Differences in the immune response elicited by two immunization schedules with an inactivated SARS-CoV-2 vaccine in a randomized phase 3 clinical trial
- Pontificia Universidad Católica de Chile, Chile
- Instituto de Salud Pública de Chile, Chile
- University of Chile, Chile
- La Jolla Institute For Allergy & Immunology, United States
- University of California, San Diego, United States
- Sinovac Biotech, China
- University College London, United Kingdom
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
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.
Reviewing Editor
- Jameel Iqbal, DaVita Labs, United States
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).
Version history
- Received: June 29, 2022
- Preprint posted: August 8, 2022 (view preprint)
- Accepted: October 9, 2022
- Accepted Manuscript published: October 13, 2022 (version 1)
- 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.
Metrics
-
- 849
- views
-
- 200
- downloads
-
- 6
- citations
Views, downloads and citations are aggregated across all versions of this paper published by eLife.
Download links
A two-part list of links to download the article, or parts of the article, in various formats.
Downloads (link to download the article as PDF)
Open citations (links to open the citations from this article in various online reference manager services)
Cite this article (links to download the citations from this article in formats compatible with various reference manager tools)
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
Further reading
-
- Immunology and Inflammation
Environmental air irritants including nanosized carbon black (nCB) can drive systemic inflammation, promoting chronic obstructive pulmonary disease (COPD) and emphysema development. The let-7 microRNA (Mirlet7 miRNA) family is associated with IL-17-driven T cell inflammation, a canonical signature of lung inflammation. Recent evidence suggests the Mirlet7 family is downregulated in patients with COPD, however, whether this repression conveys a functional consequence on emphysema pathology has not been elucidated. Here, we show that overall expression of the Mirlet7 clusters, Mirlet7b/Mirlet7c2 and Mirlet7a1/Mirlet7f1/Mirlet7d, are reduced in the lungs and T cells of smokers with emphysema as well as in mice with cigarette smoke (CS)- or nCB-elicited emphysema. We demonstrate that loss of the Mirlet7b/Mirlet7c2 cluster in T cells predisposed mice to exaggerated CS- or nCB-elicited emphysema. Furthermore, ablation of the Mirlet7b/Mirlet7c2 cluster enhanced CD8+IL17a+ T cells (Tc17) formation in emphysema development in mice. Additionally, transgenic mice overexpressing Mirlet7g in T cells are resistant to Tc17 and CD4+IL17a+ T cells (Th17) development when exposed to nCB. Mechanistically, our findings reveal the master regulator of Tc17/Th17 differentiation, RAR-related orphan receptor gamma t (RORγt), as a direct target of Mirlet7 in T cells. Overall, our findings shed light on the Mirlet7/RORγt axis with Mirlet7 acting as a molecular brake in the generation of Tc17 cells and suggest a novel therapeutic approach for tempering the augmented IL-17-mediated response in emphysema.
-
- Immunology and Inflammation
SARS-CoV-2 vaccines have been used worldwide to combat COVID-19 pandemic. To elucidate the factors that determine the longevity of spike (S)-specific antibodies, we traced the characteristics of S-specific T cell clonotypes together with their epitopes and anti-S antibody titers before and after BNT162b2 vaccination over time. T cell receptor (TCR) αβ sequences and mRNA expression of the S-responded T cells were investigated using single-cell TCR- and RNA-sequencing. Highly expanded 199 TCR clonotypes upon stimulation with S peptide pools were reconstituted into a reporter T cell line for the determination of epitopes and restricting HLAs. Among them, we could determine 78 S epitopes, most of which were conserved in variants of concern (VOCs). After the 2nd vaccination, T cell clonotypes highly responsive to recall S stimulation were polarized to follicular helper T (Tfh)-like cells in donors exhibiting sustained anti-S antibody titers (designated as ‘sustainers’), but not in ‘decliners’. Even before vaccination, S-reactive CD4+ T cell clonotypes did exist, most of which cross-reacted with environmental or symbiotic microbes. However, these clonotypes contracted after vaccination. Conversely, S-reactive clonotypes dominated after vaccination were undetectable in pre-vaccinated T cell pool, suggesting that highly responding S-reactive T cells were established by vaccination from rare clonotypes. These results suggest that de novo acquisition of memory Tfh-like cells upon vaccination may contribute to the longevity of anti-S antibody titers.
