Reactions to the WHO report on neglected tropical diseases

18 Nov 2010

Patrick Adams

Source: TropIKA.net

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The World Health Organization (WHO) recently issued its first global report on neglected tropical diseases (NTDs). Published on 14th October, the 186-page document contains first-time evidence on the epidemiology, economic burden and costs of interventions for 17 NTDs endemic in 149 countries worldwide, highlighting the considerable progress made to date as well as the various gaps and challenges that remain [1].

But it’s what the report does not contain – namely strong recognition of the vital role of research – that has vexed many in the NTD community, causing some to wonder if that paucity of emphasis could undermine efforts to attract badly needed funding or engage new stakeholders, including developing country governments and the growing ranks of young scientists in disease-endemic countries (DECs).

“I think the power of this report is that they really introduce the diseases in a very comprehensive way,” says Dr Sarah Lustigman, head of the laboratory of molecular parasitology at the New York Blood Center, USA. “But research is talked about in such a restricted way. People take these reports very seriously and refer to them. And they may think. Well, if WHO doesn’t say research is important to advancing control and prevention programmes, is it really something we need to invest in?”

Lustigman, for one, is certain that it is, and that – by ignoring the role of research – the public health community is sure to repeat mistakes made in the past. “Think about chloroquine,” she says. “They thought they had a magic bullet, and nobody paid attention. They even stopped developing drugs. They said, ‘Wow, we have a drug that kills the parasite. Let’s distribute it to everybody.’ And the intention was very good, of course. But if you don’t monitor, and you don’t continue investigating, you’re going to have a big problem.”

A member of the TDR Research think tank, Lustigman is chair of TDR’s Disease Reference Group (DRG) 4 on helminthiases and is currently writing up a technical report on the state of research in this area, including the gaps and challenges, and the research priorities going forward. That report, along with those of nine other such expert groups, will inform the forthcoming Global report for research on infectious diseases of poverty, to be published in June, 2011.

“One gap we’ve identified is that we don’t know what will happen to African children who grow up without any worms,” she says. “You would think, ‘Fantastic, they’ll be like children in London or New York, who don’t have worms’. But there are plenty of children in London and New York who have allergies because they aren’t exposed to some pathogen in childhood.”

The reality, Lustigman says, “is that we have no idea what will happen to them.” And while it’s imperative that elimination efforts continue, she says, “we have to study what else is happening – the long-term implications of elimination campaigns – not just whether we are going to distribute a billion pills or only a million.” And that’s only one disease area, she says. “There was a little paragraph about research needed for new medicines to treat leishmaniasis and trypanosomes. But what about vector control? What about vaccines for dengue? What about new diagnostics and making these accessible to all who need them?”

Preventive chemotherapy

Speaking at the report’s launch, Director-General Dr Margaret Chan said that some diseases could be eliminated by 2015, and others by 2020 “if we keep doing the right things better and on a larger scale”. Chief among those “right things” is the preventive chemotherapy carried out through mass-drug administration and largely underwritten by the pharmaceutical industry.

As the report recounts, it was under former Director-General Dr J W Lee that the traditional approach to the control and elimination of NTDs began to change – from a strategy centred on single diseases to one that targeted the health needs of marginalized communities as a whole.

Indeed, by integrating several different interventions based on a variety of proven tools, this new approach would “ensure a more efficient use of limited resources and the alleviation of poverty and accompanying illness for millions of people living in rural and urban areas”.

And so it has. From 2003 to 2007, WHO developed a framework for a coordinated attack on NTDs anchored by the mass administration of safe and effective drugs. By the end of 2008, integrated regimens of “preventive chemotherapy” targeting lymphatic filariasis, onchocerciasis, schistosomiasis, soil-transmitted helminthiases and trachoma had reached nearly 670 million people in 75 countries.

That achievement is attributable in large part to the involvement of the pharmaceutical industry, whose generous donations have afforded millions of patients access to high-quality medicines (such as albendazole and ivermectin) free-of-charge. And with the launch of the report, several industry heavyweights announced another round of giving.

GlaxoSmithKline said it would add 400 million doses of albendazole to the 600 million the company already donates - enough to treat every child in Africa for schistosomiasis. Johnson & Johnson pledged to give away 200 million doses of mebendazole to treat intestinal worms. And Sanofi-Aventis agreed to renew its five-year commitment to support WHO programmes against Buruli ulcer, African sleeping sickness and leishmaniasis.

“The reach [of these programmes] has been surprising,” says Dr Peter Hotez, president of the Sabin Vaccine Institute and (as of last week) of the American Society for Tropical Medicine & Hygiene (ASTMH). “I think the best example is lymphatic filariasis, where you’re now reaching literally half a billion people.”

Still, for all of its impact and the corporate generosity that makes it possible, mass drug administration (MDA) isn’t a cure-all. And while USAID’s decision to fund a scale-up of MDA programmes is admirable, says Hotez, “We need a parallel programme of research that’s commensurate with that”.

Hotez points to hookworm as an example of a large-scale problem for which MDA in its current form is simply not adequate. Writing in Nature Reviews Microbiology last October [2], he outlined the rationale for a human hookworm vaccine, citing new information indicating that annual deworming (via MDA) may be less effective for hookworm than for other intestinal helminth infections:

“Single-dose albendazole or mebendazole typically achieves either cure or substantial reductions in worm burdens and faecal egg counts for ascariasis. However, for hookworm, high rates of drug failure have been reported for mebendazole, with an average cure rate of only 15%. Furthermore, after repeated administration in the same population, the efficacy of mebendazole has been reported to diminish over time raising concerns about possible drug resistance. Indeed, drug failures have been shown to occur with benzimidazoles when used ubiquitously in livestock and have been associated with specific mutations in the parasite gene encoding ß-tubulin. Although the same mutations have not yet been associated with drug failure in humans, efforts are underway to determine whether benzimidazole failures for hookworm and other helminth infections result from similar resistance mechanisms.” [2]

Hotez goes on to point out that, although treatment with albendazole cures existing infections, “it does not confer protection from re-infection, which often occurs as early as six months after treatment in areas of high transmission”. This led to the creation, he says, of the Human Hookworm Vaccine Initiative (HHVI), a non-profit product development partnership based at the Sabin Vaccine Institute at George Washington University, USA.

Established in 2000 with funding from the Bill & Melinda Gates Foundation, the HHVI is the world’s only partnership working on vaccine development for hookworm, although it targets other diseases as well; in addition to a hookworm vaccine – which is based on a strategy of interfering with hookworm blood-feeding using anti-enzyme antibodies – the group’s current vaccine portfolio includes a schistosomiasis vaccine and a transmission-blocking vaccine for malaria.

And while progress has been promising on all fronts, Hotez believes a single vaccine targeting both hookworm and schistosomiasis could have the greatest impact. “We’ve found that wherever you find hookworm, you find schistosomiasis, and it turns out it’s more than just a coincidence.”

Researchers at the Swiss Tropical Institute have shown the same thing in Brazil, he says – “that if you have hookworm infection, you’re more likely to get schistosomiasis, and vice versa. So we’re very interested in making a multivalent worm vaccine that is protecting against both diseases. We think this could reduce up to 26 million DALYs annually; that’s almost half the global disease burden of malaria”.

A right to innovation

Of course, a multivalent worm vaccine won’t simply appear out of thin air. Like any new product, it will come, if it ever does, by way of a long, complex process requiring sophisticated technology, highly specialized expertise, years of research and likely hundreds of millions of dollars from numerous public and private actors.

Asked if he thought the report’s emphasis on MDA could hurt funding for vaccine R&D, Hotez was loathe to criticize what he said is essentially “a snapshot of where we are in terms of large-scale interventions”.

“[The report] does a good job of providing an overview of where we’re at,” he says. “Not only for rapid impact package diseases like ascariasis, onchocerciasis, lymphatic filariasis and trachoma, but also for things like leprosy and progress on guinea worm control.”

“Of course,” he added, “I think research is extremely important. I’m a researcher after all.” As he put it in a recent editorial in PLoS NTDs – “A Manifesto for Advancing the Control and Elimination of Neglected Tropical Diseases” – all NTDs are tool ready but all NTDs are tool deficient [3].

“That means that if you take any one of these diseases, I can point out deficiencies in all the existing methods and why we need new vaccines and new drugs and diagnostics. So it’s not ‘either or’,” he says. “Just like people have a fundamental right of access to essential medicines for NTDs, they have a fundamental right to innovation.”

Even as Hotez and team pursue the life-saving products that he believes must accompany MDA if hookworm infection is ever to be eliminated, scientists further upstream continue to grapple with questions about the effects of MDA on immune response and how such an intervention might influence control efforts in other disease areas.

“We need to study how the host-parasite interaction changes during MDA and post-MDA in order to see how this is going to affect other things,” says Lustigman. “Parasites modulate immune response in order to survive chronic diseases. But the immune response can also kill the parasite. So there is some kind of balance that we don’t fully understand.

“There are reports showing that children who are infected don’t respond well to vaccines because their immune system has been modulated. So, based on that, you can predict that if you treat them [with preventive chemotherapy], they will respond better to vaccines. But will there be one vaccine or two vaccines? We don’t know. And the moment that you remove infection, you have no idea what happened.”

Those same questions apply to a potential malaria vaccine as well. “We have to remember that every person is a host to many parasites, and a lot of people who have helminth infections also have malaria. Will vaccines against malaria work better if children are free of helminth infections? We have no idea. Nobody is looking into it because there is no cross-talk. But a human is a system, and a human being lives in a particular environment with animals and a changing climate, and it’s all connected.

“We have to look at it in a comprehensive way – with a clear commitment to control and elimination,” she says. “But you have to carefully monitor and evaluate as you go, and use information that is based on evidence to continue supporting MDA in a way that is appropriate to the region or the population. It is not one size-fits-all.”

References

1. WHO (2010). Working to overcome the global impact of neglected tropical diseases: first WHO report on neglected tropical diseases. Geneva, World Health Organization. Available from: http://www.who.int/neglected_diseases/2010report/NTD_2010report_embargoed.pdf

2. Hotez PJ et al. (2010). Developing vaccines to combat hookworm infection and intestinal schistosomiasis. Nature Reviews Microbiology; 8:814-826. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20948553

3. Hotez PJ, Pecoul B (2010). A manifesto for advancing the control and elimination of neglected tropical diseases. PLoS Neglected Tropical Diseases; 4(5):e718. Available from: http://www.ncbi.nlm.nih.gov/pubmed/20520793

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26 Nov 2010 by Paul Chinnock:

An article about the WHO report has also now been published in Lancet Infectious Diseases. A number of experts were asked for their views and one issue emerging was the concern that " the recommended interventions are not sufficient by themselves to ensure sustainability of programmes and to truly alleviate poverty ... the importance of chemotherapy and other biomedical interventions could be overestimated and will not be sustainable nor alleviate poverty".

Nevertheless, the article notes that NTDs are moving up on many priority lists and that, "This report is expected to further boost political commitment to tackle NTDs both in endemic countries and from donors".

See: http://www.thelancet.com/journals/laninf/article/PIIS1473-3099(10)70267-X/fulltext