The Onchocerciasis Vaccine for Africa (TOVA): A new tool to help … · 2020-01-20 · Loiasis, another filarial disease, is caused by the eye worm Loa loa, which is closely related

The Onchocerciasis Vaccine for Africa (TOVA):

a new tool to help prevent, control and

eliminate river blindness from Africa

The vaccine is aimed at pre-school children

who are currently excluded from ivermectin based mass treatment programmes

1

EU supported African and European laboratories EU FP5, VARBO, ICA-CT-1999-10002; EU FP6, SCOOTT, INCO 032321; EU FP7, E PIAF,

131242. Cameroon Academy of Sciences Kwame Nkrumah University, Ghana University of Buea, Cameroon Research Foundation in

Tropical Disease and Environment, Imperial College London, Muséum National d’Histoire Naturelle Paris, University Hospital of Bonn,

University of Edinburgh, University of Glasgow, University of Liverpool

NIH/NIAD supported laboratories

Louisiana State - Baton Rouge, New York Blood Center, Thomas Jefferson University - Philadelphia, National School of Tropical

Medicine, Baylor College of Medicine, and Texas Children’s Hospital Center for Vaccine Development - Houston

The Onchocerciasis Vaccine for Africa (TOVA)

A new tool to help prevent, control and eliminate river blindness from Africa

The International Community has set ambitious targets for elimination of onchocerciasis (river

blindness) as a public health problem by 2025. Considerable progress has been made through

annual and bi-annual mass treatment with ivermectin (MectizanTM) for periods of between 10

and 15 years. However, in areas of high prevalence, transmission of the infection persists after

20 years of mass treatment. Furthermore, disease modelling studies suggest that it may not be

possible to achieve complete onchocerciasis elimination using ivermectin alone, even after 50

years of annual treatment [1,2].

WHO defines elimination as the reduction to zero of the incidence of an infection caused by a

specific pathogen in a defined geographical area, with minimal risk of reintroduction. This is

not eradication, which is the permanent [complete] removal a disease from the World.

If elimination of onchocerciasis is to be achieved on a more extensive scale, new and additional

interventions will be required. A vaccine would complement and augment ivermectin treatment

and address identifiable deficiencies in current ivermectin-based control programmes which

exclude children under 5 years and cannot used in communities where onchocerciasis is co-

endemic with loiasis, a second parasitic infection.

TOVA partners have been working towards the development of a vaccine for over 25 years.

Three vaccine candidates have been selected based on their ability to evoke strong protective

responses capable of reducing parasite burden of immunised animals by more than 90%.

TOVA aims to take at least one of these vaccine candidates through Phase I trials by 2025. The

immediate task is to manufacture the vaccines and demonstrate their safety in accordance with

national and international regulations and WHO guidelines.

The onchocerciasis vaccine is initially aimed at protecting pre-school children (<5 years of

age). The vaccine will reduce adult worm burden and fecundity with consequential reduction

in pathology associated with microfilariae.

In addition, a vaccine will find use in ongoing ivermectin control programmes and contribute

to reduction in transmission rates; moreover, it will protect areas where local elimination may

have been achieved.

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The Disease

Onchocerciasis, or river blindness, is a neglected tropical disease that inflicts lifelong misery on

sufferers through skin disease, visual impairment and blindness. It is caused by Onchocerca volvulus,

a parasitic filarial nematode worm.

According to the World Health Organisation (WHO, 2017), 21 million people are infected with O

volvulus and 198 million are at risk of infection. More than 99% of onchocerciasis patients live in sub-

Saharan Africa, although there are also small isolated foci in Latin America and Yemen.

The infection is transmitted through the bite of blackflies (Simulium spp) that breed in fast flowing

streams and rivers; it is this association that gave rise to the common name of the disease. The life cycle

is summarised in Figure 1.

Figure 1, The life cycle of Onchocerca volvulus

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Infection is initiated by L3 larvae (Figure 2) that enter the skin when blackflies take a blood meal. Over

a period of about 1 year, L3 larvae mature into adults which are found in sub-cutaneous nodules over

the pelvis, pectoral girdle and/or head (Figure 3). Female worms (Figure 4) live for about 15 years and

can give birth to between 500 and 1500 microfilariae (L1 larvae, Figures 5 and 6) per day. Microfilariae

migrate from the nodules to the skin and eyes where they can be detected within a year of the initial

infection. The parasite’s life cycle is completed when microfilariae are ingested by a blackfly taking a

blood meal.

Figure 2, L3 larvae recovered from

Simulium blackflies

Figure 3, Onchocerca nodules on head of

child in Cameroon

Figure 4, Adult female Onchocerca volvulus

recovered from excise d nodule

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Figure 5, Microfilariae in uterus of

O volvulus

Figure 6, Microfilariae of O volvulus

(length 220 to 360 µm)

Microfilariae can live up to two years in the skin but when they eventually die, either naturally or due

to drug treatment, they evoke inflammatory responses, which are responsible for most symptoms of

onchocerciasis (Figures 7 and 8). Itching is the most frequent early sign of infection, but this can lead

to severe local or general and disfiguring dermatitis (Figure 7) and premature ageing of the skin. Skin

disease has a disproportionate impact on women, first through social exclusion, including reducing

prospects of marriage; and second, on their ability and willingness to breast-feed babies.

About 1% of individuals infected with O volvulus are blind and a further 10% visually impaired (Figure

8); however, up to 70% suffer from skin disease of varying severity

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Figure 7, Onchocerciasis dermatitis and

inflammatory response surrounding

microfilariae in skin

Figure 8, Punctate keratitis, an early sign

of onchocerciasis eye disease.

The lesions comprise dead or dying

microfilariae surround by an

inflammatory response

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Control For the last 30 years, control and treatment of onchocerciasis has relied on mass drug administration

(MDA) using ivermectin (Mectizan, donated by Merck & Co through the Mectizan Donation

Programme (https://mectizan.org). This drug rapidly kills microfilariae but does not kill adult parasites.

Repeated annual or biannual treatment leads to a reduction in morbidity (eye and skin disease)

associated with the death and destruction of the microfilariae. Furthermore, removal of microfilariae

from the skin blocks transmission of the infection and this has resulted in eradication of the disease

from isolated foci in Colombia, Ecuador, Mexico and Guatemala. However, in areas of Africa with high

initial prevalence of infection, transmission continues even after 25 years of annual treatment [4]

(https://doi.org/10.1371/journal.pntd.0004392). Mathematical models have shown that elimination of

onchocerciasis using ivermectin alone, if at all possible, would require at least another 25 years of MDA

[1] (https://doi.org/10.1371/journal.pntd.0003664)

The prospects for elimination of onchocerciasis through MDA alone are severely reduced because

ivermectin cannot be used across large areas of central Africa where onchocerciasis and loiasis are co-

endemic (Figure 9). Loiasis, another filarial disease, is caused by the eye worm Loa loa, which is closely

related to O volvulus and similarly gives birth to large numbers of microfilariae. However, L loa

microfilaria live in the blood and their rapid death following ivermectin treatment can be associated

with severe adverse and sometimes fatal inflammatory responses. It has been estimated that in 2015, 10

million people live in such high-risk areas and are potentially affected by this contraindication [5]

https://doi.org/10.1093/cid/ciz647), and this may rise to 17 million in 2025. In these areas,

(communities often do not receive supportive treatment; onchocerciasis transmission rates remain high;

and they provide a reservoir for reintroduction of the infection to neighbouring communities from which

the disease has been eliminated.

Additionally, the potential emergence of drug-resistant O volvulus poses a threat to the long-term

effectiveness of using ivermectin alone [6] (https://doi.org/10.1371/journal.pntd.0000998; [7]

https://doi.org/10.1371/journal.pntd.0005816). 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, which is widespread amongst parasites of veterinary importance.

Onchocerca volvulus and epilepsy Recently several epidemiological studies have suggested an association between epilepsy (including

nodding disease) with onchocerciasis [8] (https://doi.org/10.1186/s40249-018-0400-0). The prevalence

rate for epilepsy in onchocerciasis endemic areas has been recorded at between 2 and 8% which

contrasts to a rate of 1.4% in areas where onchocerciasis does not occur.

Although a causal link between O volvulus and epilepsy has yet to be proven, there is a suggestion that

control of onchocerciasis may also reduce the incidence of epilepsy. The onset of epilepsy in

onchocerciasis patients is between 3 and 18 years. Children below 5 years are excluded from ivermectin

treatment, but an onchocerciasis vaccine could offer protection against epilepsy if a true aetiological

link exists.

https://mectizan.org/

https://doi.org/10.1371/journal.pntd.0004392


https://doi.org/10.1093/cid/ciz647



https://doi.org/10.1186/s40249-018-0400-0

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Progress towards a vaccine against onchocerciasis TOVA has its origins in the river blindness (onchocerciasis) vaccine program of the Edna McConnell

Clark Foundation (EMCF) between 1985 and 1999. This investment focused on:

1 development of experimental animal models for screening candidate vaccine antigens

2 analysis of immunological mechanisms evoked by immunization with protective recombinant

vaccine antigens

3 identification of protective antigens

When 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 tested

in the O ochengi bovine model, and obtained proof-of-principle of vaccination against infection [9].

The impetus given by EMCF was carried forward by the European Union through its Directorate-

General for Research and Innovation (FP5, VARBO; FP6, SCOOTT; 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:

1 increased the understanding of the epidemiology and pathology of onchocerciasis

2 helped define the mechanisms of protective immunity against filarial parasites

3 demonstrated the role of parasite-induced immunomodulators in expression of protective immunity

4 identified three candidate vaccine antigens that have proven to be efficacious in three different

filarial animal model systems and in five independent laboratories (Table 2).

Table 2, Progress towards a vaccine against onchocerciasis

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The Vaccine

The TOVA Partnership has identified three candidate vaccine candidates by their ability to stimulate

immune responses that killed the various lifecycle stages of the parasites in model systems [14]

(https://www.ncbi.nlm.nih.gov/pubmed/28958602).

The life cycle of O volvulus cannot be maintained in the laboratory, although infective L3 larvae

recovered from blackflies can survive a short time confined in sub-cutaneous chambers in mice.

To assess killing of adult worms and microfilariae, two models were used. First, Brugia malayi in

gerbils (Meriones unguiculatus) and second Litomosoides sigmodontis in mice. B malayi causes

lymphatic filariasis or elephantiasis in humans and is found in India, Indonesia, Malaysia and Thailand.

L sigmodontis is a natural parasite of cotton rats (Sigmodon spp.) but can undergo complete cyclical

development in laboratory mice and hence is a valuable model for detailed investigation of mechanisms

of immunity against filariae.

Table 3 summarises results of immunisation experiments performed with the selected vaccine

candidates. All three are expressed on the surface of the parasites at all developmental stages, where

they provide a target for direct attack by the immune system. This is well demonstrated by the in vitro

killing of L3 larvae by antibody and neutrophils.

One of the antigens (CPI-2M) is derived from an immuno-modulator secreted by the parasite to help it

avoid potential lethal effects of acquired immune responses of infected individuals [15]

(https://doi.org/10.1371/journal.pntd.0001968). Vaccination with this antigen generates antibodies

capable of neutralising the suppressive action of the native molecule and thereby facilitating expression

of responses directed against all parasite antigens.

Table 3 Onchocerciasis vaccine candidates

https://www.ncbi.nlm.nih.gov/pubmed/28958602

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Children: the neglected hosts

Children below 5 years are excluded from ivermectin treatment and this leaves a significant proportion

of the population exposed to infection. For example, in Cameroon [2015], 16% of the population are

under 5 years [10] (United Nations, http://esa.un.org/unpd/wpp/index.htm). Similar age profiles are

found throughout filarial endemic regions of Africa and in populations that are expected to double over

the next 25 years (https://www.populationpyramid.net/world/2019/).Pre-school children comprise a

large reservoir of microfilariae that can contribute to transmission.

For the individual, the consequences of not receiving treatment would be the prospect of developing

progressive filarial disease and more general long-term health problems as well as associated socio-

economic disadvantage. Vaccination would protect the individual and make a major contribution to

public health.

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 (Figures 7 & 8). In

addition, a vaccine will find use in ongoing ivermectin MDA programmes and contribute to reduction

in transmission rates; and, will protect areas where local elimination may have been achieved.

http://esa.un.org/unpd/wpp/index.htm

https://www.populationpyramid.net/world/2019/

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The Impact A vaccine will be of greatest benefit to children and young adults.

Modelling analyses (Figure 8) have shown that an onchocerciasis vaccine will have a substantial impact

in a range of endemicity scenarios and will markedly reduce microfilarial load in those under 20 years

of age [12] (https://doi.org/10.1371/journal.pntd.0003938). 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. 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.

A vaccine is probably the only tool that could prevent infection in very young children for their

personal benefit. Young children have been completely neglected in onchocerciasis control efforts to

date because they rarely show any symptoms of disease. Nevertheless, modelling data indicate that they

are affected by excess mortality attributable to onchocerciasis

(https://doi.org/10.1371/journal.pntd.0001578), and it should not be assumed that they will always

receive ivermectin later in life to prevent disease symptoms (for instance, due to residence in loiasis-

endemic areas or migration from their community of origin).

Figure 9, The impact of childhood vaccination on parasite numbers



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Added value A vaccine would protect the substantial investments made by present and past onchocerciasis control

programmes (the Onchocerciasis Control Programme, OCP; and the African Programme for

Onchocerciasis Control, APOC; over US$1 billion), by reducing the chance of disease recrudescence

and the inevitable spread of ivermectin resistance.

The vaccine may also find application in a therapeutic role in individuals already infected with O

volvulus.

Beyond onchocerciasis, it may be possible to apply the vaccine (with or without reformulation) to

control of lymphatic filariasis. A veterinary application may be found in control and prevention of

canine heartworm (Dirofilaria immitis).

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TOVA: Next steps

The biggest challenge facing TOVA is funding for Good Manufacturing Practice to produce the

vaccine and first-in-human safety trials.

TOVA has set its goals to take at least one vaccine candidate through Phase I trials by 2025 and Phase

II trials by 2030. To achieve these goals, the following major tasks must be completed (Table 4).

1. Large scale production of the vaccines in compliance with Current Good Manufacturing Practice

(cGMP) regulations. Supporting actions will include; statutory toxicity testing (this provides a stop-go

point for vaccine selection); and, development of vaccine-specific immunological tests to monitor

responses in vaccinated individuals.

2. First-in-human safety trials. This work will be done in two stages: (1) A phase 1a trial in non-exposed

individuals, and (2) a phase 1b trials in exposed individuals. Each provides a stop-go point for vaccine

selection.

3. Assessment of immune responses in primary target cohorts. Immunological profiling of pre-school

children to define responses to vaccine candidates in populations living in onchocerciasis-only endemic

regions of Ghana, and second, children living in onchocerciasis and loiasis co-endemic areas of

Cameroon. This work will provide input to mathematical modelling of potential vaccine efficacy and

design of control programmes.

4. Investigation of social and cultural attitudes towards vaccination for the purpose of assessing the

feasibility and impact of control programmes using the vaccine.

5. Statistical analyses and monitoring of all research outputs and modelling of vaccine efficacy and

predicted impact on disease control.

Table 4, TOVA, the next steps

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Vaccine Product Profile

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.

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The Partners 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.

Name Participant’s organization, country Role in the Partnership

The partners from Africa

Prof Samuel Wanji University of Buea, Cameroon Research Foundation in Tropical Disease and Environment

Human studies in Cameroon

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 Europe

Prof David W Taylor University of Edinburgh, UK Co-ordinator of the EU consortium. Vaccine development and human studies in Cameroon

Dr Ben Makepeace

University of Liverpool, UK Proteomic and genomic analyses and vaccine development.

Screening vaccine candidates in the O ochengi cattle model. Host gene expression profile analysis

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, Paris, France

Screening vaccine candidates in the L sigmodontis mouse model. Host gene expression profile analysis

Prof Achim Hoerauf University Hospital of Bonn, Germany Immunology of filarial infections and human studies in Ghana. Host gene expression profile analysis

Prof María Gloria Basáñez Imperial College London, UK Mathematical modelling and cost-effectiveness

The partners from USA

Dr Sara Lustigman New York Blood Center, NYC, USA Program Director of the NIH funded consortium. Human studies in Cameroon, characterization of vaccine candidates

Prof David Abraham

Thomas Jefferson University, Philadelphia, PA, USA

Screening vaccine candidates in the PA, USA O volvulus mouse model

Prof Maria Elena Bottazi Prof Peter Hotez

National School of Tropical Medicine, Baylor

College of Medicine, and Texas Children’s Hospital Center for Vaccine Development, Houston, TX, USA

Product development, technology transfer for cGMP

manufacture and GLP toxicology testing, regulatory filing, early stage clinical testing

Dr Darrick Carter PAI Life Sciences Seattle, WA Product development, cGMP manufacture

https://www.liv.ac.uk/infection-and-global-health/staff/benjamin-makepeace/

http://www.gla.ac.uk/researchinstitutes/bahcm/staff/simonbabayan/

http://mcam.mnhn.fr/APE/Fiche_Martin.htm

http://www.microbiology-bonn.de/immip/node/120

http://www.imperial.ac.uk/people/m.basanez

http://nybloodcenter.org/research/research-pillars/staff/sara-lustigman-phd/

http://www.jefferson.edu/university/jmc/departments/microbiology/faculty_staff/faculty/abraham.html

https://www.bcm.edu/people/view/b1628c2c-ffed-11e2-be68-080027880ca6

https://www.bcm.edu/people/view/b1846a47-ffed-11e2-be68-080027880ca6

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https://mectizan.org/

https://doi.org/10.1093/cid/ciz647



https://doi.org/10.1186/s40249-018-0400-0

http://www.un.org/en/development/desa/population/


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The Onchocerciasis Vaccine for Africa (TOVA): A new tool to help … · 2020-01-20 · Loiasis, another filarial disease, is caused by the eye worm Loa loa, which is closely related