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| PHASE I: Identify detection antibodies and assemble trial assays for evaluation in the laboratory as follows: 1) Against standard set of dilutions of diluted virus stocks; 2) against individual and pools of known dilutions of virus stocks macerated with vector species; and 3) against laboratory infected vectors (evaluated separately by "gold standard" methods). End product are prototype assays with estimates of virus detection limits, accuracy, and maximum number of vectors per pool.
More specifically, the dengue dipstick already exists as a prototype that is sufficiently sensitive to DEN 2 and 4, but not to DEN 1 and 3. The next step in opitimizing the dengue dipstick would be to get a reliable source of dengue 1 and 3 infected mosquitoes (by intrathoracic injection of virus stocks into female Aedes aegypti at WRAIR and by oral feeding of a mixture of virus-RBCs-glucose to Aedes aegypti), retest the existing dipstick, and determine whether past failures were due to poor material or a need for technical readjustment of the dipstick. The dipstick would be readjusted by the industrial partner by increasing the concentration of DEN 1 and 3 detection antibodies or by increasing the concentration of virus in the mosquito triturate by filtering out solid material. If these adjustments do not increase sensitivity, then new monoclonal detection antibodies would be tested. These monoclonals would be created de novo by a subcontractor. Finally, if these new monoclonals were not sensitive enough, a general dengue detection antibody (monoclonal 4G2) could be added to the dipstick in order to deterimine whether any dengue type was present. For the other viruses, attempts would be made to purchase the use of existing monoclonals, but new monoclonals would be made if necessary. Following assembly of trial dipsticks, a set of approximately 10 sticks would be tested against each of a set of serial dilutions of the stock virus in order to determine whether the sticks would be sufficiently sensitive compared to published viral titers known from mosquitoes. The sticks might need optimization in order to achieve sufficient sensitivity. Once the sticks appeared to be detecting the viruses in stock solutions at sufficient sensitivity, infected mosquitoes (both intrathoracically injected and orally fed) would be tested with RT-PCR as the gold standard for comparison. Source of infected mosquitoes would have to be coordinated with partner government or academic laboratories. These laboratories would have to colonize the representative vectors of the viruses (JE: Culex tritaeniorhynchus; Ross River: Ochlerotatus vigilax; Rift Valley: Aedes lineatopennis) and maintain sufficient biocontainment to handle live, infected mosquitoes. The goal of Phase I would be reached when sticks were available capable of detecting at least one-half log less virus than occurs in infected mosquitoes. PHASE II: In this phase the contractor would perform research on whether the dipsticks would be a useful tool for evaluation of risk. The contractor from industry would assemble assays into kits with all necessary reagents and tools and distribute to at least two test centers (suggested sites: dengue: Armed Forces Research Institute for Medical Sciences and Walter Reed Army Institute of Research; Ross River virus: Australian Army Malaria Research Institute and US Army Medical Research Institute for Infectious Diseases; Rift Valley Fever virus: US Army Medical Research Unit-Kenya and US Army Medical Research Institute for Infectious Diseases; Japanese encephalitis virus: Armed Forces Research Institute for Medical Science and Walter Reed Army Institute of Research) for each virus. Test centers will receive written and personal training on the new assays and either performance of or shipment for "gold standard" method. Test centers will capture vectors from natural focus of the pathogen (at least 10 times the number of vectors expected to include one infected individual) or use laboratory infected mosquitoes, use the assay to test the vectors individually or in pools, and either perform the gold standard method or ship material so that the gold standard method can be performed at a central laboratory. Results of the evaluations will be analyzed, published in peer reviewed journals, and used as the basis for acceptance or rejection of the test. Protocols for the tests and the test results will be judged by the DoD Armed Forces Pest Management Board. The contractor would evaluate the use of the dipsticks for risk evaluation by performing research on the incidence of the pathogen, abundance of the vector, vector competence, effects of weather on transmission potential, and dipstick results. The research would include determination of the best means of collecting each vector and the minimum number required for accurate determination that the pathogen is absent from the area (a key operational decision). The research would also determine algorithms of weather, human exposure to the vector, vector abundance, and dipstick results to produce specific probability of infection with an indication of likely error in the estimation. PHASE III: The satisfactory tests will be produced and marketed, with application to the Armed Forces Pest Management Board for recommendation to assign a National Stock Number. Tests will be fielded to military field preventive medicine assets and promoted to USDA, CDC, and the Department of Homeland Defense for detection of introduction of the viruses in vectors. REFERENCES: 1) Dipsticks for rapid detection of Plasmodium in vectoring Anopheles mosquitoes. J. R. Ryan, K. Dave, E. Emmerich, L. Garcia, L. Yi, R. E. Coleman, J. Sattabongkot, R. F. Dunton, A. S. T. Chan and R. A. Wirtz – Med. and Vet. Entomology (2001) 15, 225-230 2) Evaluation of a Dipstick Malaria Sporozoite Panel Assay for Detection of Natually Infected Mosquitoes. M. Bangs, S. Rusmarto, Y. R. Gionar, A.S>T. Chan, K. Dave and J. R. Ryan, J. Med Ento 39, pp324-330 (2002). 3) Extensive Multiple Test Center Evaluation of the VecTestTM Malaria Antigen Panel Assay. J. R. Ryan, K. Davé, K. M. Collins, L. Hochberg, J. Sattabongkot, R. F. Dunton, M. J. Bangs, C. M. Mbogo, R. D. Cooper, G. B. Schoeler, Y. Rubio, M. Magris, L. I. Romero, N. Padilla, I. A. Quakyi, R. G. Leke, C. F. Curtis, B. Evans, M. Walsey, P. Patterson, R. A. Wirtz, and A. S. T. Chan –Med Vet Entomol. Sept, 2002, 16 (3), 321-328. 4) "Wicking Assays for the Rapid Detection of West Nile and St. Louis Encephalitis Viral Antigens in Mosquitoes (Diptera: Culicidae)", J. Ryan, K. Davé, É. Emmerich, B. Fernández, M. Turell, J. Johnson, K. Gottfried, K. Burkhalter, A. Kerst, A. Hunt, R. Wirtz and R. Nasci - accepted by the Journal of Medical Entomology. 5) Sensitivity of the VecTestTM Antigen Assay for Eastern Equine Encephalitis and Western Equine Encephalitis viruses. Roger S. Nasci, Kristy L. Gottfried, Kristen L. Burkhalter, Jeffrey R. Ryan, Eva Emmerich and Kirti Davé – Accepted by Journal of Journal of American Mosquito Control Association 6) Comparison of Vero cell plaque assay, TaqMan reverse transcriptase RNA assay, and VecTest antigen assay for detection of West Nile virus in field-collected mosquitoes. Nasci RS, Gottfried K L, Burkhalter K L, Kulasekera V L, Lambert A J, Lanciotti RS, Ryan J R. – Accepted by J. Am. Mosq. Control Assoc.
A03-176 TITLE: A "Personal Blood Pack" to Improve the Availability of Red Cells for Transfusion during Contingency Operations TECHNOLOGY AREAS: Biomedical ACQUISITION PROGRAM: DSA, MRMC OBJECTIVE: Improve the Availability of Red Cells for Transfusion during Contingency Operations DESCRIPTION: According to current doctrine, the only approved shipping container for the transport and storage of human Packed Red Blood Cells (PRBCs) ) in the battlefield is the “Collins Box” which keeps PRBCs at the required temperature (1-10° C) for approximately 24 hours under ideal environmental conditions. This box is a reusable cardboard and Styrofoam container, which can hold up to 30 PRBCs and weighs 44 pounds when loaded with 14 pounds of wet ice. The current weight and dimensions of the “Collins Box” makes it impossible for any soldier to carry it farther forward than the Forward Surgical Teams (FSTs). Recent military exercises have demonstrated the need for a lighter blood storage container that can be used during delayed evacuations when it may take over 12 hours to evacuate a wounded soldier. The transfusion of red cells far forward from the FSTs will enhance medical treatment and increase the survivability of wounded soldiers before evacuation takes place. A much lighter “Personal Blood Pack” that can carry one unit of PRBCs and keep them at the desired temperature for over 48 hours under extreme conditions is needed, as it would solve the weight and temperature control issues that we now face. Furthermore, since it should weigh only 2-3 pounds, any soldier can carry it during contingency operations. The “Personal Blood Pack” should be constructed with lightweight-super insulating material (i.e., vacuum insulated paneling, aerogel technology) capable of keeping PRBCs within the required temperatures under austere environments without the need for ice or batteries. PHASE I: Identify insulation materials that will be capable of maintaining a unit of PRBCs within the required temperature range (1° to 10° C) for a minimum of 48 hrs. Identify a protective outside shell material for such an insulated container. Design and construct a container with these materials that will no more than double the weight of the unit and demonstrate temperature-maintaining efficiency under extreme external conditions (-20° to +40° C). Size must be such that the container can be attached to or placed inside a standard military-issue field pack PHASE II: Demonstrate efficacy of the storage container in extending non-refrigerated red blood cell storage time by maintaining unit temperature within the prescribed range under extreme conditions. Perform or participate in clinical laboratory testing of units stored under field-simulated conditions. PHASE III DUAL USE APPLICATIONS: Produce and support use of such a storage container during its introduction into clinical use. Addresses a market for provision of current and future (i.e. hemoglobin-based oxygen carriers, lyophilized plasma and RBCs, recombinant factor VIIa ) blood products that will need to be stored at 1-10° C. REFERENCES: 1) TM 8-227-11 (Operational Procedures for the Armed Services Program Elements). 2) TM 8-227-12 (Armed Services Blood Program Joint Blood Program Handbook). 3) Food and Drug Administration, CFR #21 Section 640. KEYWORDS: blood, red blood cells, blood products, storage container, mobile blood storage container. A03-177 TITLE: Development of a Field Portable Mosquito Monitoring System with Attractant TECHNOLOGY AREAS: Biomedical ACQUISITION PROGRAM: DSA, MRMC OBJECTIVE: Adapt modern technology to incorporate observational monitoring software into a field portable mosquito monitoring system for common vectors of disease, such as adult Anopheles stephensi and Aedes aegypti, vectors of malaria and dengue respectively. REQUIREMENT: To increase the ratio of combat to support personnel and to preserve the health of combat personnel. Accurate surveillance of disease carrying mosquitoes provides risk assessment for some of the most important military infectious diseases including malaria, leishmaniasis, dengue, and West Nile virus. Current methods only approximately measure the risk, unless dangerous human-bait collections are performed. Better methods would reduce the number of vector control personnel required because their efforts could be targeted to the most problematic locations. Improved vector control would reduce the number of cases of disease among combat personnel. Development of a field exportable mosquito monitoring system to identify the true disease risk (from disease vectors) in an operational environment is therefore a high priority for the Department of Defense. DESIRED CAPABILITY/CONCEPT OF THE FINAL PRODUCT: A portable device ready to use anywhere that electronically scores the number of disease carrying insects. We envisage a field portable, durable, light, remote mosquito monitoring system that incorporates observational software with more robust algorithms to handle lower contrast settings with higher background noise levels, into a small “data logger” type device used in conjunction with a miniature camera(s)/ imagery device to accurately record both visual and time duration data of mosquitoes landing on an artificial attractant surface. This system would be used in combination with an attractant-monitoring surface. DESCRIPTION: The global prevalence of vector borne diseases such as dengue and malaria has grown dramatically in recent decades. In order to assess the effectiveness of any control effort directed against dengue mosquito vectors, it is vital to accurately and precisely sample the vector population. Such determinations must be made before, during, and after vector control in order to determine effectiveness of the control methods used. Accurate sampling provides the information necessary for operational entomologists to adjust their vector control efforts, if necessary. In addition, effective vector population sampling is necessary when attempting to predict disease outbreaks and determine when and where to apply control measures to prevent and suppress such outbreaks. The correlation between human biting/landing counts and the proportion of infected mosquitoes are key parameters in conducting effective field studies and subsequent control efforts in suppressing disease. The most common means employed and most representative of the local vector population responsible for disease transmission is the human biting/landing counts. Landing counts have the very strong advantage of converting to estimates of true risk (entomological inoculation rate). Without an accurate estimate of human biting, it is impossible to calculate risk from entomological data. Even though it is generally agreed among the scientific community that human bait collections are the most representative and reliable measure of vector populations responsible for disease transmission, the exposure it places on naïve collectors and the ethical sensitivity of using humans as bait. The difficulty of using military personnel for landing collections is that it is not only unpopular, but also exposes individuals to vector-borne pathogens, potential adverse skin reactions and exposure in tactically dangerous environments. The use of various traps have been used with varying degrees of effectiveness in sampling mosquito populations throughout the world; however, no trap exists today that correlates to human landing collections over a wide range of vector population levels, and provides the data necessary to calculate true risk. Several known factors of host-seeking behavior exhibited by mosquitoes include various visual cues, circadian rhythm, carbon dioxide, heat, moisture and host odors. Such factors in relation to human skin as an attractant have been investigated in addition to several sources of attractive stimuli from host odor such as sweat, blood, and chemical compounds. Although recently, commercial traps on the market have incorporated heat, carbon dioxide, and octenol, these traps are large, bulky, and require pressurized gas in their operation. Some of these traps also contain an electrical impulse grid that kill the mosquitoes and render them useless for identification. CDC light traps are the only adult mosquito monitoring devices provided to our Preventive Medicine personnel. These traps collect far fewer mosquitoes than human collectors and are ineffective in collecting the primary vector for dengue, Aedes aegypti. Therefore, a need exists to develop an alternative to human bait collections. The U.S. Army Medical Research and Material Command is developing a Dengue Vector Control System (DVCS) that incorporates integrated pest management principles with the objective of preventing dengue in our military and civilian forces. A very beneficial component to this system would be the inclusion of a mosquito monitoring system that can be correlated to human landing collections and has the ability to provide the data necessary in calculating true risk. This call for research will focus on the automated monitoring portion of the system. PHASE I: Demonstrate the likelihood that an effective mosquito monitoring system for Aedes aegypti can be developed that meets the broad needs discussed in this topic. A system that incorporates our existing (or develop a new) observational software program that electronically scores not only the number of mosquitoes that land, but also the time duration mosquitoes remain on a monitoring surface and stores the data in a recording device/data logger with enough memory to record visual imagery and mosquito landing data obtained through the camera(s)/imagery device under variable light conditions and backgrounds. The “data logger”/device should be small in size and interface with observational software in the performance of recording imagery data at preprogrammed time intervals determined by the user and mosquito “landings” at one second or greater intervals for at least a 24 hour period. The software program should automatically analyze the transferred data and provide the number and time duration of each mosquito that landed on the attractant/monitoring surface based on user input settings. The camera(s)/imagery device should be small in size and have enough resolution to enable identification of a mosquito under variable light conditions and backgrounds which may be refined in Phase II. The user will perform the actual mosquito identification while viewing the collected data on a laptop or personal computer. The “data logger” should easily interface with a laptop computer for data transfer in a field environment. The packaged dimensions of the system should not exceed 2304 cubic inches and the entire packaged system itself should weigh 10 lbs (i.e., including battery power, support equipment, hand held computer device, crush proof packaging) or less. If the system is electrically powered, it must use rechargeable batteries or some form of extended power source and not require permanent, hard wired electricity. The system must be field durable, waterproof, and allow for operation in a remote environment, i.e., set-up and return to collect data all of which may be refined in PHASE II. Data transfer capability to a handheld personal computer is a PHASE II requirement. The researcher may refine and expand on our initial software or develop new software to meet our goals. PHASE II: Develop and demonstrate an applicable and feasible prototype. Conduct testing to prove feasibility of the system to monitor mosquitoes that land on an attractant/monitoring surface over time. Demonstrate that the data stored in the “data logger” is easily transferred to a laptop or hand held PC. The software program should automatically analyze the transferred data and provide the number and time duration of each mosquito that landed on the attractant/monitoring surface based on user input settings. Demonstrate that the visual imagery data collected under variable light conditions and background are detailed enough for mosquito species identification. The researcher can expect that the WRAIR laboratory will support development of this system by providing disease free mosquitoes for use in our facility. PHASE III / DUAL USE APPLICATIONS: The developed technology could be used by both military forces and by government ministries of health/vector control entities or commercial vector control operations in the United States and developing countries to accurately assess the presence of a disease vector and determine the true risk of disease when combined with an attractant (similar to human emanations) monitoring surface. Additionally, may be used to enhance trap monitoring of control efforts directed against the mosquito vectors of dengue. COMMERCIAL APPLICATIONS (SPIN-OFF): Government ministries of health/vector control entities or commercial vector control operations in the United States or abroad could use this mosquito monitoring system in assessing the true risk of disease transmission. Developing countries use human landing/biting collections less frequently due to awareness of the exposure of the individual to potential disease infection. This device is different than existing commercial trapping/surveillance devices which only collect/attempt to collect the adult vector species in a given area. This mosquito monitoring system, when combined with an attractant similar to human emanations, would provide a needed device that would be commercially viable and replace the need for human landing/biting collections. COMMERCIAL APPLICATIONS (SPIN-ON): The use of existing commercial observational software applications incorporated into a small, field deployable, mosquito monitoring system. TECHNICAL RISK: There is a degree of technical risk involved in this project. Existing trapping/surveillance devices do not meet the requirements summarized in this proposal for a device that monitors by scoring and concurrently records visual imagery of target mosquitoes that land on an attractant/monitoring surface. The candidate contractor is expected to use innovation and in-house expertise to develop a prototype that meets the needs of the Department of Defense. ACCESS TO GOVERNMENT FACILITIES AND SUPPLIES: The evaluation of an efficient mosquito monitoring system will require support from the Walter Reed Army Institute of Research in Silver Spring, Maryland for both laboratory and coordination for field testing of the device in dengue endemic locations, such as Thailand. The candidate contractor should coordinate with the COR for any required support prior to the submission of the proposal. REFERENCES: 1) BioSensory, Inc. (2000) The DragonflyÒ the ultimate mosquito-eater. Available from: URL: http://nomorebites.com/dragonfly.html 2) Canyon D. V. and H. L. Hii. 1997. Efficacy of carbon dioxide, 1-octen-3-ol, and lactic acid in modified Fay-Prince traps as compared to man-landing catch of Aedes aegypti. J Am Mosq Control Assoc. Mar; 13(1):66-70. 3) Clements, A. N. (1999) The biology of mosquitoes. Volume 2. Sensory Reception and Behaviour. Cambridge: University Press.740 pp. 4) Cork, A. & Park, K. C. (1996) Identification of electrophysiologically-active compounds for the malaria mosquito, Anopheles gambiae, in human sweat extract. Physiological Entomology, 10, 269-276. 5) Driggers, D. P., R. J. O'Connor, J. T. Kardatzke, J. L. Stup, & B. S. Schiefer. 1980. The U.S. Army miniature solid state mosquito light trap. Mosq. News 40: 172-178. 6) Gibson, G. & Torr, S.J . (1999) Visual and olfactory responses of biting Diptera to host stimuli. Medical and Veterinary Entomology, 13, 2-23. 7) Jensen, T., O. R. Willis, T. Fukuda, and D. R. Barnard. 1994. Comparison of bi-directional Fay, omni-directional, CDC, and duplex cone traps for sampling adult Aedes albopictus and Aedes aegypti in north Florida. J Am Mosq Control Assoc. Mar; 10(1):74-8. 8) Khan, A. A. (1977) Mosquito attractants and repellents, pp. 305-325. In H. H. Shorey and J. J. McKelvey, Jr. [eds.], Chemical control of insect behavior. Wiley, New York. 9) Kline D. L. 1998. Olfactory responses and field attraction of mosquitoes to volatiles from Limburger cheese and human foot odor. J Vector Ecol. Dec; 23(2):186-94. 10) Lane R. P. & R. W. Crosskey. 1993. Medical Insects and Arachnids. Chapman and Hall, London, United Kingdom. 723 pp. 11) McCall P. J. , G. Harding, J. Roberts, and B. Auty. 1996. Attraction and trapping of Aedes aegypti (Diptera: Culicidae) with host odors in the laboratory. J Med Entomol. Jan; 33(1):177-9. 12) Rigau-Perez J. G., C. G. Clark, D. J. Gubler, P. Reiter, E. J. Sanders, and A. V. Vorndam. 1998. Dengue and dengue haemorrhagic fever. Lancet. Sep 19; 352 (9132): 971-7. 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