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

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


The SARS-CoV-2 pandemic sparked a breakthrough in vaccine development, resulting in the screening and approval of a range of global vaccine platforms that have demonstrated great promise in containing the pandemic. However, declining immunity and the appearance of SARS-CoV-2 variants of concern (VOCs) associated with an increase in breakthrough infections in vaccinees have begun to emphasize opportunities to enhance vaccine platforms and administration.

The lowered risk of breakthrough infections and diseases in those SARS-CoV-2-infected and vaccinated, also known as hybrid immunity, has been underlined by real-world CoV disease 2019 (COVID-19) vaccine effectiveness. The hybrid immunity suggests the possibility for a more robust or unique immunity prepped by the infection and might provide better protection from COVID-19. It is possible to characterize the immunologic correlates of COVID-19 protection to direct judicious booster vaccinating and next-generation vaccine development against newly developing viral VOCs by identifying platform-specific immune programming variations and how these may be modified through hybrid immunity.

About the study

The current study aimed to determine whether hybrid immunity might influence the functional humoral immune response to SARS-CoV-2 other than enhanced T cell immunity and neutralizing antibodies following 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 COVID-19 history with a complete vaccination status using any of the four existing SARS-CoV-2 vaccines. Subjects got either two doses of BNT162b2 (Pfizer) or mRNA-1273 (Moderna) mRNA vaccines, one dose of human adenovirus type 26 (Ad26)-vectored Ad26.COV2.S (Janssen) vaccine, or two shots of the ChAdOx-vectored vaccine AZ1222 (AstraZeneca). Blood samples were collected at the peak immunogenicity timestamps specified for each vaccine for averages of eight, eight, 34, and seven days following the final dose of Pfizer, Moderna, Janssen, and AstraZeneca vaccines, respectively.

Results and conclusions

The study results indicated that each COVID-19 vaccination under examination displayed distinct functional humoral immune characteristics in the context of hybrid or naive immunity. The different inflammatory signals elicited at the moment of vaccination were linked probably to the peculiar antibody functional profile produced by each vaccine. The distinct antibody functional profile directs specific class switch recombination and fragment crystallizable (Fc)-glycosylation patterns in helper T cell and B cell reactions. They collectively mold the overall Fc receptor (FcR) attachment and effector characteristics of vaccine-triggered polyclonal colonies of antibodies.

The authors found that hybrid immunity also influences antibody effector activities, with drastic enhancements in antibody reaction and FcR attachment following a single vectored vaccine dose and a tendency towards an added expansion of concentrations and function after the second AZD1222 dose. IgA and IgG titers for SARS-CoV-2 spike (S) subunit 2 (S2)-specific mRNA vaccines significantly increased as a result of hybrid immunity, indicating a preferential increase of immunity to the conserved region of the S antigen, with only patterns in IgG1 titer and rises upon the second dose of mRNA. In contrast, ADNP elevated markedly following the initial and second doses of mRNA vaccinations in those with hybrid immunity.

Furthermore, after considering demographics, S2-specific FcR attachment was preferentially enhanced within mRNA vaccinees having hybrid immunity. Indeed, the AZD1222 vaccinees also exhibited this trait. The structural sustainability of the S2-domain and the cross-reactivity and neutralization capacity of the S2 antibodies may lessen the impact of sequence-altering mutations. As a result, they might increase the effectiveness of vaccines against seasonal common cold CoVs and newly arising 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 substantially variable in viral evolution. The present research further points out the significance of natural infection in overcoming the S1 immunodominance and triggering immunity to the S2 areas of the SARS-CoV-2 S2 domain, more conserved among the VOCs.

*Important notice

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

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