An effective blood stage Plasmodium falciparum malaria vaccine would be of immense global health benefit, particularly for infants and young children who suffer the greatest burden of malaria morbidity and mortality. We propose to use novel molecular epidemiological and structural vaccinology approaches to understand the human immune response to and the resulting antigenic diversity of apical membrane antigen-1 (AMA1), a leading malaria vaccine candidate antigen. AMA1 is highly polymorphic;antigenic variation is likely a parasite immune escape mechanism that allows repeated infection with different variants in the face of natural immunity. We recently completed the first Phase 2 clinical trial of a monovalent AMA1- based malaria vaccine in children in Mali, West Africa. The vaccine had limited overall efficacy but good allele-specific efficacy against clinical malaria caused by parasites with AMA1 homologous to the vaccine strain with respect to immunologically relevant polymorphisms in AMA1. Molecular epidemiological and animal studies suggest that some regions of the AMA1 molecule represent "immunogenicity hot spots," i.e. residues within these regions are critical to development of strain-specific protective immunity. The combined results of these clinical and laboratory studies suggest that the vast diversity of AMA1 alleles may be consolidated into a smaller number of subgroups, thereby reducing the number of variants that would have to be included to achieve a broadly cross-protective AMA1 vaccine. The proposed translational research project will employ novel molecular epidemiological approaches that we have developed, as well as a novel autotransporter protein expression system, to analyze patient serum samples collected in prospective longitudinal studies in a malaria endemic area, with the aim of identifying cross-reactive and cross-protective AMA1 epitopes.

Public Health Relevance

One reason there is still no malaria vaccine is because malaria parasites are able to mutate and change to escape natural immunity. This project seeks to understand how the human immune system interacts with rapidly changing malaria parasites to provide natural protection against malaria infection in the field. This information will be used to better understand how to make a vaccine that could protect against the many diverse forms of malaria parasites found in nature.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
1R01AI093635-01A1
Application #
8234592
Study Section
Clinical Research and Field Studies of Infectious Diseases Study Section (CRFS)
Program Officer
MO, Annie X Y
Project Start
2012-02-02
Project End
2016-01-31
Budget Start
2012-02-02
Budget End
2013-01-31
Support Year
1
Fiscal Year
2012
Total Cost
$589,799
Indirect Cost
$204,059
Name
University of Maryland Baltimore
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
188435911
City
Baltimore
State
MD
Country
United States
Zip Code
21201