Mosquitocidal vaccines: a neglected addition to malaria and dengue control strategies Peter F. Billingsley 1, 2 , Brian Foy 3 and Jason L. Rasgon 4 1 School of Biological Sciences, University of Aberdeen, Tillydrone Avenue, Aberdeen, AB24 2TZ, UK 2 Sanaria Inc., 9800 Medical Center Drive, Rockville, MD 20850, USA 3 Arthropod-Borne and Infectious Diseases Laboratory, Department of Microbiology, Immunology and Pathology, Colorado State University, 1682 Campus Delivery, Fort Collins, CO 80523-1682, USA 4 The Johns Hopkins Malaria Research Institute and The W. Harry Feinstone Department of Molecular Microbiology and Immunology, Bloomberg School of Public Health, Johns Hopkins University, Baltimore, MD 21205, USA The transmission of vector-borne diseases is dependent upon the ability of the vector to survive for longer than the period of development of the pathogen within the vector. One means of reducing mosquito lifespan, and thereby reducing their capacity to transmit diseases, is to target mosquitoes with vaccines. Here, the principle behind mosquitocidal vaccines is described, their poten- tial impact in malaria and dengue control is modeled and the current research that could make these vaccines a reality is reviewed. Mosquito genome data, combined with modern molecular techniques, can be exploited to overcome the limited advances in this field. Given the large potential benefit to vector-borne disease control, research into the development of mosquitocidal vaccines deserves a high profile. Vaccines against bloodfeeding arthropods The concept of vaccines against bloodfeeding arthropods gained prominence with the successful demonstration of anti-tick immunity in cattle that were immunized with a recombinant protein, Bm86 [1,2]. Boophilus microplus ticks that fed on vaccinated cattle exhibited reduced fecundity and survival. Bm86, which is marketed as TickGARD PLUS , has proven to be robust in the field [3] and maintains effectiveness over several tick gener- ations. Since the immunization of hosts with mosquito antigens in 1948 [4], research into mosquitocidal vaccines has continued intermittently, but successes have been few. Mosquitoes differ greatly from ticks in feeding behavior (mosquitoes do not attach to the host long-term) and digestion (ticks digest their bloodmeal intracellularly). Nevertheless, mosquitoes ingest several times their own weight in host blood [5] and the blood- meal contains all host immune system components [6]. These immune effectors can remain active in the mos- quito for 24 h [7,8] and can kill mosquitoes [9–14]. It is surprising, therefore, that mosquitocidal vaccines con- tinue to be considered as unfeasible and research in the field suffers from a lack of acceptance. Here, the case is made for a more sustained research effort to truly test the feasibility of mosquitocidal vaccines for the control of diseases such as malaria and dengue. Mosquitocidal vaccines: pros and cons There are strong arguments in favor of immune control of vectors in general and mosquitoes in particular. Vector control is by far the most successful method for reducing the incidences of diseases such as malaria and dengue, but the emergence of widespread insecticide resistance and the potential environmental issues associated with some insec- ticides (such as DDT) indicate that additional approaches to control the vector are needed. An ‘immune insecticide’ would target biting mosquitoes much more directly than any environmentally applied insecticide and would prefer- entially kill the oldest females, which tend to drive disease transmission. Mosquitocidal vaccines have already been proven to work in the laboratory [9–14], and it might be possible to target multiple mosquito species with a multi- valent vaccine. The most compelling arguments for developing a mos- quitocidal vaccine come from modeling. In any epi- demiological model for vector-borne diseases, the most influential factor that drives transmission by a competent vector is the daily survival rate (Box 1). Essentially, the vector must survive throughout the extrinsic incubation period (i.e. ingestion into the vector, development and transmission) of the pathogen. Pathogen transmission is exquisitely sensitive to the daily survival rate of mosqui- toes [15–23], and changes in survival have an exponential impact upon the transmission and basic reproductive rate (R 0 )(Box 1), whereas most other parameters in malaria models have outcomes in linear proportion to their efficacy. This has several important implications for mosquito vaccines that add to their attractiveness. Foremost is that high efficacy is not needed; modest reductions in the sur- vival of mosquitoes that feed upon immunized hosts are sufficient to have a major impact upon transmission. In the model presented in Box 1, reducing the survival rate by only 19% (as seen in Ref. [13]) would reduce R 0 by >95% for dengue and >99% for malaria (Figure 1a). Compare this to recent vaccine trials with the anti-Plasmodium sporozoite RTS,S vaccine, in which 30% efficacy was noted in the Opinion Corresponding author: Billingsley, P.F. (pbillingsley@sanaria.com). TREPAR-749; No of Pages 5 1471-4922/$ – see front matter ß 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.pt.2008.06.003 Available online xxxxxx 1