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HIV-1 SIEVE ANALYSIS

 * About
 * VTN502
 * VTN503
 * RV144
 * VTN505


ABOUT

At the conclusion of a HIV-1 vaccine efficacy trial a characterization of the
“breakthrough” viruses that infect trial participants can help to elucidate the
mechanisms of imperfect or heterogeneous protection. The approach, known as
“sieve analysis”, can identify the functional specificities of vaccine-induced
immune responses by comparing the genetic sequences of viruses isolated from
vaccine versus placebo recipients. We have created an interactive web-based
visualization and data API for exploring the results of sieve analyses performed
on four major efficacy trials: (1) the HVTN 502/Step trial, (2) the HVTN
503/Phambili trial, (3) the MHRP/Thai Health Ministry RV144 trial, and (4) the
HVTN 505 trial. The tool acts simultaneously as a portal for organizing and
sharing the viral sequence data generated for these trials and as a platform for
discovery of pertinent sieve effects as ongoing follow-up studies of the
vaccines continue to test and validate sieve analysis findings.

Data API specification

Software for sieve analysis: PySieve


HVTN 502/STEP TRIAL

SIEVE ANALYSIS ABSTRACT

We analyzed HIV-1 genome sequences from 68 newly infected volunteers in the STEP
HIV-1 vaccine trial. To determine whether the vaccine exerted selective T cell
pressure on breakthrough viruses, we identified potential T cell epitopes in the
founder sequences and compared them to epitopes in the vaccine. We found greater
distances to the vaccine sequence for sequences from vaccine recipients than
from placebo recipients. The most significant signature site distinguishing
vaccine from placebo recipients was Gag amino acid 84, a site encompassed by
several epitopes contained in the vaccine and restricted by human leukocyte
antigen (HLA) alleles common in the study cohort. Moreover, the extended
divergence was confined to the vaccine components of the virus (HIV-1 Gag, Pol
and Nef) and not found in other HIV-1 proteins. These results represent what is
to our knowledge the first evidence of selective pressure from vaccine-induced T
cell responses on HIV-1 infection in humans..

PRIMARY MANUSCRIPT

Buchbinder, Susan P. et al. "Efficacy Assessment of a Cell-Mediated Immunity
HIV-1 Vaccine (the Step Study): A Double-Blind, Randomised, Placebo-Controlled,
Test-of-Concept Trial." Lancet 372.9653 (2008): 1881-1893.

SIEVE MANUSCRIPT

Rolland, M et al. 2011. "Genetic Impact of Vaccination on Breakthrough HIV-1
Sequences from the STEP Trial." Nature Medicine 17 (3): 366-71.

DATA API

Treatment assignment CSV

FASTA sequence alignment
 * gag (MRK_B_Ad5)
 * pol (MRK_B_Ad5)
 * nef (MRK_B_Ad5)

INTERACTIVE VISUALIZATION

Protein : reference analyses
 * gag (MRK_B_Ad5)
 * pol (MRK_B_Ad5)
 * nef (MRK_B_Ad5)


HVTN 503/PHAMBILI TRIAL

SIEVE ANALYSIS ABSTRACT

INTRODUCTION: The Merck Adenovirus-5 Gag/Pol/Nef HIV-1 subtype-B vaccine
evaluated in predominately subtype B epidemic regions (Step Study), while not
preventing infection, exerted vaccine-induced immune pressure on HIV-1
breakthrough infections. Here we investigated if the same vaccine exerted immune
pressure when tested in the Phambili Phase 2b study in a subtype C epidemic.
MATERIALS AND METHODS: A sieve analysis, which compares breakthrough viruses
from placebo and vaccine arms, was performed on 277 near full-length genomes
generated from 23 vaccine and 20 placebo recipients. Vaccine coverage was
estimated by computing the percentage of 9-mers that were exact matches to the
vaccine insert.
RESULTS: There was significantly greater protein distances from the vaccine
immunogen sequence in Gag (p=0.045) and Nef (p=0.021) in viruses infecting
vaccine recipients compared to placebo recipients. Twenty-seven putative sites
of vaccine-induced pressure were identified (p<0.05) in Gag (n=10), Pol (n=7)
and Nef (n=10), although they did not remain significant after adjustment for
multiple comparisons. We found the epitope sieve effect in Step was driven by
HLA A*02:01; an allele which was found in low frequency in Phambili participants
compared to Step participants. Furthermore, the coverage of the vaccine against
subtype C Phambili viruses was 31%, 46% and 14% for Gag, Pol and Nef,
respectively, compared to subtype B Step virus coverage of 56%, 61% and 26%,
respectively.
DISCUSSION: This study presents evidence of sieve effects in Gag and Nef;
however could not confirm effects on specific amino acid sites. We propose that
this weaker signal of vaccine immune pressure detected in the Phambili study
compared to the Step study may have been influenced by differences in host
genetics (HLA allele frequency) and reduced impact of vaccine-induced immune
responses due to mismatch between the viral subtype in the vaccine and infecting
subtypes..

PRIMARY MANUSCRIPT

Gray, GE et al. "Safety and Efficacy Assessment of the HVTN 503/Phambili Study:
A Double-Blind Randomized Placebo-Controlled Test-of-Concept Study of a Clade
B-Based HIV-1 Vaccine in South Africa." The Lancet infectious diseases 11.7
(2011): 507-515.

SIEVE MANUSCRIPT

Hertz et al. "A study of vaccine-induced immune pressure on breakthrough
infections in the Phambili phase 2b HIV-1 vaccine efficacy trial." Vaccine.
2016. 34(47): 5792-5801.

DATA API

Treatment assignment CSV

FASTA sequence alignment
 * gag (MRK_B_Ad5)
 * nef (MRK_B_Ad5)
 * pol (MRK_B_Ad5)

INTERACTIVE VISUALIZATION

Protein : reference analyses
 * gag (MRK_B_Ad5)
 * nef (MRK_B_Ad5)
 * pol (MRK_B_Ad5)


RV144/THAI TRIAL

SIEVE ANALYSIS ABSTRACT

The RV144 clinical trial showed the partial efficacy of a vaccine regimen with
an estimated vaccine efficacy (VE) of 31% for protecting low-risk Thai
volunteers against acquisition of HIV-1. The impact of vaccine-induced immune
responses can be investigated through sieve analysis of HIV-1 breakthrough
infections (infected vaccine and placebo recipients). A V1/V2-targeted
comparison of the genomes of HIV-1 breakthrough viruses identified two V2 amino
acid sites that differed between the vaccine and placebo groups. Here we
extended the V1/V2 analysis to the entire HIV-1 genome using an array of methods
based on individual sites, k-mers and genes/proteins. We identified 56 amino
acid sites or "signatures" and 119 k-mers that differed between the vaccine and
placebo groups. Of those, 19 sites and 38 k-mers were located in the regions
comprising the RV144 vaccine (Env-gp120, Gag, and Pro). The nine signature sites
in Env-gp120 were significantly enriched for known antibody-associated sites (p
= 0.0021). In particular, site 317 in the third variable loop (V3) overlapped
with a hotspot of antibody recognition, and sites 369 and 424 were linked to CD4
binding site neutralization. The identified signature sites significantly
covaried with other sites across the genome (mean = 32.1) more than did
non-signature sites (mean = 0.9) (p < 0.0001), suggesting functional and/or
structural relevance of the signature sites. Since signature sites were not
preferentially restricted to the vaccine immunogens and because most of the
associations were insignificant following correction for multiple testing, we
predict that few of the genetic differences are strongly linked to the RV144
vaccine-induced immune pressure. In addition to presenting results of the first
complete-genome analysis of the breakthrough infections in the RV144 trial, this
work describes a set of statistical methods and tools applicable to analysis of
breakthrough infection genomes in general vaccine efficacy trials for diverse
pathogens..

PRIMARY MANUSCRIPT

Rerks-Ngarm, S et al. 2009. "Vaccination with ALVAC and ADISVAX to Prevent HIV-1
Infection in Thailand." New England Journal of Medicine 361: 2209-20.

SIEVE MANUSCRIPT

Edlefsen, PT, Rolland M, et al. 2015. "Comprehensive Sieve Analysis of
Breakthrough HIV-1 Sequences in the RV144 Vaccine Efficacy Trial", 1-37.

DATA API

Treatment assignment CSV

FASTA sequence alignment
 * env (AIDSVAX_B_MN)
 * env (ALVAC_vCP1521_CRF01_AE_92TH023)
 * env (AIDSVAX_CRF01_AE_A244)
 * gag (ALVAC_vCP1521_B_LAI)
 * pol (ALVAC_vCP1521_B_LAI)
 * nef (nefCON)
 * rev (revCON)
 * tat (tatCON)
 * vif (vifCON)
 * vpr (vprCON)
 * vpu (vpuCON)
 * nef (nefHXB2)
 * rev (revHXB2)
 * tat (tatHXB2)
 * vif (vifHXB2)
 * vpr (vprHXB2)
 * vpu (vpuHXB2)

INTERACTIVE VISUALIZATION

Protein : reference analyses
 * env (AIDSVAX_B_MN)
 * env (ALVAC_vCP1521_CRF01_AE_92TH023)
 * env (AIDSVAX_CRF01_AE_A244)
 * gag (ALVAC_vCP1521_B_LAI)
 * pol (ALVAC_vCP1521_B_LAI)
 * nef (nefCON)
 * rev (revCON)
 * tat (tatCON)
 * vif (vifCON)
 * vpr (vprCON)
 * vpu (vpuCON)
 * nef (nefHXB2)
 * rev (revHXB2)
 * tat (tatHXB2)
 * vif (vifHXB2)
 * vpr (vprHXB2)
 * vpu (vpuHXB2)


HVTN 505 TRIAL

SIEVE ANALYSIS ABSTRACT

Sieve analysis manuscript submitted for publication.

PRIMARY MANUSCRIPT

Hammer, Scott M. et al. "Efficacy Trial of a DNA/rAd5 HIV-1 Preventive Vaccine".
The New England journal of medicine 369.22 (2013): 2083-2092.

SIEVE MANUSCRIPT



DATA API

Treatment assignment CSV

FASTA sequence alignment
 * env (VRC5736_GP145A_DNA)
 * env (VRC5737_GP145B_DNA)
 * env (VRC5738_GP145C_DNA)
 * gag (VRC4401_GAG_DNA)
 * pol (VRC4409_POL_DNA)
 * nef (VRC4404_NEF_DNA)
 * rev (B_ANC)
 * tat (B_ANC)
 * vif (B_ANC)
 * vpr (B_ANC)
 * vpu (B_ANC)

INTERACTIVE VISUALIZATION

Protein : reference analyses
 * env (VRC5736_GP145A_DNA)
 * env (VRC5737_GP145B_DNA)
 * env (VRC5738_GP145C_DNA)
 * gag (VRC4401_GAG_DNA)
 * pol (VRC4409_POL_DNA)
 * nef (VRC4404_NEF_DNA)
 * rev (B_ANC)
 * tat (B_ANC)
 * vif (B_ANC)
 * vpr (B_ANC)
 * vpu (B_ANC)