Differences in the immune response elicited by two immunization schedules with an inactivated SARS-CoV-2 vaccine in a randomized phase 3 clinical trial
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Curated by eLife
Evaluation Summary:
This manuscript described the effects of two different CoronaVac vaccination schedules in a Chilean adult population. They find that a 0 and 28-day two-dose schedule produced superior levels of neutralizing antibodies and antibodies with a great breadth of interaction across variants compared to a 0 and 14-day two-dose schedule. They find no differences in T cell responses or total antibody levels between the two groups. These findings demonstrate that a short two-week two-dose interval should provide sufficient immunity to reduce the likelihood of serious outcomes during a COVID infection.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Abstract
The development of vaccines to control the coronavirus disease 2019 (COVID-19) pandemic progression is a worldwide priority. CoronaVac is an inactivated severe acute respiratory syndrome coronavirus 2 (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 2 (0–14 schedule) or 4 weeks (0–28 schedule); 2302 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 (VOCs) between schedules. Stimulation of peripheral blood mononuclear cells (PBMCs) with Mega pools of Peptides (MPs) induced the secretion of interferon (IFN)-γ and the expression of activation induced markers in CD4 + T cells 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
Article activity feed
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Evaluation Summary:
This manuscript described the effects of two different CoronaVac vaccination schedules in a Chilean adult population. They find that a 0 and 28-day two-dose schedule produced superior levels of neutralizing antibodies and antibodies with a great breadth of interaction across variants compared to a 0 and 14-day two-dose schedule. They find no differences in T cell responses or total antibody levels between the two groups. These findings demonstrate that a short two-week two-dose interval should provide sufficient immunity to reduce the likelihood of serious outcomes during a COVID infection.
(This preprint has been reviewed by eLife. We include the public reviews from the reviewers here; the authors also receive private feedback with suggested changes to the manuscript. The reviewers remained anonymous to the authors.)
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Reviewer #1 (Public Review):
Overall this is a decently controlled clinical study with an investigation into both the humoral and cellular immune responses generated by a whole virus vaccine. The conclusions note that T cell immunity can likely be achieved quickly with a short-span dosing schedule but that an optimal humoral response may need longer exposure durations and likely boosters to increase breadth and neutralization capabilities. There are no overt weaknesses in the manuscript however, its applicability to the broader COVID field is limited as no comparison to mRNA-based vaccines was made.
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Reviewer #2 (Public Review):
Galvez et al., report on results from a subset of 2302 volunteers in a phase 3 trial conducted in Chile on to assess the immune responses to a 0-14-day and a 0-28-day immunization schedule for CoronaVac. This is important since a large proportion of the world's population has still not received the basic immunization against COVID-19. Broadly speaking, the manuscript is well-written, does not overstate most conclusions, and the discussion clearly indicates the shortcomings and limitations of this study. The primary conclusion is that both schedules lead to protective immune responses, and they differ only by the fact that there is a higher neutralizing antibody response against the original 2020 variant. The title is therefore somewhat misleading as it suggests greater differences between the two schedules. …
Reviewer #2 (Public Review):
Galvez et al., report on results from a subset of 2302 volunteers in a phase 3 trial conducted in Chile on to assess the immune responses to a 0-14-day and a 0-28-day immunization schedule for CoronaVac. This is important since a large proportion of the world's population has still not received the basic immunization against COVID-19. Broadly speaking, the manuscript is well-written, does not overstate most conclusions, and the discussion clearly indicates the shortcomings and limitations of this study. The primary conclusion is that both schedules lead to protective immune responses, and they differ only by the fact that there is a higher neutralizing antibody response against the original 2020 variant. The title is therefore somewhat misleading as it suggests greater differences between the two schedules. The authors also report a complex pattern of overall levels of anti-Spike and anti-Receptor Binding Domain antibodies under the two regimes. While it is clear that the levels of antibodies induced against newer variants of concern are lower, it is unclear if these differences in antibody levels lead directly to differences in neutralizing capacity between the two schedules. Although the authors have indicated that this may be addressed in a follow-up manuscript, clarity on this last point would substantially enhance the impact of this manuscript.
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Reviewer #3 (Public Review):
This paper reports the humoral (neutralizing antibody concentrations from serum) and cellular (cytopathic effect on Vero cells) immune responses of volunteers enrolled in a randomized clinical trial for the CoronaVac® SARS-CoV-2 vaccine. The findings are useful and, through solid reporting, discussion, and statistical analyses, provide context for the efficaciousness of the 0-14 day and 0-28 day dosing schedules of CoronaVac®. The results show that these two dosing schedules are similar across most metrics. Furthermore, the findings pave the way for key future work, including reporting and understanding the clinically relevant protective effects, and how long they last, of CoronaVac® against the emerging variants/subvariants.
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