Differential immune response induced by two immunization schedules with an inactivated SARS-CoV-2 vaccine in a randomized phase 3 clinical trial

Background The development of vaccines to control the COVID-19 pandemic progression is a worldwide priority. CoronaVac® is an inactivated SARS-CoV-2 vaccine approved for emergency use with robust efficacy and immunogenicity data reported in trials in China, Brazil, Indonesia, Turkey, and Chile. Methods This study is a randomized, multicenter, and controlled phase 3 trial in healthy Chilean adults aged ≥18 years. Volunteers received two doses of CoronaVac® separated by two (0-14 schedule) or four weeks (0-28 schedule). 2,302 volunteers were enrolled, 440 were part of the immunogenicity arm, and blood samples were obtained at different times. Samples from a single center are reported. Humoral immune responses were evaluated by measuring the neutralizing capacities of circulating antibodies. Cellular immune responses were assessed by ELISPOT and flow cytometry. Correlation matrixes were performed to evaluate correlations in the data measured. Results Both schedules exhibited robust neutralizing capacities with the response induced by the 0-28 schedule being better. No differences were found in the concentration of antibodies against the virus and different variants of concern between schedules. Stimulation of PBMCs with MPs induced the secretion of IFN-γ and the expression of activation induced markers for both schedules. Correlation matrixes showed strong correlations between neutralizing antibodies and IFN-γ secretion. Conclusions Immunization with CoronaVac® in Chilean adults promotes robust cellular and humoral immune responses. The 0-28 schedule induced a stronger humoral immune response than the 0-14 schedule. Funding Ministry of Health, Government of Chile, Confederation of Production and Commerce & Millennium Institute on Immunology and Immunotherapy, Chile. Clinical trial number NCT04651790. summary Two immunization schedules were evaluated for the inactivated SARS-CoV-2 vaccine, Coronavac®, with two doses of the vaccine separated by two or four weeks. We compared humoral and cellular immune responses, showing they are mostly similar, with differences in neutralization capacities. ### Competing Interest Statement R.S-R. reports funding from FONDECYT 1190156 and ANID - ICM, ICN 2021\_045. A.S. is a consultant for Gritstone Bio, Flow Pharma, ImmunoScape, Moderna, AstraZeneca, Avalia, Fortress, Repertoire, Gilead, Gerson Lehrman Group, RiverVest, MedaCorp, and Guggenheim. LJI has filed for patent protection for various aspects of T cell epitope and vaccine design work. A.S., A.G., and D.W. are under NIH contract 75N9301900065. Z.G. and M.W. are SINOVAC employees and contributed to the conceptualization of the study (clinical protocol and eCRF design). ZG and MW did not participate in the analysis or interpretation of the data presented in the manuscript. The Agencia Nacional de Investigación y Desarrollo (ANID) - Millennium Science Initiative Program - ICN09\_016 / ICN 2021_045: Millennium Institute on Immunology and Immunotherapy (former P09/016-F) and Agencia Nacional de Investigación y Desarrollo [FONDECYT grant numbers 1190830] supports S.M.B, P.A.G., and A.M.K. S.M.B acts as the Scientific Director of clinical trials PedCoronaVac03CL clinical study ([ClinicalTrials.gov][1] [NCT04992260][2]) and CoronaVac03CL ([ClinicalTrials.gov][1] [NCT04651790][3]). S.M.B. reports funding from the Agencia Nacional de Invetsigación y Desarrollo, Fondo de Fomento al Desarrollo Científico y tecnológico ID20I10082. P.A.G acts as the Executive Director of the clinical trials PedCoronaVac03CL clinical study ([ClinicalTrials.gov][1] [NCT04992260][2]) and CoronaVac03CL ([ClinicalTrials.gov][1]NCT04651790). A.M.K acts as the General Director of clinical trials PedCoronaVac03CL clinical study ([ClinicalTrials.gov][1] [NCT04992260][2]) and CoronaVac03CL ([ClinicalTrials.gov][1] [NCT04651790][3]). All other authors declare no potential conflict of interest. ### Clinical Trial NCT04651790 ### Funding Statement This work was supported by: The Ministry of Health, Government of Chile supported the funding of the CoronaVac03CL Study; The Confederation of Production and Commerce (CPC), Chile, supported the funding of the CoronaVac03CL Study; The Millennium Institute on Immunology and Immunotherapy, ANID - Millennium Science Initiative Program ICN09_016 (former P09/016-F) supports SMB, KA, PAG, and AMK; The Innovation Fund for Competitiveness FIC-R 2017 (BIP Code: 30488811-0) supports SMB, PAG, and AMK; FONDECYT grants N° 1190156 awarded to RSR, and N° 1180798 awarded to FVE; the NIH NIAID under Contract No. 75N93021C00016 supports AS and Contract No. 75N9301900065 supports AS, DW. SINOVAC Life Science Co contributed to this study with the investigational vaccine and placebo, and experimental reagents. The funding sources had no role in the study design, collection, analysis, and interpretation of data, writing of this manuscript, or the decision to submit it. All authors confirm they have full access to all the data and accept responsibility to submit for publication. ### 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: NAMES, AFFILIATIONS AND RESPONSE OF ETHICAL COMMITTEES 1. Full names and affiliations: Comité Ético Científico Ciencias de la Salud UC, Pontificia Universidad Católica de Chile, Santiago, Chile; Comité Ético Científico Universidad de Los Andes, Santiago, Chile; Comité Ético Científico Facultad de Medicina Clínica Alemana, Universidad del Desarrollo, Santiago, Chile; Comité Ético Científico Hospital Clínico Félix Bulnes, Santiago, Chile; Comité Ético Científico Servicio de Salud Valparaíso-San Antonio, Valparaíso, Chile; Comité Ético Científico Servicio de Salud Metropolitano Sur Oriente, Santiago, Chile 2. Decision of all CEC was: Approval 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][1]. 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 raw data (anonymized to protect the information of volunteers) is included with the publication of this article as a supporting file. Source Data File 1 contains the numerical data used to generate all the figures. The study protocol is also available online and was previously published in doi: 10.1101/2021.03.31.21254494. [1]: http://ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04992260&atom=%2Fmedrxiv%2Fearly%2F2022%2F08%2F08%2F2022.08.05.22278464.atom [3]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT04651790&atom=%2Fmedrxiv%2Fearly%2F2022%2F08%2F08%2F2022.08.05.22278464.atom