Human onchocerciasis (ONCHO) is a major cause of infectious blindness, skin disease, and chronic disability, infecting many millions worldwide?99% in Sub-Saharan Africa?and resulting in widespread vision impairment and blindness. Caused by the filarial nematode Onchocerca volvulus (Ov), attempts to eliminate this neglected tropical disease via annual mass drug administration (MDA) with donated ivermectin (IVM) have proved largely ineffective, decreasing its incidence only 31% in the last 20 years. Optimists call for an additional 1.15 billion treatments to achieve elimination by 2045. Mathematical modelling and expert opinions are more pessimistic, indicating that ONCHO in Africa cannot be eliminated solely through MDA with IVM. Supporting their viewpoint is that IVM cannot be administered safely in Central Africa where the disease is co-endemic with Loa loa infections, and early evidence points to the possible emergence of IVM drug resistance. New tools are needed, such as a preventive vaccine to accelerate ONCHO elimination. Our goal is to develop a safe and effective prophylactic vaccine to protect vulnerable populations of children <5 living in endemic areas against Ov infections. Reducing the adult worm burden and possibly also fecundity will inexorably reduce microfilaridermia and pathology. The vaccine could also contribute to lower transmission rates and protect areas where local elimination may have been achieved, thus lowering the number of annual MDA with IVM, forestalling drug resistance, and ensuring the success of the existing MDA. We have already identified 2 Ov protective vaccine antigens (Ov-103 and Ov-RAL-2) with a proven production pathway and with efficacy in 2 small-animal models; they were protective as monovalent vaccines, and their efficacy was enhanced when the two monovalent vaccines were co-administered in separate locations (i.e. ONCHO vaccine). We seek now to leverage these achievements by advancing to the next stage on the critical path to Ov vaccine development. Our hypothesis is that an optimal ONCHO vaccine formulation can be identified by further employing the mouse model before testing it in nave calves against a natural infection with O. ochengi, an infection system with a closely related parasite known to mimic immunologically the status of humans living in regions endemic for Ov. Notably, both vaccine antigens pose minimal risk of generating atopic responses in children <5 years of age who are naturally exposed to ONCHO; neither elicits significant functional IgE responses. We have 2 specific aims for meeting our goal: (1) Test in nave calves under field conditions the efficacy of two ONCHO vaccine formulations against O. ochengi infection. (2) Establish immune correlates and mechanisms associated in mice with protective immunity induced by two ONCHO vaccine formulations. Ascertaining which of the 2 adjuvanted ONCHO vaccines (formulated with alum or with Advax-2 with or without alum) is more efficacious in the vaccinated calves, and the parallel elucidation of their immune correlates in the bovine and mouse models will position us to move the optimal ONCHO vaccine formulation to first-in-human trials.

Public Health Relevance

Human onchocerciasis?more commonly, ?river blindness??is one of the most devastating yet neglected tropical diseases, leaving many millions in Sub-Saharan Africa blind and/or with chronic disabilities. Attempts to eradicate onchocerciasis, primarily through the mass drug administration of ivermectin, have proven ineffective, so the challenge remains and has been heightened by the alarming news that drug-resistant parasites are developing in some populations after years of drug treatment. Needed, and needed now, in the fight to eliminate onchocerciasis are new tools, such as a preventive vaccine like the one we are working to develop. The consortium of partners we have gathered to work with us is singularly placed to advance the onchocerciasis vaccine from the research lab into the clinic.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI078314-07
Application #
9444432
Study Section
Vaccines Against Microbial Diseases Study Section (VMD)
Program Officer
MO, Annie X Y
Project Start
2009-08-25
Project End
2022-02-28
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
7
Fiscal Year
2018
Total Cost
Indirect Cost
Name
New York Blood Center
Department
Type
DUNS #
073271827
City
New York
State
NY
Country
United States
Zip Code
10065
Lustigman, Sara; Makepeace, Benjamin L; Klei, Thomas R et al. (2018) Onchocerca volvulus: The Road from Basic Biology to a Vaccine. Trends Parasitol 34:64-79
Cotton, James A; Bennuru, Sasisekhar; Grote, Alexandra et al. (2016) The genome of Onchocerca volvulus, agent of river blindness. Nat Microbiol 2:16216
Hess, Jessica A; Zhan, Bin; Torigian, April R et al. (2016) The Immunomodulatory Role of Adjuvants in Vaccines Formulated with the Recombinant Antigens Ov-103 and Ov-RAL-2 against Onchocerca volvulus in Mice. PLoS Negl Trop Dis 10:e0004797
Arumugam, Sridhar; Wei, Junfei; Liu, Zhuyun et al. (2016) Vaccination of Gerbils with Bm-103 and Bm-RAL-2 Concurrently or as a Fusion Protein Confers Consistent and Improved Protection against Brugia malayi Infection. PLoS Negl Trop Dis 10:e0004586
Makepeace, Benjamin L; Babayan, Simon A; Lustigman, Sara et al. (2015) The case for vaccine development in the strategy to eradicate river blindness (onchocerciasis) from Africa. Expert Rev Vaccines 14:1163-5
Arumugam, Sridhar; Wei, Junfei; Ward, Danielle et al. (2014) Vaccination with a genetically modified Brugia malayi cysteine protease inhibitor-2 reduces adult parasite numbers and affects the fertility of female worms following a subcutaneous challenge of Mongolian gerbils (Meriones unguiculatus) with B. malayi inf Int J Parasitol 44:675-9
Bonne-Année, Sandra; Kerepesi, Laura A; Hess, Jessica A et al. (2014) Extracellular traps are associated with human and mouse neutrophil and macrophage mediated killing of larval Strongyloides stercoralis. Microbes Infect 16:502-11
Arumugam, Sridhar; Zhan, Bin; Abraham, David et al. (2014) Vaccination with recombinant Brugia malayi cystatin proteins alters worm migration, homing and final niche selection following a subcutaneous challenge of Mongolian gerbils (Meriones unguiculatus) with B. malayi infective larvae. Parasit Vectors 7:43
Hess, Jessica A; Zhan, Bin; Bonne-Année, Sandra et al. (2014) Vaccines to combat river blindness: expression, selection and formulation of vaccines against infection with Onchocerca volvulus in a mouse model. Int J Parasitol 44:637-46
Bonne-Année, Sandra; Kerepesi, Laura A; Hess, Jessica A et al. (2013) Human and mouse macrophages collaborate with neutrophils to kill larval Strongyloides stercoralis. Infect Immun 81:3346-55

Showing the most recent 10 out of 16 publications