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. 2024 Jul 19;79(1):96-107.
doi: 10.1093/cid/ciae130.

Hybrid Immunity and SARS-CoV-2 Antibodies: Results of the HEROES-RECOVER Prospective Cohort Study

James K Romine  1 , Huashi Li  1 , Melissa M Coughlin  2 , Jefferson M Jones  2 , Amadea Britton  2 , Harmony L Tyner  3 , Sammantha B Fuller  4 , Robin Bloodworth  4 , Laura J Edwards  4 , Jini N Etolue  4 , Tyler C Morrill  4 , Gabriella Newes-Adeyi  4 , Lauren E W Olsho  4 , Manjusha Gaglani  5 , Ashley Fowlkes  2 , James Hollister  1 , Edward J Bedrick  1 , Jennifer L Uhrlaub  1 , Shawn Beitel  1 , Ryan S Sprissler  6 , Zoe Lyski  7 , Cynthia J Porter  1 , Patrick Rivers  1 , Karen Lutrick  8 , Alberto J Caban-Martinez  9 , Sarang K Yoon  10 , Andrew L Phillips  10 , Allison L Naleway  11 , Jefferey L Burgess  1 , Katherine D Ellingson  1
Affiliations

Hybrid Immunity and SARS-CoV-2 Antibodies: Results of the HEROES-RECOVER Prospective Cohort Study

James K Romine et al. Clin Infect Dis. .

Abstract

Background: There are limited data on whether hybrid immunity differs by count and order of immunity-conferring events (infection with severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] or vaccination against coronavirus disease 2019 [COVID-19]). From a multi-site cohort of frontline workers, we examined the heterogeneity of the effect of hybrid immunity on SARS-CoV-2 antibody levels.

Methods: Exposures included event count and event order, categorized into 7 permutations. Outcome was level of serum antibodies against receptor-binding domain (RBD) of the ancestral SARS-CoV-2 spike protein (total RBD-binding immunoglobulin). Means were examined up to 365 days after each of the first to seventh events.

Results: Analysis included 5793 participants measured from 7 August 2020 to 15 April 2023. Hybrid immunity from infection before 1 or 2 vaccine doses elicited modestly superior antibody responses after the second and third events (compared with infections or vaccine doses alone). This superiority was not repeated after additional events. Among adults infected before vaccination, adjusted geometric mean ratios (95% confidence interval [CI]) of anti-RBD early response (versus vaccinated only) were 1.23 (1.14-1.33), 1.09 (1.03-1.14), 0.87 (.81-.94), and 0.99 (.85-1.15) after the second to fifth events, respectively. Post-vaccination infections elicited superior responses; adjusted geometric mean ratios (95% CI) of anti-RBD early response (versus vaccinated only) were 0.93 (.75-1.17), 1.11 (1.06-1.16), 1.17 (1.11-1.24), and 1.20 (1.07-1.34) after the second to fifth events, respectively.

Conclusions: Evidence of heterogeneity in antibody levels by permutations of infection and vaccination history could inform COVID-19 vaccination policy.

Keywords: COVID-19; SARS-CoV-2; antibody durability; hybrid immunity; mRNA vaccine.

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Conflict of interest statement

Potential conflicts of interest. A. L. N. reports research funding from Pfizer and Vir Biotechnology for unrelated studies. M. G. reports grants from CDC, Abt Associates, Westat, and Vanderbilt University Medical Center and participation on the Texas Pediatric Society, Texas Chapter of the American Academy of Pediatrics Infectious Diseases and Immunization Committee as co-chair. J. L. U. reports patent 16/900 798. R. S. reports consulting fees for the California legal case Ebers v. Castle Park, payment for lectures and presentations from the American Council of Life Insurers and 360 Dx/Beckman Coulter, patents 17/269 092 and 706843, and stock options for Geneticture, Inc. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.

Figures

Figure 1.
Figure 1.
Flow diagram of participant eligibility for analysis of antibody response and durability up to 365 days after ≥1 immunity-conferring event (SARS-CoV-2 infection or dose receipt of mRNA vaccination against coronavirus disease 2019). Abbreviations: ELISA, enzyme-linked immunosorbent assay; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Figure 2.
Figure 2.
Box and whisker plots showing the distribution of SARS-CoV-2 anti-RBD antibody levels (measured using ELISA AUC) 28–90 days after each of 7 immunity-conferring events (SARS-CoV-2 infection or dose receipt of mRNA vaccination against COVID-19). Abbreviations: AUC, area under the serial dilution curve; ELISA, enzyme-linked immunosorbent assay; RBD, receptor-binding domain of the ancestral SARS-CoV-2 spike protein; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Figure 3.
Figure 3.
Box and whisker plots showing the distribution of SARS-CoV-2 anti-RBD antibody levels (measured using ELISA AUC) 21–90 days after each of 5 immunity-conferring events (SARS-CoV-2 infection or dose receipt of messenger RNA vaccination against COVID-19), by order of events. Event-1 infection included infection with ancestral strain of severe acute respiratory syndrome coronavirus 2 only. Abbreviations: AUC, area under the serial dilution curve; ELISA, enzyme-linked immunosorbent assay; RBD, receptor-binding domain of the ancestral SARS-CoV-2 spike protein; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Figure 4.
Figure 4.
Multivariable-adjusted functions of anti-RBD levels (ELISA AUC) 1–365 days after each of 5 immunity-conferring events (SARS-CoV-2 infection or dose receipt of mRNA vaccination against COVID-19), by order of events. Restricted cubic splines with knots at the 5th, 25th, 50th, 75th, and 95th percentiles of interval after each event. Event-1 infection included infection with ancestral strain of SARS-CoV-2 only. The order of events notation was as follows: D1, first dose; D2, second dose; D3, third dose; D4, fourth dose; D5, fifth dose; I1, first infection; I2, second infection; I3, third infection. Empty cells reflect permutations (order of events) that, by definition, did not pertain to a respective “count of events.” For example, there was no difference between “infection only” and “event-1 infection” until after the second event. Abbreviations: AUC, area under the serial dilution curve; COVID-19, coronavirus disease 2019; ELISA, enzyme-linked immunosorbent assay; mRNA, messenger ribonucleic acid; RBD, receptor-binding domain of the ancestral SARS-CoV-2 spike protein; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
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