“Bridging the Divide” abstract: Urgent needs for R&D on human helminth infections

In December 2012, the results of the much awaited Global Burden of Disease (GBD) Study 2010 were released.  Aside from visceral leishmaniasis, the most important neglected tropical diseases (NTDs) when measured in disability adjusted life years (DALYs) were helminth infections led by the intestinal nematode infections (with hookworm infection accounting for two-thirds of the DALYs lost) followed by schistosomiasis, lymphatic filariasis, and food-borne trematode infections.  Together these NTDs in addition to onchocerciasis and trachoma are being targeted for either “elimination” (LF, onchocerciasis, and trachoma) or “control” (the intestinal nematode infections and schistosomiasis) through a scaled up program of mass drug administration (MDA) with support from USAID, UKAID, and a private END (Ending Neglected Disease Fund), and under the auspices of a 2012 London Declaration and a 2013 World Health Assembly Resolution.  However, it is unclear whether these goals can be achieved without the development of additional or improved control tools, i.e., drugs, diagnostics, vaccines, and monitoring for resistance or other operational parameters.  For instance, failure with benzimidazole anthelminthics is widespread for hookworm and trichuriasis, especially when they are used in a single dose, although the basis of this observation is not well understood.  It is uncertain whether drug resistance has emerged and is an ongoing concern.  Moreover, there are fundamental aspects of the basic biology of intestinal nematodes that we do not understand such as tissue tropisms and ecological niches, and the basis of long-term survival both within and outside of the human host.   Similar questions remain also for schistosomes and food-borne trematodes (and for praziquantel Rx) and we are just beginning to understand the basis for helminth-induced carcinogenesis and schistosome-induced female urogenital schistosomiasis and HIV/AIDS transmission.  Early stage vaccines for hookwrom and schistosomiasis are also in clinical development.  There remain a number of outstanding questions on the fundamental biology of filarial worms that cause lymphatic filariasis, onchocerciasis, and loiasis, including the basis of parasite tropisms, longevity, and immune evasion, the basis of microfilarial periodicitiy, and how parasite death occurs and its link to host immunopathogenesis.  There is a need to develop a macrofilaricide but few leads on how to achieve drug or vaccine development for this purpose.  Finally there are several important human helminth infections, such as toxocariasis and strongyloidiasis, for which we know little about in terms of disease burden and yet which may be as important as the other helminthiases mentioned.  Human Strongyloides infection has a unique interface between pathogenesis and nematode developmental biology, while toxocariasis has emerged as an important helminth infection the United States and it many be linked to asthma, developmental delays, and epilepsy, especially among under represented minority populations.