Host genetics of t cell responses and ad5 titers in the step trial a chavi hvtn collaboration
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Host genetics of T cell responses and Ad5 titers in the STEP trial A CHAVI - HVTN collaboration. David Goldstein Center for Human Genome Variation, Duke University. Adenovirus 5 serology titers.

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Host genetics of t cell responses and ad5 titers in the step trial a chavi hvtn collaboration l.jpg

Host genetics of T cell responses and Ad5 titers in the STEP trialA CHAVI - HVTN collaboration

David Goldstein

Center for Human Genome Variation, Duke University


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Adenovirus 5 serology titers trial

Could anti-Ad5 neutralizing antibody titers be merely markers of host genetic factors that confer differential susceptibility to HIV-1?


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GWAS – Ad5 titers trial

  • CHAVI-001 screening / Malawi

    • 935 HIV negative participants, >23 years old

    • Ad5 neutralizing antibodies were measured in Norm Letvin’s lab

    • Ad5 seroprevalence was very high: 92.6% of the study participants were Ad5 seropositive

  • STEP trial samples

    • Pre-vaccination Ad5 titers were analyzed in 3 ethnic groups: Whites (N=348), Hispanics (N=123), Blacks (N=93)

    • Ad5 seroprevalence was 39% in Whites, 89% in Hispanics and 69% in Blacks


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GWAS – Ad5 titers trial

No significant association in any of the analyses


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HIV-specific T cell responses trial

  • The Merck vaccine was highly immunogenic for inducing HIV-specific T cell responses

  • HIV-specific T cell responses were quantitatively highly variable

  • A significant fraction of the unexplained variability in response intensity is likely to be attributable to human genetic variation


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GWAS – HIV-specific T cell responses trial

  • Subjects: all male vaccine recipients who were HIV seronegative at week 8 (i.e. 4 weeks after the 2nd vaccination)

  • WG genotyping : Illumina’s Human 1M duo BeadChips

  • HLA Class I: high-resolution typing using sequence-based methods

  • Phenotype: HIV-specific T cell responses measured by IFN-γ ELISpot assays

  • Association study: linear regression models including age, Ad5 titer, ELISpot laboratory (HVTN vs. Merck) and EIGENSTRAT values as covariates.


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GWAS – HIV-specific T cell responses trial

 global survey of the host mechanisms associated with variability in T cell responses to the vaccine



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Results trial

  • No genome-wide significant association in any of the analyses

  • In the analysis of association with quantitative responses to Gag, we observe an enrichment of SNPs from the MHC region among the top p-values, mostly from the genomic region encompassing the HLA-B and HLA-C genes


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HLA Class I associations trial

  • In Caucasians, HLA-B*2705, *5101 and *5701 associate with higher Gag responses, whereas B*0801 and B*4501 associate with lower responses

  • Together, these 5 HLA alleles account for 13.6% of the variability in Gag responses


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HLA Class I associations trial

P=4.6E-05

P=0.02

P=0.05

P=2.7E-04

P=0.01


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HLA Class I associations trial

  • Nested regression models demonstrate that they explain most of the association signals detected in the SNP scan


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Conclusions I trial

  • Human genetic variants located in the MHC region show the strongest association with T cell responses to Gag in HIV negative individuals vaccinated in the STEP trial

  • HLA-B alleles known to associate with differences in HIV-1 control are essential contributors to the association signal


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Conclusions II trial

  • The host immunogenetic background modulates individual responses to the Merck Ad5 vaccine

  • HLA Class I typing data should be considered in the design and analysis of future T cell vaccine studies


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Duke University trial

Jacques Fellay

Kevin Shianna

Liz Cirulli

Fred Hutchinson

Cancer Research Center

Nicole Frahm

Daniel Geraghty

Juliana McElrath

SHARP

Alicia Sato

NidhiKochar

Merck Research Laboratories

DaniloCasimiro

NCI-Frederick

Mary Carrington

Harvard Medical School

Norm Letvin

Connie Gee

Carol Lord

CHAVI Clinical Core

Mike Cohen

Clinicians and nurses at Malawi sites


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