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

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.

Based on the first safety and immunogenicity results, the study design has been amended with the addition of boost injection. Heterologous prime boost vaccination strategies in HIV have been associated with short-lived responses, notably in the RV144 trial, leading to the proposal of additional early boosts as in the RV702 trial or late boosts as in the RV305 trial. In the latter trial it was shown that only the boost with the protein component of the strategy was relevant in terms of restimulation of the immune response. Data obtained during vaccination against SARS CoV2 showed that the use of lower boost doses was associated with the same immunological efficacy and probably better tolerance. B cells expressing higher affinity antigen receptors being available for competition for antigen in germinal center light zones and then requiring less antigen.

Therefore we proposed that participants who received active strategies in all groups (Solo or Combi, regardless of the initial dose level received at W0,W4 and W24) be vaccinated post-W48 visit with a single 0.3 mg dose of CD40. HIVRI.Env alone or adjuvanted with Poly ICLC- Hiltonol® . This latter arm is based on preclinical CD40 vaccine data showing the good efficacy of the non-adjuvanted vaccine when delivered as a boost after initial immunizations, which will be the case for the volunteers participating in this second phase of the trial. The demonstration of a comparable effect of a booster injection with or without adjuvant is an important contribution of this trial, as the development of a non-adjuvanted protein vaccine considerably facilitates the development of such a vaccine candidate. The clinical situation (such as protection against HIV) requiring repeated booster shots to maintain a long-term memory response, the protection of which remains to be demonstrated in phase 2b/3 trials, justifies the evaluation of a non-adjuvanted booster strategy. The long-term follow-up proposed in this amendment makes it possible to evaluate long-term tolerance, maintenance of immune responses, and the effect of a distant booster injection on the maintenance of these memory responses.

Allocation of the use of the unadjuvanted vs. adjuvanted CD40. HIVRI.Env boost will be randomized. Randomisation will be stratified by the initial group (Solo or Combi with its dose level).

This second part of the trial will be single blind and consists of 3 additional visits: the late boost injection visit (WLB) and 2 follow-up visits, one 2 weeks (WLB+02) and the other 24 weeks (WLB+24) after the WLB visit.

The window for injection of the late boost is deliberately large (W48 - W76 or after, for participants who carried out the W76 visit before this amendment) as the hypothesis is that an immune memory response will be mobilized with rapid increases in post-boost immune responses, regardless of the exact timing of the late boost. This is also in line with the heterogeneous timing of late boosts in an implementation context (e.g. as is the case for current Covid-vaccine boosts, for instance).