<p>The Onchocerciasis Vaccine for Africa—TOVA—Initiative</p

Benjamin L. Makepeace

Bin Zhan

BL Makepeace

David Abraham

David W. Taylor

HC Turner

J HP Farrar

JA Hess

K Awadzi

LA Kelly-Hope

LE Coffeng

Maria Elena Bottazzi

MO Traore

Peter J. Hotez

RK Prichard

Roger K Prichard

S Arumugam

S Lustigman

S MJ Lustigman

SA Babayan

Sara Lustigman

TG Geary

Thomas R. Klei

PubMed

Hotez, Peter J

Bottazzi, Maria Elena

Zhan, Bin

Makepeace, Benjamin L

Klei, Thomas R

Abraham, David

Taylor, David W

Lustigman, Sara

Name not available

The Onchocerciasis Vaccine for Africa-TOVA-Initiative.

Peter J. Hotez (145727)

Maria Elena Bottazzi (11043)

Bin Zhan (11041)

Benjamin L. Makepeace (369398)

Thomas R. Klei (687547)

David Abraham (36404)

David W. Taylor (107108)

Sara Lustigman (123305)

The Francis Crick Institute

The Onchocerciasis Vaccine for Africa—TOVA—Initiative

Taylor, David

Edinburgh Research Explorer

     Edinburgh Research Explorer                                      The Onchocerciasis Vaccine for Africa--TOVA--InitiativeCitation for published version:Hotez, PJ, Bottazzi, ME, Zhan, B, Makepeace, BL, Klei, TR, Abraham, D, Taylor, D & Lustigman, S 2015,'The Onchocerciasis Vaccine for Africa--TOVA--Initiative' PLoS Neglected Tropical Diseases, vol. 9, no. 1,pp. e0003422. DOI: 10.1371/journal.pntd.0003422Digital Object Identifier (DOI):10.1371/journal.pntd.0003422Link:Link to publication record in Edinburgh Research ExplorerDocument Version:Publisher's PDF, also known as Version of recordPublished In:PLoS Neglected Tropical DiseasesPublisher Rights Statement:Copyright: © 2015 Hotez et al. This is an open access article distributed under the terms of the CreativeCommons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium,provided the original author and source are creditedGeneral rightsCopyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s)and / or other copyright owners and it is a condition of accessing these publications that users recognise andabide by the legal requirements associated with these rights.Take down policyThe University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorercontent complies with UK legislation. If you believe that the public display of this file breaches copyright pleasecontact openaccess@ed.ac.uk providing details, and we will remove access to the work immediately andinvestigate your claim.Download date: 05. Apr. 2019EDITORIALThe Onchocerciasis Vaccine for Africa—TOVA—InitiativePeter J. Hotez1, Maria Elena Bottazzi1, Bin Zhan1, Benjamin L. Makepeace2, ThomasR. Klei3, David Abraham4, David W. Taylor5*, Sara Lustigman6*1 Sabin Vaccine Institute and Texas Children’s Hospital Center for Vaccine Development, National School ofTropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America, 2 Institute ofInfection and Global Health, University of Liverpool, Liverpool, England, 3 Department of PathobiologicalSciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, United Statesof America, 4 Department of Microbiology and Immunology, Sidney Kimmel Medical College, ThomasJefferson University, Philadelphia, Pennsylvania, United States of America, 5 Division of Pathway Medicine,School for Biomedical Studies, University of Edinburgh, Edinburgh, Scotland, 6 Laboratory of MolecularParasitology, Lindsley F Kimball Research Institute, New York Blood Center, New York, New York, UnitedStates of America* SLustigman@NYBloodCenter.org (SL); David.W.Taylor@ed.ac.uk (DWT)New supportive health intervention technologies, including a vaccine, may be required in orderto achieve onchocerciasis (river blindness) elimination targets. A new transatlantic partnershiphas been established to develop and test an onchocerciasis vaccine for Africa.This year marks the 40 year anniversary of a partnership between the World Bank’s AfricaRegion, the World Health Organization (WHO), Merck & Co., and several other key nongov-ernmental organizations (NGOs) and agencies who have led global efforts to control onchocer-ciasis (river blindness) [1]. By almost any measure, the partnership has achieved extraordinarypublic health successes. It began as the Onchocerciasis Control Programme (OCP) in WestAfrica, which from 1974 to 2002 initially employed vector control through aerial spraying ofinsecticides before initiating ivermectin distribution in 1989 [2]. According to WHO, throughOCP, tens of millions of onchocerciasis cases were prevented, including an estimated 600,000cases of blindness [2]. Moreover, OCP successes allowed 100,000 square miles (25 million hect-ares) of land to be reclaimed for agriculture use [2].As OCP wound down, a second major initiative, the African Programme for OnchocerciasisControl (APOC) began in 1995, focusing on community-directed mass drug administration(MDA) of ivermectin in 19 countries. According to a recent analysis in PLOS NeglectedTropical Diseases, between 1995 and 2010, APOC averted more than 8.2 million disability-adjusted life years (DALYs) and will more than double that number by 2015 [3]. Moreover, thecosts of these health benefits are below $500 million, or approximately $27 per DALY averted[3], such that APOC has emerged as one of the world’s most cost-effective global publichealth programs.These analyses and evidence that the partnership’s activities led to the elimination ofonchocerciasis in endemic foci in two African countries—Mali and Senegal [4]—have fueledgreat interest and optimism in advancing beyond control and perhaps one day eliminating on-chocerciasis from Africa [5]. Indeed, APOC may transition to the Programme for the Elimina-tion of Neglected Diseases in Africa (PENDA) in 2016 with the goal to eliminateonchocerciasis by 2025. This is an ambitious goal that will face a number of challenges.MDA using ivermectin alone may not be sufficient to achieve onchocerciasis elimination.There are several key barriers. First, a known deficiency of MDA programming is the fact thatPLOS Neglected Tropical Diseases | DOI:10.1371/journal.pntd.0003422 January 29, 2015 1 / 5OPEN ACCESSCitation: Hotez PJ, Bottazzi ME, Zhan B,Makepeace BL, Klei TR, Abraham D, et al. (2015)The Onchocerciasis Vaccine for Africa—TOVA—Initiative. PLoS Negl Trop Dis 9(1): e0003422.doi:10.1371/journal.pntd.0003422Editor: Roger K Prichard, McGill University,CANADAPublished: January 29, 2015Copyright: © 2015 Hotez et al. This is an openaccess article distributed under the terms of theCreative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in anymedium, provided the original author and source arecredited.Funding: The author(s) received no specific fundingfor this work.Competing Interests: The authors have declaredthat no competing interests exist.ivermectin cannot be used in areas coendemic to loiasis due to the risk of severe adverse events(SAEs) [6]. Communities in areas coendemic for both onchocerciasis and loiasis often do notreceive treatment [6]. This situation both blocks elimination efforts in Loa-affected communi-ties and also creates reservoir onchocerciasis infections that potentially could promote the rein-troduction of onchocerciasis in neighboring communities under MDA treatments [6]. Inresponse, Cameroon has implemented programs of post-treatment surveillance and manage-ment in areas where loiasis is coendemic with onchocerciasis, but this practice may not alwaysbe feasible elsewhere. In addition, it is common in many areas of sub-Saharan Africa to notimplement onchocerciasis MDA programs in areas of hypoendemicity, which could also leadto reintroduction in areas undergoing MDA.Of even greater concern is the potential widespread emergence of partial or completedrug-resistant Onchocerca volvulus, which poses a threat to the long-term effectiveness of usingivermectin alone in all areas [7–9].Finally, Turner et al. have recently pointed out that success in achieving onchocerciasiselimination would ultimately require irreversible reductions in O. volvulusmicrofilariae pro-duction by 30–35% following each annual round of ivermectin [9]. However, there is great un-certainty around such estimates [9]. Additional disease modeling studies have suggested that,depending on compliance and levels of parasite transmission, it may not be possible to achieveonchocerciasis elimination even after 50 years of annual ivermectin treatments, thereby neces-sitating the adoption of biannual treatments, opening the MDA program up to additional logis-tical and financial challenges [10].The development and implementation of new tools (such as drugs, diagnostics, and vac-cines) may be required if we are to ensure onchocerciasis elimination. Such products could beused to potentiate or enhance the efficiency of ivermectin treatments and address the identifieddeficiencies of current MDA programming. Examples of such products include the use ofmoxidectin in MDA programmes inasmuch as its effect in suppressing microfilaria productionfor prolonged periods [11]; the development of a macrofilaricidal drug or an antibiotic thattargets adult parasite bacterial endosymbionts [12]; the development of a new diagnostic forloiasis infection with improved sensitivity and specificity; and the development of a prophylac-tic and/or therapeutic onchocerciasis vaccine [13].The Sabin Vaccine Institute Product Development Partnership (Sabin PDP) and academicpartners in the United States (New York Blood Center, Thomas Jefferson University, LouisianaState University, Texas Children’s Hospital Center for Vaccine Development at Baylor Collegeof Medicine); Europe (Universities of Edinburgh, Glasgow, Liverpool, Bonn, Imperial CollegeLondon, and the Natural History Museum of Paris); and Africa (University of Buea, Camer-oon, Cameroon Academy of Sciences, and Kwame Nkrumah University, Ghana), have estab-lished The Onchocerciasis Vaccine for Africa (TOVA) Initiative, which is pursuingdevelopment of an onchocerciasis vaccine (Fig. 1)(S1 Text).TOVA Initiative traces its origins to initial support of more than $20 million during the1980s and 1990s from the Edna McConnell Clark Foundation, as well as continued supportfrom the European Union to develop molecular reagents, preclinical (laboratory animal) mod-els, understand the effects of infection on the host immunity, and identify key protective anti-gens across several laboratories in the US, Europe, and Africa. Ultimately, more than a dozencandidate vaccine antigens were identified using small animal models, of which eight were test-ed in bovines challenged with Onchocerca ochengi [14]. Subsequently, these activities continuedwith the support from NIAID/NIH, together with the European Union (through its Director-ate-General for Research and Innovation).Based on this past research, there are compelling reasons to believe that an onchocerciasisvaccine may be an effective tool. To date, three candidate antigens have proven to be efficaciousPLOS Neglected Tropical Diseases | DOI:10.1371/journal.pntd.0003422 January 29, 2015 2 / 5in three different filarial animal model systems and in three independent laboratories. A re-cently published study showed feasibility of eliciting significant protective immunity in miceusing selected recombinant Onchocerca volvulus antigens produced in yeast or bacteria, includ-ing Ov-103, Ov-RAL-2, and Ov-CPI-2M [15]. Moreover, the Brugia malayi homologous re-combinant antigens also elicited protective immunity in gerbils [16] (Klei et al., unpublished).Furthermore, immunization with DNA plasmids carrying the gene encoding Lg-CPI-2M pro-tects mice from patent infection with Litomosoides sigmodontis [17].There are at least two potential target product profiles (TPPs) to consider for the develop-ment of an onchocerciasis vaccine for Africa. They include the development of a preventivevaccine for use in children five years of age or less, who do not receive ivermectin, or a thera-peutic vaccine (targeting either adult worms, microfilariae, the causative agents of pathologyand transmission, or both) for children and adults with O. volvulus infection. These TPPs arenot mutually exclusive, and they could potentially also include coadministration with ivermec-tin or even one of the newer macrofilaricidal agents under parallel development [18]. Modelingstudies have shown that an onchocerciasis vaccine could have substantial impact in a range ofFigure 1. Cover page of The Onchocerciasis Vaccine Initiative prospectus.doi:10.1371/journal.pntd.0003422.g001PLOS Neglected Tropical Diseases | DOI:10.1371/journal.pntd.0003422 January 29, 2015 3 / 5endemicity settings, and when used as a preventive vaccine, could markedly reduce host micro-filarial loads in children and adolescents (Turner HC et al., unpublished).TOVA Initiative is now establishing a roadmap for developing a vaccine to meet one of thetwo described TPPs, with plans to take at least one candidate forward to phase two trials(proof-of-concept trial for efficacy) by 2020. Among the key activities envisioned for TOVAInitiative is a program of confirmatory preclinical testing, optimization, and down-selection inthe O. ochengi–cow model under conditions of natural exposure, together with scale-up processdevelopment, pilot manufacture, toxicology testing, regulatory filing, and phase one clinicaltesting. Indeed, TOVA Initiative is poised to lead on the development of this important newtool to aid in the elimination of onchocerciasis.An onchocerciasis vaccine for Africa would build on past investments in OCP and APOCand support future investments planned under PENDA to help achieve elimination of oncho-cerciasis [19]. TOVA has begun to explore innovative financing mechanisms from majorfoundations, governments in North America, Europe, and elsewhere, as well as some of themajor development banks committed to poverty reduction in sub-Saharan Africa. We stronglyencourage the global public health community to embrace the prospect of an onchocerciasisvaccine and to incorporate plans for a vaccine’s development into future public policy and stra-tegic plan considerations.Supporting InformationS1 Text. Prospectus for TOVA Initiative.(PDF)References1. World Bank (2014) World Bank Live, River Blindness: 40th Anniversary Summit. http://live.worldbank.org/river-blindness. Accessed 21 Jun 2014.2. World Health Organization (2014) Media Centre, Onchocerciasis. http://www.who.int/mediacentre/factsheets/fs374/en/. Accessed 21 June 2014.3. Coffeng LE, Stolk WA, Zoure HG, Veerman JL, Agblewonu KB, et al. (2013) African Programme ForOnchocerciasis Control 1995–2015: model-estimated health impact and cost. PLoS Negl Trop Dis 7:e2032. doi: 10.1371/journal.pntd.0002032 PMID: 233833554. Traore MO, Sarr MD, Badji A, Bissan Y, Diawara L, et al. (2012) Proof-of-principle of onchocerciasiselimination with ivermectin treatment in endemic foci in Africa: final results of a study in Mali and Sene-gal. PLoS Negl Trop Dis 6: e1825. doi: 10.1371/journal.pntd.0001825 PMID: 230295865. World Health Organization (2012) World Health Organization’s 2020 Roadmap on NTDs. http://www.who.int/neglected_diseases/NTD_RoadMap_2012_Fullversion.pdf. Accessed June 21, 2014.6. Kelly-Hope LA, Cano J, Stanton MC, Bockarie MJ, Molyneux DH (2014) Innovative tools for assessingrisks for severe adverse events in areas of overlapping Loa loa and other filarial distributions: the appli-cation of micro-stratification mapping. Parasites & vectors 7: 307. doi: 10.1111/mmi.12922 PMID:255664057. Farrar J HP, Junghanss T, Kang G, Lalloo D eds. (2014) Manson’s Tropical Diseases. 23rd ed. Edin-burgh: Saunders Elsevier. PMID: 255665848. Lustigman S, McCarter JP (2007) Ivermectin resistance in Onchocerca volvulus: toward a geneticbasis. PLoS Negl Trop Dis 1: e76. PMID: 179897899. Turner HC, Churcher TS, Walker M, Osei-Atweneboana MY, Prichard RK, et al. (2013) Uncertainty sur-rounding projections of the long-term impact of ivermectin treatment on human onchocerciasis. PLoSNegl Trop Dis 7: e2169. doi: 10.1371/journal.pntd.0002169 PMID: 2363423410. Turner HC, Walker M, Churcher TS, Osei-Atweneboana MY, Biritwum NK, et al. (2014) Reaching theLondon Declaration on Neglected Tropical Diseases Goals for Onchocerciasis: An Economic Evalua-tion of Increasing the Frequency of Ivermectin Treatment in Africa. Clinical infectious diseases: anPLOS Neglected Tropical Diseases | DOI:10.1371/journal.pntd.0003422 January 29, 2015 4 / 5official publication of the Infectious Diseases Society of America. Clin Infect Dis 59: 923–932. doi: 10.1093/cid/ciu467 PMID: 2494422811. Awadzi K, Opoku NO, Attah SK, Lazdins-Helds J, Kuesel AC (2014) A randomized, single-ascending-dose, ivermectin-controlled, double-blind study of moxidectin in Onchocerca volvulus infection. PLoSNegl Trop Dis 8: e2953 doi: 10.1371/journal.pntd.0002953 PMID: 2496800012. Geary TG, Mackenzie CD (2011) Progress and challenges in the discovery of macrofilaricidal drugs.Expert review of anti-infective therapy 9: 681–695. doi: 10.1586/eri.11.76 PMID: 2181933213. Prichard RK, Basanez MG, Boatin BA, McCarthy JS, Garcia HH, et al. (2012) A research agenda forhelminth diseases of humans: intervention for control and elimination. PLoS Negl Trop Dis 6: e1549.doi: 10.1371/journal.pntd.0001549 PMID: 2254516314. Makepeace BL, Jensen SA, Laney SJ, Nfon CK, Njongmeta LM, et al. (2009) Immunisation with a multi-valent, subunit vaccine reduces patent infection in a natural bovine model of onchocerciasis during in-tense field exposure. PLoS Negl Trop Dis 3: e544. doi: 10.1371/journal.pntd.0000544 PMID:1990198815. Hess JA, Zhan B, Bonne-Annee S, Deckman JM, Bottazzi ME, et al. (2014) Vaccines to combat riverblindness: expression, selection and formulation of vaccines against infection with Onchocerca volvu-lus in a mouse model. Int J Parasitol 44: 637–646. doi: 10.1016/j.ijpara.2014.04.006 PMID: 2490755316. Arumugam S, Wei J, Ward D, Abraham D, Lustigman S, et al. (2014) Vaccination with a geneticallymodified Brugia malayi cysteine protease inhibitor-2 reduces adult parasite numbers and affects the fer-tility of female worms following a subcutaneous challenge of Mongolian gerbils (Meriones unguiculatus)with B. malayi infective larvae. Int J Parasitol 44:675–579. doi: 10.1016/j.ijpara.2014.05.003 PMID:2492913117. Babayan SA, Luo H, Gray N, Taylor DW, Allen JE (2012) Deletion of parasite immune modulatory se-quences combined with immune activating signals enhances vaccine mediated protection against filari-al nematodes. PLoS Negl Trop Dis 6: e1968. doi: 10.1371/journal.pntd.0001968 PMID: 2330110618. Lustigman S MJ, and Bottazzi ME (2012) Vaccines Linked to Chemotherapy: A New Approach toControl Helminth Infections. In: Caffrey CR, editor. Parasitic Helminths: Targets, Screens, Drugs andVaccines. Weinheim, Germany: Wiley-VCH Verlag GmbH & Co. KGaA.19. World Health Organization (2014) African Programme for Onchocerciasis Control (APOC), TechnicalConsultative Committee (TCC). http://www.who.int/apoc/about/structure/tcc/en/. Accessed 28 Jun2014.PLOS Neglected Tropical Diseases | DOI:10.1371/journal.pntd.0003422 January 29, 2015 5 / 5

The Onchocerciasis Vaccine for Africa--TOVA--Initiative

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PLoS Neglected Tropical Diseases

New supportive health intervention technologies, including a vaccine, may be required in order to achieve onchocerciasis (river blindness) elimination targets. A new transatlantic partnership has been established to develop and test an onchocerciasis vaccine for Africa

University of Liverpool Repository

EDITORIALThe Onchocerciasis Vaccine for Africa—TOVA—InitiativePeter J. Hotez1, Maria Elena Bottazzi1, Bin Zhan1, Benjamin L. Makepeace2, ThomasR. Klei3, David Abraham4, David W. Taylor5*, Sara Lustigman6*1 Sabin Vaccine Institute and Texas Children’s Hospital Center for Vaccine Development, National School ofTropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America, 2 Institute ofInfection and Global Health, University of Liverpool, Liverpool, England, 3 Department of PathobiologicalSciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, United Statesof America, 4 Department of Microbiology and Immunology, Sidney Kimmel Medical College, ThomasJefferson University, Philadelphia, Pennsylvania, United States of America, 5 Division of Pathway Medicine,School for Biomedical Studies, University of Edinburgh, Edinburgh, Scotland, 6 Laboratory of MolecularParasitology, Lindsley F Kimball Research Institute, New York Blood Center, New York, New York, UnitedStates of America* SLustigman@NYBloodCenter.org (SL); David.W.Taylor@ed.ac.uk (DWT)New supportive health intervention technologies, including a vaccine, may be required in orderto achieve onchocerciasis (river blindness) elimination targets. A new transatlantic partnershiphas been established to develop and test an onchocerciasis vaccine for Africa.This year marks the 40 year anniversary of a partnership between the World Bank’s AfricaRegion, the World Health Organization (WHO), Merck & Co., and several other key nongov-ernmental organizations (NGOs) and agencies who have led global efforts to control onchocer-ciasis (river blindness) [1]. By almost any measure, the partnership has achieved extraordinarypublic health successes. It began as the Onchocerciasis Control Programme (OCP) in WestAfrica, which from 1974 to 2002 initially employed vector control through aerial spraying ofinsecticides before initiating ivermectin distribution in 1989 [2]. According to WHO, throughOCP, tens of millions of onchocerciasis cases were prevented, including an estimated 600,000cases of blindness [2]. Moreover, OCP successes allowed 100,000 square miles (25 million hect-ares) of land to be reclaimed for agriculture use [2].As OCP wound down, a second major initiative, the African Programme for OnchocerciasisControl (APOC) began in 1995, focusing on community-directed mass drug administration(MDA) of ivermectin in 19 countries. According to a recent analysis in PLOS NeglectedTropical Diseases, between 1995 and 2010, APOC averted more than 8.2 million disability-adjusted life years (DALYs) and will more than double that number by 2015 [3]. Moreover, thecosts of these health benefits are below $500 million, or approximately $27 per DALY averted[3], such that APOC has emerged as one of the world’s most cost-effective global publichealth programs.These analyses and evidence that the partnership’s activities led to the elimination ofonchocerciasis in endemic foci in two African countries—Mali and Senegal [4]—have fueledgreat interest and optimism in advancing beyond control and perhaps one day eliminating on-chocerciasis from Africa [5]. Indeed, APOC may transition to the Programme for the Elimina-tion of Neglected Diseases in Africa (PENDA) in 2016 with the goal to eliminateonchocerciasis by 2025. This is an ambitious goal that will face a number of challenges.MDA using ivermectin alone may not be sufficient to achieve onchocerciasis elimination.There are several key barriers. First, a known deficiency of MDA programming is the fact thatPLOS Neglected Tropical Diseases | DOI:10.1371/journal.pntd.0003422 January 29, 2015 1 / 5OPEN ACCESSCitation: Hotez PJ, Bottazzi ME, Zhan B,Makepeace BL, Klei TR, Abraham D, et al. (2015)The Onchocerciasis Vaccine for Africa—TOVA—Initiative. PLoS Negl Trop Dis 9(1): e0003422.doi:10.1371/journal.pntd.0003422Editor: Roger K Prichard, McGill University,CANADAPublished: January 29, 2015Copyright: © 2015 Hotez et al. This is an openaccess article distributed under the terms of theCreative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in anymedium, provided the original author and source arecredited.Funding: The author(s) received no specific fundingfor this work.Competing Interests: The authors have declaredthat no competing interests exist.ivermectin cannot be used in areas coendemic to loiasis due to the risk of severe adverse events(SAEs) [6]. Communities in areas coendemic for both onchocerciasis and loiasis often do notreceive treatment [6]. This situation both blocks elimination efforts in Loa-affected communi-ties and also creates reservoir onchocerciasis infections that potentially could promote the rein-troduction of onchocerciasis in neighboring communities under MDA treatments [6]. Inresponse, Cameroon has implemented programs of post-treatment surveillance and manage-ment in areas where loiasis is coendemic with onchocerciasis, but this practice may not alwaysbe feasible elsewhere. In addition, it is common in many areas of sub-Saharan Africa to notimplement onchocerciasis MDA programs in areas of hypoendemicity, which could also leadto reintroduction in areas undergoing MDA.Of even greater concern is the potential widespread emergence of partial or completedrug-resistant Onchocerca volvulus, which poses a threat to the long-term effectiveness of usingivermectin alone in all areas [7–9].Finally, Turner et al. have recently pointed out that success in achieving onchocerciasiselimination would ultimately require irreversible reductions in O. volvulusmicrofilariae pro-duction by 30–35% following each annual round of ivermectin [9]. However, there is great un-certainty around such estimates [9]. Additional disease modeling studies have suggested that,depending on compliance and levels of parasite transmission, it may not be possible to achieveonchocerciasis elimination even after 50 years of annual ivermectin treatments, thereby neces-sitating the adoption of biannual treatments, opening the MDA program up to additional logis-tical and financial challenges [10].The development and implementation of new tools (such as drugs, diagnostics, and vac-cines) may be required if we are to ensure onchocerciasis elimination. Such products could beused to potentiate or enhance the efficiency of ivermectin treatments and address the identifieddeficiencies of current MDA programming. Examples of such products include the use ofmoxidectin in MDA programmes inasmuch as its effect in suppressing microfilaria productionfor prolonged periods [11]; the development of a macrofilaricidal drug or an antibiotic thattargets adult parasite bacterial endosymbionts [12]; the development of a new diagnostic forloiasis infection with improved sensitivity and specificity; and the development of a prophylac-tic and/or therapeutic onchocerciasis vaccine [13].The Sabin Vaccine Institute Product Development Partnership (Sabin PDP) and academicpartners in the United States (New York Blood Center, Thomas Jefferson University, LouisianaState University, Texas Children’s Hospital Center for Vaccine Development at Baylor Collegeof Medicine); Europe (Universities of Edinburgh, Glasgow, Liverpool, Bonn, Imperial CollegeLondon, and the Natural History Museum of Paris); and Africa (University of Buea, Camer-oon, Cameroon Academy of Sciences, and Kwame Nkrumah University, Ghana), have estab-lished The Onchocerciasis Vaccine for Africa (TOVA) Initiative, which is pursuingdevelopment of an onchocerciasis vaccine (Fig. 1)(S1 Text).TOVA Initiative traces its origins to initial support of more than $20 million during the1980s and 1990s from the Edna McConnell Clark Foundation, as well as continued supportfrom the European Union to develop molecular reagents, preclinical (laboratory animal) mod-els, understand the effects of infection on the host immunity, and identify key protective anti-gens across several laboratories in the US, Europe, and Africa. Ultimately, more than a dozencandidate vaccine antigens were identified using small animal models, of which eight were test-ed in bovines challenged with Onchocerca ochengi [14]. Subsequently, these activities continuedwith the support from NIAID/NIH, together with the European Union (through its Director-ate-General for Research and Innovation).Based on this past research, there are compelling reasons to believe that an onchocerciasisvaccine may be an effective tool. To date, three candidate antigens have proven to be efficaciousPLOS Neglected Tropical Diseases | DOI:10.1371/journal.pntd.0003422 January 29, 2015 2 / 5in three different filarial animal model systems and in three independent laboratories. A re-cently published study showed feasibility of eliciting significant protective immunity in miceusing selected recombinant Onchocerca volvulus antigens produced in yeast or bacteria, includ-ing Ov-103, Ov-RAL-2, and Ov-CPI-2M [15]. Moreover, the Brugia malayi homologous re-combinant antigens also elicited protective immunity in gerbils [16] (Klei et al., unpublished).Furthermore, immunization with DNA plasmids carrying the gene encoding Lg-CPI-2M pro-tects mice from patent infection with Litomosoides sigmodontis [17].There are at least two potential target product profiles (TPPs) to consider for the develop-ment of an onchocerciasis vaccine for Africa. They include the development of a preventivevaccine for use in children five years of age or less, who do not receive ivermectin, or a thera-peutic vaccine (targeting either adult worms, microfilariae, the causative agents of pathologyand transmission, or both) for children and adults with O. volvulus infection. These TPPs arenot mutually exclusive, and they could potentially also include coadministration with ivermec-tin or even one of the newer macrofilaricidal agents under parallel development [18]. Modelingstudies have shown that an onchocerciasis vaccine could have substantial impact in a range ofFigure 1. Cover page of The Onchocerciasis Vaccine Initiative prospectus.doi:10.1371/journal.pntd.0003422.g001PLOS Neglected Tropical Diseases | DOI:10.1371/journal.pntd.0003422 January 29, 2015 3 / 5endemicity settings, and when used as a preventive vaccine, could markedly reduce host micro-filarial loads in children and adolescents (Turner HC et al., unpublished).TOVA Initiative is now establishing a roadmap for developing a vaccine to meet one of thetwo described TPPs, with plans to take at least one candidate forward to phase two trials(proof-of-concept trial for efficacy) by 2020. Among the key activities envisioned for TOVAInitiative is a program of confirmatory preclinical testing, optimization, and down-selection inthe O. ochengi–cow model under conditions of natural exposure, together with scale-up processdevelopment, pilot manufacture, toxicology testing, regulatory filing, and phase one clinicaltesting. Indeed, TOVA Initiative is poised to lead on the development of this important newtool to aid in the elimination of onchocerciasis.An onchocerciasis vaccine for Africa would build on past investments in OCP and APOCand support future investments planned under PENDA to help achieve elimination of oncho-cerciasis [19]. TOVA has begun to explore innovative financing mechanisms from majorfoundations, governments in North America, Europe, and elsewhere, as well as some of themajor development banks committed to poverty reduction in sub-Saharan Africa. We stronglyencourage the global public health community to embrace the prospect of an onchocerciasisvaccine and to incorporate plans for a vaccine’s development into future public policy and stra-tegic plan considerations.Supporting InformationS1 Text. Prospectus for TOVA Initiative.(PDF)References1. World Bank (2014) World Bank Live, River Blindness: 40th Anniversary Summit. http://live.worldbank.org/river-blindness. Accessed 21 Jun 2014.2. World Health Organization (2014) Media Centre, Onchocerciasis. http://www.who.int/mediacentre/factsheets/fs374/en/. Accessed 21 June 2014.3. Coffeng LE, Stolk WA, Zoure HG, Veerman JL, Agblewonu KB, et al. (2013) African Programme ForOnchocerciasis Control 1995–2015: model-estimated health impact and cost. PLoS Negl Trop Dis 7:e2032. doi: 10.1371/journal.pntd.0002032 PMID: 233833554. Traore MO, Sarr MD, Badji A, Bissan Y, Diawara L, et al. (2012) Proof-of-principle of onchocerciasiselimination with ivermectin treatment in endemic foci in Africa: final results of a study in Mali and Sene-gal. PLoS Negl Trop Dis 6: e1825. doi: 10.1371/journal.pntd.0001825 PMID: 230295865. World Health Organization (2012) World Health Organization’s 2020 Roadmap on NTDs. http://www.who.int/neglected_diseases/NTD_RoadMap_2012_Fullversion.pdf. Accessed June 21, 2014.6. Kelly-Hope LA, Cano J, Stanton MC, Bockarie MJ, Molyneux DH (2014) Innovative tools for assessingrisks for severe adverse events in areas of overlapping Loa loa and other filarial distributions: the appli-cation of micro-stratification mapping. Parasites & vectors 7: 307. doi: 10.1111/mmi.12922 PMID:255664057. Farrar J HP, Junghanss T, Kang G, Lalloo D eds. (2014) Manson’s Tropical Diseases. 23rd ed. Edin-burgh: Saunders Elsevier. PMID: 255665848. Lustigman S, McCarter JP (2007) Ivermectin resistance in Onchocerca volvulus: toward a geneticbasis. PLoS Negl Trop Dis 1: e76. PMID: 179897899. Turner HC, Churcher TS, Walker M, Osei-Atweneboana MY, Prichard RK, et al. (2013) Uncertainty sur-rounding projections of the long-term impact of ivermectin treatment on human onchocerciasis. PLoSNegl Trop Dis 7: e2169. doi: 10.1371/journal.pntd.0002169 PMID: 2363423410. Turner HC, Walker M, Churcher TS, Osei-Atweneboana MY, Biritwum NK, et al. (2014) Reaching theLondon Declaration on Neglected Tropical Diseases Goals for Onchocerciasis: An Economic Evalua-tion of Increasing the Frequency of Ivermectin Treatment in Africa. Clinical infectious diseases: anPLOS Neglected Tropical Diseases | DOI:10.1371/journal.pntd.0003422 January 29, 2015 4 / 5official publication of the Infectious Diseases Society of America. Clin Infect Dis 59: 923–932. doi: 10.1093/cid/ciu467 PMID: 2494422811. Awadzi K, Opoku NO, Attah SK, Lazdins-Helds J, Kuesel AC (2014) A randomized, single-ascending-dose, ivermectin-controlled, double-blind study of moxidectin in Onchocerca volvulus infection. PLoSNegl Trop Dis 8: e2953 doi: 10.1371/journal.pntd.0002953 PMID: 2496800012. Geary TG, Mackenzie CD (2011) Progress and challenges in the discovery of macrofilaricidal drugs.Expert review of anti-infective therapy 9: 681–695. doi: 10.1586/eri.11.76 PMID: 2181933213. Prichard RK, Basanez MG, Boatin BA, McCarthy JS, Garcia HH, et al. (2012) A research agenda forhelminth diseases of humans: intervention for control and elimination. PLoS Negl Trop Dis 6: e1549.doi: 10.1371/journal.pntd.0001549 PMID: 2254516314. Makepeace BL, Jensen SA, Laney SJ, Nfon CK, Njongmeta LM, et al. (2009) Immunisation with a multi-valent, subunit vaccine reduces patent infection in a natural bovine model of onchocerciasis during in-tense field exposure. PLoS Negl Trop Dis 3: e544. doi: 10.1371/journal.pntd.0000544 PMID:1990198815. Hess JA, Zhan B, Bonne-Annee S, Deckman JM, Bottazzi ME, et al. (2014) Vaccines to combat riverblindness: expression, selection and formulation of vaccines against infection with Onchocerca volvu-lus in a mouse model. Int J Parasitol 44: 637–646. doi: 10.1016/j.ijpara.2014.04.006 PMID: 2490755316. Arumugam S, Wei J, Ward D, Abraham D, Lustigman S, et al. (2014) Vaccination with a geneticallymodified Brugia malayi cysteine protease inhibitor-2 reduces adult parasite numbers and affects the fer-tility of female worms following a subcutaneous challenge of Mongolian gerbils (Meriones unguiculatus)with B. malayi infective larvae. Int J Parasitol 44:675–579. doi: 10.1016/j.ijpara.2014.05.003 PMID:2492913117. Babayan SA, Luo H, Gray N, Taylor DW, Allen JE (2012) Deletion of parasite immune modulatory se-quences combined with immune activating signals enhances vaccine mediated protection against filari-al nematodes. PLoS Negl Trop Dis 6: e1968. doi: 10.1371/journal.pntd.0001968 PMID: 2330110618. Lustigman S MJ, and Bottazzi ME (2012) Vaccines Linked to Chemotherapy: A New Approach toControl Helminth Infections. In: Caffrey CR, editor. Parasitic Helminths: Targets, Screens, Drugs andVaccines. Weinheim, Germany: Wiley-VCH Verlag GmbH & Co. KGaA.19. World Health Organization (2014) African Programme for Onchocerciasis Control (APOC), TechnicalConsultative Committee (TCC). http://www.who.int/apoc/about/structure/tcc/en/. Accessed 28 Jun2014.PLOS Neglected Tropical Diseases | DOI:10.1371/journal.pntd.0003422 January 29, 2015 5 / 5

The Onchocerciasis Vaccine for Africa-TOVA-Initiative

     Edinburgh Research Explorer                                      The Onchocerciasis Vaccine for Africa--TOVA--InitiativeCitation for published version:Hotez, PJ, Bottazzi, ME, Zhan, B, Makepeace, BL, Klei, TR, Abraham, D, Taylor, D & Lustigman, S 2015,'The Onchocerciasis Vaccine for Africa--TOVA--Initiative', PLoS Neglected Tropical Diseases, vol. 9, no. 1,pp. e0003422. https://doi.org/10.1371/journal.pntd.0003422Digital Object Identifier (DOI):10.1371/journal.pntd.0003422Link:Link to publication record in Edinburgh Research ExplorerDocument Version:Publisher's PDF, also known as Version of recordPublished In:PLoS Neglected Tropical DiseasesPublisher Rights Statement:Copyright: © 2015 Hotez et al. This is an open access article distributed under the terms of the CreativeCommons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium,provided the original author and source are creditedGeneral rightsCopyright for the publications made accessible via the Edinburgh Research Explorer is retained by the author(s)and / or other copyright owners and it is a condition of accessing these publications that users recognise andabide by the legal requirements associated with these rights.Take down policyThe University of Edinburgh has made every reasonable effort to ensure that Edinburgh Research Explorercontent complies with UK legislation. If you believe that the public display of this file breaches copyright pleasecontact openaccess@ed.ac.uk providing details, and we will remove access to the work immediately andinvestigate your claim.Download date: 10. Jan. 2026EDITORIALThe Onchocerciasis Vaccine for Africa—TOVA—InitiativePeter J. Hotez1, Maria Elena Bottazzi1, Bin Zhan1, Benjamin L. Makepeace2, ThomasR. Klei3, David Abraham4, David W. Taylor5*, Sara Lustigman6*1 Sabin Vaccine Institute and Texas Children’s Hospital Center for Vaccine Development, National School ofTropical Medicine, Baylor College of Medicine, Houston, Texas, United States of America, 2 Institute ofInfection and Global Health, University of Liverpool, Liverpool, England, 3 Department of PathobiologicalSciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, Louisiana, United Statesof America, 4 Department of Microbiology and Immunology, Sidney Kimmel Medical College, ThomasJefferson University, Philadelphia, Pennsylvania, United States of America, 5 Division of Pathway Medicine,School for Biomedical Studies, University of Edinburgh, Edinburgh, Scotland, 6 Laboratory of MolecularParasitology, Lindsley F Kimball Research Institute, New York Blood Center, New York, New York, UnitedStates of America* SLustigman@NYBloodCenter.org (SL); David.W.Taylor@ed.ac.uk (DWT)New supportive health intervention technologies, including a vaccine, may be required in orderto achieve onchocerciasis (river blindness) elimination targets. A new transatlantic partnershiphas been established to develop and test an onchocerciasis vaccine for Africa.This year marks the 40 year anniversary of a partnership between the World Bank’s AfricaRegion, the World Health Organization (WHO), Merck & Co., and several other key nongov-ernmental organizations (NGOs) and agencies who have led global efforts to control onchocer-ciasis (river blindness) [1]. By almost any measure, the partnership has achieved extraordinarypublic health successes. It began as the Onchocerciasis Control Programme (OCP) in WestAfrica, which from 1974 to 2002 initially employed vector control through aerial spraying ofinsecticides before initiating ivermectin distribution in 1989 [2]. According to WHO, throughOCP, tens of millions of onchocerciasis cases were prevented, including an estimated 600,000cases of blindness [2]. Moreover, OCP successes allowed 100,000 square miles (25 million hect-ares) of land to be reclaimed for agriculture use [2].As OCP wound down, a second major initiative, the African Programme for OnchocerciasisControl (APOC) began in 1995, focusing on community-directed mass drug administration(MDA) of ivermectin in 19 countries. According to a recent analysis in PLOS NeglectedTropical Diseases, between 1995 and 2010, APOC averted more than 8.2 million disability-adjusted life years (DALYs) and will more than double that number by 2015 [3]. Moreover, thecosts of these health benefits are below $500 million, or approximately $27 per DALY averted[3], such that APOC has emerged as one of the world’s most cost-effective global publichealth programs.These analyses and evidence that the partnership’s activities led to the elimination ofonchocerciasis in endemic foci in two African countries—Mali and Senegal [4]—have fueledgreat interest and optimism in advancing beyond control and perhaps one day eliminating on-chocerciasis from Africa [5]. Indeed, APOC may transition to the Programme for the Elimina-tion of Neglected Diseases in Africa (PENDA) in 2016 with the goal to eliminateonchocerciasis by 2025. This is an ambitious goal that will face a number of challenges.MDA using ivermectin alone may not be sufficient to achieve onchocerciasis elimination.There are several key barriers. First, a known deficiency of MDA programming is the fact thatPLOS Neglected Tropical Diseases | DOI:10.1371/journal.pntd.0003422 January 29, 2015 1 / 5OPEN ACCESSCitation: Hotez PJ, Bottazzi ME, Zhan B,Makepeace BL, Klei TR, Abraham D, et al. (2015)The Onchocerciasis Vaccine for Africa—TOVA—Initiative. PLoS Negl Trop Dis 9(1): e0003422.doi:10.1371/journal.pntd.0003422Editor: Roger K Prichard, McGill University,CANADAPublished: January 29, 2015Copyright: © 2015 Hotez et al. This is an openaccess article distributed under the terms of theCreative Commons Attribution License, which permitsunrestricted use, distribution, and reproduction in anymedium, provided the original author and source arecredited.Funding: The author(s) received no specific fundingfor this work.Competing Interests: The authors have declaredthat no competing interests exist.ivermectin cannot be used in areas coendemic to loiasis due to the risk of severe adverse events(SAEs) [6]. Communities in areas coendemic for both onchocerciasis and loiasis often do notreceive treatment [6]. This situation both blocks elimination efforts in Loa-affected communi-ties and also creates reservoir onchocerciasis infections that potentially could promote the rein-troduction of onchocerciasis in neighboring communities under MDA treatments [6]. Inresponse, Cameroon has implemented programs of post-treatment surveillance and manage-ment in areas where loiasis is coendemic with onchocerciasis, but this practice may not alwaysbe feasible elsewhere. In addition, it is common in many areas of sub-Saharan Africa to notimplement onchocerciasis MDA programs in areas of hypoendemicity, which could also leadto reintroduction in areas undergoing MDA.Of even greater concern is the potential widespread emergence of partial or completedrug-resistant Onchocerca volvulus, which poses a threat to the long-term effectiveness of usingivermectin alone in all areas [7–9].Finally, Turner et al. have recently pointed out that success in achieving onchocerciasiselimination would ultimately require irreversible reductions in O. volvulusmicrofilariae pro-duction by 30–35% following each annual round of ivermectin [9]. However, there is great un-certainty around such estimates [9]. Additional disease modeling studies have suggested that,depending on compliance and levels of parasite transmission, it may not be possible to achieveonchocerciasis elimination even after 50 years of annual ivermectin treatments, thereby neces-sitating the adoption of biannual treatments, opening the MDA program up to additional logis-tical and financial challenges [10].The development and implementation of new tools (such as drugs, diagnostics, and vac-cines) may be required if we are to ensure onchocerciasis elimination. Such products could beused to potentiate or enhance the efficiency of ivermectin treatments and address the identifieddeficiencies of current MDA programming. Examples of such products include the use ofmoxidectin in MDA programmes inasmuch as its effect in suppressing microfilaria productionfor prolonged periods [11]; the development of a macrofilaricidal drug or an antibiotic thattargets adult parasite bacterial endosymbionts [12]; the development of a new diagnostic forloiasis infection with improved sensitivity and specificity; and the development of a prophylac-tic and/or therapeutic onchocerciasis vaccine [13].The Sabin Vaccine Institute Product Development Partnership (Sabin PDP) and academicpartners in the United States (New York Blood Center, Thomas Jefferson University, LouisianaState University, Texas Children’s Hospital Center for Vaccine Development at Baylor Collegeof Medicine); Europe (Universities of Edinburgh, Glasgow, Liverpool, Bonn, Imperial CollegeLondon, and the Natural History Museum of Paris); and Africa (University of Buea, Camer-oon, Cameroon Academy of Sciences, and Kwame Nkrumah University, Ghana), have estab-lished The Onchocerciasis Vaccine for Africa (TOVA) Initiative, which is pursuingdevelopment of an onchocerciasis vaccine (Fig. 1)(S1 Text).TOVA Initiative traces its origins to initial support of more than $20 million during the1980s and 1990s from the Edna McConnell Clark Foundation, as well as continued supportfrom the European Union to develop molecular reagents, preclinical (laboratory animal) mod-els, understand the effects of infection on the host immunity, and identify key protective anti-gens across several laboratories in the US, Europe, and Africa. Ultimately, more than a dozencandidate vaccine antigens were identified using small animal models, of which eight were test-ed in bovines challenged with Onchocerca ochengi [14]. Subsequently, these activities continuedwith the support from NIAID/NIH, together with the European Union (through its Director-ate-General for Research and Innovation).Based on this past research, there are compelling reasons to believe that an onchocerciasisvaccine may be an effective tool. To date, three candidate antigens have proven to be efficaciousPLOS Neglected Tropical Diseases | DOI:10.1371/journal.pntd.0003422 January 29, 2015 2 / 5in three different filarial animal model systems and in three independent laboratories. A re-cently published study showed feasibility of eliciting significant protective immunity in miceusing selected recombinant Onchocerca volvulus antigens produced in yeast or bacteria, includ-ing Ov-103, Ov-RAL-2, and Ov-CPI-2M [15]. Moreover, the Brugia malayi homologous re-combinant antigens also elicited protective immunity in gerbils [16] (Klei et al., unpublished).Furthermore, immunization with DNA plasmids carrying the gene encoding Lg-CPI-2M pro-tects mice from patent infection with Litomosoides sigmodontis [17].There are at least two potential target product profiles (TPPs) to consider for the develop-ment of an onchocerciasis vaccine for Africa. They include the development of a preventivevaccine for use in children five years of age or less, who do not receive ivermectin, or a thera-peutic vaccine (targeting either adult worms, microfilariae, the causative agents of pathologyand transmission, or both) for children and adults with O. volvulus infection. These TPPs arenot mutually exclusive, and they could potentially also include coadministration with ivermec-tin or even one of the newer macrofilaricidal agents under parallel development [18]. Modelingstudies have shown that an onchocerciasis vaccine could have substantial impact in a range ofFigure 1. Cover page of The Onchocerciasis Vaccine Initiative prospectus.doi:10.1371/journal.pntd.0003422.g001PLOS Neglected Tropical Diseases | DOI:10.1371/journal.pntd.0003422 January 29, 2015 3 / 5endemicity settings, and when used as a preventive vaccine, could markedly reduce host micro-filarial loads in children and adolescents (Turner HC et al., unpublished).TOVA Initiative is now establishing a roadmap for developing a vaccine to meet one of thetwo described TPPs, with plans to take at least one candidate forward to phase two trials(proof-of-concept trial for efficacy) by 2020. Among the key activities envisioned for TOVAInitiative is a program of confirmatory preclinical testing, optimization, and down-selection inthe O. ochengi–cow model under conditions of natural exposure, together with scale-up processdevelopment, pilot manufacture, toxicology testing, regulatory filing, and phase one clinicaltesting. Indeed, TOVA Initiative is poised to lead on the development of this important newtool to aid in the elimination of onchocerciasis.An onchocerciasis vaccine for Africa would build on past investments in OCP and APOCand support future investments planned under PENDA to help achieve elimination of oncho-cerciasis [19]. TOVA has begun to explore innovative financing mechanisms from majorfoundations, governments in North America, Europe, and elsewhere, as well as some of themajor development banks committed to poverty reduction in sub-Saharan Africa. We stronglyencourage the global public health community to embrace the prospect of an onchocerciasisvaccine and to incorporate plans for a vaccine’s development into future public policy and stra-tegic plan considerations.Supporting InformationS1 Text. Prospectus for TOVA Initiative.(PDF)References1. World Bank (2014) World Bank Live, River Blindness: 40th Anniversary Summit. http://live.worldbank.org/river-blindness. Accessed 21 Jun 2014.2. World Health Organization (2014) Media Centre, Onchocerciasis. http://www.who.int/mediacentre/factsheets/fs374/en/. Accessed 21 June 2014.3. Coffeng LE, Stolk WA, Zoure HG, Veerman JL, Agblewonu KB, et al. (2013) African Programme ForOnchocerciasis Control 1995–2015: model-estimated health impact and cost. PLoS Negl Trop Dis 7:e2032. doi: 10.1371/journal.pntd.0002032 PMID: 233833554. Traore MO, Sarr MD, Badji A, Bissan Y, Diawara L, et al. (2012) Proof-of-principle of onchocerciasiselimination with ivermectin treatment in endemic foci in Africa: final results of a study in Mali and Sene-gal. PLoS Negl Trop Dis 6: e1825. doi: 10.1371/journal.pntd.0001825 PMID: 230295865. World Health Organization (2012) World Health Organization’s 2020 Roadmap on NTDs. http://www.who.int/neglected_diseases/NTD_RoadMap_2012_Fullversion.pdf. Accessed June 21, 2014.6. Kelly-Hope LA, Cano J, Stanton MC, Bockarie MJ, Molyneux DH (2014) Innovative tools for assessingrisks for severe adverse events in areas of overlapping Loa loa and other filarial distributions: the appli-cation of micro-stratification mapping. Parasites & vectors 7: 307. doi: 10.1111/mmi.12922 PMID:255664057. Farrar J HP, Junghanss T, Kang G, Lalloo D eds. (2014) Manson’s Tropical Diseases. 23rd ed. Edin-burgh: Saunders Elsevier. PMID: 255665848. Lustigman S, McCarter JP (2007) Ivermectin resistance in Onchocerca volvulus: toward a geneticbasis. PLoS Negl Trop Dis 1: e76. PMID: 179897899. Turner HC, Churcher TS, Walker M, Osei-Atweneboana MY, Prichard RK, et al. (2013) Uncertainty sur-rounding projections of the long-term impact of ivermectin treatment on human onchocerciasis. PLoSNegl Trop Dis 7: e2169. doi: 10.1371/journal.pntd.0002169 PMID: 2363423410. Turner HC, Walker M, Churcher TS, Osei-Atweneboana MY, Biritwum NK, et al. (2014) Reaching theLondon Declaration on Neglected Tropical Diseases Goals for Onchocerciasis: An Economic Evalua-tion of Increasing the Frequency of Ivermectin Treatment in Africa. Clinical infectious diseases: anPLOS Neglected Tropical Diseases | DOI:10.1371/journal.pntd.0003422 January 29, 2015 4 / 5official publication of the Infectious Diseases Society of America. Clin Infect Dis 59: 923–932. doi: 10.1093/cid/ciu467 PMID: 2494422811. Awadzi K, Opoku NO, Attah SK, Lazdins-Helds J, Kuesel AC (2014) A randomized, single-ascending-dose, ivermectin-controlled, double-blind study of moxidectin in Onchocerca volvulus infection. PLoSNegl Trop Dis 8: e2953 doi: 10.1371/journal.pntd.0002953 PMID: 2496800012. Geary TG, Mackenzie CD (2011) Progress and challenges in the discovery of macrofilaricidal drugs.Expert review of anti-infective therapy 9: 681–695. doi: 10.1586/eri.11.76 PMID: 2181933213. Prichard RK, Basanez MG, Boatin BA, McCarthy JS, Garcia HH, et al. (2012) A research agenda forhelminth diseases of humans: intervention for control and elimination. PLoS Negl Trop Dis 6: e1549.doi: 10.1371/journal.pntd.0001549 PMID: 2254516314. Makepeace BL, Jensen SA, Laney SJ, Nfon CK, Njongmeta LM, et al. (2009) Immunisation with a multi-valent, subunit vaccine reduces patent infection in a natural bovine model of onchocerciasis during in-tense field exposure. PLoS Negl Trop Dis 3: e544. doi: 10.1371/journal.pntd.0000544 PMID:1990198815. Hess JA, Zhan B, Bonne-Annee S, Deckman JM, Bottazzi ME, et al. (2014) Vaccines to combat riverblindness: expression, selection and formulation of vaccines against infection with Onchocerca volvu-lus in a mouse model. Int J Parasitol 44: 637–646. doi: 10.1016/j.ijpara.2014.04.006 PMID: 2490755316. Arumugam S, Wei J, Ward D, Abraham D, Lustigman S, et al. (2014) Vaccination with a geneticallymodified Brugia malayi cysteine protease inhibitor-2 reduces adult parasite numbers and affects the fer-tility of female worms following a subcutaneous challenge of Mongolian gerbils (Meriones unguiculatus)with B. malayi infective larvae. Int J Parasitol 44:675–579. doi: 10.1016/j.ijpara.2014.05.003 PMID:2492913117. Babayan SA, Luo H, Gray N, Taylor DW, Allen JE (2012) Deletion of parasite immune modulatory se-quences combined with immune activating signals enhances vaccine mediated protection against filari-al nematodes. PLoS Negl Trop Dis 6: e1968. doi: 10.1371/journal.pntd.0001968 PMID: 2330110618. Lustigman S MJ, and Bottazzi ME (2012) Vaccines Linked to Chemotherapy: A New Approach toControl Helminth Infections. In: Caffrey CR, editor. Parasitic Helminths: Targets, Screens, Drugs andVaccines. Weinheim, Germany: Wiley-VCH Verlag GmbH & Co. KGaA.19. World Health Organization (2014) African Programme for Onchocerciasis Control (APOC), TechnicalConsultative Committee (TCC). http://www.who.int/apoc/about/structure/tcc/en/. Accessed 28 Jun2014.PLOS Neglected Tropical Diseases | DOI:10.1371/journal.pntd.0003422 January 29, 2015 5 / 5

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Peter J Hotez

Benjamin L Makepeace

Thomas R Klei

David W Taylor

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The Onchocerciasis Vaccine for Africa--TOVA--Initiative.

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TOVAThe OnchocerciasisVaccine for AfricaI N I T I A T I V ECover photographsSection through Onchocerca nodule showing microfilariae in uteroBlackfly vector breeding site in fast flowing riverIsolated O volvulus microfilariaeOnchocerca nodule on child’s headFrom control to elimination through mass drug administrationThe London Declaration on Neglected Tropical Diseases of January 2012 called for sustained efforts to expand and extend drug access programmes to ensure the necessary supply of drugs and other interventions to help control human onchocerciasis (river blindness). The African Programme for Onchocerciasis Control (APOC) has extended its mandate, under the new Programme for the Elimination of Neglected Diseases in Africa (PENDA) to begin in 2016, with a new aim of eliminating Onchocerca volvulus, the causative agent of onchocerciasis, by 2025. APOC’s work is predicated on sole use of mass drug administration (MDA) of ivermectin (MectizanTM). Moving from control to elimination using MDA of ivermectin alone will be a challenge, and this strategy may not be sufficient to achieve onchocerciasis elimination. A known deficiency of MDA programming is the fact that ivermectin cannot be used in areas where onchocerciasis and loiasis are co-endemic due to the risk of severe adverse reactions following drug treatment.  It is estimated that 12 million people live in such high risk areas in central Africa (Figure 1) and are potentially affected by this contraindication. In these areas, communities often do not receive supportive treatment; onchocerciasis transmission rates remain high; and, reintroduction of the infection to neighbouring communities from which the disease has been eliminated is an ongoing threat. Additionally, the potential widespread emergence of drug-resistant O volvulus poses a threat to the long-term effectiveness of using ivermectin alone in all areas. In some foci, microfilariae are reappearing in the skin following ivermectin treatment at a faster rate than anticipated, and this may be indicative of development of drug resistance.Successful elimination of onchocerciasis will ultimately require irreversible reductions in O volvulus microfilariae production by 30-35% following each annual round of ivermectin treatment.  However, there is great uncertainty around such estimates.  Disease modelling studies suggest that, depending on compliance and levels of parasite transmission, it may not be possible to achieve onchocerciasis elimination even after 50 years of annual ivermectin treatments, thereby necessitating the adoption of biannual treatments. This would place additional logistical and financial challenges on MDA programmes as well as potentially increasing the rate of emergence of drug resistance. These models recognize the fact that ivermectin does not kill the (long-lived) adult worms and, in areas of high transmission, microfilariae reappear in the skin during the inter-treatment period. Development of new tools (such as drugs, diagnostics and vaccines) will be required to ensure onchocerciasis elimination and remove the risk of reintroduction of the infection to areas where elimination may have been achieved. Such new tools would potentiate or enhance the efficiency of ivermectin treatments and address the identified deficiencies of the current MDA programming.New supportive health intervention technologies, including a vaccine, may be required in order to achieve onchocerciasis (river blindness) elimination targets. A new Trans-Atlantic partnership, the Onchocerciasis Vaccine for Africa (TOVA) Initiative, has been established to develop and test an onchocerciasis vaccine for Africa.  Figure 1 Onchocerciasis and loiasis high risk areasAfrican Programme for Onchocerciasis ControlThe Onchocerciasis Vaccine for Africa  (TOVA) InitiativeVaccine as a new tool to aid in eliminationThe Onchocerciasis Vaccine for Africa (TOVA) Initiative has been launched as a response to the London Declaration on Neglected Tropical Diseases; and, the scientific and technical demands for new tools to complement ivermectin MDA to ensure elimination of onchocerciasis from Africa. TOVA has its origins in the river blindness (onchocerciasis) vaccine program of the Edna McConnell Clark Foundation (EMCF) that contributed $21.6 million between 1985 and 1999.This investment focused on:• development of experimental animal models for screening candidate vaccine antigens and analysis of   mechanisms evoked by immunization with protective recombinant vaccine antigens•  immunological studies in animals and in humans•  identification of protective antigens•  increased understanding of the epidemiology and pathology of river blindnessWhen the programme ended, the work of African, American and European laboratories had developed three animal models, identified a portfolio of 15 O volvulus vaccine candidates including eight that were tested in the O ochengi bovine model, and obtained proof-of-principle of vaccination against infection.The impetus given by EMCF was carried forward by the European Union through its Directorate-General for Research and Innovation (FP7, E PIAF, Enhanced Protective Immunity Against Filariasis, coordinated by Professor David W Taylor), and by the US NIH National Institute of Allergy and Infectious Diseases (The development of a recombinant vaccine against human onchocerciasis headed by Dr Sara Lustigman).The work of these programmes (Figure 2) has identified three candidate vaccine antigens that have proven to be efficacious in three different filarial animal model systems and in three independent laboratories (Table 1).The Onchocerciasis Vaccine for Africa (TOVA) Initiative brings established US and African-European consortia together with the best practice of product development from the Sabin Vaccine Institute and Texas Children’s Hospital Center for Vaccine Development, Sabin PDP (Professors Peter Hotez and Maria Elena Bottazzi), and mathematical modelling from Imperial College London (Professor María-Gloria Basáñez).The demandFigure 2, Progress towards a vaccine against River Blindness EMCF, Edna McConnell Clark FoundationNIH, National Institutes for Health USAEU, European UnionO. volvulus mouse chamber model EMCF river blindness programme         NIH funded projects     Progress towards a vaccine against River Blindness                                              EU DG Research funded contracts     First RB vaccine candidates ready for Phase I, first-in-human safety trials L. sigmodontis mouse model O. ochengi bovine model        Role of T regulatory cells in expression of protective immunity     Protective immunity induced by recombinant proteins Consensus on priority testing of vaccine candidates cGMP manufacturing of vaccines   B. malayi jird and mice models Protective immunity induced by recombinant Ov and Bm antigens First O. volvulus recombinant antigens produced Protective immunity induced by Lg DNA vaccines and synthetic peptides                       TOVA is here Protecting children, reducing morbidity and transmissionOur goal is production and testing of a river blindness vaccine to Phase I clinical trials in 2017 and Phase II efficacy trials by 2020.It is envisaged that the onchocerciasis vaccine will be used initially to protect vulnerable children (<5 years of age) living in loiasis co-endemic areas. The vaccine will reduce adult worm burden and fecundity with consequential reduction in pathology associated with microfilariae (Figure 3). In addition, a vaccine will find use in ongoing ivermectin MDA areas and contribute to reduction in transmission rates; and, will protect areas where local elimination may have been achieved. Table 1, Onchocerciasis (river blindness) vaccine candidatesFigure 3, The vaccine targets and objectivesAntigen (expression system) Location In vitro  L3 killing  In vivo  L3 killing In vivo  Adult killing In vivo  Microfilaria killing CPI-2M (bacteria) ES, Surface,  all stages Ov L3 94% Ov >30% (rProtein )   Ls 50% (rProtein )   Bm >45%  (rProtein)  Ls 70%  (DNA) Ls >85%  (DNA)  Ls >85% (synthetic peptide)   RAL-2 (bacteria)ES, surface,  all stages Ov L3 100% Ov >40%  (rProtein )  Bm >60%  (rProtein )  Bm >90% (rProtein )  103 (yeast)Surface,  all stages Ov L3 100%  Ov Mf >90% Ov >35%  (rProtein )  Bm >40% (rProtein)  Ls >90% (DNA)  Percentages represent killing in vitro (human antigen-specific antibodies + neutrophils) or reduction in parasite burden in vivoES, excreted-secreted antigensrProtein, recombinant proteinOv, Onchocerca volvulusBm, Brugia malayiLs, Litomosoides sigmodontisL3, third stage infective larvaeMf, microfilariaTargets To preventOnchocerca volvulus infective L3 larvaAdult female  O volvulus from noduleMicrofilariae larvae in uterusSkin and eye diseaseThe vaccineModelling analyses have shown that an onchocerciasis vaccine will have a substantial impact in a range of endemicity scenarios (Figure 4) and will markedly reduce microfilarial load in those under 20 years of age. This has important implications as studies have highlighted the increased risk of developing onchocerciasis- related morbidity and mortality in individuals who acquire heavy infections in early life.It is clear that a vaccine would have a beneficial impact by reducing onchocerciasis-related disease burden in these populations. Furthermore, a vaccine could markedly decrease the chance of recrudescence of onchocerciasis in areas where MDA treatment has stopped.The impact of vaccinationFigure 4, A vaccine will be of greatest benefit to children and young adultsAdded value A vaccine would protect the substantial investments made by present and past onchocerciasis control programmes (together, the Onchocerciasis Control Programme in West Africa (OCP) and APOC have cost over US$1 billion), by reducing the chance of disease recrudescence and the possible spread of ivermectin resistance.Turner et al (unpublished)These models are based on a vaccination programme that targets children between 1 and 5 years old during its first year, and 1 year old infants during subsequent years. An initial vaccine efficacy of 50% against the infecting L3 larvae and a 90% reduction of skin microfilarial load is assumed giving a mean duration of any protective effects of the vaccine of 20 years with an 80% coverage of vaccination.00 20 40 60 80AgeContribution to infection burden*00 20 40 60 80Age00 20 40 60 80AgeMesoendemic Hyperendemic Highly HyperendemicOverall mean mf load decreases by 30% but maximum impact on infection burden in young adultsNo Intervention15 years of vaccination0.050.100.150.200.250.300.350.10.20.30.40.50.60.70.20.40.60.81.01.21.4Turner et al. (unpublished) *age-specic mean mf load multiplied by the probability of being in each age group The way forward for vaccine development TOVA Initiative has set its goal to take at least one vaccine candidate to Phase I trials by 2017 and Phase II trials by 2020. To do this the following tasks have been identified:1. Mathematical modelling of vaccine efficacy and delivery, as well as cost-effectiveness.2. Systems analysis to identify specific molecular interactions between parasite antigens and host    immune systems to assist with formulation of the vaccine for greatest efficacy and importantly, to avoid   any interaction that may lead to adverse reactions, including allergic and physiological responses.3. Optimization of immunization strategies using the three filarial small animal models.4. Efficacy trials using the O ochengi cattle model under conditions of natural exposure. 5. Process development for human recombinant vaccine production or synthetic vaccines, including    formulation, assay development, quality control and stability.6. Technology transfer for cGMP manufacturing of vaccines.7. GLP toxicology testing of vaccines.8. Regulatory filing.9. Phase I, first-in-human safety trials in developed and in endemic countries.10. Assessment of immune responses of children up to 9 years age who are exposed to O volvulus    infections in preparation for phase II trials.What is needed to achieve our mission?Table 2, Milestones en route to an onchocerciasis vaccineActivity 2014 2015 2016 2017 2018 2019 2020 1 Mathematical modelling 2 Host and parasite systems analysis for immune correlates and avoidance of pathology 3 Optimization of immunization strategies small animal models 4 Efficacy trials using the O ochengicattle model 5 Process development for human recombinant vaccine production 6 Current GMP Manufacturing of vaccines 7 GLP Toxicology testing  8 Regulatory filing  9 Phase I first-in-human safety trials  10 Assessment of immune responses of children    Colours identify different work packages. The relative activity of individual work packages are indicated by circle area.The approachTable 3, Target product profile of a prophylactic onchocerciasis vaccine Item Desired target Indication A vaccine to protect against infection with infective (L3) larvae and to reduce adult worm burden and microfiladermia for the purpose of reducing morbidity and transmission.   Target Population Children < 5 years. Route of Administration Intramuscular injection. Product Presentation Single-dose vials; 0.5 ml volume of delivery. Dosage Schedule Maximum of 3 immunizations given 4 weeks apart. Warnings and Precautions/Pregnancy  and Lactation Mild to moderate local injection site reactions such as erythema, edema and pain, the character, frequency, and severity of which is similar to licensed recombinant protein vaccines. Less than 0.01% risk of urticaria and other systemic allergic reactions. Incidence of serious adverse reactions no more than licensed comparator vaccines. Expected Efficacy >50% efficacy at preventing establishment of incoming worms; >90% reduction of microfilariae (based on current animal model results).  Co-administration All doses may be co-administered and/or used with other infant immunization programmes. Shelf-Life 4 Years. Storage Refrigeration between 2 to 8 degrees Celsius. Cannot be frozen. Can be out of refrigeration (at temperatures up to 25 degrees) for up to 72 hours. Product Registration Licensure by the Food and Drug Administration and/or the European Medicine Agency. Target price Less than $10 per dose for use in low- and middle-income countries. TOVA Initiative represents a collaborative effort between a team of experienced investigators who have been working together on river blindness for 30 years. These investigators are supported by young scientists with expertise ranging from mathematical modelling, through immunology, proteomics and genomics, vaccinology and product development to clinical practice. TOVA Initiative will adopt the Product Development Partnership (PDP) approach used by the Sabin PDP for accelerating the development of new vaccines for global health. TOVA: who we areName Participant’s organization, country Role in the PartnershipThe partners from AfricaProfessor Samuel Wanji University of Buea, Cameroon Human studies in Cameroon  Research Foundation in Tropical Disease   and Environment  Dr Vincent Tanya Cameroon Academy of Sciences Screening vaccine candidates in the   O ochengi cow model Dr Alex Debrah Kwame Nkrumah University, Ghana Human studies in Ghana The partners from EuropeProfessor David W Taylor University of Edinburgh, UK  Co-ordinator of the EU consortium.    Host gene expression profile analysis.    Vaccine development and human     studies in Cameroon Dr Ben Makepeace University of Liverpool, UK Proteomic and genomic analyses and  Professor Jonathan Wastling  vaccine development. Screening     vaccine candidates in the O ochengi     cattle model Dr Simon Babayan University of Glasgow, UK Filarial immunology, vaccine    development and screening vaccine     candidates in the L sigmodontis     mouse model Dr Coralie Martin Muséum National d’Histoire Naturelle, Screening vaccine candidates in the L  Paris, France sigmodontis mouse model. Host     gene expression profile analysis Professor Achim Hoerauf University Hospital of Bonn, Germany  Immunology of filarial infections and Dr Sabine Specht  human studies in Ghana.    Host gene expression profile analysis    Professor María Gloria Basáñez Imperial College London, UK Mathematical modelling and    cost-effectivenessThe partners from USADr Sara Lustigman New York Blood Center, NYC, USA Program Director of the NIH funded     consortium. Human studies in     Cameroon, characterization of vaccine    candidatesProfessor David Abraham Thomas Jefferson University, Philadelphia,  Screening vaccine candidates in the   PA, USA O volvulus mouse model  Professor Thomas Klei Louisiana State University, Baton Rouge,  Screening vaccine candidates in the LA, USA B malayi-jird model Professor Maria Elena Bottazi The Sabin Vaccine Institute and Texas Product development, technology Professor Peter Hotez Children’s Hospital Center for Vaccine transfer for cGMP manufacture and  Development, Houston, TX, USA GLP toxicology testing, regulatory   filing, early stage clinical testingTable 4, TOVA Partners TOVA is an unincorporated affiliation of the institutions listed in Table 4 that are working collaboratively to meet the challenges of developing a vaccine against river blindness.TOVA: where we areFunding Acknowledgements:EU FP5, VARBO, ICA-CT-1999-10002EU FP6, SCOOTT, INCO 032321EU FP7, E PIAF, 131242NIH/NIAID R01AI078314NIH/NIAID R01A1423228For further details contact:   Professor David W TaylorSchool for Biomedical StudiesUniversity of EdinburghDavid.W.Taylor@ed.ac.ukDr Ben MakepeaceInstitute of Infection & Global Health University of Liverpoolblm1@Liverpool.ac.ukDr Sara LustigmanLindsley F Kimball Research InstituteNew York Blood CenterSLustigman@nybloodcenter.orgTOVAThe OnchocerciasisVaccine for AfricaI N I T I A T I V E

The Onchocerciasis Vaccine for Africa--TOVA--Initiative

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