Multivalent vaccine formulation with BmVAL-1 and BmALT-2 confer significant protection against challenge infections with Brugia malayi in mice and jirds

Research and Reports in Tropical Medicine Dovepress open access to scientific and medical research O r i g i n al R e s e ar c h Research and Reports in Tropical Medicine downloaded from https://www.dovepress.com/ by 37.59.46.207 on 12-Jul-2018 For personal use only. Open Access Full Text Article Multivalent vaccine formulation with BmVAL-1 and BmALT-2 confer significant protection against challenge infections with Brugia malayi in mice and jirds This article was published in the following Dove Press journal: Research and Reports in Tropical Medicine 23 March 2011 Number of times this article has been viewed Ramaswamy Kalyanasundaram Padmavathi Balumuri Department of Biomedical Sciences, College of Medicine, University of Illinois Rockford, IL, USA Correspondence: Kalyanasundaram R Professor and Head, Department of Biomedical Sciences, University of Illinois Rockford, College of Medicine, 1601 Parkview Avenue, Rockford, IL 61107, USA Tel +1 815 395-5696 Fax +1 815 395-5684 Email submit your manuscript | www.dovepress.com Dovepress DOI: 10.2147/RRTM.S13679 Powered by TCPDF (www.tcpdf.org) Purpose: Lymphatic filariasis, a mosquito-borne infection, affects 120 million people in 83 different countries. Mass drug administration is fully underway in several parts of the world to eradicate this infection by year 2020. Drugs alone are highly efficient treatments, but long-term sustainable prophylaxis requires an effective vaccine. No vaccines are available for humans and animals despite several potential candidate vaccine antigens having been identified. Brugia malayi vespid venom allergen homolog-like protein (BmVAL-1) and B. malayi abundant larval transcript (BmALT-2) are two of the most promising vaccine candidates. We 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 humans to elucidate the characteristics of the protective immune responses. Results: Vaccination with monovalent BmVAL-1 vaccine conferred 39% (DNA vaccine) to 54% (DNA prime and protein boost) protection in mice. A similar degree of protection was observed in jirds (50% to 52%). Monovalent BmALT-2 afforded 51% to 75% protection in mice and 58% to 79% protection in jirds. Our testing of a multivalent formulation of BmVAL-1 and BmALT-2, showed 57% to 82% protection in mice and 77% to 85% protection in jirds. A 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-γ and IL-5 in response to BmVAL-1, and IL-4, and IL-5 in response to BmALT-2. Conclusion: A multivalent vaccine formulation of BmVAL-1 and BmALT-2 given as a prime boost regimen gave significant protection against lymphatic filariasis caused by B. malayi in mice and jirds. Because putatively immune endemic normal subjects also carry protective antibodies against BmVAL-1 and BmALT-2, developing this multivalent formulation as a prophylactic vaccine against B. malayi for human and veterinary use has great potential. Keywords: Brugia malayi, BmALT-2, BmVAL-1, vaccine, lymphatic filariasis Research and Reports in Tropical Medicine 2011:2 45–56 45 © 2011 Kalyanasundaram and Balumuri, publisher and licensee Dove Medical Press Ltd. This is an Open Access article which permits unrestricted noncommercial use, provided the original work is properly cited. Kalyanasundaram and Balumuri Research and Reports in Tropical Medicine downloaded from https://www.dovepress.com/ by 37.59.46.207 on 12-Jul-2018 For personal use only. Introduction Human lymphatic filariasis is a mosquito-borne disease caused mainly by two filarial parasites, Brugia malayi and Wuchereria bancrofti. The disease affects over 120 million people living in over 83 different countries in the tropical and subtropical regions of the world.1 Diethylcarbamazine (DEC) is an effective drug against this infection.2,3 Essentially, this drug clears the microfilaria stage of the parasite thereby preventing transmission. A combination of DEC with albendazole or ivermectin is currently used as a drug of choice for multidrug administration (MDA) strategy to control this infection in regions where it is endemic.3 The ultimate goal is to eliminate the disease by 2020. MDA strategy is proving to be very successful in several parts of the world. Despite its initial success, some endemic regions have already started facing significant difficulties in implementing the MDA program due to political unrest or lack of compliance.4–7 To be effective, MDA needs to be repeated annually for at least 5 years (WHO).8 Vector control measures are not as successful as treating the patient, to control the infection. However, since the vector population is very high in these regions, multiple treatments with MDA are necessary for consistent protection. MDA, especially albendazole as part of such a regimen raises concern because of the potential for drug resistance. In fact, resistance to the benzimidazole group of drugs has already been reported in the treatment of B. malayi and W. bancrofti.9 Thus repeated administration of albendazole each year in the endemic region may not be ideal. A more practicable and sustainable approach to preventing this infection in a large population would be a prophylactic vaccination possibly with simultaneous mass screening and treating infected individuals with DEC or combination drugs such as that used in MDA. Protective immunity against lymphatic filarial parasite has been demonstrated in both humans and animals. 10,11 Certain individuals living in the endemic areas under the same environmental conditions as infected individuals do not show any symptoms of the disease, but carry a high titer of antibodies against the filarial parasites in their sera. Previous studies from our laboratory showed that these circulating antibodies can participate in the killing of infective third stage (L3) B. malayi larvae in vitro through an antibody dependent cell cytotoxicity (ADCC) mechanism.12 Similarly, animal studies have also shown that vaccination with irradiat (...truncated)