Humoral immune responses against novel recombinant replication-competent poxvirus candidate vaccines expressing full length and chimeric lyssavirus glycoprotein genes

Abstract

Rabies is a neurological disease caused by viruses of the genus Lyssavirus belonging to the family Rhabdoviridae and order Mononegavirales. The Lyssavirus genus consists of eleven species namely rabies virus; Lagos bat virus; Mokola virus , Duvenhage virus; European bat lyssavirus virus type 1; European bat lyssavirus type 2; Australian bat lyssavirus; Aravan; Khujand; Irkut; West Caucasian bat viruses and recently isolated Shimoni bat virus. The prototype virus of the Lyssavirus genus is represented by rabies virus. The remaining lyssaviruses are collectively denoted as rabies-related viruses. It has been proposed that these lyssavirus genotypes/species could be divided into 2 and possibly 3 phylogroups, based on diversity and shared biological/pathogenicity properties. Currently available vaccines have proven efficacy against viruses that would make up phylogroup I, but fail to cross-protect against those lyssaviruses belonging to phylogroup II and III. The potential public health burden associated with mortality due to rabies-related virus infection has prompted several vaccine studies to focus on the pan-lyssavirus vaccine cross-protection. The studies demonstrated that lyssaviruses glycoprotein domains (antigenic sites) can be exchanged to generate chimeric vaccine constructs and that combining antigenic sites II and III of different lyssaviruses raised virus neutralizing antibodies against different lyssaviruses. The objective of our study was to determine the cross protective capacity of similar constructs in a vaccinia virus Copenhagen strain based recombinant in proof of concept to ascertain cross protection in a murine model. The current study substantiates findings of preceding studies that chimeric lyssavirus glycoprotein vaccine constructs conferred protection against homologous and heterologous lyssaviruses. The replicating vaccinia virus based vector demonstrated the benefit of a replicating recombinant vaccine vector as illustrated by the high protective neutralizing antibody titers obtained. The value of administering a booster dose was also highlighted in the higher antibody titers obtained upon a vaccine boost. The study clearly demonstrated that glycoprotein antigenic site II and III are not equal in inducing protection and that site II confers better protection against a homologous virus.