Quantifying how HIV-1 envelope sequence features impact vaccine efficacy in the HVTN 705/HPX2008 randomised trial in southern African women
EBioMedicine, vol. 131, pp. 106459
Abstract
BACKGROUND: A heterologous Ad26.Mos4.HIV and clade C gp140 vaccine regimen did not show overall significant efficacy against HIV-1 acquisition [point estimate 14.1%; 95% confidence interval (CI), -22.0 to 39.5] in the HVTN 705/HPX2008 trial in southern African women. We examined whether and how vaccine efficacy (VE) against HIV-1 diagnosis over 7-24 months post-first dose varied by HIV-1 Envelope (Env) amino acid sequence features. METHODS: HIV-1 viral sequences were generated by PacBio SMRT-UMI sequencing from the first RNA-positive sample of participants who acquired HIV-1. Env amino acid sequence features were prespecified for analyses based on 1) being hypothesised to impact VE; and 2) having sufficient variability. Sieve analyses assessed VE by a single representative sequence and by viral population composition. FINDINGS: The majority of Env features showed no evidence of differential VE, with only two signals having familywise error rate (FWER) P-values <0.10. In single-sequence analyses, VE declined with increasing physicochemical-weighted Hamming distance from the C97ZA vaccine insert in clade C broadly neutralising antibody resistance-associated signature positions (FWER P = 0.08). Sequence-predicted Env structural features showed no significant vaccine vs. placebo differences in structural divergence from the C97ZA vaccine-insert Env sequence. In multi-sequence analyses (median 121 sequences/individual), VE was higher against viral populations with ≥99% vs. <99% L832 prevalence (VE = 91.7%; 95% CI, 67.4-97.9 vs. VE = -7.0%; 95% CI, -55.5 to 26.4) (unadjusted P = 0.0002 for differential VE, FWER P = 0.023). INTERPRETATION: Despite extensive prespecified and exploratory analyses including Env features supported by prior studies to potentially impact VE, there was only limited, weak evidence that Env sequence features modified VE in HVTN 705. Although previous work suggested a protective role of IgG3 binding to V1V2 in a small subgroup of vaccine recipients, a V1V2 sieve signal was absent. FUNDING: National Institutes of Health and Johnson & Johnson.
Authors 36
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Affiliation as printed
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA. Electronic address: mjuraska@fredhutch.org
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Affiliation as printed
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
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Affiliation as printed
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
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University of Washington · Fred Hutch Cancer Center
Affiliation as printed
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA; Department of Biostatistics, University of Washington, Seattle, WA, 98195, USA
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Affiliation as printed
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
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Affiliation as printed
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
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Affiliation as printed
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
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Affiliation as printed
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
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Affiliation as printed
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
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Affiliation as printed
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
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Affiliation as printed
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
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Affiliation as printed
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
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Affiliation as printed
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
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Affiliation as printed
Department of Microbiology, University of Washington School of Medicine, Seattle, WA, 98195, USA
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Affiliation as printed
Department of Microbiology, University of Washington School of Medicine, Seattle, WA, 98195, USA
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Affiliation as printed
Department of Microbiology, University of Washington School of Medicine, Seattle, WA, 98195, USA
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Affiliation as printed
Department of Microbiology, University of Washington School of Medicine, Seattle, WA, 98195, USA
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National Health Laboratory Service · University of Cape Town · Wellcome Centre for Infectious Diseases Research in Africa · Institute of Infectious Disease and Molecular Medicine
Affiliation as printed
Institute of Infectious Disease and Molecular Medicine and CIDRI-Africa Wellcome Centre, Department of Pathology, Faculty of Health Sciences, University of Cape Town and National Health Laboratory Service, Cape Town, 7701, South Africa
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National Health Laboratory Service · University of Cape Town · Wellcome Centre for Infectious Diseases Research in Africa · Institute of Infectious Disease and Molecular Medicine
Affiliation as printed
Institute of Infectious Disease and Molecular Medicine and CIDRI-Africa Wellcome Centre, Department of Pathology, Faculty of Health Sciences, University of Cape Town and National Health Laboratory Service, Cape Town, 7701, South Africa
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National Health Laboratory Service · University of Cape Town · Wellcome Centre for Infectious Diseases Research in Africa · Institute of Infectious Disease and Molecular Medicine
Affiliation as printed
Institute of Infectious Disease and Molecular Medicine and CIDRI-Africa Wellcome Centre, Department of Pathology, Faculty of Health Sciences, University of Cape Town and National Health Laboratory Service, Cape Town, 7701, South Africa
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National Health Laboratory Service · University of Cape Town · Wellcome Centre for Infectious Diseases Research in Africa · Institute of Infectious Disease and Molecular Medicine
Affiliation as printed
Institute of Infectious Disease and Molecular Medicine and CIDRI-Africa Wellcome Centre, Department of Pathology, Faculty of Health Sciences, University of Cape Town and National Health Laboratory Service, Cape Town, 7701, South Africa
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National Health Laboratory Service · University of Cape Town · Wellcome Centre for Infectious Diseases Research in Africa · Institute of Infectious Disease and Molecular Medicine
Affiliation as printed
Institute of Infectious Disease and Molecular Medicine and CIDRI-Africa Wellcome Centre, Department of Pathology, Faculty of Health Sciences, University of Cape Town and National Health Laboratory Service, Cape Town, 7701, South Africa
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National Health Laboratory Service · University of Cape Town · Wellcome Centre for Infectious Diseases Research in Africa · Institute of Infectious Disease and Molecular Medicine
Affiliation as printed
Institute of Infectious Disease and Molecular Medicine and CIDRI-Africa Wellcome Centre, Department of Pathology, Faculty of Health Sciences, University of Cape Town and National Health Laboratory Service, Cape Town, 7701, South Africa
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National Health Laboratory Service · University of Cape Town · Wellcome Centre for Infectious Diseases Research in Africa · Institute of Infectious Disease and Molecular Medicine
Affiliation as printed
Institute of Infectious Disease and Molecular Medicine and CIDRI-Africa Wellcome Centre, Department of Pathology, Faculty of Health Sciences, University of Cape Town and National Health Laboratory Service, Cape Town, 7701, South Africa
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National Health Laboratory Service · University of Cape Town · Wellcome Centre for Infectious Diseases Research in Africa · Institute of Infectious Disease and Molecular Medicine
Affiliation as printed
Institute of Infectious Disease and Molecular Medicine and CIDRI-Africa Wellcome Centre, Department of Pathology, Faculty of Health Sciences, University of Cape Town and National Health Laboratory Service, Cape Town, 7701, South Africa
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National Institute of Allergy and Infectious Diseases
Affiliation as printed
Division of AIDS, National Institute of Allergy and Infectious Diseases, Bethesda, MD, 20852, USA
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Affiliation as printed
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
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Affiliation as printed
Janssen Vaccines & Prevention BV, Leiden, 2333, the Netherlands
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San Francisco Department of Public Health
Affiliation as printed
San Francisco Department of Public Health, San Francisco, CA, 94102, USA
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Janssen Research & Development (United States)
Affiliation as printed
Janssen Research & Development, LLC, Titusville, NJ, 08560, USA
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University of Washington · Fred Hutch Cancer Center
Affiliation as printed
Department of Medicine, University of Washington School of Medicine, Seattle, WA, 98195, USA; Department of Laboratory Medicine, University of Washington School of Medicine, Seattle, WA, 98195, USA; Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
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Affiliation as printed
The Aurum Institute, Johannesburg, 1609, South Africa
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South African Medical Research Council
Affiliation as printed
South African Medical Research Council, Cape Town, 7505, South Africa
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University of Washington · Fred Hutch Cancer Center
Affiliation as printed
Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA; Department of Biostatistics, University of Washington, Seattle, WA, 98195, USA; Public Health Sciences Division, Fred Hutchinson Cancer Center, Seattle, WA, 98109, USA
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National Health Laboratory Service · University of Cape Town · Wellcome Centre for Infectious Diseases Research in Africa · Institute of Infectious Disease and Molecular Medicine
Affiliation as printed
Institute of Infectious Disease and Molecular Medicine and CIDRI-Africa Wellcome Centre, Department of Pathology, Faculty of Health Sciences, University of Cape Town and National Health Laboratory Service, Cape Town, 7701, South Africa
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Affiliation as printed
Department of Microbiology, University of Washington School of Medicine, Seattle, WA, 98195, USA
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