We administered Ad26, modified vaccinia Ankara vectors containing mosaic HIV-1 antigens or placebo in 26 individuals who initiated antiretroviral therapy during acute human immunodeficiency virus infection as an exploratory study to determine the safety and duration of viremic control after treatment interruption. The vaccine was safe and generated robust immune responses, but delayed time to viral rebound compared to that in placebo recipients by only several days and did not lead to viremic control after treatment interruption (clinical trial NCT02919306).
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The nucleic acid sequences reported in this paper have been deposited in GenBank (accession nos. MK867514-MK867645). The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through the Yale Open Data Access (YODA) Project site at http://yoda.yale.edu.
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We thank the HTX1001/RV405 Study Team. The HTX1001/RV405 Study Team consists of the following: from the Thai Armed Forces Research Institute of Medical Sciences: R. O’Connell, S. Vasan, D. Hsu, S. Akapirat, R. Trichavaroj, N. Tantibul, B. Nuntapinit, P. Rakyat, A. Phramtong, S. Booncharoenraksa, Y. Phuang-Ngern, C. Sajjaweerawan, P. Saetun; from Beth Israel Deaconess Medical Center: A. Agarwal, B. Alimonti, E. Borducchi, A. Chandrashekar, P. Gandhi, L. Howe, M. Kamath, S. Khatiwada, D. Jetton, S. Mojita and D. Quijada; from Janssen: I. Beeksma, S. P. Chai, D. D. Herdt, Z. Euler, M. Habets, A. Knaapen, V. Oriol Mathieu, C. McShane, M. Pagany, L. Scheppler, S. Sprangers, R. Roten, O. Yuan, W. Vandermeiren, I. V. Dromme, M. Weijtens; from the US Military HIV Research Program: M. Milazzo, L. A. Eller, L. Trautmann, H. Takata, D. Bolton, A. Tokarev, M. Rao, S. Krebs, B. Slike, M. Rolland, D. J. Curtis, A. Simmons, V. Polonis, L. Wieczorek, S. Shangguan, M. Bose, E. Turk, C. McCullough, O. Butterworth; from the Thai Red Cross AIDS Research Centre: P. Phanuphak, S. Chottanapund, P. Tantivitayakul, P. Chan, P. Eamyoung, C. Munkong, R. Kanaprach, T. Luekasemsuk. We thank J. Kim of the International Vaccine Institute, who is a co-inventor on a patent that has relevance to the vaccine regimen used for the target population in this manuscript (the patent applicants include Janssen Vaccines & Prevention BV, Beth Israel Deaconess Medical Center, Henry M. Jackson Foundation for the Advancement of Military Medicine, and The United States of America, as represented by the Secretary of the Army). This work was supported by Janssen Vaccines & Prevention BV and a cooperative agreement (W81XWH-07-2-0067) between the Henry M. Jackson Foundation for the Advancement of Military Medicine and the US Department of Defense (DoD). The US Army Medical Research Acquisition Activity is the awarding and administering acquisition office for the cooperative agreement. Medical writing support was provided by K. Holmes (Zoetic Science) and funded by Janssen Pharmaceuticals. Role of Sponsor: this study was funded by Janssen Pharmaceuticals, who participated in designing the study, safety monitoring, data analysis, interpretation and writing the manuscript. We are grateful to the participants who have made this research possible.
J.A. has received an honorarium for participation in advisory committees from ViiV Healthcare, Merck, Gilead, AbbVie and Roche. J.A., D.H.B., N.M., M.G.P., M.L.R., H. Schuitemaker and F.L.T. are co-inventors on patents (US application no. 15/693,650, granted as US patent no. 10,307,477; US application no. 16/385,062, granted as US patent no. 10,525,123; international application no. PCT/US2017/049817, pending in Australia, Canada, China, Europe, Japan and South Africa), which have relevance to the vaccine regimen used for the target population in this manuscript. Patent applicants include Janssen Vaccines & Prevention BV, Beth Israel Deaconess Medical Center, Henry M. Jackson Foundation for the Advancement of Military Medicine and The United States of America (represented by the Secretary of the Army). M.S., D.J.S., J.V., C.T., M.G.P., H. Schuitemaker and F.T. are employees of Janssen (Pharmaceutical Companies of Johnson & Johnson) and may be stockholders. All other authors declare no competing interests.
Peer review information Alison Farrell is the primary editor on this article and managed its editorial process and peer review in collaboration with the rest of the editorial team.
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
CONSORT of trial procedures.
Extended Data Fig. 2 Phylogenetic relationship of pre-ART viral sequences from nine participants and the genetic distance between the T/F strains and mosaic vaccine antigens.
Phylogenetic relationship of pre-ART viral sequences from nine participants and the genetic distance between the T/F strains and mosaic vaccine antigens. (A) Maximum-likelihood tree showing the phylogenetic relationship of SGA-derived envelope sequences (nucleic acid) from nine sequenced participants. Red and blue branches indicate vaccine and placebo arms, respectively. Individual SGA sequences from different participants were color-coded. For two participants infected by multiple T/Fs, different T/F lineages were indicated. The tree was constructed using the general time reversible model and gamma correction (GTR+G+I) with 100 bootstrap replicates. The CRF01_AE strain A244 and the subtype B strain HXB2 were used as references. (B) Genetic distance between the T/F strains and different mosaic vaccine antigens in the vaccine arm. The genetic distance was calculated as the percentage of amino acid differences between a T/F strain and the vaccine antigens (that is, the number of mismatches per 100 amino acids). For multiple T/F infections, the distance was shown as the average difference for different T/F lineages. The line shows the median distance to Mosaic 1 or Mosaic 2 antigens.
Binding antibody response to vaccination. (A‒E) Total IgG and (F‒H) IgG Subclass gp140 ELISA response rates are shown for each arm after the third and fourth vaccinations at week 26 and week 50, respectively. (A) Clade A 92UG037.1, (B) Clade B 1990a, (C) Consensus Clade C ConC, (D) Clade C97ZA012.012, (E) Mos1 gp140, (F) C97ZA012.012 IgG1, (G) C97ZA012.012 IgG2, (H) C97ZA012.012 IgG3. Vaccine responses was defined as an ELISA value more than threshold (if baseline is less than threshold or is missing); otherwise, it was defined as a value with a three-time increase from baseline (if baseline is greater than or equal to threshold). The dotted lines are the lower limit of quantification thresholds. Responders are shown as solid colored dots; non-responders as dots with colored outlines. Median response refers to the median value of the responders, based on the responders shown in the graph.
Extended Data Fig. 4 Baseline Ad26-specific neutralizing antibodies and ELISA/ELISPOT response correlations.
Baseline Ad26-specific neutralizing antibodies and ELISA/ELISPOT response correlations. Immune responses were measured by various assays at week 50 and stratified by the presence of detectable pre-existing Ad26 vector neutralizing antibody. (A) Mos1 gp140 ELISA, (B) Env, (C) Gag and (D) Pol Clinical PTE ELISPOT. Vaccine response was defined as a titer greater than threshold (if baseline is less than threshold or is missing); otherwise, response was a titer with a 3-fold increase from baseline (if baseline is greater than or equal to threshold). Responders are shown as solid colored dots; non responders as dots with colored outlines. All panels show responder rates for each vaccine arm for various time points beneath the graph. The dotted horizontal lines show the threshold for each assay performed.
Extended Data Fig. 5 IFN-γ ELISPOT assays in responses to vaccine-matched and clinical potential T-cell epitope (PTE) peptide pools.
IFN-γ ELISPOT assays in responses to vaccine-matched and clinical potential T-cell epitope (PTE) peptide pools. ELISPOT response rates are shown for both arms after the third and fourth vaccinations at week 26 and week 50, respectively. (A‒C) Mosaic 1 (Mos1) peptide pools for Env, Gag and Pol matched to vaccine inserts. (D‒F) Mosaic 2 (Mos2) peptide pools for Env, Gag and Pol matched to vaccine inserts. (G‒I) Clinical PTE peptide pools for Env, Gag and Pol to peptide pools representative of global HIV-1 diversity. Vaccine response was defined as an ELISPOT value more than threshold (if baseline is less than threshold or is missing); otherwise, it was defined as value with a three-time increase from baseline (if baseline is greater than or equal to threshold). The dotted lines are the thresholds defined based on responses in HIV-1-uninfected individuals5. Responders are shown as solid colored dots; non-responders as dots with colored outlines.
IFN-γ ICS responses to vaccine-matched peptide pool. Intracellular cytokine staining for IFN-γ is shown for both arms at baseline and after the third and fourth vaccinations at week 26 and week 50, respectively. (A‒D) CD4 T cell IFN-γ responses to Mos1 Env and Pol peptides, (E-I) CD8 T cell IFN-γ responses to Mos1 Env, Gag and Pol peptides. Vaccine response was defined as a percentage positive cell value more than threshold (if baseline is less than threshold or is missing); otherwise, it was defined as a value with a three-time increase from baseline (if baseline is greater than or equal to threshold). The dotted lines are the lower limit of quantification defined during assay qualification. Responders are shown as solid colored dots; non-responders as dots with colored outlines.
ICS assay (CD4 and CD8 T cell map).
COMPASS analysis of RV405. Heat map of posterior probabilities for RV405 data at the time of the peak cellular immune response post vaccination for A) HIV-1 Env specific CD4 T cells and CD8 T cells B) HIV-1 Gag specific CD4 T cells and CD8 T cells C) HIV-1 Pol specific CD4 T cells and CD8 T cells. Columns correspond to the functional cell subsets modelled by COMPASS, color coded by the type of function (white is not expressed while shaded is positive for that specific function). Responses are grouped by color and ordered by degree of functionality from one function on the left to five functions on the right. Rows correspond to subjects, which are ordered by their vaccine group. Each cell of the heat map shows the probability that the corresponding functional cell-subset exhibits an antigen-specific response and is color coded from white (zero) to purple (one).
Total HIV DNA in CD4 T cells. a, Total HIV DNA at baseline (pre-vaccination) and pre-ATI (post-vaccination) did not significantly differ between the vaccine versus placebo arms. Open symbols depict levels below the limit of detection of the assay and were plotted at the limit of detection, which varies between participants (1–2 copies/106 CD4 T cells). b, Longitudinal total HIV DNA values demonstrated significant decline of DNA between acute infection and pre-vaccination in both arms after approximately 2 years on ART. The total HIV DNA decline achieved borderline significance in the placebo arm between pre- and post-vaccination, which was driven primarily by the single PTC in that arm. In both arms, the total HIV DNA rose after ATI but returned to baseline values after ART resumption. Open symbols depict levels below the limit of detection of the assay and were plotted at the limit of detection, which varies between participants (1–2 copies/106 CD4 T cells). c, This sole PTC with HLAB57:01:01 was in the placebo arm. He had a delay in viral rebound and subsequent spontaneous control. His total HIV DNA declined after vaccination and did not rise above pre-vaccination values after ATI. His CD4 T cell count did not significantly decline during the study. Open symbols depict measurements from the ATI period.
Flow cytometry analyses. a, Representative flow plots showing the gating strategy for flow cytometry analysis of intracellular cytokine staining to determine cytokine expression by CD4 and CD8 T lymphocytes upon stimulation with vaccine-insert matched peptide pools. b, Representative flow plots showing the gating strategy for flow cytometry analysis to determine the frequency of PKH26+CFSE- target cells. Each sample was run in triplicates and the average was calculated. c, Flow cytometry gating scheme used to quantitate monocytic THP-1 ADCP is shown for representative plasmas sample collected at baseline (left) and week 50 (right) from a vaccinated individual. THP-1 cells were gated on based on FSC-A and SSC-A. Then, doublets were excluded based on low outlier events for FSC-H against FSC-A. Final histogram gating was used to determine bead positive THP-1 cells. The phagocytic score was calculated by multiplying the percentage of bead-positive cells by the geometric mean fluorescence intensity of the bead-positive cells and dividing by 104. Each sample was run in duplicate and the average was calculated.
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Colby, D.J., Sarnecki, M., Barouch, D.H. et al. Safety and immunogenicity of Ad26 and MVA vaccines in acutely treated HIV and effect on viral rebound after antiretroviral therapy interruption. Nat Med 26, 498–501 (2020). https://doi.org/10.1038/s41591-020-0774-y
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