Herpes simplex virus (HSV) types 1 and 2 (HSV-1 and HSV-2) are the most common 
infectious agents of humans. No safe and effective HSV vaccines have been 
licensed. Reverse vaccinology is an emerging and revolutionary vaccine 
development strategy that starts with the prediction of vaccine targets by 
informatics analysis of genome sequences. Vaxign 
(http://www.violinet.org/vaxign) is the first web-based vaccine design program 
based on reverse vaccinology. In this study, we used Vaxign to analyze 52 
herpesvirus genomes, including 3 HSV-1 genomes, one HSV-2 genome, 8 other human 
herpesvirus genomes, and 40 non-human herpesvirus genomes. The HSV-1 strain 17 
genome that contains 77 proteins was used as the seed genome. These 77 proteins 
are conserved in two other HSV-1 strains (strain F and strain H129). Two 
envelope glycoproteins gJ and gG do not have orthologs in HSV-2 or 8 other human 
herpesviruses. Seven HSV-1 proteins (including gJ and gG) do not have orthologs 
in all 40 non-human herpesviruses. Nineteen proteins are conserved in all human 
herpesviruses, including capsid scaffold protein UL26.5 (NP_044628.1). As the 
only HSV-1 protein predicted to be an adhesin, UL26.5 is a promising vaccine 
target. The MHC Class I and II epitopes were predicted by the Vaxign Vaxitop 
prediction program and IEDB prediction programs recently installed and 
incorporated in Vaxign. Our comparative analysis found that the two programs 
identified largely the same top epitopes but also some positive results 
predicted from one program might not be positive from another program. Overall, 
our Vaxign computational prediction provides many promising candidates for 
rational HSV vaccine development. The method is generic and can also be used to 
predict other viral vaccine targets.