to neutralization, as well as the region primarily responsible for this reduction. These findings may help to predict possible future rotavirus outbreaks in humans and facilitate the development of effective rotavirus vaccines.IMPORTANCERotavirus, the leading cause of severe acute gastroenteritis in infants, is responsible for approximately 128,500 infant deaths globally each year. The virus's surface proteins are highly diverse, comprising approximately 100 genotypes. This diversity affects susceptibility to neutralizing antibodies and the efficacy of vaccines. Here, we found that certain genotypes are highly resistant to serum neutralizing antibodies induced by vaccination and natural infections. Furthermore, we identified a specific region in the viral outer capsid protein that plays a significant role in determining susceptibility to neutralization. These findings may be important for predicting outbreak-causing strains and for developing more effective vaccines, ultimately contributing to the prevention of future outbreaks and improving global infant health.
轮状病毒感染仍是婴儿发病和死亡的重要原因。病毒表面蛋白VP4和VP7各自被分为多个基因型（VP4为P[1]-P[58]，VP7为G1-G42），它们对中和抗体的敏感性不同；然而，对这些差异的详细分析仍然有限。本研究调查了不同VP4和VP7基因型对疫苗接种或自然感染诱导的中和抗体的敏感性。基于人轮状病毒奥黛丽亚株（G4P[8]）的反向遗传学系统被用于通过用临床分离株（在泰国获得）或原型株的VP4或VP7基因替换来创建单重配病毒。我们产生了11个VP4重配体和19个VP7重配体，分别涵盖7种和17种基因型。使用单重配病毒、免疫血清和MA104细胞进行的中和试验表明，主要影响中和敏感性的是VP7基因型，而非VP4基因型。此外，G2、蝙蝠样G3、G11、G12、G25和G33基因型对泰国自然感染个体的血清敏感性显著较低，突出了监测这些基因型的重要性。为了确定负责中和敏感性的蛋白区域，我们通过交换高敏感性和低敏感性VP7基因型的结构域产生了嵌合病毒，并发现结构域I似乎在决定敏感性方面起重要作用。因此，我们确定了多种对中和敏感性降低的轮状病毒基因型，以及对此降低主要负责的区域。这些发现可能有助于预测未来人类可能发生的轮状病毒疫情，并促进有效的轮状病毒疫苗的开发。
重要性
轮状病毒是婴儿严重急性胃肠炎的主要病因，每年在全球导致约128,500例婴儿死亡。该病毒的表面蛋白高度多样化，包括约100种基因型。这种多样性影响对中和抗体的敏感性和疫苗的效力。在这里，我们发现某些基因型对疫苗接种和自然感染诱导的血清中和抗体具有高度抗性。此外，我们在病毒外衣壳蛋白中确定了一个特定区域，该区域在决定中和敏感性方面起重要作用。这些发现对于预测引起疫情的毒株和开发更有效的疫苗可能很重要，最终有助于预防未来的疫情爆发并改善全球婴儿健康。
