Dose Escalation Trial of CD40.HIVRI.Env Vaccine Combined or Not With a DNA-HIV-PT123 HIV-1 Vaccine in Healthy Volunteers

Healthy Adults Clinical Trial

Official title: A Phase I Multicenter Double-blind Placebo Controlled Dose Escalation Trial of an Adjuvanted Anti-CD40 mAb Fused to Env GP140 HIV Clade C ZM-96 (CD40.HIVRI.Env) Vaccine Combined or Not With a DNA-HIV-PT123 HIV-1 Vaccine in Healthy Participants

Status Recruiting

Clinical Trial Summary

Multicenter double-blind placebo controlled phase I dose-escalation trial that will be conducted in France and Switzerland to evaluate different dose levels of CD40.HIVRI.Env (adjuvanted with Hiltonol) alone and in co-administration with DNA-HIV-PT123.

A total of 72 eligible healthy participants will be recruited into 6 groups. Within each group, participants will be randomized in a double blind manner to active intervention or placebo in a 5:1 ratio. Enrolment into a given group (other than group "Solo 0.3") will open sequentially depending on the " go-criterion " based on the safety data of the preceding group(s).

The primary objective is to assess the safety of three dose levels of CD40.HIVRI.Env (0.3; 1; 3 mg) adjuvanted with Poly-ICLC (Hiltonol®), alone and in combination with DNA-HIV-PT123, administered at weeks 0, 4 and 24 in healthy participants.

Secondary objectives are to assess the capacity of poly-ICLC-adjuvanted CD40.HIVRI.Env alone and in combination with DNA-HIV-PT123 to elicit immune responses against HIV (immunogenicity):

• Humoral (antibody) responses ;

• B-cell responses ;

• T-cell responses.

Clinical Trial Description

The ANRS VRI06 clinical trial follows the prophylactic vaccine strategies developed since the encouraging results obtained during the RV144 trial. The RV144 study identified binding IgG antibodies directed at conserved regions of the V1/V2 loop and antibody-dependent cell-mediated cytotoxicity as immune correlates of reduced risk of HIV infection in the absence of inhibiting serum IgA antibodies.

We have developed DC-targeting vaccines, in order to increase protein antigen efficacy through their selective delivery to dendritic cell (DC), the key cell type for initiating and regulating immune responses, via the endocytic receptors expressed at the DC surfaces. Following the screening of vaccines targeting different several DC-receptors, the CD40-targeting vaccine has been shown to be the best candidate for inducing both cellular and humoral responses. Anti-CD40.Env GP140 vaccine (CD40.HIVRI.Env) adjuvanted with Poly-ICLC (Hiltonol®), in a prime/boost association with poxvirus vector vaccines, has shown to be safe and elicit robust Env specific T and B cell responses in a non-human primate study.

In this trial we will also capitalize on data generated in a recent phase I/II trial showing that co-administration of DNA-HIV-PT123 with an Env protein vaccine (as compared to other vaccine regimens which do not co-administer the protein during the priming) results in the rapid generation of high titers of binding anti V1/V2 Env region IgG Abs and Tier 1 nAb responses (HVTN 096 study).

We therefore hypothesize that co-administration of CD40.HIVRI.Env adjuvanted with Poly-ICLC (Hiltonol®) with the DNA-HIV-PT123 vaccine will be safe and induce high titers of binding anti V1/V2 Env region IgG Abs and other immunological parameters considered as immune correlates in RV144 trial.

When the first 6 participants of given dose group have reached W6 (2 weeks after the second injection), the Protocol Safety Review Team (PSRT), composed of sponsor's pharmacovigilance expert, coordinating investigator, co-coordinating investigator and methodologist, will review all accumulated Adverse Event (AE) data so far, in a blinded manner. All AE, in particular grade 3 and grade 4 AEs, as well as Serious Adverse Events (SAEs) will be reviewed. The current version FDA grading scale will be used for grading.

Go-criterion for opening enrolment into the next groups: If no grade 3 or 4 clinical solicited local/systemic or unsolicited AE or grade 3 or 4 biological clinical significant, is reported at W6, in any of the first 6 participants of a given group, the Data and Safety Monitoring Board (DSMB) assessment will not be requested for the go to the next group and the " go-criterion " is met. The trial can be continued by opening to the inclusions following the protocol.

Otherwise (occurrence of grade 3 or 4 AE), the DSMB will review all accumulated AE data. Enrolment in next group will only start after the DSMB gives the green light.

In addition, the following pausing rule (pausing of all injections) will apply during the trial:

Pausing rule for vaccine related safety events : If a serious adverse reaction (relatedness as judged by the pharmacovigilance department or the investigator responsible of the SAE notification) is reported during any stage of the study, all vaccinations will be halted, inclusions in the trial will be suspended, competent authorities must be informed and an ad-hoc DSMB meeting convened for recommendations on the trial continuation. Vaccinations may resume only after authorization is given by competent authority.

By the conservative method, if the causality assessment could not be provided by the investigator, the AE will be considered as possibly related. ;

Related Conditions & MeSH terms

• Healthy Adults

• NCT number: NCT04842682
• Study type: Interventional
• Source: ANRS, Emerging Infectious Diseases
• Contact: Yves LEVY, Pr
• Phone: +33(0)149814442
• Email: yves.levy@aphp.fr
• Status: Recruiting
• Phase: Phase 1
• Start date: March 29, 2021
• Completion date: September 30, 2024