Development of a recombinant vaccine against human onchocerciasis

Abstract

Introduction: Human onchocerciasis caused by the filarial nematode parasite Onchocerca volvulus remains a major cause of debilitating disease infecting millions primarily in Sub-Saharan Africa. The development of a prophylactic vaccine, along with mass drug administration, would facilitate meeting the goal of onchocerciasis elimination by 2030. Areas covered: Models used to study immunity to Onchocerca include natural infection of cattle with Onchocerca ochengi and O. volvulus infective third-stage larvae implanted within diffusion chambers in mice. A vaccine, comprised of two adjuvanted recombinant antigens, induced protective immunity in genetically diverse mice suggesting that it will function similarly in diverse human populations. These antigens were recognized by immune humans and also induced protective immunity against Brugia malayi. We describe the development of a fusion protein composed of the two vaccine antigens with the plan to test the vaccine in cows and non-human primates as a prelude to the initiation of phase 1 clinical trials. Expert opinion: The adjuvanted O. volvulus vaccine composed of two antigens Ov-103 and Ov-RAL-2 was shown to be consistently effective at inducing protective immunity using multiple immune mechanisms. The vaccine is ready for further evaluation in other animal models before moving to clinical trials in humans.

Advancing a Human Onchocerciasis Vaccine From Antigen Discovery to Efficacy Studies Against Natural Infection of Cattle With Onchocerca ochengi

“…The O. volvulus parasite only naturally infects human and gorillas and has rarely been observed in other primates ( Vandenberghe et al., 1964 ; Duke, 1980 ; Abraham et al., 2002 ). Even though some primates were able to be experimentally infected with O. volvulus and in which adult filarial worms can develop ( Eberhard et al., 1991 ; Eberhard et al., 1995 ), it is not feasible or practical to use non-human primates as an animal model on which to test a vaccine against onchocerciasis at the early stage due to high cost, logistical limitations, and ethical constraints ( Abraham et al., 2002 ; Lustigman et al., 2002 ; Abraham et al., 2021 ). Another limitation for vaccine development against onchocerciasis is the difficulty to obtain the third-stage infective larvae (L3) without definitive animal hosts infected with the parasite to provide the microfilariae needed to infect blackflies.…”

“…Vaccination of gerbils with irradiated B. malayi L3 induced a 56%–91% reduction in recovered worms and a complete protection against microfilaremia ( Yates and Higashi, 1985 ). This is a potential backup model to test the vaccine efficacy of the homologues of O. volvulus vaccine candidates for preventive, therapeutic, or even transmission-blocking vaccines ( Abraham et al., 2021 ).…”

“…Immunoscreening of a stage-specific cDNA library of O. volvulus with the sera from individuals who acquired protective immunity against infection after many years of exposure to natural infection in endemic areas or developed concomitant immunity ( Lustigman et al., 2002 ) is the major approach to identifying the immunodominant antigens with potential as vaccine candidates. The antigens recognized by these protective sera could be the promising targets of prophylactic and/or therapeutic vaccines against O. volvulus infection ( Abraham et al., 2021 ). The construction of cDNA libraries from critical life-cycle stages for the establishment of O. volvulus infection including infective L3 and the molting L3 (mL3), or microfilariae (Mf), has provided an important platform to screen for such vaccine targets.…”

“…Based on the observations highlighted above, two strategies are extensively used to identify antigens from O. volvulus with vaccine potential. One is the immunoscreening of stage-specific cDNA libraries including those critical for establishment of O. volvulus infection (L3 and mL3) with sera from people living in endemic areas who are putatively immune or from animals immunized with irradiated L3 and acquired protective immunity against challenge infection ( Lustigman et al., 2002 ; Abraham et al., 2021 ). Another is to identify functional proteins that are essential during the infection process or maintenance of the life cycle in the host by analyzing the O. volvulus genome or transcriptome ( Lizotte-Waniewski et al., 2000 ) or by studying functional homologs that induce protective immunity in other nematode host–parasite systems ( Gregory et al., 2000 ).…”

“…Analysis of ESPs in nodule fluid in cows infected with O. ochengi identified 85 proteins with drug or vaccine potential ( Eberle et al., 2015 ). Vaccination with these crucial molecules may induce immune responses that block or interfere with the establishment of the parasite in the host ( Lustigman et al., 2017 ; Abraham et al., 2021 ). Another 26 protein antigens were identified through immunoscreening of a cDNA library with different protective sera, 12 of which demonstrated partial or significant protection when tested in the O. volvulus mouse model ( Abraham et al., 2001 ; Lustigman et al., 2002 ; Lustigman et al., 2003 ).…”