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

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.

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.

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.

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.