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
Authors: Pasquevich Karina A. , Coria Lorena M. , Ceballos Ana , Mazzitelli Bianca , Rodriguez Juan Manuel , Demaría Agostina , Castro Celeste Pueblas , Bruno Laura , Saposnik Lucas , Salvatori Melina , Varese Augusto , González Soledad , González Martínez Veronica V. , Geffner Jorge , Álvarez Diego ,   Laboratorio Pablo Cassará R&D and CMC group for ARVAC-CG, Feleder Ethel , Halabe Karina , Perez Lera Pablo E. , de Oca Federico Montes , Vega Julio C. , Lombardo Mónica , Yerino Gustavo A. , Fló Juan , Cassataro Juliana 
Published: January 2023

SUMMARYBackgroundIn 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.MethodsEighty 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 inClinicalTrials.gov(NCT05656508).FindingsThe 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.InterpretationARVAC-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.FundingLaboratorio Pablo Cassará S.R.L. (Argentina).Research in contextEvidence before this studyNext-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 studyTo 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 evidenceHere, 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.