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HIV-1 Env markers of prevention efficacy in HVTN 704/HPTN 085, the Antibody-Mediated Prevention (AMP) trial of broadly neutralizing antibody (bnAb) VRC01 in the Americas and Europe: genotypic sieve analysis

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BACKGROUND: HVTN 704/HPTN 085 evaluated HIV prevention efficacy (PE) of VRC01, a bnAb against the CD4 binding site. PE depended on in vitro neutralization resistance of the acquired virus. No efficacy was observed against resistant viruses, whereas, against sensitive viruses (IC80<1 "µg/ml), 73.0% efficacy (95% CI, 27.6% to 89.9%) was observed. Whether PE might be influenced by Env amino acid (AA) sequence features was evaluated.
METHODS: From 2016'2018, 2,699 HIV-uninfected MSM and transgender adults in the Americas and Switzerland were randomized 1:1:1 to receive q8-weekly infusions of VRC01 10mg/kg, 30mg/kg or placebo, with q4-weekly HIV testing, over 80 weeks. Viral populations (mean=184 rev-env-(partial) nef sequences/visit) from 90 infections with neutralization sensitivity data were used here. Twenty-four sequence features were pre-specified for predicted impact on VRC01 neutralization: 3 proteomic antibody resistance scores, 21 VRC01-important AA positions, and geometry features. Data were analyzed using feature-specific proportional hazards models.
RESULTS: PE decreased with the predicted probability of IC80>1 "µg/ml (p=0.017), with estimated PE=80% against viruses with resistance probability 0.3, decreasing to 0% against viruses with probability 0.72 (Fig1). Estimated PE was 75% (95% CI, 16 to 92%, p=0.015) and 5% ('51 to 41%, NS) against N144 and notN144, and '24% (95% CI, '118 to 29%, NS) and 64% (26 to 82%, p=0.004) against D230 and notD230 (Fig2), with differential PE unadjusted p-values of 0.044 and 0.008, respectively.


CONCLUSIONS: Viral sequence predicts IC80 and VRC01 PE. Assessment of viral sequences can inform identification and development of bnAbs and vaccine immunogens that may prevent HIV acquisition.