Patrick Kiser of the University of Utah in the U.S. will design a vaginal gel that blocks HIV by becoming impermeable in response to the pH change induced by the presence of semen, and includes a polymer engineered to bind to HIV surface proteins to halt viral transport to susceptible tissues and HIV target cells. In this project's Phase I research, Kiser and his team engineered a synthetic polymer that has many of the properties of mucus, and demonstrated that the polymers slow or stops the movement of cells in the presence of semen. In Phase II, Kiser will focus on developing a pericoital contraceptive gel that will prevent the movement of spermatozoa into the uterus.

Kuan-Teh Jeang of the National Institutes of Health in the U.S. will investigate whether cells infected by one virus become resistant to infection from other viruses, and if this viral interference can confer protection against HIV. The team will develop an attenuated virus to test whether over-expression of viral envelope proteins within cells can confer resistance to further HIV infection.

Enterotoxigenic E. coli (ETEC) is the leading cause of diarrhea in the developing world. Roy Robins-Browne, of the University of Melbourne, in Australia will evaluate the effectiveness of a prototype vaccine that combines enterotoxin of E. coli (which lacks immunogenicity by itself) with another epitope to attract helper T cells and a lipid adjuvant to ensure delivery of the antigen directly into the cell.

Ines Atmosukarto of Lipotek Pty Ltd. in Australia proposes to develop a novel TB vaccine utilizing synthetic “nano-sacs” called liposomes that carry TB antigens and are anchored with a self-adjuvanting protein that binds to and stimulates dendritic cells.

Fasséli Coulibaly of Monash University in Australia will design a vaccine platform based on protein crystals (MicroCubes) produced by insect viruses to produce new and more potent vaccines with increased stability, obviating the need for refrigerated storage. The crystal structure will be engineered to present multiple antigens that will then be tested for their ability to induce an effective immune response. In Phase I, a proof-of-concept study was performed to establish MicroCubes as a promising vaccine platform, focusing on production versatility, potential vaccine delivery routes, and efficacy for inducing an immune response in mice. In Phase II, they will investigate the broader potential of MicroCubes as a generic vaccine platform that can be used to deliver a wide range of antigens, and will use it to develop a candidate vaccine against HIV.

Golam Rabbani of International Centre for Diarrhoeal Disease Research, Bangladesh (ICDDR,B) will study the effects that a new model of indoor cooking stove with concealed combustion chambers and ventilation chimney has in reducing indoor air pollution and subsequently, reducing acute lower respiratory infections and TB in children.

Julio Scharfstein of Universidade Federal do Rio de Janeiro in Brazil will study whether a pre-dose of captopril, an established angiotensin-converting enzyme (ACE) inhibitor and anti-hypertension drug, can increase the potency of vaccines by increasing the activation of dendritic cells.

Chen Yangchao of the Chinese University of Hong Kong proposes developing a lentiviral vector that targets the entry and replication of influenza viruses in domestic chickens. The team plans to test the ability of these modified chickens to be resistant to various influenza viruses in an effort to reduce the frequency of flu epidemics in poultry and, ultimately, in humans.

Uri Selome McKakpo of the University of Ghana will develop and test a rapid dipstick test that utilizes monoclonal antibodies to detect parasite antigens present in urine of infected individuals. Using this technology, the team hopes to create a new diagnostic test for malaria that requires minimal training to use and does not depend on invasive blood samples.

Because tuberculosis manipulates host cells to resist the immune response and current drug therapies, Nigel Savage of Leiden University Medical Center in the Netherlands will utilize RNAi analysis to identify the essential pathways used by the bacteria to modify its host cell. By discovering these pathways, novel therapies can be developed to counteract this host manipulation without directly targeting the pathogen and causing the development of resistance.

To optimize the effectiveness of current anti-tuberculosis drugs, Boitumelo Semete of the CSIR in South Africa will work with collaborators to develop “sticky nanoparticles” that specifically attach to TB-infected cells. Once taken in by these cells, the nanoparticles will slowly degrade, releasing the anti-TB drugs and killing the bacteria. With this novel drug delivery system, the team aims to improve the bioavailability of the current therapies, with the possibility of shortening the treatment period for TB as well as reduce drug side effects.

Maria Lerm of Linkoping University in Sweden will test her hypothesis that TB latency is a dynamic process in which a portion of the bacilli, when ingested by macrophages, trigger a genetic program where bacteria cycle between active and latent phases. Understanding whether this dynamic cycle exists could give new insights into maintaining or targeting the latent bacteria, which is the major reservoir of TB globally.

Erich Cerny of Wissenschaftlicher Fonds Onkologie in Switzerland will test whether inducing antibodies against anti-malarial drugs can significantly prolong the half- life of that drug. Antibodies elicited via immunization may form a reservoir of the active drug for long-lasting treatment for malaria. Such a “small molecule vaccine” has significant implications for efficacy and cost of malaria prevention.

Bongkoch Tarnchompoo of the National Center for Genetic Engineering and Biotechnology in Thailand will attempt to develop and test a novel drug that binds to the two pathways used by the DHFR enzyme in P. falciparum to mutate. By tethering these active sites, the dual-binding drug will suppress the development of resistance to anti-malarial drugs.

Because human carriage of pneumococcus usually results in improved immunity to future infections without any development of disease, Stephen Gordon of the Liverpool School of Tropical Medicine in the United Kingdom will use an intranasal inoculation with a safe strain of the bacteria to study the mechanisms of mucosal immunity in the lungs and to explore the potential for a vaccine based on his findings. In this project's Phase I research, Gordon successfully demonstrated that human carriage of pneumococcus provides improved immunity to future infections, and that nasal inoculation immunizes the lungs against the pathogen. In Phase II, Gordon will work to assess the reproducibility of his model to ensure its robustness as a candidate for a pneumococcal vaccine.

Existing malaria vector control methods (e.g. nets and insecticide sprays) primarily target mosquitoes that enter or attempt to enter human dwellings, yet mosquitoes also obtain significant proportions of essential resources outdoors. Fredros Okumu of Ifakara Health Institute in Tanzania and his co-investigators therefore proposed the use of strategically-located outdoor vector control devices. In this project's Phase I research, the team created new and easy-to-use outdoor methods for luring, trapping and killing mosquitoes, including major African malaria vectors. By combining mosquito lures with mosquito-killing agents, they showed that in addition to trapping, it was consistently possible to contaminate and slowly kill between 74% and 95% of wild malaria vectors visiting the outdoor devices. In Phase II, the team will improve their decoy prototypes and explore practical ways in which the outdoor mosquito control strategy can be implemented by rural and remote communities in malaria endemic areas.

Marcus Horwitz and colleagues at UCLA in the U.S. will develop and test a novel drug delivery system in which nanoparticles loaded with anti-TB drugs selectively target macrophages, and release the drugs intracellularly via a pH-dependent gate, allowing delivery of high concentrations on antibiotics into the host cells for Mycobacterium tuberculosis.

Antimicrobial peptides (AMPs) are essential components of the innate immune system that provides resistance to a variety of pathogenic organisms by selectively lysing, or bursting, cellular membranes of invading pathogens. Doron Greenbaum of the University of Pennsylvania in the U.S. will test whether small molecules that mimic the natural AMPs can selectively kill the parasite that causes malaria. Such an approach could reduce costs of production as well as limit the emergence of drug resistance.

Alice Telesnitsky of the University of Michigan in the U.S. seeks to define and characterize HIV interactions with host RNA. The team will attempt to determine whether disrupting or mimicking essential interactions with host RNAs may lead to antiviral strategies to which HIV cannot readily develop resistance.

To test the theory that certain metabolic pathways essential to the survival of bacteria are immutable and therefore promising targets of drug therapy, Krishna Kodukula and colleagues at SRI International in the U.S. will identify peptides that bind key metabolites of M. tuberculosis, and test their ability to kill the bacteria.

Larry Walker of the University of Mississippi in the U.S. will test an innovative approach to mitigate the toxicity of primaquine, a promising and powerful malaria drug. Walker will separate the drug into two components, called isomers, to see if a single form retains the ability to eliminate the malaria parasite in its latent liver stages and the mature gametocytes while reducing toxic side effects.

Guirong Wang and colleagues at Vanderbilt University in the U.S. have recently identified key sensory heat receptors used by mosquitoes to target hosts. Wang will use these proteins as molecular targets to develop insect repellents and masking agents that block or hyper-stimulate these receptors and reduce the ability of the vectors to find hosts and spread disease.

Jefferson Vaughan of the University of North Dakota will seek to augment zooprophylaxis, the practice of using livestock to divert mosquito blood feeding away from humans, by developing an anti-mosquito vaccine for cattle that kill the insect before they bite humans.

Little is known about the role taste plays in the mosquito feeding process. Paul Breslin of the Monell Chemical Sense Center in the U.S. will test the sensitivity of the mosquito taste system to human skin compounds in an effort to identify key compounds that cue the insects to accept or reject blood meals from humans.