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Clinical Trial
. 2023 Apr 18;227(8):939-950.
doi: 10.1093/infdis/jiac445.

Safety and Immunogenicity of Ad26-Vectored HIV Vaccine With Mosaic Immunogens and a Novel Mosaic Envelope Protein in HIV-Uninfected Adults: A Phase 1/2a Study

Daniel J Stieh  1 , Dan H Barouch  2   3 , Christy Comeaux  1 , Michal Sarnecki  4 , Kathryn E Stephenson  2 , Stephen R Walsh  5   6 , Sheetal Sawant  7 , Jack Heptinstall  7 , Georgia D Tomaras  7 , James G Kublin  8 , M Juliana McElrath  8 , Kristen W Cohen  8 , Stephen C De Rosa  8 , Galit Alter  3 , Guido Ferrari  7 , David Montefiori  7 , Philipp Mann  8 , Steven Nijs  9 , Katleen Callewaert  9 , Paul A Goepfert  10 , Srilatha Edupuganti  11 , Etienne Karita  12 , Michael S Seaman  2 , Lawrence Corey  8 , Lindsey R Baden  6 , Maria G Pau  1 , Hanneke Schuitemaker  1 , Frank Tomaka  13 ; ASCENT/HVTN118/HPX2003 Study Team
Collaborators, Affiliations
Clinical Trial

Safety and Immunogenicity of Ad26-Vectored HIV Vaccine With Mosaic Immunogens and a Novel Mosaic Envelope Protein in HIV-Uninfected Adults: A Phase 1/2a Study

Daniel J Stieh et al. J Infect Dis. .

Abstract

Background: Developing a cross-clade, globally effective HIV vaccine remains crucial for eliminating HIV.

Methods: This placebo-controlled, double-blind, phase 1/2a study enrolled healthy HIV-uninfected adults at low risk for HIV infection. They were randomized (1:4:1) to receive 4 doses of an adenovirus 26-based HIV-1 vaccine encoding 2 mosaic Gag and Pol, and 2 mosaic Env proteins plus adjuvanted clade C gp140 (referred to here as clade C regimen), bivalent protein regimen (clade C regimen plus mosaic gp140), or placebo. Primary end points were safety and antibody responses.

Results: In total 152/155 participants (clade C, n = 26; bivalent protein, n = 103; placebo, n = 26) received ≥1 injection. The highest adverse event (AE) severity was grade 3 (local pain/tenderness, 12%, 2%, and 0% of the respective groups; solicited systemic AEs, 19%, 15%, 0%). HIV-1 mosaic gp140-binding antibody titers were 79 595 ELISA units (EU)/mL and 137 520 EU/mL in the clade C and bivalent protein groups (P < .001) after dose 4 and 16 862 EU/mL and 25 162 EU/mL 6 months later. Antibody response breadth against clade C gp140 and clade C/non-clade C gp120 was highest in the bivalent protein group.

Conclusions: Adding mosaic gp140 to the clade C regimen increased and broadened the elicited immune response without compromising safety or clade C responses. Clinical Trials Registration. NCT02935686.

Keywords: Ad26 HIV vaccine; broad immunogenicity; cross-clade; heterologous regimen; mosaic HIV antigen; tetravalent.

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Conflict of interest statement

Potential conflicts of interest. D. H. B. reports grants from Janssen Vaccines and Prevention outside the submitted work, as well as an HIV vaccine patent licensed to Janssen Vaccines and Prevention. S. S. reports grants from the National Institutes of Health (NIH) and HIV Vaccine Trials Network (HVTN) during the conduct of the study. J. H. reports grants from the NIH and HVTN during the conduct of the study; and support for travel to attend meetings from HVTN outside the submitted work. G. D. T. reports grants from the NIH during the conduct of the study; consulting fees from Janssen Vaccine and Prevention, Axon Pharma, and Gilead Sciences outside the submitted work; payment or honoraria for lectures, presentations, speakers bureaus, or manuscript writing/educational events from the University of North Carolina Scientific Advisory Board, the NIH Board of Scientific Counselors, and Johns Hopkins University; and support for attending meetings/travel from the NIH and Gates travel. J. G. K. reports grants from the NIH during the conduct of the study. M. J. M. reports grants from the National Institute of Allergy and Infectious Diseases (NIAID; funding for Seattle CTU Grant and funding for HVTN Lab) during the study. K. W. C. reports grants from NIH, NIAID during the conduct of this study. S. C. D. reports grants from the NIH and Gates Foundation during the conduct of the study; and a contract from Janssen Vaccines and Prevention outside the submitted work. G. A. reports grants from the NIH, Gates Foundation, Sanofi, Moderna, Pfizer, Janssen, Abbvie, Medicago, Gilead Sciences, and GSK during the conduct of the study; grants from BioNTech, Merck, and Bristol Myers Squibb outside the submitted work; consulting fees from Sanofi and Moderna; payment or honoraria for lectures, presentations, speakers bureaus, or manuscript writing/educational events from GSK and AstraZeneca; a patent pending for REFORM-Antibody Engineering (MGH); participation in a data safety monitoring board (DSMB) for CAPRISA CAP276 HIV monoclonal; leadership in a scientific advisory board for Sanofi; and stock or stock options in Systems Seromyx and Leyden Labs. G. F. reports grants from the NIH during the conduct of the study; and grants from the NIH outside the submitted work. D. M. reports grants from HVTN during the conduct of the study. P. M. reports holding stock/stock options in CureVac outside the submitted work. P. A. G. reports grants from the NIH outside the submitted work; and consulting fees from Johnson and Johnson. S. E. reports grants from HVTN and Janssen Vaccines and Prevention during the study; and grants from Sanofi outside the submitted work. M. S. S. reports grants from the NIH during the conduct of the study. L. R. B. reports grants from the NIH during the conduct of the study; grants from the NIH (Harvard Medical School), Bill and Melinda Gates Foundation, and Wellcome Trust outside the submitted work; participation in a DSMB for the NIH; participation in an advisory board for the Food and Drug Administration, and involvement in HIV and SARS-CoV-2 vaccine clinical trials conducted in collaboration with the NIH, HVTN, COVID Vaccine Prevention Network, International AIDS Vaccine Initiative, Janssen Vaccines and Prevention, Moderna, Military HIV Research Program, Bill and Melinda Gates Foundation, and Harvard Medical School. S. R. W. reports grants from Janssen Vaccines and Prevention and from NIH-NIAID during the conduct of the study; grants from Sanofi Pasteur, ModernaTx, Vir Biotechnology, and Worcester HIV Vaccine outside the submitted work; participation in a DSMB or advisory board for Janssen Vaccines and Prevention; and other financial or nonfinancial interests with Regeneron Pharmaceuticals (spouse employment and stock/stock options). D. J. S., C. C., M. S., K. C., M. G. P., H. S., and F. T. are employees of Janssen and hold Johnson and Johnson stock. S. N. is an employee of Janssen. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Vaccine composition, regimens, and immunization schedules. A, Composition of the vaccine regimen components used in the study: Ad26.Mos4.HIV, clade C gp140, and Mos1 gp140. B, Participants were administered Ad26.Mos4.HIV or placebo at day 0 and week 12, followed by Ad26.Mos4.HIV in combination with either clade C gp140 (clade C regimen) or clade C gp140 and Mos1 gp140 (bivalent protein regimen) at weeks 24 and 48. aSera and peripheral blood mononuclear cells were collected for analysis of humoral and cellular immune responses at day 0 and at weeks 28 (4 weeks after third vaccination), 52 (4 weeks after fourth vaccination), and 72 (6 months after fourth vaccination). Abbreviations: gp, glycoprotein; HIV, human immunodeficiency virus; Mos, mosaic; vp, viral particle.
Figure 2.
Figure 2.
Humoral binding antibody immune responses: total IgG responses. Total IgG response against vaccine-matched gp140 mosaic (A) and clade C (B) proteins. The analysis was performed using the data from the per-protocol immunogenicity set. Dots represent data from each participant. Geometric means and 95% confidence intervals of the magnitude are presented for each group at each time point. Horizontal bar at the top represents significant difference in 2-sample t test at P < .05. Abbreviations: Ab, antibody; ELISA, enzyme-linked immunosorbent assay; Env, envelope; EU, ELISA units; GM, geometric mean; HIV, human immunodeficiency virus; IgG, immunoglobulin G; LLOQ, lower limit of quantification; ULOQ, upper limit of quantification.
Figure 3.
Figure 3.
Humoral immune responses: binding antibody breadth. Binding antibody multiplex assay breadth panels of multiple clade C and non-clade C gp120, gp140, and V1V2 antigen panels. The analysis was performed using the data from the per-protocol immunogenicity set. Lines represent the proportion of participants in each group with magnitude > X at each time point. Abbreviations: MFI, mean fluorescence intensity; V1V2, first and second hypervariable regions.
Figure 4.
Figure 4.
Cellular immune responses. IFN-γ ELISPOT response to stimulation with PTE pools of HIV-1 Env, Gag, and Pol immunogens (A), and ICS to detect IFN-γ– and/or IL-2–producing CD4+ (B) and CD8+ T cells (C) in response to HIV-1 Env gp120 vaccine-matched mosaic immunogens. The analysis was performed using the data from the per-protocol immunogenicity set. ELISPOT responders were defined as a 3-fold increase from baseline for participants with baseline values greater than the threshold, or a postvaccination result greater than threshold for participants with baseline values less than the threshold. ICS responders were defined by Fisher exact test comparison between stimulated and unstimulated cells with resultant P < 1 × 10−5. Dots represent the data from each participant, open circles represent nonresponders, closed circles represent vaccine responders. Median and interquartile range (bars) of the magnitude are presented for each group at each time point. Horizontal bar at the top represents significant difference in Wilcoxon rank sum test at P < .05. Abbreviations: ELISPOT, enzyme-linked immunosorbent spot; Env, envelope; Gag, group-specific antigen; HIV, human immunodeficiency virus; ICS, intracellular cytokine staining; IFN-γ, interferon γ; IL, interleukin; M, median; pep, peptide; Pol, polymerase; PTE, potential T-cell epitope.
Figure 5.
Figure 5.
Vector immunity prevaccination and vaccine-induced immune response. The baseline Ad26 neutralization titers of participants in the United States and East Africa (A), and the Ad26 neutralization titers of participants in the bivalent group prior to each vaccination (B) were measured. Correlation analysis was performed in the population described in (A) to assess the association between Ad26 neutralization titers prevaccination and the corresponding IgG response against clade C postvaccination among participants receiving the regimen with the bivalent protein vaccine in the United States (C) and East Africa (D). A, Individual data, geometric mean, and 95% confidence interval are presented. C and D, line represents the Pearson correlation and the shaded areas indicate the 95% confidence interval. *P < .05, Pearson statistical test. Abbreviations: ELISA, enzyme-linked immunosorbent assay; GM, geometric mean; IC90, 90% inhibitory concentration; IgG, immunoglobulin G; LLOQ, lower limit of quantification; Serop. %, percentage seropositive; VNA, virus neutralization assay.
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