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Comparative Study
. 2023 Feb 8;76(3):e439-e449.
doi: 10.1093/cid/ciac392.

Understanding "Hybrid Immunity": Comparison and Predictors of Humoral Immune Responses to Severe Acute Respiratory Syndrome Coronavirus 2 Infection (SARS-CoV-2) and Coronavirus Disease 2019 (COVID-19) Vaccines

Nusrat J Epsi  1   2 , Stephanie A Richard  1   2 , David A Lindholm  3   4 , Katrin Mende  1   2   3 , Anuradha Ganesan  1   2   5 , Nikhil Huprikar  5 , Tahaniyat Lalani  1   2   6 , Anthony C Fries  7 , Ryan C Maves  8 , Rhonda E Colombo  1   2   4   9 , Derek T Larson  10   11 , Alfred Smith  6 , Sharon W Chi  1   2   4 , Carlos J Maldonado  12 , Evan C Ewers  10 , Milissa U Jones  13 , Catherine M Berjohn  4   11 , Daniel H Libraty  1   2   11 , Margaret Sanchez Edwards  1   2 , Caroline English  1   2 , Julia S Rozman  1   2 , Rupal M Mody  14 , Christopher J Colombo  4   9 , Emily C Samuels  15 , Princess Nwachukwu  15 , Marana S Tso  15 , Ann I Scher  16 , Celia Byrne  16 , Jennifer Rusiecki  16 , Mark P Simons  1 , David Tribble  1 , Christopher C Broder  15 , Brian K Agan  1   2 , Timothy H Burgess  1 , Eric D Laing  15 , Simon D Pollett  1   2 ; Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential COVID-19 Cohort Study Group
Collaborators, Affiliations
Comparative Study

Understanding "Hybrid Immunity": Comparison and Predictors of Humoral Immune Responses to Severe Acute Respiratory Syndrome Coronavirus 2 Infection (SARS-CoV-2) and Coronavirus Disease 2019 (COVID-19) Vaccines

Nusrat J Epsi et al. Clin Infect Dis. .

Abstract

Background: Comparison of humoral responses in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccinees, those with SARS-CoV-2 infection, or combinations of vaccine/ infection ("hybrid immunity") may clarify predictors of vaccine immunogenicity.

Methods: We studied 2660 US Military Health System beneficiaries with a history of SARS-CoV-2 infection-alone (n = 705), vaccination-alone (n = 932), vaccine-after-infection (n = 869), and vaccine-breakthrough-infection (n = 154). Peak anti-spike-immunoglobulin G (IgG) responses through 183 days were compared, with adjustment for vaccine product, demography, and comorbidities. We excluded those with evidence of clinical or subclinical SARS-CoV-2 reinfection from all groups.

Results: Multivariable regression results indicated that vaccine-after-infection anti-spike-IgG responses were higher than infection-alone (P < .01), regardless of prior infection severity. An increased time between infection and vaccination was associated with greater post-vaccination IgG response (P < .01). Vaccination-alone elicited a greater IgG response but more rapid waning of IgG (P < .01) compared with infection-alone (P < .01). BNT162b2 and mRNA-1273 vaccine-receipt was associated with greater IgG responses compared with JNJ-78436735 vaccine-receipt (P < .01), regardless of infection history. Those with vaccine-after-infection or vaccine-breakthrough-infection had a more durable anti-spike-IgG response compared to infection-alone (P < .01).

Conclusions: Vaccine-receipt elicited higher anti-spike-IgG responses than infection-alone, although IgG levels waned faster in those vaccinated (compared to infection-alone). Vaccine-after-infection elicits a greater humoral response compared with vaccine or infection alone; and the timing, but not disease severity, of prior infection predicted these post-vaccination IgG responses. While differences between groups were small in magnitude, these results offer insights into vaccine immunogenicity variations that may help inform vaccination timing strategies.

Keywords: IgG; SARS-CoV-2; antibody response; vaccine; vaccine breakthrough.

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Conflict of interest statement

Conflicts of interest. S. D. P., T. H. B., D. T., and M. P. S. report that the Uniformed Services University (USU) IDCRP, a US Department of Defense institution, and the Henry M. Jackson Foundation were funded under a cooperative research and development agreement to conduct an unrelated phase 3 COVID-19 monoclonal antibody immunoprophylaxis trial sponsored by AstraZeneca. The Henry M. Jackson Foundation, in support of the USU IDCRP, was funded by the Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense to augment the conduct of an unrelated phase 3 vaccine trial sponsored by AstraZeneca. Both of these trials were part of the US government COVID-19 response. Neither is related to the work presented here. C. M. B. reports a leadership or fiduciary role on the Infectious Diseases Society of America Clinical Affairs Committee. R. C. M. reports grants or contracts to his institution and unrelated to this work from AiCuris, Sound Pharmaceutical, and AstraZeneca; consulting fees and honorarium for advisory panel membership from the Society of Critical Care Medicine; honorarium for a lecture from the California Thoracic Society; travel support from the American Thoracic Society, American College of Chest Physicians, and Society of Critical Care Medicine; a US patent for investigational dengue vaccine candidate (no payments made or current commercial development planned); data and safety monitoring board membership (funds to author) for Trauma Insights, LLC; member of The Society of Critical Care Medicine (SCCM) Congress Program Committee (travel support for official meetings [pre-March 2020]), chair of the American College of Chest Physicians (CHEST) COVID-19 Task Force and Disaster/Global Health Section (travel support for official meetings), and member of the CHEST Scientific Program Committee (travel support for official meetings). All remaining authors: No reported conflicts of interest. 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.
Peak anti-spike–IgG MFI by sampling time (sampling time defined as time since vaccination or infection, whatever is latest). The y-axis depicts anti-spike–IgG MFI values, and the x-axis depicts sampling time (days). Each data point represents a single participant with a single peak humoral response. The locally estimated scatterplot smoothing (LOESS) curves were fit to SARS-CoV-2 infection alone (those who tested SARS-CoV-2–positive and did not receive any subsequent vaccination) (A), vaccination alone without a known history of SARS-CoV-2 infection (B), vaccine after infection (those who tested SARS-CoV-2–positive and then received a complete series of vaccination) (C), and vaccine breakthrough infection (those who were infected by SARS-CoV-2 after complete doses of vaccination) (D). These curves report moving averages but are not adjusted rates of decay; 95% confidence intervals are shaded in pink. Orange dots depict pre-vaccination samples, and green data points depict sampling greater than 2 weeks after complete vaccination. Abbreviations: IgG, immunoglobulin G; MFI, median fluorescence intensity; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Figure 2.
Figure 2.
Unadjusted comparison of peak observed anti-spike–IgG MFI by category of infection and/or vaccination. P value determined using the Mann-Whitney U test. These comparisons do not adjust for sampling time, which varies by group. Box plots denote median, first quartile (25th percentile), and third quartile (75th percentile) of anti-spike–IgG MFI levels (y-axis) and each group (x-axis) representing SARS-CoV-2 infection alone (yellow), vaccination alone (blue), vaccine after infection (light green), and vaccine breakthrough infection (coral). SARS-CoV-2 infection alone and vaccination alone did not portray any statistically significant difference, but vaccination after vaccine-breakthrough SARS-CoV-2 infection shows greater humoral response compared with infection alone or vaccination alone. Abbreviations: IgG, immunoglobulin G; MFI, median fluorescence intensity; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
Figure 3.
Figure 3.
Anti-spike–IgG MFI by sampling time (time since vaccination or infection, whatever is latest), restricted to longitudinal analysis using at least 2 sera samples per participant, stratified by SARS-CoV-2 infection alone (yellow), vaccination alone (blue), vaccine after infection (light green), and vaccine breakthrough infection (coral). The y-axis depicts anti-spike–IgG MFI values, and the x-axis depicts sampling time. Each data point represents a sera sample. The solid line is the estimated slope derived from mixed-effects regression models in Table 5; shaded area depicts confidence interval. Abbreviations: IgG, immunoglobulin G; MFI, median fluorescence intensity; SARS-CoV-2, severe acute respiratory syndrome coronavirus 2.
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