This revised K23 application is submitted by Lauren Cohee, M.D., a pediatric infectious disease specialist in the Division of Malaria Research at the University of Maryland School of Medicine. Dr. Cohee's long-term goal is to become an independent investigator focused on advancing the elimination of malaria by designing and evaluating interventions to decrease P. falciparum transmission. Towards this goal, she proposes a career development plan which provides mentored training in mosquito feeding assays, genomics, and microarray analysis. Interventions to decrease P. falciparum transmission are critical to achieving the goal of malaria eradication. One promising approach is the development of transmission blocking vaccines. These vaccines aim to induce antibodies that limit parasite development in the mosquito and prevent transmission to the next human host. Current vaccine candidate antigens have been identified based on naturally-acquired immune responses to these antigens resulting in decreased transmission. However, it is not known if either naturally-acquired or vaccine-induced transmission reducing immune responses (TRI) are strain-specific. Strain specificity, meaning failure of immune responses based on a single strain to provide protection from other strains, has led to limited efficacy of prior malaria vaccines targeting the asexual disease-causing stage of the parasite. Understanding the strain-specificity of naturally-acquired and vaccine-induced TRI has significant implications for the potential success of transmission blocking vaccines as well as studies of the epidemiology of TRI. In the context of a larger study of the dynamics of malaria transmission in Malawi, Dr. Cohee will evaluate the strain-specificity of naturally-acquired and vaccine-induced transmission reducing immunity. Specifically, she will use mosquito feeding assays to measure TRI against multiple parasite strains, including common laboratory strains and Malawian field isolates, using serum from Malawian study participants and monoclonal antibodies to transmission blocking vaccine candidate antigens (Aim 1). She will then identify antibody correlates of these responses using a novel diversity-based peptide microarray (Aim 2). The knowledge gained from accomplishing these aims will 1) inform the rational development of transmission blocking vaccines and 2) identify antibody correlates that can be used on a large scale to study the development and epidemiology of TRI to advance our understanding of the dynamics of P. falciparum transmission. Upon completion of this mentored research and training period, Dr. Cohee will be well-positioned to apply for an R01 to evaluate the development of transmission reducing immunity and determine the dynamics of transmission reducing immunity in response to malaria control interventions.
Interventions to decrease P. falciparum transmission are critical to achieving the goal of eradicating malaria, which remains a significant cause of morbidity and mortality worldwide. Increased understanding of immune responses that limit transmission of malaria from the human to the mosquito can be used for the development of vaccines to decrease transmission and further characterization the dynamics of malaria transmission. In this study, we will evaluate the ability of naturally-acquired and vaccine-induced immune responses to decrease transmission of multiple P. falciparum strains and identify serologic correlates of these responses.
