Hybrid immunity from severe acute respiratory syndrome coronavirus 2 infection and vaccination in Canadian adults: A cohort study
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Curated by eLife
eLife assessment
This study assessed antibody levels, which are indicative of protection, resulting from both COVID-19 vaccination and natural infection in a representative sample of the Canadian population. The work provides solid evidence that Individuals who received a booster vaccination and had a prior infection had the highest antibody levels, particularly when either the vaccination or natural infection had occurred within the past six months. These findings are of fundamental importance in supporting the value of booster vaccination in populations vulnerable to severe COVID-19.
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Abstract
Few national-level studies have evaluated the impact of ‘hybrid’ immunity (vaccination coupled with recovery from infection) from the Omicron variants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).
Methods:
From May 2020 to December 2022, we conducted serial assessments (each of ~4000–9000 adults) examining SARS-CoV-2 antibodies within a mostly representative Canadian cohort drawn from a national online polling platform. Adults, most of whom were vaccinated, reported viral test-confirmed infections and mailed self-collected dried blood spots (DBSs) to a central lab. Samples underwent highly sensitive and specific antibody assays to spike and nucleocapsid protein antigens, the latter triggered only by infection. We estimated cumulative SARS-CoV-2 incidence prior to the Omicron period and during the BA.1/1.1 and BA.2/5 waves. We assessed changes in antibody levels and in age-specific active immunity levels.
Results:
Spike levels were higher in infected than in uninfected adults, regardless of vaccination doses. Among adults vaccinated at least thrice and infected more than 6 months earlier, spike levels fell notably and continuously for the 9-month post-vaccination. In contrast, among adults infected within 6 months, spike levels declined gradually. Declines were similar by sex, age group, and ethnicity. Recent vaccination attenuated declines in spike levels from older infections. In a convenience sample, spike antibody and cellular responses were correlated. Near the end of 2022, about 35% of adults above age 60 had their last vaccine dose more than 6 months ago, and about 25% remained uninfected. The cumulative incidence of SARS-CoV-2 infection rose from 13% (95% confidence interval 11–14%) before omicron to 78% (76–80%) by December 2022, equating to 25 million infected adults cumulatively. However, the coronavirus disease 2019 (COVID-19) weekly death rate during the BA.2/5 waves was less than half of that during the BA.1/1.1 wave, implying a protective role for hybrid immunity.
Conclusions:
Strategies to maintain population-level hybrid immunity require up-to-date vaccination coverage, including among those recovering from infection. Population-based, self-collected DBSs are a practicable biological surveillance platform.
Funding:
Funding was provided by the COVID-19 Immunity Task Force, Canadian Institutes of Health Research, Pfizer Global Medical Grants, and St. Michael’s Hospital Foundation. PJ and ACG are funded by the Canada Research Chairs Program.
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eLife assessment
This study assessed antibody levels, which are indicative of protection, resulting from both COVID-19 vaccination and natural infection in a representative sample of the Canadian population. The work provides solid evidence that Individuals who received a booster vaccination and had a prior infection had the highest antibody levels, particularly when either the vaccination or natural infection had occurred within the past six months. These findings are of fundamental importance in supporting the value of booster vaccination in populations vulnerable to severe COVID-19.
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Reviewer #1 (Public Review):
This study holds significant importance as it assessed antibody levels arising from both COVID-19 vaccination and natural infection in a representative population-based sample. The analysis was conducted with thoughtfulness and rigor. The sampling methodology ensured the representation of the broader Canadian population, including minorities and indigenous communities. Findings suggest, that despite a substantial number of individuals having been previously infected, especially following the first omicron wave, repeat booster vaccination is essential to ensure that individuals develop an optimal antibody response against new exposures to infection, given the waning of antibodies over time. The study findings carry global significance as it informs decisions about the relevance of booster vaccination for …
Reviewer #1 (Public Review):
This study holds significant importance as it assessed antibody levels arising from both COVID-19 vaccination and natural infection in a representative population-based sample. The analysis was conducted with thoughtfulness and rigor. The sampling methodology ensured the representation of the broader Canadian population, including minorities and indigenous communities. Findings suggest, that despite a substantial number of individuals having been previously infected, especially following the first omicron wave, repeat booster vaccination is essential to ensure that individuals develop an optimal antibody response against new exposures to infection, given the waning of antibodies over time. The study findings carry global significance as it informs decisions about the relevance of booster vaccination for reducing infection incidence amid the ongoing challenge of vaccine hesitancy and the continual emergence of new variants.
Among the weaknesses of the study, from my perspective, is the lack of explicit clarification that one objective of achieving repeat booster vaccination is to impart a robust level of protection against acquiring infections. Previous studies have demonstrated that the effectiveness of even only primary-series vaccination against COVID-19 severe disease was high, with slow waning over time. However, even when effectiveness against severity is high, infections may still present a risk for progression to severe COVID-19 among older individuals and those with comorbidities. Another limitation is that the study did not investigate whether there were variations in spike levels based on the last vaccine type administered. Furthermore, it is important to comment on the generalizability of the findings considering that individuals who participated in the research may have been different from those who did not participate and therefore residual confounding cannot be eliminated.
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Reviewer #2 (Public Review):
Strengths
(1) The study benefits from a Large sample size, encompassing serial assessments of 4000-9000 adults over an extended period. This large cohort enhances the reliability and generalizability of the findings.
(2) The study employs a rigorous methodology, including serial assessments, self-collected dried blood spots, and highly sensitive antibody assays. The use of multiple measures ensures a robust evaluation of hybrid immunity and SARS-CoV-2 incidence within the Canadian population.
(3) The manuscript provides detailed analyses of antibody levels, vaccination history, infection rates, and demographic factors. The inclusion of stratified analyses by age, sex, and ethnicity enhances the understanding of population-level immunity dynamics.
(4) The study's findings contribute valuable insights into the …Reviewer #2 (Public Review):
Strengths
(1) The study benefits from a Large sample size, encompassing serial assessments of 4000-9000 adults over an extended period. This large cohort enhances the reliability and generalizability of the findings.
(2) The study employs a rigorous methodology, including serial assessments, self-collected dried blood spots, and highly sensitive antibody assays. The use of multiple measures ensures a robust evaluation of hybrid immunity and SARS-CoV-2 incidence within the Canadian population.
(3) The manuscript provides detailed analyses of antibody levels, vaccination history, infection rates, and demographic factors. The inclusion of stratified analyses by age, sex, and ethnicity enhances the understanding of population-level immunity dynamics.
(4) The study's findings contribute valuable insights into the dynamics of hybrid immunity and SARS-CoV-2 incidence, particularly during the emergence of the Omicron variant. The observed decline in COVID-19 death rates amidst rising infection rates underscores the potential protective role of hybrid immunity against severe outcomes.Weaknesses
(1) Sampling Limitations: While the study claims to be representative of the Canadian population, there are potential limitations in sampling methods, particularly reliance on an online polling platform. This approach may introduce selection bias and limit the generalizability of findings to certain demographic groups.
(2) Assay Limitations: The study acknowledges limitations associated with antibody assays and the potential for assay saturation, the reliance on self-reported vaccination history and infection status may introduce recall bias and affect the accuracy of estimates.
(3) Data Interpretation: While the study presents compelling data on hybrid immunity and SARS-CoV-2 incidence, some interpretations may be speculative. The assertion of a causal relationship between hybrid immunity and reduced COVID-19 mortality warrants cautious interpretation, given the complexity of factors influencing disease outcomes.
(4) Lack of inclusion and exclusion criteria: The manuscript does not have specific inclusion and exclusion criteria for participants and the methods used for data analysis.
(5) The protocol does not include disaggregated data, this is only available on page 25 as an annex. -
