Generation of Recombinant Authentic Live Attenuated Human Rotavirus Vaccine Strain RIX4414 (Rotarix®) from Cloned cDNAs Using Reverse Genetics

Author:

Fukuda Saori1ORCID,Kugita Masanori2,Kumamoto Kanako2,Akari Yuki13,Higashimoto Yuki45ORCID,Nagao Shizuko2ORCID,Murata Takayuki16ORCID,Yoshikawa Tetsushi56,Taniguchi Koki1,Komoto Satoshi136ORCID

Affiliation:

1. Department of Virology, Fujita Health University School of Medicine, Toyoake 470-1192, Aichi, Japan

2. Education and Research Facility of Animal Models for Human Diseases, Fujita Health University, Toyoake 470-1192, Aichi, Japan

3. Division of One Health, Research Center for GLOBAL and LOCAL Infectious Diseases (RCGLID), Oita University, Yufu 879-5593, Oita, Japan

4. Department of Clinical Microbiology, Fujita Health University School of Medical Sciences, Toyoake 470-1192, Aichi, Japan

5. Department of Pediatrics, Fujita Health University School of Medicine, Toyoake 470-1192, Aichi, Japan

6. Center for Infectious Disease Research, Research Promotion Headquarters, Fujita Health University, Toyoake 470-1192, Aichi, Japan

Abstract

The live attenuated human rotavirus vaccine strain RIX4414 (Rotarix®) is used worldwide to prevent severe rotavirus-induced diarrhea in infants. This strain was attenuated through the cell culture passaging of its predecessor, human strain 89-12, which resulted in multiple genomic mutations. However, the specific molecular reasons underlying its attenuation have remained elusive, primarily due to the absence of a suitable reverse genetics system enabling precise genetic manipulations. Therefore, we first completed the sequencing of its genome and then developed a reverse genetics system for the authentic RIX4414 virus. Our experimental results demonstrate that the rescued recombinant RIX4414 virus exhibits biological characteristics similar to those of the parental RIX4414 virus, both in vitro and in vivo. This novel reverse genetics system provides a powerful tool for investigating the molecular basis of RIX4414 attenuation and may facilitate the rational design of safer and more effective human rotavirus vaccines.

Funder

AMED

JSPS KAKENHI

RCGLID, Oita University

GSK Japan Research Grant 2021

Mochida Memorial Foundation for Medical and Pharmaceutical Research

Takeda Science Foundation

Public Foundation of Vaccination Research Center

Publisher

MDPI AG

Reference58 articles.

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2. Rotavirus vaccination and the global burden of rotavirus diarrhea among children younger than 5 years;Troeger;JAMA Pediatr.,2018

3. Knipe, D.M., Howley, P.M., Cohen, J.I., Griffin, D.E., Lamb, R.A., Martin, M.A., Racaniello, V.R., and Roizman, B. (2013). Rotaviruses. Fields Virology, Wolters Kluwer Health/Lippincott Williams & Wilkins. [6th ed.].

4. Rotarix: Development of a live attenuated monovalent human rotavirus vaccine;Bernstein;Pediatr. Ann.,2006

5. Global impact of rotavirus vaccination on diarrhea hospitalizations and deaths among children <5 years old: 2006–2019;Burnett;J. Infect. Dis.,2020

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