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T-cell sieve analysis 

In randomized case-control clinical trials of vaccines, participants are followed over time after randomly being assigned to a placebo or vaccine treatment group. In vaccine efficacy trials, we are now able to sequence the breakthrough viruses of participants who become infected during the course of the trial. The genetic characterization of 'breakthrough viruses' - viruses that evade a vaccine-induced host immune response in vaccine and placebo recipients can provide key insights into vaccine efficacy and subsequent immunogen design. Since participants are randomly assigned to a treatment group at study entry and both investigators and study subjects are blinded to treatment arms, vaccine and placebo recipients are expected to be exposed to similar circulating  strains during a vaccine efficacy trial. Therfore, genetic differences between viral sequences from the two treatment groups can be attributed to vaccination. Thus, vaccine-induced immune pressure on viral strains can be ascertained against the background of non vaccine-induced immune pressure in placebo recipients. The association of specific viral variants with vaccine efficacy can provide powerful clues to the mechanism of viral evasion of vaccine-induced immune pressure. This approach has been termed ‘sieve analysis.’ 


We are developing computational tools for analysis of breakthrough infection sequence data from clinical trials in order to identify vaccine ‘sieve’ effects - selective blockage of specific viral lineages, and/or vaccine-induced post acquisition effects. Using prediction models for HLA binding, and proteasomal cleavage, we defined novel methods for identifying potential immune escape from vaccine induced T-cell responses. We used these methods to study sieve effects in vaccine trials of HIV-1 and of influenza. We have reported significant differences between breakthrough HIV-1 infections in vaccine and placebo recipients in several recent HIV vaccine trials including the RV-144 HIV vaccine trial. Specifically, we have uncovered an association between an HLA class I allele and vaccine efficacy in this trial, which is the first report of an interaction between immunogenetics and vaccine efficacy. 





Vaccine efficacy is modified by an HLA class-I allele in the RV-144 HIV vaccine trial. A T-cell sieve anlaysis of the V2 region identified two HLA class I alleles with evidence of T-cell sieve effects. We then tested whether each of these alleles: A*02 and A*11 modifed (or interacted with) vaccine efficacy (VE). We found greater VE in A*02􏰅 participants. The figure plots estimated VE in the RV144 trial for the entire cohort and also for participants with and without the HLA A*02 allele. Error bars indicate 95% confidence intervals. For each group along the x axis, significant P values are given for the hypothesis test that VE 􏰈 0. The P value shown between the A*02􏰅/􏰉 subgroups indicates a significant difference in VE between the two groups. 

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