• Malaria Vaccine
• Hookworm Vaccine
• Schistosome Vaccine
• Genomic tools for Malaria
• Interactive maps and epidemiology
• Immune Evasion
• Allergy and Ascariasis
• Mosquito control
• Immunocompromised
  Hosts
• Anti-malarial drug development
• Anti-parasitic drug development
• Conflict and Parasites
• Parasites of Bees
• Morgellons:
  Fact or Fiction?
• Eradication of
  Chaga’s Disease
• The world’s most successful parasite
• Guinea worm eradication

A Look at Developments: Novel Approaches to Control and Eradication

This section will focus broadly on new or developing tools against NTDs. For more information, please refer to the Further Info section.

Vaccines for Helminths and Shistosomiasis

Currently disease control and treatment focuses on chemotherapy, but re-infection often occurs without continued treatment, making vaccination a far preferable option as a simple, one-step procedure to interrupt transmission. Many advances are under way in parasite genomics, as well as new vaccine delivery systems.

First, some barriers to vaccine development for helminths in general:

-few good animal models exist for human helminths

-there is still lack of understanding of the basic events of helminth infection

-without fully understanding and targeting the specific antigens of immunopathology, there is a danger that a vaccine would exacerbate the body’s immune response

-requirements for expensive biotechnologies

Infection with helminth parasites typically leads to a strong type-2 immune response characterised by IgE antibodies, eosinophilia and mast cell proliferation. Many diverse immune mechanisms can kill helminths: antibody-independent macrophages, antibody-dependent granulocyte killing, and nonlymphoid actions, particularly in the gut. Combining our knowledge of immune mechanisms with a precise understanding of parasite antigens holds the most promise for vaccine development. Existing vaccine candidates have been selected with host antibodies, rather than T-cell responses, and include many highly conserved proteins with similarities to mammalian or invertebrate antigens (Maizels, et al.).

Hookworm Vaccine

Specific barriers to vaccine development for hookworm include: absence of in vitro systems; absence of traditional market; and the absence of critical mass of investigators. However, the development of a vaccine would have a dramatic effect on this important parasitic disease. It would improve maternal and child health in developing countries, and diminish reliance on benzimidazoles and other anthelminthics.

There are currently two approaches to hookworm vaccine development:

Approach 1: Since living third stage infective hookworm larvae (L3) elicit immunity, scientists can reproduce the effect of live L3 vaccines using L3 secreted proteins. This would require producing such proteins in large enough quantities through genetic engineering.

Approach 2: This involves using adult hookworm secreted proteins to create a vaccine. Scientists collect proteins by blocking hookworm feeding at the site of attachment, or producing proteins through genetic engineering.

A hookworm vaccine would thus essentially be a “cocktail vaccine”:

L3 Secreted Protein (worm burden reduction) + A

dult Secreted Protein (diminish pathogenesis at attachment site) +

Adjuvant (GSK SBAS2)

Vaccination with an adult secreted protein shifts the hookworm parasite out of intestine and into colon. Such proteins include MEP-1, AP (the antibodies to AP force hookworm out of small intestine), and TMP (which causes eosiniphil downregulation and inflammation downregulation).

One possible “cocktail vaccine” would be ASP-1 (L3 secreted protein) + MEP-1(adult secreted protein) + SBAS2 (adjuvant).

The Bill & Melinda Gates Foundation has provided donor support for vaccination initiatives (Sabin).

Schistosomiasis Vaccine

Vaccines against the three main schistosomal parasites have proven difficult to develop. Difficulties in producing antigenic proteins have slowed the process (Hagan), and another obstacle to development has been scaling up production according to GMP standards. Nonetheless, most scientists remain convinced that vaccine development is feasible for a number of reasons: human populations in endemic areas invariably develop some degree of natural immunity; after immunization with irradiated cercariae mice were afforded 80% protection; and a transmission-blocking vaccine has been developed for Chinese water buffalo (Bergquist). To determine viable vaccine antigen candidates, scientists must identify antibody isotypes and cytokine correlates of resistance and susceptibility in humans. One compound has demonstrated considerable promise in reducing female worm fecundity and egg viability. This 28 kDa protein, glutathione-S-transferase (Sh28-GST) has gone onto Phase III human trials. Another serious vaccine candidate is Sm14-FABP, which is in the process of industrial scale-up. Also of great interest is a new line of adjuvants for modulating human immune responses (Bergquist). Providing vaccines along with chemotherapy will undoubtedly reduce morbidity and transmission, but will likely increase the total costs of disease control.

The Promise of Miltefosine for Leishmaniasis and Artemisins for Schistosomiasis

A study by Jha, et al. demonstrated the efficacy of oral miltefosine in visceral leishmaniasis in India. Miltefosine is a cell signaling and membrane development inhibitor. The cure rate was found to be between 95-98% depending on the dosage administered, with the only side effect being mild intestinal discomfort (Jha, et al.). Following this and other studies, miltefosine was approved for use in India in 2002, with efforts to reduce the cost of this treatment. Another development in visceral leishmaniasis treatment that passed through phase III regulatory procedures in 2004 is aminosidine (Cottand, et al.). In order to prevent development of drug resistance, researchers are advocating co-treatment with older first line antimonial drugs (Jha, 1998). This dual treatment makes it less likely that leishmaniasis protozoa will develop resistance to newer, more effective oral treatments. Like most new and soon to come online drugs, cost of production and efficient distribution are obstacles to widespread use.

Initial studies in schistosomiasis vaccine are still wanting but several avenues of research exist that have great potential for future drug breakthroughs. Among these are the potential for creating analogues to the commonly used PZQ in the laboratory. Another is to create fluorescent or radio-labeled PZQ to elucidate the drugs target in the body. This would identify a target for novel small molecule or protein production. Additionally, preliminary findings show that the new artemisin drugs for malaria also suppress S. japonicum infections (Hagan, et al).

Chagas’, lymphatic filariasis and river blindness all have effective and proven treatment, making them targets for elimination as health care problems. Both river blindness and lymphatic filariasis need better strategies and practices in mass drug administration (duration, roll out, etc), better diagnostics to find infected people in the larger population, and development of a macrofilaricide. Chagas disease requires better drug therapies for the millions of people already infected (Remme).

Molecular Biology Approaches and DNA Vaccines

Molecular biology and genomics have opened new areas for drug and vaccine research in parasitic diseases. Remme’s paper has highlighted some key areas where genomic techniques have the potential of generating breakthroughs in parasitic disease treatment.

(1) The full genomic sequences of tropical disease pathogens are coming online. The genomes for the organisms causing sleeping sickness, hookworms, leishmaniasis and lymphatic filariasis are all being sequenced or have been completed. This has the potential of opening up a host of protein antigen development or receptor targets in the parasite for drugs. As part of the Gate’s initiative these four diseases are being targeted for the following deliverables (Henk):

(2) Bioinformatics: mining data for targets and genome sequence analysis.

(3) Functional genomic approaches to drug and vaccine discovery.

(4) Pharmacogenomics: the development of drugs or targeting of drugs based on a person’s genetic makeup, since current one size fits all drug therapy can prove ineffective or even toxic to subsets of the population.

In addition to these developing strategies are a whole host of new and improved analysis methods, policy development concepts, and program deployment and efficacy indicators.

DNA Vaccines and Recombinant DNA

Another avenue of exploration are the development of DNA vaccines. These vaccines introduce a recombinant plasmid containing an antigenic protein from the parasitic organism into the patient via injection. The goal is to have the plasmid picked up by the person’s cells and then have the antigen produced by cellular machinery, eliciting an immune response. This approach has been demonstrated in proof-of-principal experiments in mice for a leishmaniasis vaccine. The upshot of such an approach is the stability of plasmid DNA and the potential for a robust vaccine not requiring cold storage. Also, complex proteins could insure proper folding if translated by host cellular machinery. The potential for this approach for leishmaniasis and other parasitic disease is currently limited. Though the process has been shown to work, some candidate proteins cannot generate a strong enough immune response to confer resistance, or are not general enough to create immunity for other leishmaniasis causing organisms. Associated risks of this type of approach have not been entirely clarified. Autoimmunity against antigen-producing cells is a possibility, and the efficiency of plasmid uptake has to be high to ensure that the vaccine offers a high rate of protection. The diagram below depicts a model plasmid vector for introducing a “gene of interest” (in the preceding example a leishmaniasis protein) into an animal cell. Similar to this approach is introducing a protein into a bacterial host such as E. coli, where it could then be produced at industrial levels for later introduction into a vaccine regimen. This approach has shown some promise for leishmaniasis, as several antigenic proteins have been characterized and successfully introduced into E. coli cells. Though no definitive breakthroughs have risen from either of these approaches, research continues, as does the potential for future treatments (Schallig, Smooker).

(Smooker, et al. 1)

Orphaned Drugs: Compounds Waiting To Be Tested

Several websites exist with the purpose of providing information on under-studied disease in the hopes of spurring research interests. One effort is the Low Hanging Fruit website, developed by the McKerrow lab and the Sandler Center for Basic Research in Parasitic Diseases. The site compiles data for several FDA approved compounds that have shown some effect on African trypanosomes and the leishmaniasis protozoa in the hope that other groups are willing to test these compounds in clinical trials. Open source databases such as these have great potential in spreading awareness and interest, as well as increasing the levels of funding directed towards neglected diseases.

Cost-Benefit Analysis

As stated previously, NTDs often result in impaired physical and cognitive development, affecting the educational achievement of school-age children as well as productivity in adults. Furthermore, NTD’s may increase susceptibility and transmission of malaria, as well as HIV/AIDS. According to Unite for Sight, neglected tropical diseases total account for 56.6 million DALYs, coming in 6th worldwide after lower respiratory infections, HIV/AIDS, unipolar depression, diarrheal disease, and ischemic heart disease. Despite the far-reaching effects of NTD’s, funding remains paltry at best.

To defray the costs of prevention and treatment, since those afflicted often live in poor, developing countries, several big pharmaceutical companies have donated drugs for NTD’s. Merck has donated Mectizan for river blindness; GlaxoSmithKline has donated albendazole for lymphatic filariasis; MedPharm has donated praziquantel for schistosomiasis; and Johnson & Johnson has donated albendazole for intestinal worms (Stoever).

Mass drug administration programs can be easily implemented and executed. Teachers can be trained to administer the drugs and can incorporate distribution into existing activities, thus achieving low-cost delivery. Integrating NTD treatment programs would save costs and come out to less than $0.50 for packaged intervention and delivery costs for donated drugs. Creating an improved, efficient sanitation infrastructure would likely have high costs, but would result positive outcomes across the board for the health and economy of populations. Also, in many cases health education can decrease costs as well as re-infection rates. Effective vaccine programs may cost more in the short-term because of research, development, and delivery, but may ultimately prove cost-effective in interrupting transmission and preventing infection and/or re-infection. Providing public health programs aimed at preventing and treating NTDs, with elimination as an objective if feasible, is cost-effective and has broad positive ramifications for the health, and socioeconomic status of afflicted populations.

Conclusion

Health and well-being are linked to economic development in a relationship with ties to access and funding for healthcare initiatives. Addressing these neglected (in both funding and research) tropical diseases has the potential to go a long way towards reaching development and health goals. It has been written that the number of lives saved from childhood vaccines in the 20th century comes close to the number of people killed by warfare. With so many people affected worldwide, working to tackle these relatively low-grade, yet persistent and destructive ailments are a crucial part of a larger strategy to ultimately benefit humanity.