Development of new recombinant vaccines for rabies and dog population management

Abstract

Development of new recombinant vaccines for rabies and dog population management Domestic dogs are responsible for the majority of human rabies cases. To eliminate rabies from a given population, two components are crucial, namely mass vaccination of dogs and provision of PEP to bite victims. Achieving the recommended 70% vaccination coverage can be difficult in developing countries. This study aimed to develop recombinant vaccines that could address two factors that hinder the success of vaccination campaigns: 1) vaccinating unreachable dogs and 2) preventing high population turnover. In considering the first aim, oral vaccination of dogs in developing countries can be a useful adjunct in remote areas or communities with large numbers of free-roaming dogs. Given its host specificity (canines), transmission mechanism (oral) and safety, a recombinant canine adenovirus type 2 expressing the rabies glycoprotein gene (CAV2- RG) could be an ideal candidate oral vaccine. To assess the potential use of this vaccine in dog populations, we investigated the prevalence of antibodies against canine adenovirus type 2 (CAV2) in South African dogs. Blood was collected from 241 dogs from 2 provinces in South Africa. Sampled dogs had not previously been vaccinated against canine adenovirus (CAV1 or CAV2). The high seropositivity observed (45% and 62%) in animals from both provinces suggests that CAV2 circulates extensively among domestic dogs in South Africa. Given this finding, we evaluated the effect of pre-existing CAVspecific antibodies on the efficacy of the CAV2-RG vaccine in dogs. Purpose-bred Beagle dogs, which received prior vaccination against CAV, were immunized by oral administration of CAV2-RG. After rabies lyssavirus (RABV) infection, all animals, except one vaccinated dog, developed rabies. This study demonstrated that pre-existing antibodies against CAV, such as naturally occurs in South African dogs, inhibits the development of neutralizing antibodies against RABV when immunized with a CAV-based rabies recombinant vaccine. Considering the second aim of this study, high population turnover in free-roaming dogs is a major factor that influences the efficiency and cost of vaccination programmes. As a population management intervention, surgical sterilization is cost-prohibitive in developing countries while chemical sterilization presents many difficulties associated with safety and acceptance of such practices. Immunocontraceptives may offer an ideal, non-permanent mechanism to interrupt breeding cycles and contribute to population management. We have therefore developed 6 candidate immunocontraceptive vaccines expressing gonadotropin-releasing hormone (GnRH). Two human adenovirus type 5 (HAd5) vaccines and four DNA-based vaccines were constructed. Expression of the GnRH-gene from all inserts was confirmed in cell culture and vaccines were evaluated for immunogenicity in a murine model. No animals developed anti-GnRH antibody responses after 2 intramuscular doses of the DNA vaccines. In a heterologous primeboost strategy all animals that received DNA vaccines also received a booster dose of one HAd5 vaccine but failed to develop any anti-GnRH antibodies. After 2 intramuscular vaccinations with the respective HAd5 constructs, mice from both groups developed GnRH-specific antibody responses. This study demonstrated the potential of recombinant viral vectored vaccines to induce an antibody response against GnRH. These findings may represent an important step in the development of an effective immunocontraceptive vaccine for use in domestic dogs