MVA.HIVconsvX vaccination–evoked T cell expansion inversely associates with age in people with HIV-1 on antiretroviral therapy
Cynthia L. Gay, Yinyan Xu, Ann Marie K. Weideman, Fiona R. Shaw, JoAnn D. Kuruc, Shayla Z. Conrad, Sofia A. Mariano, Shahryar Samir, Sallay Kallon, Alexis T. Sponaugle, Joanna A. Warren, Genevieve T. Clutton, Maria Abad-Fernandez, Carolina Kapper, Alex B. Bradley, Caroline E. Baker, Susan M. Pedersen, Matthew J. Moeser, Lauren Burke, Edmund G.-T. Wee, Alison Crook, Gregory M. Laird, Joshua C. Cyktor, John W. Mellors, Shuntai Zhou, Lawrence Fox, Joseph J. Eron, David M. Margolis, Michael G. Hudgens, Tomáš Hanke, Nilu Goonetilleke
Cynthia L. Gay, Yinyan Xu, Ann Marie K. Weideman, Fiona R. Shaw, JoAnn D. Kuruc, Shayla Z. Conrad, Sofia A. Mariano, Shahryar Samir, Sallay Kallon, Alexis T. Sponaugle, Joanna A. Warren, Genevieve T. Clutton, Maria Abad-Fernandez, Carolina Kapper, Alex B. Bradley, Caroline E. Baker, Susan M. Pedersen, Matthew J. Moeser, Lauren Burke, Edmund G.-T. Wee, Alison Crook, Gregory M. Laird, Joshua C. Cyktor, John W. Mellors, Shuntai Zhou, Lawrence Fox, Joseph J. Eron, David M. Margolis, Michael G. Hudgens, Tomáš Hanke, Nilu Goonetilleke
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Clinical Research and Public Health AIDS/HIV Aging Immunology

MVA.HIVconsvX vaccination–evoked T cell expansion inversely associates with age in people with HIV-1 on antiretroviral therapy

Abstract

BACKGROUND Approaches to achieving antiretroviral therapy–free (ART-free) remission from HIV-1 must consider that people over 50 years now comprise the majority of people with HIV (PWH) on ART in various regions, including the United States.METHODS We report a double-blind, randomized trial in which PWH on ART, aged 21–60 years, received modified vaccinia Ankara–vectored (MVA-vectored) vaccines, MVA.tHIVconsv3 (M3) and MVA.tHIVconsv4 (M4), either alone or in combination (n = 7/group), or saline placebo (n = 3). M3 and M4 contain complementary HIVconsvX immunogens that each span the same regions in HIV-1 Gag and Pol but differ by approximately 8% at the amino acid level.RESULTS M3, M4, and M3M4 regimens were well tolerated and all significantly increased both the frequency (peak median increase ~3-fold) and breadth of the HIVconsvX-specific T cell response while redirecting T cells to target conserved regions in HIV-1 for up to 10 weeks after vaccination. We also demonstrated that vaccination increased frequencies of T cells targeting participant autologous HIV-1 sequences. Vaccination mostly expanded preexisting HIV-1–specific T cells and did not impact CD4+ T cell activation, low-level viremia, or integrated HIV-1 provirus. Linear regression indicated that age was independently and negatively associated with the change in T cell frequency at 1, 2, and 10 weeks after vaccination (~1.41-fold decrease per 10 years older). After adjusting for age, years on ART was positively associated with HIVconsvX-specific T cell frequencies at 1 and 2 weeks following vaccination.CONCLUSION In PWH receiving ART, MVA.HIVconsvX vaccines significantly increased T cells targeting conserved regions of HIV-1. Novel strategies may be required to enhance anti–HIV-1 immunity in older adults.TRIAL REGISTRATION ClinicalTrials.gov NCT03844386FUNDING NIH National Institute of Allergy and Infectious Diseases (NIAID) grants U01AI131310, HHSN272201100021I/HHSN27200037 (subcontract OX-14007.004.0037-212), UM1TR004406, P30AI050410, and P30CA016086; International AIDS Vaccine Initiative; European and Developing Countries Clinical Trials Partnership SRIA2015-1066; European Commission’s Horizon 2020 Research and Innovation Programme 681137.

Authors

Cynthia L. Gay, Yinyan Xu, Ann Marie K. Weideman, Fiona R. Shaw, JoAnn D. Kuruc, Shayla Z. Conrad, Sofia A. Mariano, Shahryar Samir, Sallay Kallon, Alexis T. Sponaugle, Joanna A. Warren, Genevieve T. Clutton, Maria Abad-Fernandez, Carolina Kapper, Alex B. Bradley, Caroline E. Baker, Susan M. Pedersen, Matthew J. Moeser, Lauren Burke, Edmund G.-T. Wee, Alison Crook, Gregory M. Laird, Joshua C. Cyktor, John W. Mellors, Shuntai Zhou, Lawrence Fox, Joseph J. Eron, David M. Margolis, Michael G. Hudgens, Tomáš Hanke, Nilu Goonetilleke

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Figure 4

Vaccination levels did not impact persistent HIV-1 or CD4+ T cell activation.

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Vaccination levels did not impact persistent HIV-1 or CD4+ T cell activa...
(A) Plasma virus load and low-level plasm viremia measured by SCA in participant 1264. Green dotted line indicates SCA threshold (0.38 copies/mL), and black dotted lines indicate 20 and 40 copies/mL in HIV RNA testing. (B) SCA (median, IQR) before (–28 days, D0) and after vaccination (n = 20 vaccinees, excluding 1264). Dotted line indicates SCA threshold (0.38 copies/mL). (C) Levels of integrated, total, and defective HIV-1 provirus in vaccinees (n = 17) measured at a single baseline visit (pre, –56 to –4 days before vaccination; median, –7 days) and a single postvaccination visit (post, 16–64 days after vaccination; median 28 days), measured by IPDAs. (D) Levels of Ki67, CD38, HLA-DR, PD-1, and CCR5 in central (CCR7+CD45RA–) and effector (CCR7–CD45RA–) memory CD4+ T cell frequencies of Treg (FoxP3+CD25+CD127–/lo) CD4+ T cells at days 0 (day of vaccination), 14, and 56, measured by mass cytometry (n = 9, 3 per M4 and M3M4 group and 3 placebo). In D, 1264 is indicated with an open circle. (C and D) 2-sided, exact Wilcoxon’s signed-rank test. NS, nonsignificant or P > 0.05.