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Pathogenic microbes evolve continuously to adapt to the immune responses of their infected hosts. For some pathogens, this presents a formidable challenge, because host adaptive immune responses may neutralize key virulence attributes of the microbe, thereby establishing immunity to subsequent infection (1). Under such immune selection, microbes evolve variants with altered antigenic but unaltered functional properties, thereby restoring virulence for invasion of hosts with neutralizing immunity because of prior exposure with another isolate of the same pathogen (2). How then can one find the key protective antigens of microbes, and what technologies may be applied to thwart their evasive strategies? Answers to these queries are provided in a paper by Nuccitelli et al. (3) in PNAS. Large-scale DNA sequencing of microbial genomes combined with bioinformatic analyses of their predicted products provide access to the genetic information of all isolated variants of a pathogen (4). Reverse vaccinology involves the exhaustive testing of recombinant translational products as vaccine candidates in search of subunits that elicit specific protective immunity in animal models (Fig. 1). Applied to the Gram-positive pathogen Streptococcus agalactiae, these approaches led to the identification of pilus genes that are critically important for the disease process but display variation among different isolates (5). Combining structural biology approaches with domain mapping of protective epitopes, Nuccitelli et al. (3) string together six antigenic variants of the same functional unit into a single recombinant antigen that elicits antibody-mediated vaccine protection against all of S. agalactiae isolates examined. Structural vaccinology to develop vaccines against variant microbes. Microbes evolve variants of protective surface antigens to infect hosts with existing immunity. Key protective antigen genes …

Structural vaccinology to thwart antigenic variation in microbial pathogens