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

Abstract

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-g and the expression of activation induced markers for both schedules. Correlation matrixes showed strong correlations between neutralizing antibodies and IFN-g 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.

Data availability

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.

Article and author information

Author details

  1. Nicolas M S Gálvez

    Departamento de Genética Molecular y Microbiología, Pontificia Universidad Católica de Chile, Santiago, Chile
    Competing interests
    No competing interests declared.
  2. Gaspar A Pacheco

    Departamento de Genética Molecular y Microbiología, Pontificia Universidad Católica de Chile, Santiago, Chile
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-5748-5027
  3. Barbara M Schultz

    Departamento de Genética Molecular y Microbiología, Pontificia Universidad Católica de Chile, Santiago, Chile
    Competing interests
    No competing interests declared.
  4. Felipe Melo-González

    Departamento de Genética Molecular y Microbiología, Pontificia Universidad Católica de Chile, Santiago, Chile
    Competing interests
    No competing interests declared.
  5. Jorge A Soto

    Departamento de Genética Molecular y Microbiología, Pontificia Universidad Católica de Chile, Santiago, Chile
    Competing interests
    No competing interests declared.
  6. Luisa F Duarte

    Departamento de Genética Molecular y Microbiología, Pontificia Universidad Católica de Chile, Santiago, Chile
    Competing interests
    No competing interests declared.
  7. Liliana A Gonzalez

    Departamento de Genética Molecular y Microbiología, Pontificia Universidad Católica de Chile, Santiago, Chile
    Competing interests
    No competing interests declared.
  8. Daniela S Rivera

    Departamento de Genética Molecular y Microbiología, Pontificia Universidad Católica de Chile, Santiago, Chile
    Competing interests
    No competing interests declared.
  9. Mariana Ríos

    Departamento de Genética Molecular y Microbiología, Pontificia Universidad Católica de Chile, Santiago, Chile
    Competing interests
    No competing interests declared.
  10. Roslye V Berrios

    Departamento de Genética Molecular y Microbiología, Pontificia Universidad Católica de Chile, Santiago, Chile
    Competing interests
    No competing interests declared.
  11. Yaneisi Vázquez

    Departamento de Genética Molecular y Microbiología, Pontificia Universidad Católica de Chile, Santiago, Chile
    Competing interests
    No competing interests declared.
  12. Daniela Moreno-Tapia

    Departamento de Genética Molecular y Microbiología, Pontificia Universidad Católica de Chile, Santiago, Chile
    Competing interests
    No competing interests declared.
  13. Omar P Vallejos

    Departamento de Genética Molecular y Microbiología, Pontificia Universidad Católica de Chile, Santiago, Chile
    Competing interests
    No competing interests declared.
  14. Catalina A Andrade

    Departamento de Genética Molecular y Microbiología, Pontificia Universidad Católica de Chile, Santiago, Chile
    Competing interests
    No competing interests declared.
  15. Guillermo Hoppe-Elsholz

    Departamento de Genética Molecular y Microbiología, Pontificia Universidad Católica de Chile, Santiago, Chile
    Competing interests
    No competing interests declared.
  16. Carolina Iturriaga

    Departamento de Enfermedades Infecciosas e Inmunología Pediátrica, Pontificia Universidad Católica de Chile, Santiago, Chile
    Competing interests
    No competing interests declared.
  17. Marcela Urzua

    Departamento de Enfermedades Infecciosas e Inmunología Pediátrica, Pontificia Universidad Católica de Chile, Santiago, Chile
    Competing interests
    No competing interests declared.
  18. María S Navarrete

    Departamento de Enfermedades Infecciosas del Adulto, Pontificia Universidad Católica de Chile, Santiago, Chile
    Competing interests
    No competing interests declared.
  19. Álvaro Rojas

    Departamento de Enfermedades Infecciosas del Adulto, Pontificia Universidad Católica de Chile, Santiago, Chile
    Competing interests
    No competing interests declared.
  20. Rodrigo Fasce

    Departamento de Laboratorio Biomédico, Instituto de Salud Pública de Chile, Santiago, Chile
    Competing interests
    No competing interests declared.
  21. Jorge Fernández

    Departamento de Laboratorio Biomédico, Instituto de Salud Pública de Chile, Santiago, Chile
    Competing interests
    No competing interests declared.
  22. Judith Mora

    Departamento de Laboratorio Biomédico, Instituto de Salud Pública de Chile, Santiago, Chile
    Competing interests
    No competing interests declared.
  23. Eugenio Ramirez

    Departamento de Laboratorio Biomédico, Instituto de Salud Pública de Chile, Santiago, Chile
    Competing interests
    No competing interests declared.
  24. Aracelly Gaete-Argel

    Laboratory of Molecular and Cellular Virology, University of Chile, Santiago, Chile
    Competing interests
    No competing interests declared.
  25. Mónica Acevedo

    Laboratory of Molecular and Cellular Virology, University of Chile, Santiago, Chile
    Competing interests
    No competing interests declared.
  26. Fernando Valiente-Echeverria

    Laboratory of Molecular and Cellular Virology, University of Chile, Santiago, Chile
    Competing interests
    No competing interests declared.
  27. Ricardo Soto-Rifo

    Laboratory of Molecular and Cellular Virology, University of Chile, Santiago, Chile
    Competing interests
    Ricardo Soto-Rifo, has received funding from ANID - ICM, ICN 2021_045. The author has no other competing interests to declare.
  28. Daniela Weiskopf

    Center for Infectious Disease and Vaccine Research, La Jolla Institute For Allergy & Immunology, La Jolla, United States
    Competing interests
    Daniela Weiskopf, has received funding support from the NIH under contract number 75N93019C00065. The Jolla Institute for Immunology (LJI) has filed for patent protection for various aspects of T cell epitope and vaccine design work. The author has no other competing interests to declare.
  29. Alba Grifoni

    Center for Infectious Disease and Vaccine Research, La Jolla Institute For Allergy & Immunology, La Jolla, United States
    Competing interests
    Alba Grifoni, Alba Grifoni has received funding support from the NIH under contract number 75N93021C00016. The Jolla Institute for Immunology (LJI) has filed for patent protection for various aspects of T cell epitope and vaccine design work. The author has no other competing interests to declare.
  30. Alessandro Sette

    Department of Medicine, University of California, San Diego, La Jolla, United States
    Competing interests
    Alessandro Sette, is a consultant for Gritstone Bio, Flow Pharma, Arcturus, Immunoscape, CellCarta, Moderna, AstraZeneca, Fortress, Repertoire, Gilead, Gerson Lehrman Group, RiverVest, MedaCorp, Guggenheim, OxfordImmunotech, and Avalia. The author has received funding support from the NIH under contract 75N93021C00016. The Jolla Institute for Immunology (LJI) has filed for patent protection for various aspects of T cell epitope and vaccine design work. The author has no other competing interests to declare.
  31. Gang Zeng

    Sinovac Biotech, Beijing, China
    Competing interests
    Gang Zeng, is a SINOVAC employee and contributed to the conceptualization of the study (clinical protocol and eCRF design)..
  32. Weining Meng

    Sinovac Biotech, Beijing, China
    Competing interests
    Weining Meng, is a SINOVAC employee and contributed to the conceptualization of the study (clinical protocol and eCRF design)..
  33. José V Gonzalez-Aramundiz

    Departamento de Farmacia, Pontificia Universidad Católica de Chile, Santiago, Chile
    Competing interests
    No competing interests declared.
  34. Marina Johnson

    Department of Infection, University College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  35. David Goldblatt

    Department of Infection, University College London, London, United Kingdom
    Competing interests
    No competing interests declared.
  36. Pablo A González

    Departamento de Genética Molecular y Microbiología, Pontificia Universidad Católica de Chile, Santiago, Chile
    Competing interests
    Pablo A González, acts as the Executive Director of the clinical trials PedCoronaVac03CL clinical study (ClinicalTrials.gov NCT04992260) and CoronaVac03CL (ClinicalTrials.govNCT04651790) (funds to the institution), and receives research support from Millennium Institute on Immunology and Immunotherapy. The author received funding from Agencia Nacional de Investigación y Desarrollo, Fondo de Fomento al Desarrollo Científico y tecnológico. The author has no other competing interests to declare.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7709-6870
  37. Katia Abarca

    Departamento de Genética Molecular y Microbiología, Pontificia Universidad Católica de Chile, Santiago, Chile
    Competing interests
    No competing interests declared.
  38. Susan M Bueno

    Departamento de Genética Molecular y Microbiología, Pontificia Universidad Católica de Chile, Santiago, Chile
    For correspondence
    sbueno@bio.puc.cl
    Competing interests
    Susan M Bueno, acts as the Scientific Director of clinical trials PedCoronaVac03CL clinical study (ClinicalTrials.gov NCT04992260) and CoronaVac03CL (ClinicalTrials.govNCT04651790) (funds to the institution), and receives research support from Millennium Institute on Immunology and Immunotherapy. The author has received funding from Agencia Nacional de Invetsigación y Desarrollo, Fondo de Fomento al Desarrollo Científico y tecnológico ID20I10082. The author has no other competing interests to declare.
  39. Alexis M Kalergis

    Departamento de Genética Molecular y Microbiología, Pontificia Universidad Católica de Chile, Santiago, Chile
    For correspondence
    akalergis@bio.puc.cl
    Competing interests
    Alexis M Kalergis, acts as the General Director of clinical trials PedCoronaVac03CL clinical study (ClinicalTrials.gov NCT04992260) and CoronaVac03CL (ClinicalTrials.govNCT04651790). The author has received funding from Agencia Nacional de Investigación y Desarrollo (ANID) - Millennium Science Initiative Program - ICN09_016 / ICN 2021_045: Millennium Institute on Immunology and Immunotherapy (ICN09_016 / ICN 2021_045; former P09/016-F) and Agencia Nacional de Investigación y Desarrollo [FONDECYT grant numbers 1190830. The author has no other competing interests to declare.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-7622-5263

Funding

Ministry of Health, Government of Chile (N/A)

  • Alexis M Kalergis

The Confederation of Production and Commerce, Chile (N/A)

  • Alexis M Kalergis

The Millenium Institute in Immunology and Immunotherapy (ICN09_016)

  • Pablo A González
  • Susan M Bueno
  • Alexis M Kalergis

The Innovation fund for competitiveness FIC-R 2017 (30488811-0)

  • Pablo A González
  • Susan M Bueno
  • Alexis M Kalergis

FONDECYT Grant (1190156)

  • Ricardo Soto-Rifo

FONDECYT Grant (1180798)

  • Fernando Valiente-Echeverria

NIH NIAID Contract (75N93021C00016)

  • Alessandro Sette

NIH NIAID Contract (75N9301900065)

  • Daniela Weiskopf
  • Alessandro Sette

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Human subjects: This clinical trial (clinicaltrials.gov NCT04651790) is a randomized and controlled study held in Chile with eight different sites. The study protocol adhered to the current Tripartite Guidelines for Good Clinical Practices, the Declaration of Helsinki, and local regulations and was approved by the Institutional Scientific Ethical Committee of Health Sciences of the Pontificia Universidad Católica de Chile, (#200708006). The execution was approved by the Chilean Public Health Institute (#24204/20).

Reviewing Editor

  1. Jameel Iqbal, DaVita Labs, United States

Publication history

  1. Received: June 29, 2022
  2. Preprint posted: August 8, 2022 (view preprint)
  3. Accepted: October 9, 2022
  4. Accepted Manuscript published: October 13, 2022 (version 1)
  5. Version of Record published: October 25, 2022 (version 2)

Copyright

© 2022, Gálvez et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Nicolas M S Gálvez
  2. Gaspar A Pacheco
  3. Barbara M Schultz
  4. Felipe Melo-González
  5. Jorge A Soto
  6. Luisa F Duarte
  7. Liliana A Gonzalez
  8. Daniela S Rivera
  9. Mariana Ríos
  10. Roslye V Berrios
  11. Yaneisi Vázquez
  12. Daniela Moreno-Tapia
  13. Omar P Vallejos
  14. Catalina A Andrade
  15. Guillermo Hoppe-Elsholz
  16. Carolina Iturriaga
  17. Marcela Urzua
  18. María S Navarrete
  19. Álvaro Rojas
  20. Rodrigo Fasce
  21. Jorge Fernández
  22. Judith Mora
  23. Eugenio Ramirez
  24. Aracelly Gaete-Argel
  25. Mónica Acevedo
  26. Fernando Valiente-Echeverria
  27. Ricardo Soto-Rifo
  28. Daniela Weiskopf
  29. Alba Grifoni
  30. Alessandro Sette
  31. Gang Zeng
  32. Weining Meng
  33. José V Gonzalez-Aramundiz
  34. Marina Johnson
  35. David Goldblatt
  36. Pablo A González
  37. Katia Abarca
  38. Susan M Bueno
  39. Alexis M Kalergis
(2022)
Differences in the immune response elicited by two immunization schedules with an inactivated SARS-CoV-2 vaccine in a randomized phase 3 clinical trial
eLife 11:e81477.
https://doi.org/10.7554/eLife.81477
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