Safety, tolerability, and immunogenicity of a new SARS-CoV-2 recombinant Gamma variant RBD-based protein adjuvanted vaccine, used as heterologous booster in healthy adults: a Phase 1 interim report

Background In view of the emergence of SARS-CoV-2 immune escape variants and evidence of waning immunity, new immunisation strategies and variant-adapted vaccines are needed. Based on preclinical proof of concept studies and requirement of variant-adapted and booster vaccines, the Gamma Variant RBD-based ARVAC-CG vaccine was selected for a first clinical trial in humans. Methods Eighty participants (healthy adults, 18-55 years-old) were sequentially assigned to receive two (28 days apart) intramuscular doses of 25-μg (n=60) or 50-μg (n=20) of a Gamma RBD-based subunit vaccine adjuvanted with aluminium hydroxide. The primary endpoint was safety. The secondary objective was to describe the neutralising antibody response against the SARS-CoV-2 Ancestral strain and several variants of concern (Gamma, Delta, Omicron BA.1 and Omicron BA.5) measured by a live virus-based neutralisation assay. Cellular immune responses were studied as an exploratory objective by an enzyme-linked immunospot (ELISpot) assay. This trial is registered in [ClinicalTrials.gov][1] (NCT05656508). Findings The interim results from the ongoing phase 1 study are described. ARVAC-CG exhibited a satisfactory safety profile, a robust and broad booster response of neutralising antibodies against the Ancestral strain of SARS-CoV-2, the Gamma variant, and other VOCs (Delta, Omicron BA.1 and Omicron BA.5) and a booster effect on T cell immunity. Interpretation ARVAC-CG is safe and highly immunogenic when used as booster in individuals previously immunised with different COVID-19 vaccine platforms. These results warrant further clinical evaluation of this vaccine candidate for boosting other COVID-19 vaccines. Funding Laboratorio Pablo Cassará S.R.L. (Argentina). Evidence before this study Next-generation COVID-19 vaccines are based on a variant-adapted approach, using a strain other than the parental strain of SARS-CoV-2 (Wuhan or D614G strain). It has been suggested that the use of vaccines containing Beta spike protein may be an interesting strategy to acquire wider protection against SARS-CoV-2 variants. The Beta variant has been tested as booster in different monovalent or bivalent vaccine platforms. Indeed, Sanofi and GSK VidPrevtyn® Beta has recently been approved in Europe representing the first protein-based next-generation COVID-19 booster vaccine. While the receptor binding domain (RBD) of the spike protein of Gamma and Beta SARS-CoV-2 variants are very similar, no clinical data on Gamma variant-based COVID-19 vaccines has been published so far. Preclinical data in mice indicate that the Gamma variant-based vaccine is more immunogenic and induces a broader nAb response than the ancestral RBD-based vaccine. Added value of this study To our knowledge, these is the first clinical trial reported from any monovalent Gamma variant RBD protein adjuvanted vaccine used as heterologous booster of different primary series vaccine platforms. Two different vaccine doses were tested, and both exhibited a good profile of safety, tolerability and reactogenicity. ARVAC-CG as a single heterologous booster induced a significant increase of broad-spectrum neutralising antibodies against Ancestral, Gamma, Delta, Omicron BA.1 and Omicron BA.5 variants of concern (VOCs), binding antibodies, and IFN-γ producing cells. All these immune responses were significantly boosted in individuals primed with vaccines from different platforms. Plasma from vaccinees receiving a heterologous booster with ARVAC-CG was superior to plasma from BTN16b2 boosted individuals in neutralising Omicron BA.1 and BA.5 SARS-CoV-2 VOCs. Implications of all the available evidence Here, we present the available data from the phase I study of ARVAC-CG vaccine, involving healthy adults who had previously received a complete primary vaccination schedule with a COVID-19 vaccine. The positive safety and immunogenicity results of the ARVAC-CG vaccine candidate presented here justify further evaluation of its immunogenicity against currently circulating SARS-CoV-2 VOCs in a comprehensive Phase 2/3 trial. Further research is required to assess the antibody persistence over time after a booster dose of ARVAC-CG. ### Competing Interest Statement Declaration of interests JMR, LPC R&D and CMC Group, FMO, JCV are employees of Laboratorio Pablo Cassara S.R.L., which developed the vaccine and funded the trial. ML and JF are external consultants and received honoraria from Laboratorio Pablo Cassara S.R.L. All other authors declare no competing interests. ### Clinical Trial NCT05656508 ### Funding Statement The study was funded by Laboratorio Pablo Cassara S.R.L. (Argentina). ### Author Declarations I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained. Yes The details of the IRB/oversight body that provided approval or exemption for the research described are given below: Ethics committee/IRB in clinical investigation (COMITE DE ETICA EN INVESTIGACION CLINICA (CEIC)) Centro de Estudios Infectologicos S.A. IRB Registration 00010971 U.S.A. gave ethical approval for this work. I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals. Yes I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance). Yes I have followed all appropriate research reporting guidelines and uploaded the relevant EQUATOR Network research reporting checklist(s) and other pertinent material as supplementary files, if applicable. Yes All data produced in the present work are contained in the manuscript. Anonymised individual participant data will be made available when the study is complete, on reasonable requests made to the corresponding author. Proposals will be reviewed and approved by the sponsor, investigator, and collaborators on the basis of scientific merit. After approval of a proposal, data can be shared through a secure online platform. All data will be made available for a minimum of 5 years from the end of the trial. [1]: http://ClinicalTrials.gov