How does hybrid immunity shape the humoral immune response to SARS-CoV-2?

In a recent study posted to the medRxiv* preprint server, researchers illustrated that hybrid immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) broadens the effective humoral signatures of SARS-CoV-2 vaccinations.

Study: Hybrid immunity increases the functional humoral footprint of both mRNA- and vector-based SARS-CoV-2 vaccines. ​​​​​​​Image Credit: vitstudio/Shutterstock


The SARS-CoV-2 pandemic provided a breakthrough in vaccine development, resulting in the screening and approval of a series of global vaccine platforms that have shown promise in containing the pandemic. However, the waning immunity and emergence of SARS-CoV-2 variants of care (VOCs) associated with an increase in breakthrough infections in vaccinees are beginning to focus on opportunities to improve vaccine platforms and administration.

The reduced risk of breakthrough infections and disease in those infected and vaccinated with SARS-CoV-2, also known as hybrid immunity, has been underlined by the effectiveness of the true CoV disease 2019 (COVID-19) vaccine. The hybrid immunity suggests the possibility for a more robust or unique immunity primed by the infection and potentially offering better protection against COVID-19. It is possible to characterize the immunological correlates of COVID-19 protection to guide judicious booster vaccination and next-generation vaccine development against newly evolved viral VOCs by identifying platform-specific variations in immune programming and how these can be modified by hybrid immunity .

About the study

The present study aimed to determine whether hybrid immunity could affect the functional humoral immune response to SARS-CoV-2, unlike enhanced T-cell immunity and neutralizing antibodies after vaccination with Moderna mRNA1273 and Pfizer/BNT162b2 messenger ribonucleic acid (mRNA) based ChadOx1. /AZ1222 and Ad26.COV2.S vector-based COVID-19 vaccines.

The team examined serum samples from individuals with and without a COVID-19 history with full vaccination status using one of four existing SARS-CoV-2 vaccines. Subjects received either two doses of BNT162b2 (Pfizer) or mRNA-1273 (Moderna) mRNA vaccines, one dose of human adenovirus type 26 (Ad26) vectorized Ad26.COV2.S (Janssen) vaccine, or two shots of the ChAdOx vaccine. vectorized vaccine AZ1222 (AstraZeneca). Blood samples were collected at the maximum immunogenicity time-stamps specified for each vaccine for an average of eight, eight, 34 and seven days after the last dose of the Pfizer, Moderna, Janssen and AstraZeneca vaccines, respectively.

Results and conclusions

The study results indicated that each COVID-19 vaccination examined showed different functional humoral immune characteristics in the context of hybrid or naive immunity. The different inflammatory signals elicited at the time of vaccination were likely linked to the peculiar functional antibody profile produced by each vaccine. The distinctive functional profile of the antibody directs specific recombination of class switches and fragment crystallizable (Fc) glycosylation patterns in helper T cell and B cell responses. Together they form the general Fc receptor (FcR) attachment and effector features of vaccine-induced polyclonal antibody colonies.

The authors found that hybrid immunity also affects antibody effector activities, with drastic improvements in antibody response and FcR attachment after a single vectorized vaccine dose and a tendency for an additional increase in concentrations and function after the second dose of AZD1222. IgA and IgG titers for SARS-CoV-2 spike (S) subunit 2 (S2)-specific mRNA vaccines increased significantly as a result of hybrid immunity, indicating a preferential increase in immunity against the conserved region of the S antigen, with only patterns in IgG1 titer and increases with the second dose of mRNA. In contrast, ADNP increased significantly after the initial and second dose of mRNA vaccinations in people with hybrid immunity.

Moreover, after considering demographics, S2-specific FcR attachment was preferentially enhanced within mRNA vaccinees with hybrid immunity. Indeed, the AZD1222 vaccinees also exhibited this property. The structural durability of the S2 domain and the cross-reactivity and neutralization capacity of the S2 antibodies may reduce the impact of sequence-altering mutations. As a result, they may increase the effectiveness of vaccines against seasonal colds CoVs and newly emerging VOCs.

Overall, the study data emphasize the immunodominant impact of the S1 domain in the context of natural SARS-CoV-2 immunity. SARS-CoV-2 S1 domain was significantly variable in viral evolution. The current study further points to the importance of natural infection in overcoming the S1 immunodominance and in raising immunity against the S2 regions of the SARS-CoV-2 S2 domain, which is more conserved among the VOCs.

*Important announcement

medRxiv publishes preliminary scientific reports that have not been peer-reviewed and therefore should not be considered conclusive, that should guide clinical practice/health-related behavior or be treated as established information.

Reference magazine:

  • Hybrid immunity increases the functional humoral footprint of both mRNA- and vector-based SARS-CoV-2 vaccines; Paulina Kaplonek, Yixiang Deng, Jessica Shih-Lu Lee, Heather Zar, Dace Zavadska, Marina Johnson, Douglas A Lauffenburger, David Goldblatt, Galit Alter. medRxiv preprint 2022, DOI:,

Leave a Comment