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Detection of mutations in the VP7 gene of vaccine-derived strains shed by monovalent rotavirus vaccine recipients.

ABSTRACT: Strains of Rotarix, a live attenuated monovalent oral rotavirus vaccine, replicate in the intestine and are shed for about one month in immunocompetent recipients. The current study aimed to identify genetic changes of shed strains to reveal any significant mutations and their clinical impact on recipients. Stool samples of recipients of the first dose of Rotarix were sequentially collected for one month from the day of administration. Sequence analyses of the VP7 gene in eight recipients revealed five amino acid substitutions. Among them, two were observed in aa123, which is located in antigenic region 7-1a. Since there were no associated clinical symptoms, the genetic changes were unlikely to have caused reversion of pathogenicity of vaccine strain. Of interest, the virus in one case became closer to wild-type rotavirus via an amino acid change at aa123 occurring 14?days after administration, which might have resulted from multiple replications and long-term shedding of the vaccine strain.

SUBMITTER: Kaneko M

PROVIDER: S-EPMC7470403 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Detection of mutations in the VP7 gene of vaccine-derived strains shed by monovalent rotavirus vaccine recipients.

Kaneko Mei M Takanashi Sayaka S Inoue Mana M Sakiyama Hiroshi H Okitsu Shoko S Mizuguchi Masashi M Ushijima Hiroshi H

Access microbiology 20190903 8

Strains of Rotarix, a live attenuated monovalent oral rotavirus vaccine, replicate in the intestine and are shed for about one month in immunocompetent recipients. The current study aimed to identify genetic changes of shed strains to reveal any significant mutations and their clinical impact on recipients. Stool samples of recipients of the first dose of Rotarix were sequentially collected for one month from the day of administration. Sequence analyses of the VP7 gene in eight recipients reveal ...[more]

PMID: 32974546

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Project description:Species A rotaviruses (RVs) are a leading cause of severe acute gastroenteritis in infants and children younger than 5 years. Currently available RV vaccines were adapted from wild-type RV strains by serial passage of cultured cells or by reassortment between human and animal RV strains. These traditional methods require large-scale screening and genotyping to obtain vaccine candidates. Reverse genetics is a tractable, rapid, and reproducible approach to generating recombinant RV vaccine candidates carrying any VP4 and VP7 genes that provide selected antigenicity. Here, we developed a vaccine platform by generating recombinant RVs carrying VP4 (P[4] and P[8]), VP7 (G1, G2, G3, G8, and G9), and/or VP6 genes cloned from human RV clinical samples using the simian RV SA11 strain (G3P[2]) as a backbone. Neutralization assays using monoclonal antibodies and murine antisera revealed that recombinant VP4 and VP7 monoreassortant viruses exhibited altered antigenicity. However, replication of VP4 monoreassortant viruses was severely impaired. Generation of recombinant RVs harboring a chimeric VP4 protein for SA11 and human RV gene components revealed that the VP8* fragment was responsible for efficient infectivity of recombinant RVs. Although this system must be improved because the yield of vaccine viruses directly affects vaccine manufacturing costs, reverse genetics requires less time than traditional methods and enables rapid production of safe and effective vaccine candidates.IMPORTANCE Although vaccines have reduced global RV-associated hospitalization and mortality over the past decade, the multisegmented genome of RVs allows reassortment of VP4 and VP7 genes from different RV species and strains. The evolutionary dynamics of novel RV genotypes and their constellations have led to great genomic and antigenic diversity. The reverse genetics system is a powerful tool for manipulating RV genes, thereby controlling viral antigenicity, growth capacity, and pathogenicity. Here, we generated recombinant simian RVs (strain SA11) carrying heterologous VP4 and VP7 genes cloned from clinical isolates and showed that VP4- or VP7-substituted chimeric viruses can be used for antigenic characterization of RV outer capsid proteins and as improved seed viruses for vaccine production.

Project description:BackgroundRotaviral diarrhoea kills about half a million children annually in developing countries and accounts for one third of diarrhea related hospitalizations. Drugs and vaccines against the rotavirus are handicapped, as in all viral diseases, by the rapid mutational changes that take place in the DNA and protein sequences rendering most of these ineffective. As of now only two vaccines are licensed and approved by the WHO (World Health Organization), but display reduced efficiencies in the underdeveloped countries where the disease is more prevalent. We approached this issue by trying to identify regions of surface exposed conserved segments on the surface glycoproteins of the virion, which may then be targeted by specific peptide vaccines. We had developed a bioinformatics protocol for these kinds of problems with reference to the influenza neuraminidase protein, which we have refined and expanded to analyze the rotavirus issue.ResultsOur analysis of 433 VP7 (Viral Protein 7 from rotavirus) surface protein sequences across 17 subtypes encompassing mammalian hosts using a 20D Graphical Representation and Numerical Characterization method, identified four possible highly conserved peptide segments. Solvent accessibility prediction servers were used to identify that these are predominantly surface situated. These regions analyzed through selected epitope prediction servers for their epitopic properties towards possible T-cell and B-cell activation showed good results as epitopic candidates (only dry lab confirmation).ConclusionsThe main reasons for the development of alternative vaccine strategies for the rotavirus are the failure of current vaccines and high production costs that inhibit their application in developing countries. We expect that it would be possible to use the protein surface exposed regions identified in our study as targets for peptide vaccines and drug designs for stable immunity against divergent strains of the rotavirus. Though this study is fully dependent on computational prediction algorithms, it provides a platform for wet lab experiments.

Dataset Information

Detection of mutations in the VP7 gene of vaccine-derived strains shed by monovalent rotavirus vaccine recipients.

Publications

Detection of mutations in the VP7 gene of vaccine-derived strains shed by monovalent rotavirus vaccine recipients.

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