Malaria Vaccines, Therapies, and Drug Resistance
Improving prevention and therapy with better vaccines and predictions about drug resistance
Malaria kills more than 400,000 people a year, mostly children under the age of five. Drugs to treat malaria are available but their widespread use selects for parasite resistance to the drugs and treatment failures. Currently, there is increasing drug resistance in Southeast Asia to the front line antimalarial artemisinin, as well as the partner drugs used to cure uncomplicated malaria. The spread of drug resistant parasites to Africa could devastate the great gains made in malaria elimination.
Dr. Ashley Vaughan studies the human malaria parasites Plasmodium falciparum and Plasmodium vivax. His group improves malaria prevention through the development of live, attenuated vaccines. In addition, his group works to extend effective treatments by identifying genetic markers linked to drug resistance.
Expertise with a humanized mouse model
Dr. Vaughan’s group uses chimeric mice with human liver cells (FRG huHep mice) to study the malaria parasite life cycle. These mice facilitate work on a critical part of the parasite life cycle: maturation and growth in the liver and transition to the blood. Dr. Vaughan and colleagues use the mice to develop clinical tools such as vaccines and to understand the evolution of drug resistance.
The Vaughan lab’s innovations with these humanized animal models include in vivo imaging of whole mice. For example, using their expertise in creating transgenic parasites, researchers can create transgenic Plasmodium falciparum parasites with luciferase reporters and visualize and track parasite development in the human liver-chimeric mouse liver.
Ability to determine when resistance occurs and why
Dr. Vaughan pioneered a method that uses the mouse model for genetic crosses of Plasmodium falciparum. Compared to previous methods, crossing drug-resistant and drug-susceptible strains and analyzing the recombinant progeny will now allow for more rapid identification of loci and genetic markers associated with resistance.
In addition to genetic crosses to determine why resistance emerges, the Vaughan lab collaborates with investigators to measure parasite fitness under drug pressure. They can use this data to understand how the parasite develops resistance which could ultimately help in the design of the next generation anti-malarial drugs.
Experience with clinical trials of malaria vaccines
The Vaughan lab collaborates with Stefan Kappe's group to develop malaria vaccines. The team has generated genetically attenuated parasites (GAPs) – Plasdmodium falciparum parasites with gene deletions that arrest during liver stage development. These liver stage-arrested parasites act as potent vaccines and can provide protection from malaria infection.
Dr. Vaughan led clinical trials using GAPs as vaccines that yielded early promising results. The team has now developed GAPs that arrest later in the liver stage. Based on results in mice, these GAPs are expected to present more antigen to the immune system and require a lower immunizing dose than previous versions.
Dr. Vaughan is interested in partnerships that use his group's expertise to develop and test vaccines, monitor and reduce drug resistance, and screen antimalarial drugs.
Stage of Development
- Preclinical in vitro, in vivo, and ex vivo
- Clinical trials
- Collaborative research opportunity
- Sponsored research agreement
- Licensing agreement
- Consultation agreement
- Medium-throughput drug and drug-resistance screening
- Goswami D, Betz W, Locham NK, Parthiban C, Brager C, Schafer C, Camargo N, Nguyen T, Kennedy SY, Murphy SC, Vaughan AM, Kappe SH. A replication-competent late liver stage-attenuated human malaria parasite. JCI Insight. 2020;5(13).
- Vaughan AM, Sack BK, Dankwa D, Minkah N, Nguyen T, Cardamone H, Kappe SHI. A Plasmodium parasite with complete late liver stage arrest protects against preerythrocytic and erythrocytic stage infection in mice. Infect Immun. 2018. 23;86(5). pii: e00088-18.
- Kublin JG, Mikolajczak SA, Sack BK, Fishbaugher ME, Seilie A....Vaughan AM....Complete attenuation of genetically engineered Plasmodium falciparum sporozoites in human subjects. Sci Transl Med. 2017;9(371). pii: eaad9099.
- Vaughan AM, Pinapati RS, Cheeseman IH, Camargo N, Fishbaugher M, Checkley LA, Nair S.....Plasmodium falciparum genetic crosses in a humanized mouse model. Nat Methods. 2015;12(7):631-633.
- Mikolajczak SA, Vaughan AM, Kangwanrangsan N, Roobsoong W, Fishbaugher M, Yimamnuaychok N....Plasmodium vivax liver stage development and hypnozoite persistence in human liver-chimeric mice. Cell Host Microbe. 2015;17(4):526-535.
- Vaughan AM, Mikolajczak SA, Wilson EM, Grompe M, Kaushansky A, Camargo N, Bial J, Ploss A, Kappe SHI. Complete Plasmodium falciparum liver-stage development in liver-chimeric mice. J Clin Invest. 2012;122(10):3618-3628.
- Vaughan AM, O'Neill MT, Tarun AS, Camargo N, Phuong TM, Aly AS, Cowman AF, Kappe SHI. Type II fatty acid synthesis is essential only for malaria parasite late liver stage development. Cell Microbiol. 2009;11(3):506-520.