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 3

Age is linearly and inversely correlated with T cell response to vaccination.

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Age is linearly and inversely correlated with T cell response to vaccina...
(A) Comparisons of the categorical variables sex at birth (top left), race (bottom left), HIV-1 staging at ART initiation (top right), and protective HLA I alleles (bottom right) with fold change in T cell response (median, IQR) to Mos-1 and Mos-2 at day 14, measured by ex vivo IFN-γ ELISpot (n = 21). Ages of the 3 female participants are displayed in gray beside their corresponding fold change in Mos-2 T cell frequency. (B) Spearman’s rank-order correlations between log2FC in T cell response to Mos-1 and Mos-2 (n = 21), baseline virologic measurements (SCA, n = 20; IPDA, n = 17), and vaccinee demographic and clinical characteristics (n = 21). VL, viral load. *P < 0.05, **P < 0.005, ***P < 0.0005. (C) Pearson’s correlation between age at enrollment and fold change in Mos-1– and Mos-2–specific T cell frequencies from baseline to days 7, 14, and 70 after vaccination. Horizontal dotted lines correspond to 2-fold change relative to participant baseline. Vertical line = median age of 41 years. (D) Linear regression slope estimates from day 14 and 70 data, detailed in Table 3, were used to estimate the impact of age on Mos-1– and Mos-2–specific T cell response to MVA.HIVconsvX vaccination. See also Supplemental Table 7. (E) Spearman’s rank correlation age at enrollment and percentage of new T cell responses [log2(% + 0.1)] against both Mos-1 and Mos-2 to vaccination at day 14 after vaccination. Baseline was defined as the average of 1–3 (median = 3) prevaccination visits, mostly from day –0 to day –85. AA, African American; acute, participant in acute HIV-1 infection at ART initiation; chronic, participant in chronic HIV infection at ART initiation; unknown, HIV status unknown at ART initiation.