Essential Logistic Needs to Implement the C.L.E.A.R. Phase-I HIV Vaccine Trial

Division Of Basic Sciences - Nci

Investigators

Abstract

The project will exploit the DNA/ALVAC-HIV vaccine platform's ability to induce lasting trained monocyte memory in combination with a clade AE (A244 strain) V1-deleted HIV-gp160 prime and a novel V1-deleted HIV gp120/alum protein boost. The deletion of V1 from the gp120 envelope will be specially engineered to minimize antibody interference and elicit a high level of antibodies to V2, the primary correlate of risk in RV144. Alum hydroxide will be used as adjuvant for its ability to maximize the induction of trained immunity (through its ability to induce IL-1beta) and CD4+ T-cell responses that constituted the secondary correlate of decreased risk of HIV acquisition in RV144. The overall objective of this proposal is to design and produce both a novel HIV V1-deleted A244 gp160 (A244 DeltaV1 gp160) DNA vaccine and a novel HIV V1-deleted A244 gp120 (A244 DeltaV1 gp120) in GMP conditions for testing in a phase I human HIV vaccine trial. The immunogens will be tested in a phase I-HIV vaccine clinical trial, the Combined Long-term Efferocytosis and ADCC Responses (CLEAR). The detailed protocol for the Phase-I HIV vaccine clinical trial CLEAR (Study ID: IRB002260), has been provided to the NCI Office of Sponsor and Regulatory Oversight (OSRO) for review and it is currently in the latest phase of approval by the CCR Scientific Review committee (SRC ID: SRC00001684). In brief, CLEAR will test the safety and immunogenicity of three vaccine regimens in human volunteers: a combination of A244 DeltaV1gp160 and p55 Gag plasmid DNAs (producing VLPs) and recombinant ALVAC vCP2438 clade C (producing VLPs) followed by monomeric A244deltaV1 gp120 boost formulated in ALFQA (arm 1); or monomeric A244 DeltaV1 gp120 boost formulated in Rehydragel (alum hydroxide; arm 2); recombinant ALVAC vCP2438 clade C alone followed by A244 wild-type gp120 boost formulated in Rehydragel (arm 3). In arm 3, volunteers will receive the V1 replete ALVAC vCP2438 and boosted with wild type A244gp120 in Rehydragel. Sanofi Pasteur has licensed the Canarypox-based vaccine for HIV to the U.S. Military HIV Research Program and donated 13,000 vials of vCP2438 to NCI plus the diluent). The logistics necessary for the import, storage, and stability testing for these components are in place. Wild type A244 gp120 (required for arm 3) and aluminum hydroxide suspension-fluid gel under the trade name Rehydragel (required for arms 2 and 3) will be provided by Michael Pensiero and Michael Eller (Vaccine Research Program, NIAID). ALFQA (arm 1) will be provided by WRAIR (Dr. Rao). Dr. Frank Maldarelli, head of the NCI Clinical Retrovirology Section, will serve as the PI for this trial, and I will serve as Chair. Additionally, these immunogens have been tested in macaques and the assessment of whether this approach also induces long-lasting, non-interfering antibodies, innate monocyte memory, and adaptive CD4+ T-cells with a low inflammatory profile is ongoing. The investigation of protective monocyte, or NK memory trained immunity, will prove beneficial in combatting additional infectious diseases and cancer. Evolutionary conserved from invertebrates, trained immunity is an ancient trait of the human immune system that is defined by durable epigenetic reprogramming of monocytes, providing the first line of defense against pathogens. This will lead not only to the production and testing of a novel HIV vaccine, but also to the thorough investigation of unexplored host protective immune responses in non-human primates (NHP) whose immune system mirrors that of humans. The rationale behind the design of the CLEAR trial rests on seven key findings: 1. A shortened (3 month) SIV/DNA/ALVAC/bivalent gp120/alum boost regimen was more effective than the longer (6 month) SIV/ALVAC/ALVAC/bivalent gp120/alum boost regimen. 2. Antibody binding to envelope variable region V1 correlated with an increased risk of virus acquisition, by interfering with V2-specific ADCC. 3. ADCC specific for helical V2 conformations correlates with decreased risk of SIV and HIV acquisition. ADCC was inhibited by Fab' of NCI-05 and CH58 monoclonal antibodies respectively binding to SIV and HIV helical V2. 4. Antibodies to helical V2 contribute to vaccine efficacy as revealed by passive transfer in macaques of monoclonal antibodies (mAbs) to coil-helical V2 (NCI-05) or beta-sheet V2 (NCI-09). While neither NCI-05 nor NCI-09 completely protected from infection compared to control, only mucosal NCI-05 correlated with delayed SIVmac251 acquisition. 5. The helical V2 epitope recognized by NCI-05 (dependent on CD4 binding), but not the beta sheet epitope recognized by NCI-09, licenses killing of infected cells. Helical V2 reveals virus vulnerability on the surface of SIV infected cells by transient exposure. 6. V1 counteracts engagement of the CD73/adenosine axis linked to M2-like polarization of mucosal macrophages, a correlate of decreased risk of virus acquisition. Thus, V1 is an immunological decoy for HIV that not only induces interfering antibodies, but also promotes T-cell activation, fueling viral infection. 7. The combination of Army Liposome Formulation QS-21 (ALFQ) with Alum (ALFQA) augments innate and adaptive responses correlating with decreased risk of infection. Our data in macaques indicate that the efficacy of the DeltaV1DNA/ALVAC/DeltaV1 monovalent gp120 boost vaccine regimen in macaques does not rest on canonical immunity, such as neutralizing antibodies or cytotoxic T-cells. Rather, it rests on a combination of innate (NK cells, monocytes, dendritic cells) and adaptive (binding antibodies to helical V2 and CD4+ T-cells) immunity able to decrease the risk of virus acquisition. Specifically, SIV/HIV envelope-specific mucosal NKp44 production of IL-17 may reduce virus trespassing the epithelial barrier; antibodies to helical V2 able to bind and kill infected cells by ADCC; CD73+ macrophages prevent inflammation by clearing apoptotic cells (efferocytosis) and avoid the accumulation of pro-inflammatory necrotic bodies generated by viral infection and by ADCC; CD73+ tolerogenic mucosal DC-10 contributes to macrophage efferocytosis via IL-10 production; and adenosine release decreases CCR5 expression on CD4+ cells, minimizing the number of target cells for viral infection and enabling complete eradication of infected cells by ADCC and efferocytosis. This scenario is further supported by our serendipitous finding that vaginal gel-formulated SAMT-247, a zinc protein inhibitor that targets the highly conserved HIV/HIV nucleocapsid, together with our vaccine regimen that decreases the expression level of zinc protein ZC3H7A in blood, (a correlate of increased risk of virus acquisition) synergizes with vaccination, raising efficacy to 92.7% and protecting 80% of female macaques from infection. SAMT-247 virucidal activity is complemented by its ability to augment NK and myeloid cell functions, in part due to the mobilization of intracellular zinc. Supplemental funding provided for this project from the NIH Office of AIDS Research will support additional FY2025 costs associated with production logistics, storage, vaccine import, and regulatory requirements of the different vaccine components.