title: Defining epitope coverage requirements for T cell-based HIV vaccines: theoretical considerations and practical applications.
abstract: BACKGROUND
  HIV vaccine development must address the genetic diversity and plasticity of the virus that permits the presentation of diverse genetic forms to the immune system and subsequent escape from immune pressure. Assessment of potential HIV strain coverage by candidate T cell-based vaccines (whether natural sequence or computationally optimized products) is now a critical component in interpreting candidate vaccine suitability.
  
  
  METHODS
  We have utilized an N-mer identity algorithm to represent T cell epitopes and explore potential coverage of the global HIV pandemic using natural sequences derived from candidate HIV vaccines. Breadth (the number of T cell epitopes generated) and depth (the variant coverage within a T cell epitope) analyses have been incorporated into the model to explore vaccine coverage requirements in terms of the number of discrete T cell epitopes generated.
  
  
  RESULTS
  We show that when multiple epitope generation by a vaccine product is considered a far more nuanced appraisal of the potential HIV strain coverage of the vaccine product emerges. By considering epitope breadth and depth several important observations were made: (1) epitope breadth requirements to reach particular levels of vaccine coverage, even for natural sequence-based vaccine products is not necessarily an intractable problem for the immune system; (2) increasing the valency (number of T cell epitope variants present) of vaccine products dramatically decreases the epitope requirements to reach particular coverage levels for any epidemic; (3) considering multiple-hit models (more than one exact epitope match with an incoming HIV strain) places a significantly higher requirement upon epitope breadth in order to reach a given level of coverage, to the point where low valency natural sequence based products would not practically be able to generate sufficient epitopes.
  
  
  CONCLUSIONS
  When HIV vaccine sequences are compared against datasets of potential incoming viruses important metrics such as the minimum epitope count required to reach a desired level of coverage can be easily calculated. We propose that such analyses can be applied early in the planning stages and during the execution phase of a vaccine trial to explore theoretical and empirical suitability of a vaccine product to a particular epidemic setting.
authors.affiliation: US Military HIV Research Program (MHRP), Rockville, MD, USA. jcurrier@hivresearch.org
authors.forename: Jeffrey R
authors.initials: JR
authors.lastname: Currier
authors.forename: Merlin L
authors.initials: ML
authors.lastname: Robb
authors.forename: Nelson L
authors.initials: NL
authors.lastname: Michael
authors.forename: Mary A
authors.initials: MA
authors.lastname: Marovich
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology*; D000465:Algorithms; D000595:Amino Acid Sequence; D002986:Clinical Trials as Topic; D019992:Databases as Topic; D000939:Epitopes / Q000276:immunology*; D015497:HIV-1 / Q000276:immunology / Q000302:isolation & purification; D006801:Humans; D018448:Models, Immunological; D013601:T-Lymphocytes / Q000276:immunology*; D054299:env Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000276:immunology; D054301:gag Gene Products, Human Immunodeficiency Virus / Q000737:chemistry / Q000276:immunology
chemical_list: D016915:AIDS Vaccines; D000939:Epitopes; D054299:env Gene Products, Human Immunodeficiency Virus; D054301:gag Gene Products, Human Immunodeficiency Virus