Standard Template for a Candidate Demonstration Project

Note: the questions with asterisk should be filled.

1.* Title of the project:

Improving health quality and wellbeing of the economically marginalized populations in Southeast Asia: An initiative towards the introduction of a human hookworm vaccine (IIHHVac)

2.* Submitted by:

3.* Target disease or health condition:

(Focus on type II and III diseases and special RandD needs of developing countries in type I diseases where there is an identified health technology gap.)

Hookworm disease

4.* The suggested health technology that project seeks to develop:

(e.g. medicine; diagnostic test; medical device; vaccine etc.)

Hookworm vaccine 5.* Project summary: (Maximum 500 words)

Hookworm disease is the leading cause of iron deficiency anemia in the world’s poorest regions [1]. It is a major socioeconomic and public health concern. It is estimated that 600 million people are chronically infected, with up to135,000 deaths annually [2]. Most infections occur in the Asian region (60-70million people in each), followed by Nigeria and the Democratic Republic of Congo in Africa and Brazil (30-40 million people in each) [3]. The economic burden of chronic hookworm infection is estimated at 4.5 million DALYs annually [4] and is among the most important neglected tropical disease [5].

Southeast Asia (SEA) has a large percentage of populations living in rural and remote areas where hookworm infection is common [6]. These areas generally have poor sanitation and access to untreated water, which increase the opportunity of hookworm transmission and infection. Hookworm infection has been associated with impaired learning and decrease in productivity [7]. Eradicating hookworm disease will have the potential to improve the health quality and well-being of the economically marginalized communities living especially in the remote areas of SEA. Here, we propose an initiative to explore the possibility of introducing hookworm vaccine to the vulnerable communities in the SEA using select communities in Malaysia as a starting point. Hookworm disease is highly endemic in certain communities in Malaysia with prevalence of 3.0–44.7%. It is notable especially amongst the underprivileged or minority communities such as the Orang Asli (aborigine) children [8-11], amongst Indians living in estates [12], amongst multiracial communities living in the squatter areas [13] and in poor Malay living in traditional villages [14, 15] in which sanitation is poor.

The excellent availability of research infrastructure, efficient technical support coupled with the presence of local expertise with well-connected regional counterparts makes Malaysia an ideal study site. The model developed and knowledge gained from the study can be expanded to other SEA countries, where hookworm disease is highly endemic. Published reports have suggested that the Sabin Vaccine Institute (SVI) at Baylor College of Medicine, Houston, Texas, USA has developed lead vaccine targets against the hookworm disease. The Phase II trials of the vaccine started in November 2012 with volunteers receiving 3 injections over 4 months and will be monitored for an additional 12 months (http://www.sabin.org/updates/pressreleases/clinical-trials-first-ever-human-hookworm-vaccine-advance). In anticipation of the need to undertake similar studies in the SEA, we propose here to: 1) Undertake a study to update the epidemiology, prevalence and risk factors of

hookworm infections targeted for vaccination among the economically

disadvantaged communities in rural areas of Peninsular Malaysia with focus on the Orang Asli communities and the native communities of Sarawak and Sabah in Malaysia.

2) Identify potential cohorts for the eventual vaccine trials 3) Estimate the cost-impact of vaccine introduction among the identified

communities 4) Determine community perception and acceptance of vaccine 5) Identify, characterize and full genome sequencing of vaccine-targeted hookworm

species from the identified communities 6) Develop diagnostic tools and competency to detect the various hookworm

species needed for eventual assessment of vaccine efficacy. 7) Identify additional potential vaccine targets from hookworm species identified

from the communities

6.* Public health need that the proposed project aims to address:

(Explain the public health need in terms of burden of disease; prevalence; incidence; fatality rate; geographical spread; current interventions and their limitations; and what proposed new technology would change in terms of disease prevention, control, diagnosis, treatment etc. If detailed information is not possible at present then please provide some basic level information)(Maximum 400 words)

Human hookworm infection is caused by blood feeding nematode of the genus Ancylostoma and the species Necator americanus. The predominant etiology of human hookworm infection is N. americanus whereas A. duodenale occurrence is more scattered [1]. The highest prevalence of hookworm occurs in sub-Saharan Africa and eastern Asia with certain parts of SEA having up to 80% hookworm prevalence [16]. There is also a striking relationship between hookworm prevalence and low socioeconomic status [16] because hookworm causes chronic anemia that can impair neurological and cognitive functions in children, reduce work capacity in adults and adverse outcomes of pregnancy in mother and child [17]. Iron deficiency anemia is the hallmark of hookworm infection and it is associated with about 841,000 deaths and about 35 million DALYs annually [18]. The WHO has proposed that ‘deworming’ with albendazole or mebendazole is the most cost-effective method to reduce childhood morbidity related to chronic intestinal helminth infection [19]. However, there is increasing evidence indicating that deworming may be less effective for hookworm than other intestinal helminth infections. For example, deworming typically achieves total clearance or substantial reductions in worm burdens and egg counts for ascariasis but high failure rates have been reported for hookworm with an average cure of only 15% [20]. Furthermore, efficacy of mebendazole has been reported to diminish over time after prolong and repeated administration [21], suggesting that it could be due to drug resistance. Concerns of widespread drug resistance strongly suggest that we cannot rely solely on deworming as a means to control human hookworm. Hence, a new human hookworm vaccine that ultimately aims to prevent moderate to heavy hookworm

infections that is associated with substantial intestinal blood loss, is proposed. The current leading candidate vaccine is reported to consist of recombinant hookworm antigens that will raise antibodies to protective levels and will interfere with key enzymes of the hookworm life cycle.

7.* Explain which new and innovative approaches and mechanisms to supporting

financing and coordination of RandD this project would demonstrate? (This is a very important part to be filled. The idea of these demonstrations projects is

“to address identified gaps that disproportionately affect developing countries, particularly the poor, and for which immediate action can be taken” (WHA66.22).

66th WHA considered these demonstration projects as part of the efforts to “take forward action in relation to monitoring, coordination and financing for health research and development”. The assembly decided to identify such projects that: “(a) address identified research and development gaps related to discovery, development and/or delivery, including promising product pipelines, for diseases that disproportionally affect developing countries, particularly the poor, and for which immediate action can be taken; (b) utilize collaborative approaches, including open-knowledge approaches, for research and development coordination; (c) promote the de-linkage of the cost of research and development from product price; and (d) propose and foster financing mechanisms including innovative, sustainable and pooled funding; (2) The demonstration projects should provide evidence for long-term sustainable solutions.”) (Maximum 300 words)

Since the most recent global financial meltdown in 2008, many developed economies have taken longer than expected to recover their financial health. Hence, the engine to propel economic growth now rests in the hands of several rapidly developing regions namely, China, Brazil, India, Southeast Asia and Africa. Coincidentally, these are the regions that are also highly endemic for hookworm disease. The Human Hookworm Vaccine Initiative (HHVI) has already identified promising candidates that can already be developed into an eventual vaccine. SVI which initiated the HHVI has internationally recognized Product-Development-Partnership arrangements with many leading health organizations for the development of safe and effective vaccines against neglected tropical diseases. This approach is filling an important gap by developing inexpensive vaccines to control neglected tropical diseases which have little market value. Moreover, SVI has established a well-rounded model that serves as the blueprint for the development of vaccines for neglected tropical diseases. These include technology transfer and manufacturing to scale up processes for the manufacturing of pilot vaccines under current good manufacturing practices (cGMP). It will allow an almost effortless duplication of technology in a local setting and cost of investment to be minimal. The Malaysian government alone has allocated almost 10% of its annual budget towards the health sector. This shows that the government is committed in improving the wellbeing of the people and there are many channels to approach for funding the eventual hookworm vaccination program especially for the SEA where

The Association of Southeast Asian Nations (ASEAN) has a significant interest in improving the regional community health and wellbeing. University Malaya and Baylor College of Medicine has also recently signed a memorandum of agreement to collaborate in this area.

8.* Evidence of market failure/research landscape: (Explain why there has been no investment in this technology or why investment has not resulted in access to the health care product.)(Maximum 200 words)

Hookworm has been neglected for decades partly because it affects human health without causing substantial mortality. It was also omitted from the list of diseases covered by WHO’s Special Programme for Research and Training in Tropical Diseases in the 1970s-1990s [22]. When its morbidity, as expressed in DALYs is considered, it typically ranks among the most important diseases in poor developing countries. However, private pharmaceutical companies also are not keen to develop a product that is not profitable because the disease largely affects the poor and neglected communities. Furthermore, there are already existing deworming drugs in use, which are largely donated by Johnson and Johnson, and GlaxoSmithKline, albeit concerns of its efficacy. Hence, there is little stimulus for organizations to substantially invest in development of new therapeutic modality.

9. The scientific and technical feasibility: (Describe the scientific and technical basis for the proposed technology in terms of the state of the art e.g. candidate molecules; biomarkers; pipeline; previous efforts, if any, to develop same or similar technology etc. Include some risk analysis) (Maximum 500 words)

Since the molecular pathway of hookworm nutrition has already been elucidated, the main approach of vaccine development against human hookworm has been to identify key components involved in blood feeding, to genetically engineer these components as recombinant proteins and then to combine the recombinant proteins with adjuvants to elicit protective antibodies upon vaccination [23]. These protective antibodies would either neutralize hookworm macromolecules required for blood feeding or damage important hookworm structures [24]. Protective immunity would result in diminished hookworm related blood loss and reduced number of hookworms in the intestine as compared to unvaccinated people. The two lead antigens (GST1 and APR1) that have been selected for clinical development are involved in hookworm blood feeding and it was thought that they could induce antibodies that would interfere with hookworm physiology and survival [24]. Although hookworms depend on human blood for nutrition, the breakdown of hemoglobin into heme and hematin is potentially toxic to them because these compounds can generate oxygen radicals that damage hookworm structures [25]. GST1 functions to protect hookworms by detoxifying heme and hematin byproducts that are generated during blood feeding [26]. It was also shown

in hamsters that vaccination with recombinant A. caninum GST1 resulted in cross-protection following heterologous challenge with N. americanus [27], prompting the idea that this antigen could be cross-protective across different hookworm species. APR1 was selected based on successful laboratory animal trials. High levels of antibodies was induced in dogs vaccinated with either N. americanus or A. caninum APR1, which substantially reduced worm burden and blood loss from heterologous challenge as compared with unvaccinated dogs [28]. These findings suggest that cross-reactive immunity may occur between Necator spp. and Ancylostoma spp. hookworms. It will be very useful to produce recombinant GST1 and APR1 based on the proteins of localized hookworms. This would ensure that laboratory outcomes can be replicated safely in people living at highly endemic sites and not cause any untoward allergic reactions. With the recent discovery that A. ceylanicum infection may not be uncommon among rural populations in West Malaysia and other parts of Asia such as Thailand, Indonesia and India, a cross-protective vaccine that can protect against different hookworm species is highly desired. The burden of A. ceylanicum was perceived to emerge as a result of the relative reduction of other hookworm species [29]. The emergence of A. ceylanicum could be due to the added advantage of easing density-dependent intra-specific competition for limited resources [30], although this has not been proven and where study is still needed.

10. Reasons for proposing:

(Provide details if any priority setting and/or selection criteria that has underpinned the consideration to take up this area of technology for development.)(Approximately 200 words)

ASEAN is an organization of eleven countries (including East Timor as an observer) located in Southeast Asia. Collectively, ASEAN has a population of approximately 600 million people, which is about 9% of the global population. However, a large percentage of this population lives in rural areas which are hookworm endemic. ASEAN has a blueprint that mirrors the Millennium Development Goals for improving wellbeing and reducing poverty. The deployment of a potent human hookworm vaccine would reduce maternal morbidity and mortality, and improve children’s physical and cognitive growth. Hence, when these children become adults entering the workforce, they are capable of unleashing their full wage-earning potential, hence alleviating poverty.

11. Who could potentially develop the technology/carry out the research? (Provide known details: individual researcher? Group of researchers? Research/coordination organization including PDPs? Group of research organizations working together? Combination of these; What would be the process of selection of developers?)(Maximum 100 words)

Researchers at TIDREC, University of Malaya headed by Professor Sazaly AbuBakar and Dr. Yvonne Lim together with the Ministry of Health, Malaysia (Dr. Lokman Hakim, Deputy Director General) will undertake the study in Malaysia with TIDREC

as the lead organization. The National School of Tropical Medicine at Baylor College

of Medicine will be the technology collaborator with Professor Peter Hotez as lead

collaborator. The work on vaccine development will be conducted in partnership with NSTM, Sabin Vaccine Institute, USA where University of Malaya and NSTM has signed memorandum of agreement for collaborative research.

12. Who could potentially manufacture the final product?

Multinational company? Local production? Joint venture? How the decision will be made about the producer?(Maximum 100 words)

A possibility of a major local Malaysian company such as CCM Pharmaceuticals Sdn. Bhd. to be involved in the eventual manufacturing of the eventual vaccine has been mooted. The model of public-private funding for neglected tropical diseases vaccine is espoused as a model by SVI (http://www.sabin.org/)

13. What could be the role of WHO, if any, in this demonstration project to bring

this venture to fruition? (Maximum 200 words) WHO with its vast network and linkages with other international organizations

could facilitate the expansion of this project to other countries within ASEAN and beyond. The expansion could be implemented in stages within individual countries to align the project activities with guidelines, practices and priorities of each country. WHO could also perhaps help improve the design of the study to meet the expectation of other at large stakeholders.

14. Please outline a timeframe and projected milestones for the project covering

the first 5 years. This should also highlight the immediate actions that need to be taken? (Maximum 200 words)

Activity Milestones Year

1 Year

2 Year

3 Year

4 Year

5

Identify sites of hookworm

prevalence studies

Species identification

Risk factors

Development of rapid

diagnostic tool

High resolution melt analysis

Hookworm antigen

Selection of local hookworm strains

selection Create recombinant

proteins based on local hookworm

species

Scaling up antigen production

Animal testing

Prevent blood loss

Reduce adult worm count

Reduce faecal egg count

Cross-protection

Clinical development

Phase I study

Product development

Technology transfer to local

counterparts

15. What is the intellectual property (IP) landscape relative to this project? Is there any IP, e.g. patents that need to be licensed in to be able to develop and market the product in developing countries? How would IP and related intellectual assets, including knowhow, proposed to be managed in this project? (Maximum 400 words)

The hookworm vaccine of interest is being developed by SVI and in phase II clinical trials elsewhere (http://www.sabin.org/). The suitability of the vaccine for deployment in ASEAN needs assessment. The current proposal is to address this later issue. It is envisage that following after SVI may work through a private-public funding model to allow the right to manufacture and/or fill and finish of the vaccine to a local/ASEAN manufacturer to take up for the region. Hence, the initial IP leading to the vaccine development would remain probably with the inventor.

16.* What would be the strategy to ensure access to the product once it is developed? (Access is an important dimension of these demonstration projects, it is important for

the projects to begin with the end in mind, explain how this project would deliver the technologies to the needy patients i.e. price and affordability; modes of supply; storage; prescription; dispensing; and compliance; WHO will develop guiding principles for ensuring access to any products coming out of the demonstration projects)(Maximum 400 words)

Preliminary cost estimation by SVI of an adjuvanted vaccine consisting the two

recombinant proteins (GST1 and APR1) could be produced for less than $1 per dose [31]. We will be working very closely with SVI to register the vaccine in Malaysia first, while in parallel apply for regulatory approval in other ASEAN countries. In Malaysia, many underprivileged and minority communities living deep inside the rainforests actually work for logging companies for a living. Some of these companies provide funding for medical treatment for the workers in the rainforest. They have arrangements with the state health authorities to transport volunteer medical personnel to the logging sites for a period of up to one week. Matters concerning logistics are all taken care of by the logging companies. This way, communities living in logging sites can easily seek medical treatment and those communities that are not working for these logging companies can also travel to logging sites to be treated. There are many companies that hold timber concessions in Malaysia that are very willing to fund such activities or expeditions as part of their corporate social responsibility programs. Besides the logging companies, this effort can be extended to other companies that operate near or within rural areas such as oil palm and rubber plantation companies. Malaysia is the second largest producer of palm oil in the world, behind first-placed Indonesia. This shows that countries in Southeast Asia actually have many overlapping economic sectors. The scale of human hookworm vaccine accessibility will be enormous when we have the support of public-private partnerships. The initiation of partnerships between governments (ASEAN) and private companies would enable this project to be successful because as a region that shares so many overlapping economic activities, the strategies to supply and distribute the vaccines to economically marginalized populations could also be similar, coordinated and replicated to result in the same outcome.

17. How could the project be financed paying particular attention to the need to

demonstrate new and innovative forms of financing? Also provide an estimated cost of the project.(Maximum 200 words)

One reason why Malaysia was proposed to spearhead this project was because of its National Biotechnology Policy, which recognized biotechnology as one of the key

drivers to propel the country towards major economic development. BiotechCorp, a government agency, will provide strategic direction and operational assistance to companies that are interested in commercializing the human hookworm vaccine. Industrial scaling up of vaccine production could be carried out by CCM Pharmaceuticals Sdn Bhd, a subsidiary of CCM Bhd, in which the Malaysian government has a substantial stake through a Product Development Partnership (PDP) arrangement. Essentially, an effort of this scale has to depend on the support by the government in one way or another. Once this model is proven to be successful in Malaysia, we are sure that there will be many interested private investors that would want to market this vaccine, regionally.

18. How could the project be governed and coordinated paying particular

attention to the need to demonstrate better way of coordination? (Maximum 200 words)

The Performance Management and Delivery Unit (PEMANDU), a Malaysian government unit, functions to oversee the implementation, assess the progress, facilitate, support and drive the progress of the Government Transformation Programme (GTP). One of the National Key Results Area (NKRA) listed under the GTP is Improving Rural Development, which aims to provide at least 95% access to clean water. Improvements in sanitation and clean water, coupled with the deployment of human hookworm vaccine would translate into major reductions in endemic hookworm in the rural areas. The latter part could be included into the NKRA for improvement of rural development as one of the deliverables. The coordination of the human hookworm vaccine deployment will be strengthened and organized when it is part of a national economic transformation agenda for Malaysia and can be translated across ASEAN.

19. Have any donor agencies/governments already indicated interest in

supporting the project? (Maximum 200 words) None has currently expressed explicit interest to participate but discussions have been made in Malaysia with the following relevant agencies:

i) PEMANDU ii) Biotech Corp iii) CCM Pharmaceuticals Sdn Bhd

References

1. Hotez PJ. et al. (2004). Hookworm infection. N Engl J Med. 351:799–807. 2. Hotez PJ. (2009). One World Health: Neglected Tropical Diseases in a Flat World.

PLoS Negl Trop Dis 3(4):e405. 3. Bethony J. et al. (2006). Soil-transmitted helminth infections: ascariasis, trichuriasis,

and hookworm. Lancet. 367:1521–32.

4. Hotez PJ. et al. (2006). Incorporating a rapid-impact package for neglected tropical diseases with programs for HIV/AIDS, tuberculosis, and malaria. PLoS Med. 3:e102.

5. Hotez PJ. et al. (2009). Rescuing the bottom billion through control of neglected tropical diseases. Lancet. 373:1570–5.

6. Ngui R. et al. (2011). Prevalence and risk factors of intestinal parasitism in rural and remote West Malaysia. PloS NTD. 5:e974.

7. Bleakley H. (2003). Disease and development: Evidence from the American South. J Eur Econ Assoc. 1: 376–86.

8. Al-Mekhlafi HM. et al. (2006) Prevalence and distribution of soil-transmitted helminthiases among Orang Asli children in peripheral areas in Selangor, Malaysia. Southeast Asian J Trop Med Public Health. 37:40–7.

9. Nasr NA. et al. (2013). Towards an effective control program of soil-transmitted helminth infections among Orang Asli in rural Malaysia. Part 1: Prevalence and associated key factors. Parasit Vectors. 6:27.

10. Ngui R. et al. (2011). Prevalence and risk factors of intestinal parasitism in rural and remote West Malaysia. PLoS NTD. 5:e974.

11. Norhayati M. et al. (1997). The prevalence of Trichuris, Ascaris and hookworm infection in Orang Asli children. Southeast Asian J Trop Med Public Health. 8:161–8.

12. Kan SP. (1989). Soil transmitted helminthiases in Selangor, Malaysia. Med J Malaysia. 92:263–9.

13. Hanjeet K. et al. (1991). Soil-transmitted helminthiases in squatter populations around Kuala Lumpur by ethnic distribution. Trop Biomed. 8:33–7.

14. Huat LB. et al. (2012). Prevalence and risk factors of intestinal helminth infection among rural children. J Glob Infect Dis. 4(1):10–4.

15. Zulkifli A. et al. (2000). The prevalence of malnutrition and geo-helminth infections among primary schoolchildren in rural Kelantan. Southeast Asian J Trop Med Public Health 31:339–45.

16. de Silva NR. et al. (2003). Soil-transmitted helminth infections: Updating the global picture. Trends Parasitol. 19:547–51.

17. Tolentino K. and Friedman JF. (2007). An update on anemia in less developed countries. Am J Trop Med Hyg. 77:44–51.

18. Stoltzfus RJ. (2003). Iron deficiency: global prevalence and consequences. Food Nutr Bull. 24:S99–S103.

19. Smith JL and Brooker S. (2010). Impact of hookworm infection and deworming on anaemia in non-pregnant populations: a systematic review. Trop Med Int Health. 15:776–95.

20. Keiser J and Utzinger J. (2008). Efficacy of current drugs against soil-transmitted helminth infections: systematic review and meta-analysis. JAMA. 299:1937–48.

21. Albonico M. et al. (2003). Efficacy of mebendazole and levamisole alone or in combination against intestinal nematode infections after repeated targeted mebendazole treatment in Zanzibar. Bull World Health Organ. 81:343–52.

22. Hotez PJ. et al. (2005). Hookworm: "the great infection of mankind". PLoS Med. 2(3):e67.

23. Loukas A. et al. (2006). Hookworm vaccines: past, present, and future. Lancet Infect Dis. 6:733–41.

24. Hotez PJ. (2010). Developing vaccines to combat hookworm infection and intestinal schistosomiasis. Nat Rev Microbiol. 8(11):814-26.

25. Brophy PM and Pritchard DI. (1992). Metabolism of lipid peroxidation products by the gastro-intestinal nematodes Necator americanus, Ancylostoma ceylanicum and Heligmosomoides polygyrus. Int J Parasitol. 22:1009–12.

26. Zhan B. et al. (2002). Molecular cloning and purification of Ac-TMP, a developmentally regulated putative tissue inhibitor of metalloprotease released in relative abundance by adult Ancylostoma hookworms. Am J Trop Med Hyg. 66:238–44.

27. Xiao S. et al. (2008). The evaluation of recombinant hookworm antigens as vaccines in hamsters (Mesocricetus auratus) challenged with human hookworm, Necator americanus. Exp Parasitol. 118:32–40.

28. Pearson MS. et al. (2009). An enzymatically inactivated hemoglobinase from Necator americanus induces neutralizing antibodies against multiple hookworm species and protects dogs against heterologous hookworm infection. FASEB J. 23:3007–19.

29. Traub RJ. (2013). Ancylostoma ceylanicum, a re-emerging but neglected parasitic zoonosis. Int J Parasitol. 43(12-13):1009-15.

30. Paterson S and Viney ME. (2002). Host immune responses are necessary for density dependence in nematode infections. Parasitology. 125(Pt 3):283-92.

31. Hotez PJ. et al. (2013). The Human Hookworm Vaccine. Vaccine. 31 Suppl 2:B227-32.