Multivalent Vaccine Formulation with BmVAL-1 and BmALT-2 Confer Significant Protection against Challenge Infections with Brugia malayi in Mice and Jirds

Purpose: Lymphatic filariasis is a mosquito borne infection affecting 120 million people in 83 different countries. Despite several setbacks, mass drug administration is fully underway in several parts of the world to eradicate this infection by year 2020. Even though drug alone is highly efficient in treating this infection, long term sustainable prophylaxis needs effective vaccine. Unfortunately there are no vaccines available to control this infection in human and animals despite the fact that several potential candidate vaccine antigens have been identified by several laboratories. Brugia malayi Vespid venom Allergen homologue-Like protein (BmVAL-1) and B. malayi Abundant Larval Transcript (BmALT-2) are two of the most promising vaccine candidates. In this study we have evaluated various vaccination regimens consisting of DNA and protein antigens and evaluated the potential of monovalent and multivalent vaccine formulations in mice and jird animal models. Methods: Mice and jirds were vaccinated with monovalent DNA preparations of BmVAL-1 or BmALT-2 in pVAX-1 vector or monovalent protein preparations of rBmVAL-1 and rBmALT-2 in alum using a homologous or heterologous prime boost approach. These vaccine regimens were then compared with a multivalent vaccine formulation consisting of DNA or hybrid protein formulation of the two antigens. Challenge experiments were performed with B. malayi L3 in mice and jirds to evaluate the degree of protection and immunological parameters were determined in mice and human to elucidate the characteristics of the protective immune responses. Results: Results presented in this study show that vaccination with monovalent BmVAL-1 vaccine confers from 39% (DNA vaccine) protection to 54% (DNA prime and protein boost) protection in mice. Similar degree of protection was observed in jirds (50% to 52% protection). Monovalent BmAT-2 afforded 51% to 75% protection in mice and 58% to 79% protection in jirds. When we tested a multivalent formulation of BmVAL-1 and BmALT-2, there was 57% to 82% protection in mice and 77% to 85% protection in jirds. Heterologous prime boost approach using the multivalent vaccine gave the highest degree of protection in both mice and jirds. Serological analysis in mice showed that BmVAL-1 vaccination induced an IgG1, IgG2a and IgG3 antibody response, whereas, BmALT-2 vaccination predominantly induced an IgG1 and IgG3 antibody response. Cytokine responses of antigen responding cells in the spleen secreted predominantly IFN-y and IL-5 in response to BmVAL-1 and IL-4 and IL-5 in response to BmALT-2. Conclusion: In conclusion, results presented in this study show that a multivalent vaccine formulation of BmVAL-1 and BmALT-2 when given as a prime boost regimen gave significant protection against lymphatic filariasis caused by B. malayi in mice and jirds. Since putatively immune EN subjects also carry protective antibodies against BmVAL-1 and BmALT-2, there is a great potential for developing this multivalent formulation as a prophylactic vaccine against B. malayi for human and veterinary use.