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
Authors: Epsi Nusrat J , Richard Stephanie A , Lindholm David A , Mende Katrin , Ganesan Anuradha , Huprikar Nikhil , Lalani Tahaniyat , Fries Anthony C , Maves Ryan C , Colombo Rhonda E , Larson Derek T , Smith Alfred , Chi Sharon W , Maldonado Carlos J , Ewers Evan C , Jones Milissa U , Berjohn Catherine M , Libraty Daniel H , Edwards Margaret Sanchez , English Caroline , Rozman Julia S , Mody Rupal M , Colombo Christopher J , Samuels Emily C , Nwachukwu Princess , Tso Marana S , Scher Ann I , Byrne Celia , Rusiecki Jennifer , Simons Mark P , Tribble David , Broder Christopher C , Agan Brian K , Burgess Timothy H , Laing Eric D , Pollett Simon D ,   for the Epidemiology, Immunology, and Clinical Characteristics of Emerging Infectious Diseases with Pandemic Potential COVID-19 Cohort Study Group, Cowden J , Darling M , DeLeon S , Lindholm D , Markelz A , Mende K , Merritt S , Merritt T , Turner N , Wellington T , Bazan S , Love P K , Dimascio-Johnson N , Ewers E , Gallagher K , Larson D , Rutt A , Blair P , Chenoweth J , Clark D , Chambers S , Colombo C , Colombo R , Conlon C , Everson K , Faestel P , Ferguson T , Gordon L , Grogan S , Lis S , Mount C , Musfeldt D , Odineal D , Perreault M , Robb-McGrath W , Sainato R , Schofield C , Skinner C , Stein M , Switzer M , Timlin M , Wood S , Banks S , Carpenter R , Kim L , Kronmann K , Lalani T , Lee T , Smith A , Smith R , Tant R , Warkentien T , Berjohn C , Cammarata S , Kirkland N , Libraty D , Maves R , Utz G , Chi S , Flanagan R , Jones M , Lucas C , Madar C , Miyasato K , Uyehara C , Agan B , Andronescu L , Austin A , Broder C , Burgess T , Byrne C , Chung K , Davies J , English C , Epsi N , Fox C , Fritschlanski M , Grother M , Hadley A , Hickey P , Laing E , Lanteri C , Livezey J , Malloy A , Mohammed R , Morales C , Nwachukwu P , Olsen C , Parmelee E , Pollett S , Richard S , Rozman J , Rusiecki J , Samuels E , Nwachukwu P , Tso M , Sanchez M , Scher A , Simons M , Snow A , Telu K , Tribble D , Ulomi L , Chao T , Chapleau R , Christian M , Fries A , Harrington C , Hogan V , Huntsberger S , Lanter K , Macias E , Meyer J , Purves S , Reynolds K , Rodriguez J , Starr C , Iskander J , Kamara I , Barton B , Hostler D , Hostler J , Lago K , Maldonado C , Mehrer J , Hunter T , Mejia J , Montes J , Mody R , Resendez R , Sandoval P , Wayman M , Barahona I , Baya A , Ganesan A , Huprikar N , Johnson B , Peel S 
Published: May 2022

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 &lt; .01), regardless of prior infection severity. An increased time between infection and vaccination was associated with greater post-vaccination IgG response (P &lt; .01). Vaccination-alone elicited a greater IgG response but more rapid waning of IgG (P &lt; .01) compared with infection-alone (P &lt; .01). BNT162b2 and mRNA-1273 vaccine-receipt was associated with greater IgG responses compared with JNJ-78436735 vaccine-receipt (P &lt; .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 &lt; .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.