Safety and immunogenicity of CD40.HIVRI.Env, a dendritic cell-based HIV vaccine, in healthy HIV-uninfected adults: a first-in-human randomized, placebo-controlled, dose-escalation study (ANRS VRI06)

Yves Levy; Christiane Moog; Aurélie Wiedemann; Odile Launay; Fabio Candotti; Lucile Hardel; Mélany Durand; Véronique Rieux; Alpha Diallo; Christine Lacabaratz; Sylvain Cardinaud; Sandra Zurawski; Gerard Zurawski; Georgia D Tomaras; Song Ding; Mireille Centlivre; Rodolphe Thiebaut; Giuseppe Pantaleo; Jean-Daniel Lelièvre; Laura Richert; ANRS VRI06 Study Group

doi:10.1016/j.eclinm.2024.102845

Safety and immunogenicity of CD40.HIVRI.Env, a dendritic cell-based HIV vaccine, in healthy HIV-uninfected adults: a first-in-human randomized, placebo-controlled, dose-escalation study (ANRS VRI06)

EClinicalMedicine. 2024 Oct 2:77:102845. doi: 10.1016/j.eclinm.2024.102845. eCollection 2024 Nov.

Authors

Yves Levy^{1

2

3}, Christiane Moog^{3

4}, Aurélie Wiedemann^{1

3}, Odile Launay^{5

6}, Fabio Candotti⁷, Lucile Hardel^{3

8}, Mélany Durand^{3

8}, Véronique Rieux⁹, Alpha Diallo⁹, Christine Lacabaratz^{1

3}, Sylvain Cardinaud^{1

3}, Sandra Zurawski^{3

10}, Gerard Zurawski^{3

10}, Georgia D Tomaras¹¹, Song Ding¹², Mireille Centlivre^{1

3}, Rodolphe Thiebaut^{3

13

14

15}, Giuseppe Pantaleo⁷, Jean-Daniel Lelièvre^{1

2

3}, Laura Richert^{3

13

14

15}; ANRS VRI06 Study Group

Collaborators

ANRS VRI06 Study Group:
Yves Levy, Fabio Candotti, Mireille Centlivre, Mathilde Desvallées, Alpha Diallo, Mélany Durand, Song Ding, Laurent Hanot, Lucile Hardel, Hakim Hocini, Christine Lacabaratz, Jean-Daniel Lelièvre, Léa Levoyer, Christiane Moog, Giuseppe Pantaleo, Stéphane Paul, Laura Richert, Véronique Rieux, Laure Surgers, Aurélie Wiedemann, Jean-Paul Viard, Frédéric Batteux, Sophie Grabar, Hélène Pollard, Mathilde Desvallées, Marie Lachatre, Noémie Mercier, Laura Molinari, Loretxu Pinoges, Anaïs Boston, Valérie Boilet, Cécilia Campion, Solenne Delahaye, Mohamed Dembélé, Quentin Guillochon, Youssra Khalil, Anne-Aygline Soutthiphong, Ludivine Taïeb, Linda Wittkop, Rodolphe Thiebaut, Emile Foucat, Corinne Krief, Alexandre Ribeiro, Cécile Rodrigues, Thomas Decoville, Géraldine Laumond, Li-Yun Li, Sylvie Schmidt, Craig Fenwick, Tapia Gonzalo, Philippe Kiehl, Raida Ben Rayana, Magali Bouvier, Harouna Diombera, Hanane Mehawej, Muriel Verlinde-Carvalho, Marta Zatta, Odile Launay, Motolete Alaba Tanah, Kahina Cheref, Aurélie Durel-Maurisse, Mathilde Favreau, Pascal Grange, Corinne Guerin, Liem Binh Luong, Béatrice Parfait, Vanessa Christinet, Rosemary Hottinger, Isabelle Sommer, Francesco Tommasini, Aline Voidey, Andres Salazar

Affiliations

¹ INSERM U955, IMRB, Univ. Paris Est Créteil, Créteil, France.
² Groupe Henri-Mondor Albert-Chenevier, AP-HP, Créteil, France.
³ Vaccine Research Institute, France.
⁴ INSERM UMR_S1109, Université de Strasbourg, Strasbourg, France.
⁵ CIC 1417 F-CRIN I-REIVAC, INSERM, Hôpital Cochin, AP-HP, Paris, France.
⁶ Université Paris Descartes, Paris, France.
⁷ Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland.
⁸ Univ. Bordeaux, INSERM, MART, UMS 54, Bordeaux, France.
⁹ ANRS MIE, Paris, France.
¹⁰ Baylor Scott & White Research Institute, Dallas, TX, USA.
¹¹ Duke University School of Medicine, Durham, NC, USA.
¹² EuroVacc Foundation, Lausanne, Switzerland.
¹³ Univ. Bordeaux, INSERM, Bordeaux Population Health Research Center, UMR1219, Bordeaux, France.
¹⁴ Inria SISTM Team, Talence, France.
¹⁵ CHU de Bordeaux, Service d'Information Médicale, Bordeaux, France.

Abstract

Background: Current HIV prophylactic vaccines evaluate HIV Env as purified proteins. CD40.HIVRI.Env is an innovative antigen delivery targeting gp140 Env from HIV Clade C 96ZM651 to CD40-expressing antigen-presenting cells, thus harnessing the intrinsic immune-stimulant properties. DNA-HIV-PT123 vaccine encodes 96ZM651 gp140/Gag and 97CN54 Pol/Nef.

Methods: Seventy-two HIV-negative volunteers were enrolled between 05/2021 and 10/2022 in a phase 1 placebo-controlled trial conducted in France and Switzerland (N° EudraCT: 2020-001814-40; NCT04842682). Volunteers were randomized (5:1 active versus placebo) in groups receiving either 0.3, 1.0, or 3.0 mg CD40.HIVRI.Env (Hiltonol® adjuvanted) alone or co-administered with DNA-HIV-PT123 at weeks (W) 0, 4, and 24. Safety and immunogenicity were monitored until W48. The primary safety endpoint was the proportion of participants per dose cohort and randomized arm without any grade 3 or 4 biological (abnormal laboratory values), or clinical local or systemic solicited, or unsolicited adverse events between W0 and W48 considered to be related or possibly related to the investigational products.

Findings: CD40.HIVRI.Env was well tolerated. Env-specific CD4⁺ T-cells (IL-2⁺ or IFN-γ⁺ or TNF⁺) were detected in all vaccinees from W6 to W26 and persisted until W48 without a dose-response signal or an effect of DNA-HIV-PT123 co-administration. At W26, IgG response rates (RR) against autologous and nine heterologous gp120/gp140 were 89-100% across all groups and 56-100% at W48. RR against 96ZM651gp70V1V2 were high (90-100%) at W6 and W26 in all groups. Tier1A MW965.26 neutralizing antibody (nAb) titres were detectable in 50-100% of vaccinated individuals at W26, with a dose-response signal, while one volunteer developed nAbs against five Tier2 viruses.

Interpretation: CD40.HIVRI.Env alone or administered with DNA-HIV-PT123 was safe and induced early, and sustained anti-Env cellular and V1V2 IgG responses, identified as correlates of protection in the RV144 trial. CD40 targeting Env-based vaccines may be instrumental for inducing protective vaccine responses in prime-boost strategies.

Funding: ANRS Emerging infectious diseases (ANRS MIE); Vaccine Research Institute (VRI).

Keywords: DNA vaccine; Dendritic cell targeting; First-in-human clinical trial; HIV vaccines; Immunogenicity.