Although live attenuated vaccine has been used since the 1960s, measles virus (MV) is still a major killer in developing countries. As a specialist in child health care, healthy growth of children in China is in Dr. Zhengyan Zhao’s greatest concern. It brought us attention that adverse effects associated with the current MV vaccine and outbreaks of measles have been increasing significantly in the past a few years in China. Therefore, we conceived the idea whether we could further improve the Chinese MV vaccine and develop a safer, more efficient MV vaccine. In collaboration with two molecular virologists, Drs. Yao-Wei Huang and Jianrong Li, we used a reverse genetics system to rationally design an improved MV vaccine based on MV-Hu191 backbone, which is a widely used vaccine strain in China.
To do this, we first developed a novel method that allows us to assemble an infectious cDNA of the Chinese MV vaccine strain MV-Hu191 in a single step. Previously, in the field of negative-sense RNA viruses, all scientists have been using a multiple-step cloning method to assemble an infectious cDNA, which is time consuming, labor extensive, and technically challenging. Subsequently, the amino acids responsible for mRNA cap MTase activity were mutated in the infectious cDNA clone. We targeted the MTase domain in the large (L) polymerase protein of MV since MTase is important for mRNA stability, translation, and discrimination of self and non-self RNA by host innate immunity. It was expected that MTase-deficient MVs are more attenuated in vitro and in vivo, since this novel concept has recently been tested and verified in several non-segmented, negative-sense RNA viruses including vesicular stomatitis virus (VSV), avian metapneumovirus (aMPV), human metapneumovirus (hMPV), and rabies virus (RABV). These studies have shown that recombinant viruses lacking MTase activity are highly attenuated in vitro and in vivo, yet retain optimal immunogenicity. In our study, the resultant MTase-deficient recombinant MV strains were not only significantly more attenuated but also more immunogenic compared to the parental MV vaccine strain and provided complete protection against MV infection in cotton rats (an animal model for MV research). Thus, these MTase-deficient recombinant MV strains enhance both the safety and efficacy of the current MV vaccine, and may serve as improved vaccine candidates for MV in China.
Introducing the authors
Yilong Wang is a Ph.D. student at Zhejiang University School of Medicine, China. Jianrong Li is a professor at Department of Veterinary Biosciences, College of Veterinary Medicine, The Ohio State University, USA. Yao-Wei Huang is a professor at Institute of Preventive Veterinary Medicine and Key Laboratory of Animal Virology of Ministry of Agriculture, Zhejiang University, China. Zhengyan Zhao is a professor at Children’s Hospital, Zhejiang University School of Medicine, China.
About the research
Enhancement of safety and immunogenicity of the Chinese Hu191 measles virus vaccine by alteration of the S-adenosylmethionine (SAM) binding site in the large polymerase protein
Virology, May 2018, Pages 210-220