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Establishing a controlled hookworm human infection (CHHI) model for Africa: A report from the stakeholders meeting held in Lambaréné, Gabon, November 10–11, 2019

Establishing a controlled hookworm human infection (CHHI) model for Africa: A report from the... Background: Hookworm is a major contributor to worldwide disease burden with over 230 million people infected. It has been identified as one of the Neglected Tropical Diseases that can be controlled and even eliminated through mass drug administration and other effective interventions. Mathematical models have shown that hookworm can only be eliminated via a vaccine. Controlled Hookworm Human Infection (CHHI) models can facilitate rapid development of vaccines and drugs. Methods: As a first step towards the establishment of CHHI in Africa, we held a stakeholders meeting in Lamberene, Gabon from 10 to 11 November 2019. Results: Discussions revolved around the roles of the different regulatory institutions concerned; the need to strengthen existing regulatory capacity and the role of legislation; creating Gabon-specific ethical guidelines to govern Controlled Human Infection (CHI) studies; development of a study protocol; consideration of cultural and social peculiarities; the need for regular joint review meetings between interested parties throughout the process of protocol implementation; and participant compensation. Moreover, operational considerations concerning the introduction of CHHI in Gabon include the use of the local strain of hookworm for the challenge infections, capacity building for the local production of challenge material, and the establishment of adequate quality assurance procedures. Conclusion: The workshop addressed several of the anticipated hurdles to the successful implementation of CHHI in Gabon. It is our aim that this report will stimulate interest in the implementation of this model in the sub-Saharan African setting. Keywords: Controlled human infection model, Necator americanus, Vaccine development, Gabon, The Netherlands * Correspondence: a.alabi@lumc.nl; ayodele.alabi@cermel.org Centre de Recherches Médicales de Lambaréné, BP242, Lambaréné, Gabon Department of Parasitology, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Alabi et al. Archives of Public Health (2021) 79:120 Page 2 of 8 Background complementary tools such as drug therapy, a sanitation Hookworm infects around 230 million people worldwide strategy, and the development of a vaccine. Extensive [1], and is hyperendemic in several sub-Saharan countries, modelling indicates that along with annual MDA pro- some of which have a disease prevalence of a third of the grams, the vaccination of 9–12 month old infants (along- pediatric population [2]. Subsequently, these may result in side EPI), with a booster vaccine in those > 15 years, up to 40% reduction in future wage-earning [3, 4], per- would best reduce disease prevalence and morbidity [15]. petuating the poverty of the infected. The global economic A human hookworm vaccine has been developed that burden of hookworm infection is estimated to cost be- is a combination of two recombinant antigens known as tween $7.5 to $138.9 billion annually [5]. In the Central Na-GST-1 and Na-APR-1 [15]. Challenge studies con- African region, Gabon is estimated to have the highest ducted in laboratory animals were used to provide prevalence of hookworm infection at 26% [2](Table 1). proof-of-concept of its efficacy [16]. Phase 1 clinical tri- Preventative measures such as the mass drug adminis- als in healthy Gabonese adults was shown to be safe and tration of anthelmintic agents i.e. albendazole have already to induce Immunoglobulin G to each antigen [17]. How- been undertaken however their efficacy is questionable ever, rNaGST-1, which showed highly neutralizing im- [6]. The WHO had set the target to implement annual or munogenicity in mice challenge trials, has shown only semi-annual preventive chemotherapy for preschool and negligible neutralizing immunogenicity in humans [18, school-aged children in endemic areas with an overall 19]. All of the available animal models for hookworm do coverage of at least 75% by 2020 [7]. A total of 483,207 not replicate natural human hookworm infection; thus children were deemed to be in need of preventive chemo- limiting the understanding of the disease including the therapy against Soil Transmitted Helminth Infections human-host interactions that are essential in character- (STHIs) in Gabon in 2018 [8]. Indeed, of the 320,000 izing host responses, and mechanisms of pathogen school-aged children (SAC) at risk in Gabon in 2018, only evasion. 120,000 (39%) received chemotherapy, in comparison to An Australian group has begun investigating the safety 50,000 (19%) that had received chemotherapy in 2016. and tolerability of an attenuated live hookworm vaccine However effective coverage (> = 75% of SAC) occurred at (ACTRN12617001007325). only 10% of implementation units. Periodical deworming, despite numerous success stories The controlled human infection model [9, 10], is increasingly viewed as unfavorable because of high A total of 15 controlled hookworm human infection reinfection rates and the looming threat of anthelmintic re- studies involving 194 volunteers have been conducted in sistance [11, 12]. Hence, novel anthelmintic drugs and vac- the USA, UK, Australia and the Netherlands (Add- cines are needed to add to hookworm control tools. itional file 1). Hoogerwerf and colleagues at the Leiden Controlled human infection (CHI) models are a rapidly scal- University Medical Centre (LUMC) have continued with able approach used to establish product safety and proof of the development of a controlled human infection model efficacy, allowing for quick selection of promising drug and for N. americanus (CHHI) to improve it. The infection vaccine candidates for phase II or III clinical trials [13, 14]. model was refined in Dutch volunteers [20], reaching stable egg counts that were comparable to what is seen Vaccine development for hookworm disease in low-endemic regions. However, these Dutch volun- The ideal anthelmintic control strategy would involve a teers originate from a non-endemic region and have multimodal approach comprising a combination of never been exposed to hookworm. Table 1 Population-adjusted prevalence of Hookworm from 2000 onwards and annual anthelmintic treatment needs in the Central African region Population aged < 20 years (1000s) Prevalence of hookworm (%) Number of anthelmintic doses for school-aged children (1000s) Cameroon 9199 9·9 (8·3–11·3) 3340 (3094–3550) Central African Republic 2037 15·5 (12·1–19·9) 512 (388–660) Chad 6405 7·4 (5·6–10·2) 415 (214–689) Congo 1869 12·9 (7·6–34·5) 461 (203–942) DR Congo 37 088 17·9 (15·5–21·3) 15 551 (13 586–17 628) Equatorial Guinea 273 11·2 (6·0–21·1) 125 (82–188) Gabon 592 26·0 (12·9–40·6) 347 (262–420) Adapted from Dimitrios-Alexios Karagiannis-Voules et al. [2] WHO definition, age 5–14 years Alabi et al. Archives of Public Health (2021) 79:120 Page 3 of 8 It will be important to establish this model replicating detailed dossier to the ethics board. The ethics board the same procedure in Gabon to look at possible bio- will then review this and make recommendations both logical and immunological parameter changes that are for the concerned institutions to improve the proposal exclusive to the SSA region, as has been observed during and the Ministry of Health so that it may begin the the Covid-19 pandemic [21]. These changes might ac- groundwork for legislation and regulation with regards count for varying efficacies of vaccines and drugs within to CHHI in Gabon. the region in comparison to non-endemic regions. The Another area that generated interest was whether development of a CHHI model in Africa will also allow existing legislation was robust enough to be adapted for for vaccine and drug development within the continent innovative clinical research strategies that do not fall (see Table 2). into the classical framework of vaccine trials. That is to say, whilst most clinical trials test a drug or vaccine that Methods could protect or cure you, CHI intentionally infects vol- As a first step towards establishing the Controlled Hook- unteers before treating them. According to the Helsinki worm Human Infection model in a hookworm-endemic Accords, there must be legislation in place for any trials setting, we held a stakeholders meeting in Lambaréné, to take place. There was a suggestion that new legisla- Gabon in November 2019, to identify key challenges and tion needs to be created to accommodate controlled hu- develop strategies to address them. man infection, but after extensive discussions, it was The stakeholders meeting addressed anticipated hur- deemed not necessary to distinguish CHHI legislation dles to the successful implementation of CHHI. Partici- from the legislation of clinical trials (see Table 3). pants included representatives of Gabon’s Ministry of Health, the National Drug Authority, the National Ethics Ethical considerations Committee, researchers and clinicians who manage At the ethical level, do no harm, the principle of non- hookworm infection and its complications, sociologists, maleficence, states one must avoid needless harm or in- community representatives, colleagues with experience jury that can arise through acts of commission or omis- of implementing controlled human schistosomiasis in- sion. The key consideration in this definition rests in the fections (CHI-S) from Uganda; and a team from Leiden word ‘needless’; and whether or not it can be argued that University Medical Center, Leiden, The Netherlands in the case of CHHI, it is ‘needed’ to infect patients in who have experience in establishing the hookworm CHI. order to achieve benefit. But there is understandable concern about infecting people in Africa for the purpose Results of medical advancement, even if there is a guaranteed Regulatory and legislative considerations cure. There was a debate about the roles of different institu- This lies in a number of socio-political reasons. Histor- tions and how they should interact in the legal process. ical atrocities involving deliberate infection of vulnerable It was agreed that the most appropriate way to bring this populations have an important influence on thinking in project to fruition will be to present a protocol or a this field [22]. And it should not be forgotten that western Table 2 The whys and hows of the controlled human infection model. Concepts particular to endemic regions are presented in bold Why? How Need to develop and assess vaccine and drug candidates � CHHI provides expedient assessment of vaccine and drug candidates � Allows for mining for vaccine candidates when combined with proteome and glycan arrays � Creates a benchmark for assessing vaccine and drug efficacy in endemic populations Unwanted/allergic responses to candidate vaccines � Report IgE reactivity to hookworm antigens � De-risks future development of candidates by testing antibody recognition in hookworm endemic population (in particular testing for IgE recognition and eosinophilia with challenge material) Differing immune profiles between Africans and residents � Provides data on innate and adaptive cellular responses to hookworm infection of non-endemic areas where vaccines are often developed � Report on IgM, IgG, IgG subclasses, and IgA reactivity to hookworm antigens � Provides insight into local (skin, airway mucosa, and gut) immune responses � Allows for comparison between responses of volunteers from the Netherlands and Gabon Need to develop Correlates of protection � Establish a profile of immune responses to hookworm as a surrogate of past exposure � Using vaccine candidates, CHHI allows for the identification of molecular patterns that could correlate with protection (CHHI) Controlled human hookworm infection model Alabi et al. Archives of Public Health (2021) 79:120 Page 4 of 8 Table 3 Regulatory framework for ethics approval of CHHI in The Netherlands and Gabon, and CHI-S in Uganda Country Institutional and National Ethics review Process of ethical approval for CHI Legislation boards studies The Netherlands Universities have their own institutional Approval given by LUMC local medical ethics Applicable law is the Wet medisch- ethics committees committee wetenschappelijk Onderzoek in mensen (WMO): in English, Medical Research involving human subjects Act Gabon Institutional review board (CERMEL) and Scientific approval from institution precedes Under auspices of the Ministry of National Ethics Committee (NEC) submission for institutional ethics review. This Health is then followed by submission to the NEC Uganda There are 23 Institutional Research Ethics Scientific approval from institution precedes No legislation or acts pertaining to Committee in Uganda. All these are submission for institutional ethics review. This human challenge studies exist in accredited and regulated by the Uganda is then followed by submission to the UNCST Uganda. Ministry of Health does not National Council for Science and directly regulate research in Uganda Technology (UNCST) CHHI is not formally a study with a medicinal product so European Medicines Agency regulations do not apply medicine and medical practitioners are viewed with a de- communities, and individual households are also key de- gree of scepticism in many parts of Africa. This was cision makers. Therefore, the traditional approaches brought to light in the West African Ebola Outbreak when such as contacting the head of the community as the key doctors were attacked and accused of spreading the virus person to decide on the commencement of a study [23]. Given this context, it is particularly important in might not work in Gabon. In addition, some community Gabon to fully meet any ethical guidelines with regards to beliefs such as being used as guinea pigs or the worry CHI. The challenge in African countries though is that that researchers are there to kill them have to be coun- these guidelines are either underdeveloped or do not exist. tered through public enlightenment and awareness. Also In this respect, the work being done on this project is pio- there is a lack of exposure to western medicine in the neering within the Francophonie. rural areas as most people rely on their local traditions So, what might these ethical guidelines be? One area for healing. Changing such traditional beliefs and atti- of discussion was whether to adopt international ethical tudes will require adequately educating the target popu- frameworks, those that have been laid down in France or lation about the CHHI approach, and that practitioners to pursue a Gabon-specific set of ethical criteria. Cer- also educate themselves about the target population. tainly, the principles articulated by the WHO in 2016 The same thought was re-iterated in a parallel workshop and benchmarks developed at the Malawi meeting on on the role of social sciences in clinical trials. The com- Controlled Human Infection Models in Low Income mon conclusion drawn by both groups illustrates the Countries could be employed to govern the ethical and need for close collaboration between the disciplines and regulatory approval process [24]. However, it was also the need for multi-sectoral approach to clinical trials to noted that Gabon is one of a handful of African coun- obtain the best possible results. Furthermore, a joint re- tries where the National Ethics Committee (NEC) oper- view meeting, with all regulatory authorities represented, ates as the sole arbitrator of ethical issues (unlike was recommended, as well as engagement between the Uganda for example where many institutions have their researchers and ethical and regulatory review bodies own ethics committees that can influence policy) [25]. throughout the process of protocol development and im- This, it was proposed, should be used to give credence plementation (see Table 4). to and bolster scientific and technological research. The discussions also touched on the subject of participant Operational considerations compensation, with the major question being how much The operational considerations for the implementation to compensate. Compensation will cover transport, food, of the Leiden CHHI model in Gabon include the estab- and any other costs incurred due to lost income. lishment of donors from within the local population, the preparation of the L3 larvae locally in Gabon under Socio-cultural considerations GMP protocols at an “international standard”, and the The working group concluded that the social and cul- creation of an adequately regulated hookworm labora- tural peculiarities of the communities in Gabon which tory dedicated to the manufacture of challenge material. will form the target group for CHI should be taken into This would involve research into locally acquired Gab- consideration in the design of the study protocol. Cul- onese N. americanus (G-Na) so that the exact strain of turally Gabon differs from most countries in Africa, in the challenge material is known, training of technical that there is less of a hierarchical structure within staff, development of infrastructure, trial runs in Gabon Alabi et al. Archives of Public Health (2021) 79:120 Page 5 of 8 Table 4 Summary of topics discussed by workshop attendees with regards to the novelty of CHHI in Gabon and its appropriate implementation Topics discussed during the workshop Workshop proposals Protocol development � Regular consultations between researchers and interested regulatory authorities throughout process of protocol development and implementation � Protocol to be submitted to the Gabonese National Ethics Committee. NEC will then report to the Gabonese Ministry of Health � Study protocol and product dossier can be submitted as a single protocol document to the NEC � Develop a protocol that takes into consideration social and cultural peculiarities in Gabon CHHI in a “vulnerable” population � Develop pioneering national ethical guidelines for CHIM’s, in consultation with WHO recommendations, that will be strictly followed � Ensure full understanding of concept of CHI in communities where education level can be low Appropriateness of current Gabonese legislation � Existing legislation able to cover all aspects of CHHI for the regulation of CHHI � New legislation unnecessary Media engagement � Plan public engagement efforts that ensure the public can independently decide to or not to participate in CHHI in Gabon � Information management to be planned so the public is well informed and involved parties are prepared to alleviate undesired publicity for verification of strict adherence to the procedural or errors during the preparation process would make protocol, and the determination of the safest dose of the entire process uncertain and expensive. In addition, challenge material to be used in the trial. A different op- when patent infection of the PNG strain is achieved, a tion would be, to use the hookworm strain currently risk assessment will have to be made concerning the used at LUMC as challenge material, with samples being consequences of a possible introduction of the PNG transferred from Leiden for final preparation of larvae in strain into Gabonese soil. The consideration of an “in- Gabon, eliminating the requirement for donation of par- patient” trial could be contemplated, and the costs of asites from infected Gabonese subjects. housing individuals for 12 weeks and compensation for In the LUMC model, an N. americanus originating containment for such a period of time would have to be from Madang, Papua New Guinea (PNG) is used as chal- budgeted for. Consultation and partnership with the lenge material; however, the use of Gabonese Na (G-Na) Gabonese Agence Nationale des Parcs Nationaux is a is preferred in this case. Going forward, LUMC and must if such a scheme were to be adopted. Centre de Recherches Médicales de Lambaréné (CERM EL) staff will work in tandem to validate the LUMC Discussion model in Gabon, with the only difference being the use The establishment of CHHI in Gabon provides the op- of the local strain. G-Na will need to be genotyped and portunity to develop a regulatory, social, and ethical characterized, and the genetic distance between PNG framework that suits Gabonese needs. The CHHI proto- and G-Na strains identified alongside their relative safety col will be expected to meet all standards of a Phase I and infectivity. Transfer of the Quality Assurance (QA) trial. Years of experience with clinical trials at CERMEL procedure already implemented at LUMC will be key. In [26], including challenge infections [13], mean that inter- addition, adoption of this QA would allow for capacity national standards for obtaining informed consent from building in CERMEL, the local site. participants will be adhered to. In anticipation of audits A second option would be to transport hookworm- of the site, a quality control plan, data management plan positive stool specimens from Leiden to Gabon, and and quality records will need to be available at all times. then prepare the larvae in Gabon for challenge infection. In any vaccine trial that includes the study of disease As the time between larvae preparation and challenge prevention as an endpoint, participants would require infection is about 30 min, this procedure must be per- treatment before vaccination. Depending on the number formed locally. The stool specimens can be shipped at of participants involved and the ratio of infected vs unin- ambient temperature, would have to arrive within 3–5 fected in the community, this treatment may decrease days from time of collection in Leiden. It will also re- community transmission to a point where the efficacy of quire strictly following the International Air Transport a vaccine is difficult to measure or is measured inad- Association (IATA) guidelines for the shipping of infec- equately. In this case it is especially applicable in regions tious materials. It will be important to work with cus- where mass drug administration of anthelmintics is toms officials and handling agents to ensure efficient regularly practiced. CHHI in these regions will allow for release on arrival in Gabon. The risks of transport failure identification of correlates of protection in individuals Alabi et al. Archives of Public Health (2021) 79:120 Page 6 of 8 with previous exposure and background immune re- established in Europe where they have been improved in sponses to hookworm infection, providing vital informa- such a way that level of infection, measured as egg out- tion for vaccine development and efficacy. put, is not only stable but also reaches levels that repre- sent what is found in endemic areas. Successful Adaptation of the controlled human hookworm infection implementation and application of a CHHI model in Af- model in Gabon rica has the potential to address many of the roadblocks The Leiden CHHI model has been rigorously tested to to the development of an effective vaccine for hookworm ensure high quality of the infectious agent, reproducibil- infection. Currently, controlled human infection models ity, and the highest possible safety for the volunteers. (CHIM) are seldom performed in Africa due to various The larval production is standardized in a GMP-like social, ethical, infrastructural, and financial issues [24]. process before infective larvae are administered to vol- In this report we describe how these issues were thor- unteers. Larvae are cultured from chronically infected oughly discussed at a forum between experts and local donors through a process involving multiple checks par- authorities, resulting in recommendations that fit inter- ticularly to ensure N. americanus larvae are viable and national standards and attempt to match local expecta- clear of other pathogens. Motile larvae are dispensed tions. The successful implementation of the CHHI onto gauzes and applied on the skin of the upper arms model requires that the local context is taken into con- and legs of the volunteers. Twenty seven Dutch volun- sideration, that public education targets the communi- teers have been successfully infected using the model ties and authorities involved, and that community [20, 27]. No major safety concerns were identified, infec- concerns are adequately addressed. The workshop is the tion was reasonably well-tolerated by all participants. first step in an iterative process that will call for deep The well- developed protocols that work in LUMC with commitment and continued collaboration between the all safety precautions will be practiced in Gabon, and if stakeholders. We also aim at stimulating further interest needed changes will be made to adjust to the local situ- in the implementation of this model in the sub-Saharan ation. Healthy volunteers, with a good level of education, African setting. no intestinal helminth infections, and minimal risk of ac- quiring them during the trial period, will be selected. Abbreviations Following informed consent, it will be emphasized that CERMEL: Centre de recherches médicales de lambaréné; CHHI: Controlled hookworm human infection; CHI: Controlled human infection; G- they would need to adhere strictly to the procedure min- Na: Gabonese Necator americanus; LUMC: Leiden university medical center; imizing infection from outside of the trial. Volunteers NEC: National ethics committee; PNG: Papua New Guinea; QA: Quality will be followed up for 16 weeks and then treated with assurance; SAC: School-aged children albendazole. Infection will be detected by microscopy and real-time PCR. Supplementary Information The online version contains supplementary material available at https://doi. Challenges org/10.1186/s13690-021-00650-z. It will be difficult to find donors that are positive for N. americanus alone without coinfection with the hel- Additional file 1. Previous Controlled Human Hookworm Infection minths Strongyloides stercoralis or A. duodenale as coin- studies. fection rates are high. There is also a concern of hookworm transmission from a volunteer to others. All Acknowledgements study participants will be counselled to practice good hy- We thank all workshop participants for their valuable contributions. giene and to always defecate in a flush toilet/latrine. The Workshop Participants: Pierre Blaise Matsiegui, Jacquelines Obone-Mba, study protocol must include measures to document toi- Célestin Bilolo (Gabonese National Ethics Committee for research), Carine Mbadinga, Cathérine Ondo Eyene, Ines Temby Ngouessy (Gabonese Ministry leting habits of participants. of Health, Department of Pharmacy and Medicine), Célestine Koumba, Mous- It is important to consider that Gabon is a hookworm sounda Ibouanga Firmin (Université Omar Bongo), Mewono Ludovic (Ecole endemic region, therefore ensuring control over the in- Normal Supérieur), Florent Mounguengui (Etudes Maitre Florent Mounguen- gui), Julien Chongwang (SciDev.Net), Moses Egesa, Emmanuella Driciru fection given during the trial versus infection acquired (MRC/UVRI and LSHTM Uganda Research Unit), Maria Yazdanbakhsh, Erliyani naturally from the environment can be an important fac- Sartono, Mosarrof Hussain (Leiden University Medical Center), Angoissa Min- tor. Potentially, if the parasite is sufficiently genetically soko Pamela, Chanélie Mboumba, Gaylord Lucien Ondoumbe, Christine Ndong Mengome, Ayodele Alabi, Selidji Todagbe Agnandji (Centre de diverse, genetic markers could be used to confirm source Recherches Médicales de Lambaréné). of infection, but these can be costly. We would also like to acknowledge Alison M Elliott, Meta Roestenberg and Eric AT Brienen for their contributions to the project. The CHHI workshop would not have been possible without the invaluable Conclusion support from NWO-WOTRO Science for Global Development in the form of a This will be the first attempt at establishing a CHHI grant, Centre de Recherches Médicales de Lambaréné, and Leiden University model in Africa. These models have already been Medical Center. Alabi et al. Archives of Public Health (2021) 79:120 Page 7 of 8 Authors’ contributions in different settlements of Gabon, Central Africa. Infect Dis Poverty. 2018;7 AA drafted the manuscript. MH, MAH, CM, ME, ED, LW, YK, ES, AAA, PK, MY, [cited 2020 Feb 8] Available from: https://www.ncbi.nlm.nih.gov/pmc/a and SA contributed, commented, and revised the drafts of the manuscript. rticles/PMC5789590/. All authors read and approved the final manuscript. 7. Coffeng L, Bakker R, de Vlas S. Individual-based modelling of hookworm infection: predicted feasibility of achieving control and elimination by 2020. Tropical Med Int Health. 2015;20:6–6. Funding Funding for the workshop was provided by NWO-WOTRO Science for Global 8. WHO | World Health Organization [Internet]. [cited 2020 Feb 10]. Available Development Programme [grant no. W 07.30318.019]. ME, and ED received sup- from: http://apps.who.int/neglected_diseases/ntddata/sth/sth.html port from HIC-Vac, a GCRF Network in Vaccines Research and Development 9. Bah YM, Bah MS, Paye J, Conteh A, Saffa S, Tia A, et al. 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Establishing a controlled hookworm human infection (CHHI) model for Africa: A report from the stakeholders meeting held in Lambaréné, Gabon, November 10–11, 2019

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10.1186/s13690-021-00650-z
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Abstract

Background: Hookworm is a major contributor to worldwide disease burden with over 230 million people infected. It has been identified as one of the Neglected Tropical Diseases that can be controlled and even eliminated through mass drug administration and other effective interventions. Mathematical models have shown that hookworm can only be eliminated via a vaccine. Controlled Hookworm Human Infection (CHHI) models can facilitate rapid development of vaccines and drugs. Methods: As a first step towards the establishment of CHHI in Africa, we held a stakeholders meeting in Lamberene, Gabon from 10 to 11 November 2019. Results: Discussions revolved around the roles of the different regulatory institutions concerned; the need to strengthen existing regulatory capacity and the role of legislation; creating Gabon-specific ethical guidelines to govern Controlled Human Infection (CHI) studies; development of a study protocol; consideration of cultural and social peculiarities; the need for regular joint review meetings between interested parties throughout the process of protocol implementation; and participant compensation. Moreover, operational considerations concerning the introduction of CHHI in Gabon include the use of the local strain of hookworm for the challenge infections, capacity building for the local production of challenge material, and the establishment of adequate quality assurance procedures. Conclusion: The workshop addressed several of the anticipated hurdles to the successful implementation of CHHI in Gabon. It is our aim that this report will stimulate interest in the implementation of this model in the sub-Saharan African setting. Keywords: Controlled human infection model, Necator americanus, Vaccine development, Gabon, The Netherlands * Correspondence: a.alabi@lumc.nl; ayodele.alabi@cermel.org Centre de Recherches Médicales de Lambaréné, BP242, Lambaréné, Gabon Department of Parasitology, Leiden University Medical Center, Albinusdreef 2, 2333, ZA, Leiden, The Netherlands Full list of author information is available at the end of the article © The Author(s). 2021 Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Alabi et al. Archives of Public Health (2021) 79:120 Page 2 of 8 Background complementary tools such as drug therapy, a sanitation Hookworm infects around 230 million people worldwide strategy, and the development of a vaccine. Extensive [1], and is hyperendemic in several sub-Saharan countries, modelling indicates that along with annual MDA pro- some of which have a disease prevalence of a third of the grams, the vaccination of 9–12 month old infants (along- pediatric population [2]. Subsequently, these may result in side EPI), with a booster vaccine in those > 15 years, up to 40% reduction in future wage-earning [3, 4], per- would best reduce disease prevalence and morbidity [15]. petuating the poverty of the infected. The global economic A human hookworm vaccine has been developed that burden of hookworm infection is estimated to cost be- is a combination of two recombinant antigens known as tween $7.5 to $138.9 billion annually [5]. In the Central Na-GST-1 and Na-APR-1 [15]. Challenge studies con- African region, Gabon is estimated to have the highest ducted in laboratory animals were used to provide prevalence of hookworm infection at 26% [2](Table 1). proof-of-concept of its efficacy [16]. Phase 1 clinical tri- Preventative measures such as the mass drug adminis- als in healthy Gabonese adults was shown to be safe and tration of anthelmintic agents i.e. albendazole have already to induce Immunoglobulin G to each antigen [17]. How- been undertaken however their efficacy is questionable ever, rNaGST-1, which showed highly neutralizing im- [6]. The WHO had set the target to implement annual or munogenicity in mice challenge trials, has shown only semi-annual preventive chemotherapy for preschool and negligible neutralizing immunogenicity in humans [18, school-aged children in endemic areas with an overall 19]. All of the available animal models for hookworm do coverage of at least 75% by 2020 [7]. A total of 483,207 not replicate natural human hookworm infection; thus children were deemed to be in need of preventive chemo- limiting the understanding of the disease including the therapy against Soil Transmitted Helminth Infections human-host interactions that are essential in character- (STHIs) in Gabon in 2018 [8]. Indeed, of the 320,000 izing host responses, and mechanisms of pathogen school-aged children (SAC) at risk in Gabon in 2018, only evasion. 120,000 (39%) received chemotherapy, in comparison to An Australian group has begun investigating the safety 50,000 (19%) that had received chemotherapy in 2016. and tolerability of an attenuated live hookworm vaccine However effective coverage (> = 75% of SAC) occurred at (ACTRN12617001007325). only 10% of implementation units. Periodical deworming, despite numerous success stories The controlled human infection model [9, 10], is increasingly viewed as unfavorable because of high A total of 15 controlled hookworm human infection reinfection rates and the looming threat of anthelmintic re- studies involving 194 volunteers have been conducted in sistance [11, 12]. Hence, novel anthelmintic drugs and vac- the USA, UK, Australia and the Netherlands (Add- cines are needed to add to hookworm control tools. itional file 1). Hoogerwerf and colleagues at the Leiden Controlled human infection (CHI) models are a rapidly scal- University Medical Centre (LUMC) have continued with able approach used to establish product safety and proof of the development of a controlled human infection model efficacy, allowing for quick selection of promising drug and for N. americanus (CHHI) to improve it. The infection vaccine candidates for phase II or III clinical trials [13, 14]. model was refined in Dutch volunteers [20], reaching stable egg counts that were comparable to what is seen Vaccine development for hookworm disease in low-endemic regions. However, these Dutch volun- The ideal anthelmintic control strategy would involve a teers originate from a non-endemic region and have multimodal approach comprising a combination of never been exposed to hookworm. Table 1 Population-adjusted prevalence of Hookworm from 2000 onwards and annual anthelmintic treatment needs in the Central African region Population aged < 20 years (1000s) Prevalence of hookworm (%) Number of anthelmintic doses for school-aged children (1000s) Cameroon 9199 9·9 (8·3–11·3) 3340 (3094–3550) Central African Republic 2037 15·5 (12·1–19·9) 512 (388–660) Chad 6405 7·4 (5·6–10·2) 415 (214–689) Congo 1869 12·9 (7·6–34·5) 461 (203–942) DR Congo 37 088 17·9 (15·5–21·3) 15 551 (13 586–17 628) Equatorial Guinea 273 11·2 (6·0–21·1) 125 (82–188) Gabon 592 26·0 (12·9–40·6) 347 (262–420) Adapted from Dimitrios-Alexios Karagiannis-Voules et al. [2] WHO definition, age 5–14 years Alabi et al. Archives of Public Health (2021) 79:120 Page 3 of 8 It will be important to establish this model replicating detailed dossier to the ethics board. The ethics board the same procedure in Gabon to look at possible bio- will then review this and make recommendations both logical and immunological parameter changes that are for the concerned institutions to improve the proposal exclusive to the SSA region, as has been observed during and the Ministry of Health so that it may begin the the Covid-19 pandemic [21]. These changes might ac- groundwork for legislation and regulation with regards count for varying efficacies of vaccines and drugs within to CHHI in Gabon. the region in comparison to non-endemic regions. The Another area that generated interest was whether development of a CHHI model in Africa will also allow existing legislation was robust enough to be adapted for for vaccine and drug development within the continent innovative clinical research strategies that do not fall (see Table 2). into the classical framework of vaccine trials. That is to say, whilst most clinical trials test a drug or vaccine that Methods could protect or cure you, CHI intentionally infects vol- As a first step towards establishing the Controlled Hook- unteers before treating them. According to the Helsinki worm Human Infection model in a hookworm-endemic Accords, there must be legislation in place for any trials setting, we held a stakeholders meeting in Lambaréné, to take place. There was a suggestion that new legisla- Gabon in November 2019, to identify key challenges and tion needs to be created to accommodate controlled hu- develop strategies to address them. man infection, but after extensive discussions, it was The stakeholders meeting addressed anticipated hur- deemed not necessary to distinguish CHHI legislation dles to the successful implementation of CHHI. Partici- from the legislation of clinical trials (see Table 3). pants included representatives of Gabon’s Ministry of Health, the National Drug Authority, the National Ethics Ethical considerations Committee, researchers and clinicians who manage At the ethical level, do no harm, the principle of non- hookworm infection and its complications, sociologists, maleficence, states one must avoid needless harm or in- community representatives, colleagues with experience jury that can arise through acts of commission or omis- of implementing controlled human schistosomiasis in- sion. The key consideration in this definition rests in the fections (CHI-S) from Uganda; and a team from Leiden word ‘needless’; and whether or not it can be argued that University Medical Center, Leiden, The Netherlands in the case of CHHI, it is ‘needed’ to infect patients in who have experience in establishing the hookworm CHI. order to achieve benefit. But there is understandable concern about infecting people in Africa for the purpose Results of medical advancement, even if there is a guaranteed Regulatory and legislative considerations cure. There was a debate about the roles of different institu- This lies in a number of socio-political reasons. Histor- tions and how they should interact in the legal process. ical atrocities involving deliberate infection of vulnerable It was agreed that the most appropriate way to bring this populations have an important influence on thinking in project to fruition will be to present a protocol or a this field [22]. And it should not be forgotten that western Table 2 The whys and hows of the controlled human infection model. Concepts particular to endemic regions are presented in bold Why? How Need to develop and assess vaccine and drug candidates � CHHI provides expedient assessment of vaccine and drug candidates � Allows for mining for vaccine candidates when combined with proteome and glycan arrays � Creates a benchmark for assessing vaccine and drug efficacy in endemic populations Unwanted/allergic responses to candidate vaccines � Report IgE reactivity to hookworm antigens � De-risks future development of candidates by testing antibody recognition in hookworm endemic population (in particular testing for IgE recognition and eosinophilia with challenge material) Differing immune profiles between Africans and residents � Provides data on innate and adaptive cellular responses to hookworm infection of non-endemic areas where vaccines are often developed � Report on IgM, IgG, IgG subclasses, and IgA reactivity to hookworm antigens � Provides insight into local (skin, airway mucosa, and gut) immune responses � Allows for comparison between responses of volunteers from the Netherlands and Gabon Need to develop Correlates of protection � Establish a profile of immune responses to hookworm as a surrogate of past exposure � Using vaccine candidates, CHHI allows for the identification of molecular patterns that could correlate with protection (CHHI) Controlled human hookworm infection model Alabi et al. Archives of Public Health (2021) 79:120 Page 4 of 8 Table 3 Regulatory framework for ethics approval of CHHI in The Netherlands and Gabon, and CHI-S in Uganda Country Institutional and National Ethics review Process of ethical approval for CHI Legislation boards studies The Netherlands Universities have their own institutional Approval given by LUMC local medical ethics Applicable law is the Wet medisch- ethics committees committee wetenschappelijk Onderzoek in mensen (WMO): in English, Medical Research involving human subjects Act Gabon Institutional review board (CERMEL) and Scientific approval from institution precedes Under auspices of the Ministry of National Ethics Committee (NEC) submission for institutional ethics review. This Health is then followed by submission to the NEC Uganda There are 23 Institutional Research Ethics Scientific approval from institution precedes No legislation or acts pertaining to Committee in Uganda. All these are submission for institutional ethics review. This human challenge studies exist in accredited and regulated by the Uganda is then followed by submission to the UNCST Uganda. Ministry of Health does not National Council for Science and directly regulate research in Uganda Technology (UNCST) CHHI is not formally a study with a medicinal product so European Medicines Agency regulations do not apply medicine and medical practitioners are viewed with a de- communities, and individual households are also key de- gree of scepticism in many parts of Africa. This was cision makers. Therefore, the traditional approaches brought to light in the West African Ebola Outbreak when such as contacting the head of the community as the key doctors were attacked and accused of spreading the virus person to decide on the commencement of a study [23]. Given this context, it is particularly important in might not work in Gabon. In addition, some community Gabon to fully meet any ethical guidelines with regards to beliefs such as being used as guinea pigs or the worry CHI. The challenge in African countries though is that that researchers are there to kill them have to be coun- these guidelines are either underdeveloped or do not exist. tered through public enlightenment and awareness. Also In this respect, the work being done on this project is pio- there is a lack of exposure to western medicine in the neering within the Francophonie. rural areas as most people rely on their local traditions So, what might these ethical guidelines be? One area for healing. Changing such traditional beliefs and atti- of discussion was whether to adopt international ethical tudes will require adequately educating the target popu- frameworks, those that have been laid down in France or lation about the CHHI approach, and that practitioners to pursue a Gabon-specific set of ethical criteria. Cer- also educate themselves about the target population. tainly, the principles articulated by the WHO in 2016 The same thought was re-iterated in a parallel workshop and benchmarks developed at the Malawi meeting on on the role of social sciences in clinical trials. The com- Controlled Human Infection Models in Low Income mon conclusion drawn by both groups illustrates the Countries could be employed to govern the ethical and need for close collaboration between the disciplines and regulatory approval process [24]. However, it was also the need for multi-sectoral approach to clinical trials to noted that Gabon is one of a handful of African coun- obtain the best possible results. Furthermore, a joint re- tries where the National Ethics Committee (NEC) oper- view meeting, with all regulatory authorities represented, ates as the sole arbitrator of ethical issues (unlike was recommended, as well as engagement between the Uganda for example where many institutions have their researchers and ethical and regulatory review bodies own ethics committees that can influence policy) [25]. throughout the process of protocol development and im- This, it was proposed, should be used to give credence plementation (see Table 4). to and bolster scientific and technological research. The discussions also touched on the subject of participant Operational considerations compensation, with the major question being how much The operational considerations for the implementation to compensate. Compensation will cover transport, food, of the Leiden CHHI model in Gabon include the estab- and any other costs incurred due to lost income. lishment of donors from within the local population, the preparation of the L3 larvae locally in Gabon under Socio-cultural considerations GMP protocols at an “international standard”, and the The working group concluded that the social and cul- creation of an adequately regulated hookworm labora- tural peculiarities of the communities in Gabon which tory dedicated to the manufacture of challenge material. will form the target group for CHI should be taken into This would involve research into locally acquired Gab- consideration in the design of the study protocol. Cul- onese N. americanus (G-Na) so that the exact strain of turally Gabon differs from most countries in Africa, in the challenge material is known, training of technical that there is less of a hierarchical structure within staff, development of infrastructure, trial runs in Gabon Alabi et al. Archives of Public Health (2021) 79:120 Page 5 of 8 Table 4 Summary of topics discussed by workshop attendees with regards to the novelty of CHHI in Gabon and its appropriate implementation Topics discussed during the workshop Workshop proposals Protocol development � Regular consultations between researchers and interested regulatory authorities throughout process of protocol development and implementation � Protocol to be submitted to the Gabonese National Ethics Committee. NEC will then report to the Gabonese Ministry of Health � Study protocol and product dossier can be submitted as a single protocol document to the NEC � Develop a protocol that takes into consideration social and cultural peculiarities in Gabon CHHI in a “vulnerable” population � Develop pioneering national ethical guidelines for CHIM’s, in consultation with WHO recommendations, that will be strictly followed � Ensure full understanding of concept of CHI in communities where education level can be low Appropriateness of current Gabonese legislation � Existing legislation able to cover all aspects of CHHI for the regulation of CHHI � New legislation unnecessary Media engagement � Plan public engagement efforts that ensure the public can independently decide to or not to participate in CHHI in Gabon � Information management to be planned so the public is well informed and involved parties are prepared to alleviate undesired publicity for verification of strict adherence to the procedural or errors during the preparation process would make protocol, and the determination of the safest dose of the entire process uncertain and expensive. In addition, challenge material to be used in the trial. A different op- when patent infection of the PNG strain is achieved, a tion would be, to use the hookworm strain currently risk assessment will have to be made concerning the used at LUMC as challenge material, with samples being consequences of a possible introduction of the PNG transferred from Leiden for final preparation of larvae in strain into Gabonese soil. The consideration of an “in- Gabon, eliminating the requirement for donation of par- patient” trial could be contemplated, and the costs of asites from infected Gabonese subjects. housing individuals for 12 weeks and compensation for In the LUMC model, an N. americanus originating containment for such a period of time would have to be from Madang, Papua New Guinea (PNG) is used as chal- budgeted for. Consultation and partnership with the lenge material; however, the use of Gabonese Na (G-Na) Gabonese Agence Nationale des Parcs Nationaux is a is preferred in this case. Going forward, LUMC and must if such a scheme were to be adopted. Centre de Recherches Médicales de Lambaréné (CERM EL) staff will work in tandem to validate the LUMC Discussion model in Gabon, with the only difference being the use The establishment of CHHI in Gabon provides the op- of the local strain. G-Na will need to be genotyped and portunity to develop a regulatory, social, and ethical characterized, and the genetic distance between PNG framework that suits Gabonese needs. The CHHI proto- and G-Na strains identified alongside their relative safety col will be expected to meet all standards of a Phase I and infectivity. Transfer of the Quality Assurance (QA) trial. Years of experience with clinical trials at CERMEL procedure already implemented at LUMC will be key. In [26], including challenge infections [13], mean that inter- addition, adoption of this QA would allow for capacity national standards for obtaining informed consent from building in CERMEL, the local site. participants will be adhered to. In anticipation of audits A second option would be to transport hookworm- of the site, a quality control plan, data management plan positive stool specimens from Leiden to Gabon, and and quality records will need to be available at all times. then prepare the larvae in Gabon for challenge infection. In any vaccine trial that includes the study of disease As the time between larvae preparation and challenge prevention as an endpoint, participants would require infection is about 30 min, this procedure must be per- treatment before vaccination. Depending on the number formed locally. The stool specimens can be shipped at of participants involved and the ratio of infected vs unin- ambient temperature, would have to arrive within 3–5 fected in the community, this treatment may decrease days from time of collection in Leiden. It will also re- community transmission to a point where the efficacy of quire strictly following the International Air Transport a vaccine is difficult to measure or is measured inad- Association (IATA) guidelines for the shipping of infec- equately. In this case it is especially applicable in regions tious materials. It will be important to work with cus- where mass drug administration of anthelmintics is toms officials and handling agents to ensure efficient regularly practiced. CHHI in these regions will allow for release on arrival in Gabon. The risks of transport failure identification of correlates of protection in individuals Alabi et al. Archives of Public Health (2021) 79:120 Page 6 of 8 with previous exposure and background immune re- established in Europe where they have been improved in sponses to hookworm infection, providing vital informa- such a way that level of infection, measured as egg out- tion for vaccine development and efficacy. put, is not only stable but also reaches levels that repre- sent what is found in endemic areas. Successful Adaptation of the controlled human hookworm infection implementation and application of a CHHI model in Af- model in Gabon rica has the potential to address many of the roadblocks The Leiden CHHI model has been rigorously tested to to the development of an effective vaccine for hookworm ensure high quality of the infectious agent, reproducibil- infection. Currently, controlled human infection models ity, and the highest possible safety for the volunteers. (CHIM) are seldom performed in Africa due to various The larval production is standardized in a GMP-like social, ethical, infrastructural, and financial issues [24]. process before infective larvae are administered to vol- In this report we describe how these issues were thor- unteers. Larvae are cultured from chronically infected oughly discussed at a forum between experts and local donors through a process involving multiple checks par- authorities, resulting in recommendations that fit inter- ticularly to ensure N. americanus larvae are viable and national standards and attempt to match local expecta- clear of other pathogens. Motile larvae are dispensed tions. The successful implementation of the CHHI onto gauzes and applied on the skin of the upper arms model requires that the local context is taken into con- and legs of the volunteers. Twenty seven Dutch volun- sideration, that public education targets the communi- teers have been successfully infected using the model ties and authorities involved, and that community [20, 27]. No major safety concerns were identified, infec- concerns are adequately addressed. The workshop is the tion was reasonably well-tolerated by all participants. first step in an iterative process that will call for deep The well- developed protocols that work in LUMC with commitment and continued collaboration between the all safety precautions will be practiced in Gabon, and if stakeholders. We also aim at stimulating further interest needed changes will be made to adjust to the local situ- in the implementation of this model in the sub-Saharan ation. Healthy volunteers, with a good level of education, African setting. no intestinal helminth infections, and minimal risk of ac- quiring them during the trial period, will be selected. Abbreviations Following informed consent, it will be emphasized that CERMEL: Centre de recherches médicales de lambaréné; CHHI: Controlled hookworm human infection; CHI: Controlled human infection; G- they would need to adhere strictly to the procedure min- Na: Gabonese Necator americanus; LUMC: Leiden university medical center; imizing infection from outside of the trial. Volunteers NEC: National ethics committee; PNG: Papua New Guinea; QA: Quality will be followed up for 16 weeks and then treated with assurance; SAC: School-aged children albendazole. Infection will be detected by microscopy and real-time PCR. Supplementary Information The online version contains supplementary material available at https://doi. Challenges org/10.1186/s13690-021-00650-z. It will be difficult to find donors that are positive for N. americanus alone without coinfection with the hel- Additional file 1. Previous Controlled Human Hookworm Infection minths Strongyloides stercoralis or A. duodenale as coin- studies. fection rates are high. There is also a concern of hookworm transmission from a volunteer to others. All Acknowledgements study participants will be counselled to practice good hy- We thank all workshop participants for their valuable contributions. giene and to always defecate in a flush toilet/latrine. The Workshop Participants: Pierre Blaise Matsiegui, Jacquelines Obone-Mba, study protocol must include measures to document toi- Célestin Bilolo (Gabonese National Ethics Committee for research), Carine Mbadinga, Cathérine Ondo Eyene, Ines Temby Ngouessy (Gabonese Ministry leting habits of participants. of Health, Department of Pharmacy and Medicine), Célestine Koumba, Mous- It is important to consider that Gabon is a hookworm sounda Ibouanga Firmin (Université Omar Bongo), Mewono Ludovic (Ecole endemic region, therefore ensuring control over the in- Normal Supérieur), Florent Mounguengui (Etudes Maitre Florent Mounguen- gui), Julien Chongwang (SciDev.Net), Moses Egesa, Emmanuella Driciru fection given during the trial versus infection acquired (MRC/UVRI and LSHTM Uganda Research Unit), Maria Yazdanbakhsh, Erliyani naturally from the environment can be an important fac- Sartono, Mosarrof Hussain (Leiden University Medical Center), Angoissa Min- tor. Potentially, if the parasite is sufficiently genetically soko Pamela, Chanélie Mboumba, Gaylord Lucien Ondoumbe, Christine Ndong Mengome, Ayodele Alabi, Selidji Todagbe Agnandji (Centre de diverse, genetic markers could be used to confirm source Recherches Médicales de Lambaréné). of infection, but these can be costly. We would also like to acknowledge Alison M Elliott, Meta Roestenberg and Eric AT Brienen for their contributions to the project. The CHHI workshop would not have been possible without the invaluable Conclusion support from NWO-WOTRO Science for Global Development in the form of a This will be the first attempt at establishing a CHHI grant, Centre de Recherches Médicales de Lambaréné, and Leiden University model in Africa. These models have already been Medical Center. Alabi et al. Archives of Public Health (2021) 79:120 Page 7 of 8 Authors’ contributions in different settlements of Gabon, Central Africa. Infect Dis Poverty. 2018;7 AA drafted the manuscript. 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Journal

Archives of Public Health – Springer Journals

Published: Jul 5, 2021

Keywords: Controlled human infection model; Necator americanus; Vaccine development; Gabon; The Netherlands

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