Date Published: November 19, 2015
Publisher: Public Library of Science
Author(s): Wolfgang W. Leitner, Tonu Wali, Randall Kincaid, Adriana Costero-Saint Denis, Mark Quentin Benedict. http://doi.org/10.1371/journal.pntd.0004107
Partial Text: Numerous diseases are transmitted by arthropod vectors, and for many of those diseases, effective vaccines are still not available. The contribution of the vector to the process of pathogen transmission is often overlooked, despite providing new avenues for combating vector-borne diseases, some of which could complement and significantly enhance ongoing efforts. To explore novel approaches to fighting vector-borne diseases, the National Institute of Allergy and Infectious Disease (NIAID) convened a workshop with experts in parasite immunology, vector biology, and entomology (listed in Table 1), who discussed possibilities of translating these basic research ideas into potential commercial products. The feasibility of product development was analyzed for four types of approaches: the use of vector-derived factors, such as arthropod saliva, as vaccine candidates to prevent transmission; the evaluation of bioactive vector saliva proteins as novel drugs; the use of vector saliva molecules as biomarkers of vector exposure; and the modification of the vector microbiome to alter vector competence. Some of these approaches are highly promising, some are already quite advanced, and all have the potential to significantly reduce the transmission of vector-borne diseases. However, the discussions also revealed significant regulatory and market challenges in the path toward a commercial product, even for the most promising approaches.
Traditionally, vaccines against vector-borne infectious diseases target antigens expressed by the infectious agent in an attempt to neutralize the pathogen or, at least, reduce the disease burden and, thus, reduce morbidity and mortality associated with the disease. However, a few vaccines instead target pathogen-associated antigens expressed during life stages of the parasite that are associated with uptake by a vector (e.g., gametocyte) or development inside the vector. Such transmission-blocking vaccines represent a distinct second category of vaccines against vector-borne diseases and provide benefit to the community in an endemic area, not in terms of affecting disease pathogenesis, but by limiting the spread of the pathogen. A separate category of transmission-blocking vaccines (vector-targeting, transmission-blocking vaccines) targets molecules inside the vector, such as the Galectin PpGalec (Table 2) in the midgut of the sand fly . When antibodies in the blood meal of the sand fly’s host bind to these molecules in the vector’s gut, they interfere with the attachment and, thus, development of Leishmania parasites. The discovery that vector saliva includes immunosuppressive or immunomodulatory molecules, which facilitate the establishment of an infection (reviewed in ), has given rise to a third category of vaccines against vector-borne pathogens. The objective of these vaccines is simple and elegant: Targeting vector saliva molecules that assist pathogens during infection may either “unmask” the infectious inoculum and allow the host’s immune system to eliminate it (e.g., tick-borne diseases as reviewed in ), or induce an immune response that interferes with the establishment of an infection by the vector-borne pathogen (as shown for Leishmania [4,5]). Such vaccines could, in principle, be effective against multiple infectious diseases transmitted by the same type of vector and would not be rendered ineffective by mutations in immunodominant epitopes on pathogen-derived antigens, which conventional vaccines against infectious diseases target. Despite the identification of numerous potent, immunomodulatory saliva molecules from a broad spectrum of blood-feeding arthropods, the vast majority of studies investigating them as vaccine candidates have, unfortunately, not moved beyond early preclinical studies. Such saliva-based vaccines may have potential as stand-alone products or, more likely, as an adjunctive component of traditional vaccines against vector-borne diseases. In the latter case, they may be able to reduce the infectious inoculum during a blood meal and facilitate recognition of the infectious agent by the vaccine-primed host immune system. Combining saliva-based with pathogen-based vaccines , though scientifically highly appealing, is, however, significantly more complicated from a regulatory and intellectual property standpoint, as well as a manufacturing and formulations standpoint, since it would involve multiple active components.
The vertebrate host mounts an antibody response to at least certain arthropod saliva proteins, providing a “signature” or “record” of prior—and mostly recent—vector exposure, despite the minute amounts of saliva injected into the bite site, and despite the host’s suppressed immune response to the inoculum. It remains unclear if these antibodies significantly affect the ability of the vector species to obtain an efficient blood meal or interfere with a vector-borne infection since certain saliva proteins clearly aid during the initial stages of infection. It is possible that the subtype or specificity of those naturally induced anti-saliva antibodies is significantly different from those induced by a saliva protein-based vaccine. Nevertheless, the bite-induced humoral response represents a useful indicator of bite frequency. Humoral responses against saliva proteins correlate well with the extent of exposure at a population level and can, therefore, be used as an objective method to assess the usefulness of vector-control measures. While the majority of susceptible animals in an endemic area tend to be uninfected, the relative rate of infected vectors can easily be determined and, together with the serological data from those living in the area, be used to estimate the risk of infection.
The saliva of blood-feeding arthropods contains bioactive molecules, which have evolved over the course of more than 100 million years to exert specific pharmacological effects even when only minute amounts are present at the bite site. They modify the bite site to facilitate the blood meal, but are also exploited by vector-borne pathogens, which take advantage of the immunosuppressive environment established by certain saliva proteins. The vector sialome is an enormous, largely unexplored, and virtually untapped source of pharmacological agents. Its size is largely due to the fact that blood feeding was independently invented by multiple vector species, thus giving rise to multiple sets of evolutionarily unrelated saliva proteins with overlapping functions (e.g., anticoagulants, which are used by virtually every vector species).
Traditionally, efforts to combat vector-borne diseases have focused on either vector control or the elimination of the pathogen inside the host following transmission through an arthropod vector. However, both approaches have significant limitations. Insecticides can be quite effective in eliminating a vector species temporarily and locally, but this approach is expensive. For example, a nationwide spraying campaign was conducted in Guatemala starting in 2002 to combat triatomine-transmitted Chagas disease  at a cost of US$10/house, but the impact of the campaign was short-lived. Long-term application of pesticides harms other species (e.g., honey bees) and results in the selection of insecticide-resistant vectors. Bed nets protect against blood-feeding by vectors during peak times of transmission only when properly used and maintained. Environmental modifications such as the draining of swamps are not feasible everywhere and are extremely costly, in addition to having potentially devastating effects on the environment. Finally, repellants only work as long as they are used properly (i.e., continuously), thus limiting their usefulness.
The process of “translating” exciting scientific ideas into tangible products begins with a simple acknowledgment—that the motivations and goals of basic scientists differ from those involved in the business of developing products. Numerous non-scientific aspects need to be considered and addressed before advancing a promising scientific discovery, such as those discussed above, into the pathway for product development. Most of these translational considerations are pragmatic ones and require a fundamentally different mindset than that found in basic research, which often seeks to explore and pursue new ideas. By contrast, business development is driven by cycles of planning and risk assessment designed to anticipate known problems that are often encountered by product developers. There are a few basic guidelines that may be helpful to those seeking to go beyond the bench and into the world of translational development.