Phase I interim results of a phase I/II study of the IgG-Fc fusion COVID-19 subunit vaccine, AKS-452

Abstract

To address the coronavirus disease 2019 (COVID-19) pandemic caused by infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), a recombinant subunit vaccine, AKS-452, is being developed comprising an Fc fusion protein of the SARS-CoV-2 viral spike protein receptor binding domain (SP/RBD) antigen and human IgG1 Fc emulsified in the water-in-oil adjuvant, Montanide™ ISA 720. A single-center, open-label, phase I dose-finding and safety study was conducted with 60 healthy adults (18–65 years) receiving one or two doses 28 days apart of 22.5 µg, 45 µg, or 90 µg of AKS-452 ( i.e. , six cohorts, N = 10 subjects per cohort). Primary endpoints were safety and reactogenicity and secondary endpoints were immunogenicity assessments. No AEs ≥ 3, no SAEs attributable to AKS-452, and no SARS-CoV-2 viral infections occurred during the study. Seroconversion rates of anti-SARS-CoV-2 SP/RBD IgG titers in the 22.5, 45, and 90 µg cohorts at day 28 were 70%, 90%, and 100%, respectively, which all increased to 100% at day 56 (except 89% for the single-dose 22.5 µg cohort). All IgG titers were Th1-isotype skewed and efficiently bound mutant SP/RBD from several SARS-CoV-2 variants with strong neutralization potencies of live virus infection of cells (including alpha and delta variants). The favorable safety and immunogenicity profiles of this phase I study ( ClinicalTrials.gov: NCT04681092 ) support phase II initiation of this room-temperature stable vaccine that can be rapidly and inexpensively manufactured to serve vaccination at a global scale without the need of a complex distribution or cold chain.

Broad immunity to SARS-CoV-2 variants of concern mediated by a SARS-CoV-2 receptor-binding domain protein vaccine

“…A possible limitation of these hamster studies is that, as shown previously, RBD-based vaccines may be less immunogenic in hamsters, for reasons that are unclear 39 . This limitation does not apply to humans where RBD-based vaccines are effective 8,40,41 .…”

“…While the vaccine has been extensively tested in mice, including mouse and human Fc versions, as well as rats and hamsters, we await the results of clinical trials to determine how immunogenic our vaccine is in humans. Based on results from phase I/II clinical trials of other experimental ancestral strain RBD-Fc protein vaccines used in prime-boost regimen in humans, albeit with different adjuvants 40, 41, 51 , and our preclinical data, we anticipate that our vaccine used as a fourth dose boost will augment nAb responses in humans. While hamsters also responded to a prime-boost regimen with our RBD vaccines, the response was more varied and not as robust as was observed in mice and rats, which may reflect findings in a recent report of limitations in the extent to which hamsters respond to RBD-based vaccines 39 .…”

“…This vaccine was well tolerated and induced nAb in all subjects, generally exceeding those of convalescent serum. Interim results from a phase I/II trial of an RBD-human IgG1 Fc vaccine (ancestral strain) with montenide oil-in-water adjuvant in a two-dose prime-boost schedule provided evidence of strong neutralising antibody responses with low levels of reactogenicity 41 . Another approach used to develop an RBD-based vaccine was to fuse two RBDs to a hepatitis B surface antigen (PreS) plus Alum, which generated robust responses in rabbits and in a single human volunteer 53 .…”

A circular mRNA vaccine prototype producing VFLIP-X spike confers a broad neutralization of SARS-CoV-2 variants by mouse sera

“…Other RBD-targeted neutralizing monoclonal antibodies are unaffected by mutations in the RBD of emerging variants ( Dejnirattisai et al, 2021b ; Cerutti et al, 2021 ; Cameroni et al, 2022 ). Moreover, the utilization of RBD as an immunogen in several vaccine platforms has shown promising clinical immunogenicity results ( Mulligan et al, 2020 ; Yang et al, 2021 ; Janssen et al, 2022 ; Chen et al, 2022 ). Thus, rationally engineered SARS-CoV-2 RBD and spike proteins could serve as potential immunogens to elicit potent protective immune responses.…”

Broad neutralization of SARS-CoV-2 variants by circular mRNA producing VFLIP-X spike in mice

“…Promisingly, neutralization efficacy of multiple identified RBD-targeted neutralizing monoclonal antibodies is unaffected by mutations in the RBD of emerging variants [10][11][12] . Moreover, the utilization of RBD as an immunogen in several vaccine platforms has shown promising clinical immunogenicity results [13][14][15][16] . Thus, rationally engineered SARS-CoV-2 RBD and spike proteins could serve as potential immunogens to elicit potent protective immune responses.…”