A rotavirus vaccine candidate attenuated by codon deoptimization protects neonatal mice against wild-type virus...

Rotavirus infection is a leading cause of acute viral gastroenteritis and diarrhea in infants and young children. Owing to the limited development of effective antiviral therapies, vaccination has become the primary and most efficient strategy to reduce rotavirus-associated morbidity and mortality. Compared with classical virus attenuation strategies, reverse genetics approaches such as codon deoptimization are safer, more time-saving, more cost-effective, and more controllable. The present study describes the development of an oral live-attenuated rotavirus vaccine candidate using codon deoptimization. Based on a simian rotavirus SA11 strain, eight gene segments, encoding the structural proteins VP1, VP2, VP3, and VP6, and the non-structural proteins NSP2, NSP3, NSP4, and NSP5, were subjected to codon deoptimization. Attenuated rotavirus by multi-segment codon deoptimization (MS8cd) exhibited markedly attenuated replication both in vitro and in vivo, attributable to reduced protein production independent of mRNA stability. Despite the attenuation, MS8cd elicited robust systemic and mucosal antibody responses which were sufficient to protect neonatal mice against challenge with wild-type rotavirus in a maternal immunization model. To alter the immunogenicity, MS8cd was manipulated to encapsidate outer capsid proteins of several prevalent human rotaviruses. These reassortants exhibited altered antigenic and immunogenic properties associated with the differing genotypes of the outer capsid proteins. In conclusion, this study describes the generation of promising rotavirus vaccine candidates attenuated by codon deoptimization. They are capable of eliciting genotype-specific and broad-spectrum protective immunity against circulating strains of rotavirus. This represents a rapid-response platform for the development of novel vaccines against emerging variants.