Phase II/III Double-Blind Study Evaluating Safety and Immunogenicity of a Single Intramuscular Booster Dose of the Recombinant SARS-CoV-2 Vaccine "Patria" (AVX/COVID-12) Using an Active Newcastle Disease Viral Vector (NDV) during the Omicron Outbreak in Healthy Adults with Elevated Baseline Antibody Titers from Prior COVID-19 and/or SARS-CoV-2 Vaccination

Background: The urgent need for safe, effective, and economical coronavirus disease 2019 (COVID-19) vaccines, especially for booster campaigns targeting vulnerable populations, prompted the development of the AVX/COVID-12 vaccine candidate. AVX/COVD-12 is based in a Newcastle disease virus La Sota (NDV-LaSota) recombinant viral vector. This vaccine expresses a stabilized version of the spike protein of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), specifically the ancestral Wuhan strain. The study aimed to assess its safety, immunogenicity, and potential efficacy as an anti-COVID-19 booster vaccine. Methods: In a phase II/III clinical trial conducted from November 9, 2022, to September 11, 2023, a total of 4,056 volunteers were enrolled. Participants received an intramuscular booster dose of either AVX/COVID-12 or AZ/ChAdOx-1-S vaccines. Safety, immunogenicity, and potential efficacy were assessed through various measures, including neutralizing antibody titers, interferon (IFN)-γ-producing CD4+ T cells, and CD8+ T cells. The evaluation also involved immunobridging, utilizing the AZ/ChAdOx-1-S vaccine as an active comparator, and monitoring the incidence of COVID-19 cases. Findings: The AVX/COVID-12 vaccine induced neutralizing antibodies against both the ancestral SARS-CoV-2 and the BA.2 and BA.5 Omicron variants. The geometric mean ratio of neutralizing antibody titers between individuals immunized with the AVX/COVID-12 vaccine and those with the AZ/ChAdOx-1-S vaccine at 14 days is 0.96, with a confidence interval (CI) of 0.85-1.06. The outcome aligns with the non-inferiority criterion recommended by the World Health Organization (WHO), indicating a lower limit of the CI greater than or equal to 0.67. Induction of IFN-γ-producing CD8+ T cells at day 14 post-immunization was exclusively observed in the AVX/COVID-12 group. Finally, a trend suggested a potentially lower incidence of COVID-19 cases in AVX/COVID-12 boosted volunteers compared to AZ/ChAdOx-1-S recipients. Conclusion: The AVX/COVID-12 vaccine proved safe, well-tolerated, and immunogenic. AVX/COVID-12 meets the WHO non-inferiority standard compared to AZ/ChAdOx-1-S. These results strongly advocate for AVX/COVID-12 as a viable booster dose, supporting its utilization in the population. ### Competing Interest Statement The vaccine candidate administered in this study was developed by faculty members at the Icahn School of Medicine at Mount Sinai including P.P., F.K. and A.G.-S. Mount Sinai is seeking to commercialize this vaccine; therefore, the institution and its faculty inventors could benefit financially. The Icahn School of Medicine at Mount Sinai has filed patent applications relating to SARS-849 CoV-2 serological assays (USA Provisional Application Numbers: 62/994,252, 63/018,457, 63/020,503, and 63/024,436) and NDV-based SARS-CoV-2 vaccines (USA Provisional Application Number: 63/251,020) which list FK as co-inventor. A.G.-S. and P.P. are a co-inventor in the NDV-based SARS-CoV-2 vaccine patent application. Patent applications were submitted by the Icahn School of Medicine at Mount Sinai. Mount Sinai has spun out a company, Kantaro, to market serological tests for SARS-CoV-2 and another company, CastleVax, to commercialize SARS-CoV-2 vaccines. F.K., P.P. and A.G.-S. serve on the scientific advisory board of CastleVax and are listed as co-founders of the company. F.K. has consulted for Merck, Seqirus, Curevac, and Pfizer, and is currently consulting for Gritstone, Third Rock Ventures, GSK, and Avimex. The F.K. laboratory has been collaborating with Pfizer on animal models of SARS-CoV-2. C.L.-M. has consulted for AstraZeneca. The A.G.-S. laboratory has received research support from GSK, Pfizer, Senhwa Biosciences, Kenall Manufacturing, Blade Therapeutics, Avimex, Johnson & Johnson, Dynavax, 7Hills Pharma, Pharmamar, ImmunityBio, Accurius, Nanocomposix, Hexamer, N-fold LLC, Model Medicines, Atea Pharma, Applied Biological Laboratories and Merck. A.G.-S. has consulting agreements for the following companies involving cash and/or stock: Amovir, Vivaldi Biosciences, Contrafect, 7Hills Pharma, Avimex, Pagoda, Accurius, Esperovax, Farmak, Applied Biological Laboratories, Pharmamar, CureLab Oncology, CureLab Veterinary, Synairgen, Paratus, Pfizer and Prosetta. A.G.-S. has been an invited speaker in meeting events organized by Seqirus, Janssen, Abbott, and AstraZeneca. P.P. has a consulting agreement with Avimex. Members of Avimex developed the live vaccine used in this study. Avimex filed patent applications with Mount Sinai and CONAHCYT. M.T., D.S.-M., C.L.-M., H.E.C.-C., F.C.-P., G.P.D.L., and B.L.-D. are named as inventors on at least one of those patent applications. The clinical study was entirely performed in Mexico and Mount Sinai had no role in the clinical study. The rest of the participants are employees of their corresponding institutions and declare no competing interests. ### Clinical Trial NCT05710783 ### Funding Statement The funding for the clinical study was provided by the National Council for Humanities, Science and Technology (CONAHCYT, Mexico), except for all the production and vaccine product supply, which was funded solely by Laboratorio Avi-Mex, S. A. de C. V. (Avimex). CONAHCYT did not participate in the trial design but did evaluate it and approved the project through their National Committee for Science, Technology and Innovation in Public Health. Funding was managed by Avimex and used to pay for all laboratory tests, clinical sites, and clinical professionals. CONAHCYT also facilitated the identification, purchase, and importation of certain supplies and the communication with other entities of the Federal Mexican Government to facilitate the study. ### 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 approval for the study was obtained from the Federal Commission for the Protection against Sanitary Risks (COFEPRIS) in Mexico, with the assigned number RNEC2022-AVXSARSCoV2VAC005. As a prerequisite, local ethics clearance was secured from the institutional ethics committees at each participating research site. 1. Research Site: Unidad de Investigacion Medica en Epidemiologia Clinica, UMAE Hospital de Especialidades, Centro Medico Nacional Siglo XXI, Instituto Mexicano del Seguro Social (IMSS), Ciudad de Mexico, Mexico. Ethics Committee: IMSS Scientific Research National Committee. Approval Number: CNIC-2022-785-10. 2. Research Site: Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran, Ciudad de Mexico, Mexico. Ethics Committee: Comite de Etica en Investigacion del Instituto Nacional de Ciencias Medicas y Nutricion Salvador Zubiran. Reference: 4371. 3. Research Site: CAIMED Investigacion en Salud, S.A. de C.V., Ciudad de Mexico, Mexico. Ethics Committee: Comite de Etica en Investigacion de Investigacion Biomedica para el Desarrollo de Farmacos SA de CV. Approval Number: 6030.sEswXEyH. 4. Research Site: Oaxaca Site Management Organization (OSMO) S.C., Oaxaca, Mexico. Ethics Committee: Comite de Etica en Investigacion de Oaxaca Site Management Organization S. C. Approval Number: CEI-OSMO: 1597/2022. 5. Research Site: Centro de Investigacion Clinica Acelerada (CICA), S.C., Ciudad de Mexico, Mexico. Ethics Committee: Comite de Etica en Investigacion de Centro de Investigacion Clinica Acelerada, S.C. Approval Date: 03-sep-22. 6. Research Site: Clinical Research Institute (CRI) S.C., Estado de Mexico, Mexico. Ethics Committee: Comite de Etica en Investigacion Biomedica para el Desarrollo de Farmacos SA de CV. Approval Number: 6389.gjx2xhoih. 7. Research Site: Centro de Investigacion Clinica Chapultepec, Ciudad de Mexico, Mexico. Ethics Committee: Comite de Etica en Investigacion de Sociedad Administradora de Servicios de Salud S.C. Approval Number: 967.hL3XFeyCZscR. 8. Research Site: Unidad de Atencion Medica e Investigacion en Salud (UNAMIS), Yucatan, Mexico. Ethics Committee: Comite de Etica en Investigacion de Unidad de Atencion Medica e Investigacion en Salud. Approval Number: 89244E882AF143D. 9. Research Site: Kohler & Milstein Research (K&M) Facultad de Medicina, Universidad Autonoma de Yucatan, Merida, Yucatan, Mexico. Ethics Committee: Comite de Etica en Investigacion Biomedica para el Desarrollo de Farmacos SA de CV. Approval Number: 6007.MHWWA1. 10. Research Site: Centro Multidisciplinario para el Desarrollo Especializado de la Investigacion Clinica en Yucatan (CEMDEICY) S.C.P, Yucatan, Mexico. Ethics Committee: Comite de Etica en Investigacion Biomedica para el Desarrollo de Farmacos SA de CV. Approval Number: 6007.MHWWA1. 11. Research Site: Centro de Investigacion Clinica del Pacifico (CICPA), Guerrero, Mexico. Ethics Committee: Comite de Etica en Investigacion Biomedica para el Desarrollo de Farmacos SA de CV. Approval Number: 6429.85DQ2ND. 12. Research Site: Red OSMO, Centro de Investigacion y Avances Medicos Especializados (CIAME), Quintana Roo, Mexico. Ethics Committee: Comite de Etica en Investigacion de Oaxaca Site Management Organization S. C. Approval Number: CEI-OSMO: 1732/2022. 13. Research Site: Instituto Veracruzano de Investigacion Clinica (IVIC) S.C., Veracruz, Mexico. Ethics Committee: Comite de Etica en Investigacion Biomedica para el Desarrollo de Farmacos SA de CV. Approval Number: 6676.UjTJ4KUpK. 14. Research Site: Hospital de Cardiologia Aguascalientes, Aguascalientes, Mexico. Ethics Committee: Comite de Etica en Investigacion de Promotora Medica Aguascalientes S.A. DE C.V. Approval Number: 2394.ceipma.2022. The research was conducted in full compliance with Mexican regulations and in accordance with the principles outlined in the Declaration of Helsinki and Good Clinical Practice 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, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable. Yes The protocol was registered in the National Registry of Clinical Studies under number RNEC2022-AVXSARSCoV2VAC005 and published under [NCT05710783][1]. Individual de-identified participant data will not be shared beyond the limits permitted by the informed consent and Mexican law. Specifically, this includes the sharing of the study protocol, statistical analysis plan, informed consent form, and approved clinical study report. Additionally, other de-identified data allowed under the informed consent and Mexican law may be shared. The data will be made available immediately upon publication and for 12 months thereafter. Access to the data will be granted solely to investigators with methodologically sound proposals, subject to authorization by an independent review committee and the ethics committees involved in approving the protocol. If required by law, authorization from the Federal Commission for the Protection against Sanitary Risks (COFEPRIS) in Mexico will also be obtained. Any use of the data must strictly adhere to the authorized purposes outlined during the approval process. [1]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT05710783&atom=%2Fmedrxiv%2Fearly%2F2024%2F02%2F14%2F2024.02.11.24302530.atom