Genetic diversity and malaria vaccine design, testing and efficacy: preventing and overcoming 'vaccine resistant malaria'

Abstract

The development of effective malaria vaccines may be hindered by extensive genetic diversity in the surface proteins being employed as vaccine antigens. Understanding of the extent and dynamics of genetic diversity in vaccine antigens is needed to guide rational vaccine design and to interpret the results of vaccine efficacy trials conducted in malaria endemic areas. Molecular epidemiological, population genetic, and structural approaches are being employed to try to identify immunologically relevant polymorphism in vaccine antigens. The results of these studies will inform choices of which alleles to include in multivalent or chimeric vaccines; however, additional molecular and immuno-epidemiological studies in a variety of geographic locations will be necessary for these approaches to succeed. Alternative means of overcoming antigenic diversity are also being explored, including boosting responses to critical conserved regions of current vaccine antigens, identifying new, more conserved and less immunodominant antigens, and developing whole-organism vaccines. Continued creative application and integration of tools from multiple disciplines, including epidemiology, immunology, molecular biology, and evolutionary genetics and genomics, will likely be required to develop broadly protective vaccines against Plasmodium and other antigenically complex pathogens.

Figure 1. Prevalence of MSP-1₁₉ haplotypes over three years in Bandiagara, Mali

Parasites with haplotypes corresponding to the FVO and FUP strains of P. falciparum predominated while the vaccine strain 3D7 was at low frequency throughout three consecutive malaria transmission seasons at a malaria vaccine testing site in Mali (26).

Figure 2. Polymorphic residues in AMA-1

View of the top of the AMA-1 molecule showing the hydrophobic trough (green and blue residues) and the polymorphic face of the protein. Yellow and blue residues indicate polymorphic amino acid positions. Many polymorphic residues cluster around the hydrophobic trough hypothesized to be a receptor binding pocket (47,48). Crystal structure was kindly provided by Adrian Batchelor.

Figure 3. Analysis of within-host dynamics of vaccine antigen alleles to identify immunologically relevant polymorphisms

Circles represent time points when parasites are detected within infected individuals. “A” represents asymptomatic time points, and “S” represents symptomatic time points when individuals are treated (“Rx”). Different colored circles indicate different alleles at each polymorphic site. In this hypothetical example, at site 1, an allele change occurs both when the individual goes from being asymptomatic to symptomatic and when they have consecutive asymptomatic infections. However, at site 2, allele changes occur when the individual goes from being asymptomatic to symptomatic but not when they remain asymptomatic at consecutive time points. If consecutive infections from multiple individuals are compared, it can be determined whether there is an association between allele changes at certain positions and the development of clinical malaria.

Figure 4. Grouping MSP-1₁₉ haplotypes into “serotypes”

In the top half of the figure, circles represent 14 MSP-1₁₉ haplotypes (based on six polymorphic sites), with circle area proportional to the prevalence of the haplotypes among infections in a Malian cohort. These haplotypes can be grouped into six putative “serotypes” (lower part of figure) based only on amino acids at positions 1691, 1700, and 1701. Amino acid changes at these three sites were associated with the development of clinical malaria in individuals in the cohort. FVO and 3D7 haplotypes and putative serotypes correspond to these two leading vaccine strains. Parasites with residues KNG, respectively, at these putatively important sites were observed in nearly 90% of infections, suggesting that MSP-1 corresponding to the FVO vaccine strain would have been the best initial choice for inclusion in a vaccine (26).