Home Immunity Correlates of anamnestic humoral immunity in all SARS-CoV-2 variants of concern

Correlates of anamnestic humoral immunity in all SARS-CoV-2 variants of concern


A recent book posted on bioRxiv* The preprint server assessed indicators of anamnestic humoral immunity among variants of concern (COVs) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).

Study: Anamnestic humoral correlates of immunity across SARS-CoV-2 variants of concern. Image Credit: Corona Borealis Studio / Shutterstock


The decrease in vaccine conferred immunity and the awakening of SARS-CoV-2 VOCs resistant to neutralizing antibodies, such as B.1.612 (Delta) and B.1.529 (Omicron), led to a rapid increase of CoV disease 2019 (COVID -19) transmission events around the world, regardless of the impressive vaccine efficacy seen in SARS-CoV-2 phase III vaccine experiments. However, the incidence of severe illness and mortality did not increase simultaneously, indicating that other post-transmission inhibitory immune responses help eliminate and manage COVID-19 once it has subsided. product.

Immune correlates may have a mechanistic role in protective immunity. Yet they may also indicate surrogates for other immune systems vital for anti-pathogen control. Immune correlates to SARS-CoV-2 are usually determined at peak immunogenicity after vaccination. Nonetheless, immune responses that specifically increase during the anamnestic response after infection can offer comprehensive and mechanistic details regarding protective immune pathways. Additionally, it is unknown whether any anamnestic correlates are shared by SARS-CoV-2 COVs, such as the more distant Delta and Omicron COVs.

About the study

In the present study, researchers carefully assessed the humoral immune response in individuals vaccinated against COVID-19 who had recently acquired Omicron or Delta VOC infections to characterize anamnestic markers of immunity among SARS-CoV-COVs. 2.

A significant association exists between non-neutralizing antibody effector patterns and the natural resolution of severe COVID-19. In light of this link, the team performed systemic serology on the sera of 37 and 23 subjects who had completed their series of SARS-CoV-2 vaccinations and had a recorded breakthrough infection of VOC Delta or Omicron, respectively. , one week and two to three weeks after infection. They sought to identify particular humoral traits linked to infection resolution.

Additionally, the authors assessed the fold increase in immunoglobulin G1 (IgG1) concentrations in all spike (S) protein subdomains of SARS-CoV-2, COVs, and common human CoVs ( HCoV). This involved comparing the degree of anamnestic expansion between S domains across breakthrough instances. They used partial least squares discriminant analysis (PLS-DA) on antibody responses obtained in breakthrough cases two to three weeks after infection to determine a minimal multivariate fingerprint of Omicron or Delta breakthrough infections in vaccinated people.

Breakthrough cases were split between people who received one of two messenger ribonucleic acid (mRNA) COVID-19 vaccines (mRNA-1273 (Moderna) or BNT162b2 (Pfizer)). It was to see if they produced an identical anamnestic reaction. Additionally, the team mapped the broadening of the breakthrough infection response among peptides spanning the S2 domain of the S antigen to determine whether S2-specific responses targeted distinct areas of S2.


Study results indicated that after breakthrough infections of Omicron and Delta, limited specific immune enhancement of N-terminal domain (NTD) and receptor-binding domain (RBD) of SARS-CoV -2 was observed. On the contrary, one week after the infection breakthrough, opsonophagocyte S-specific antibody responses showed a remarkable immunodominant expansion, focusing mainly on the conserved SARS-CoV-2 S2 domain.

Conserved regions of Spike are selectively expanded in breakthrough cases.  (A) Fold changes in IgG1 binding of Spike subdomains (NTD in black, RBD in blue, and S2 in red) for Delta breakthrough cases vaccinated at <1 week or 2-3 weeks post-breakthrough.  (B) Same as A, but for vaccinated Omicron breakthrough cases.  (C) Fold changes in IgG1 binding of full-length VoC spikes in Delta breakthrough cases.  (D) Same as C, but for Omicron breakthrough cases.  (E) Fold changes in spike IgG1 binding of common CoV spikes in Delta breakthrough infections at <1 week or 2-3 weeks post-breakthrough.  The SARS-CoV-2 (N) nucleocapsid is used as an infection control.  (F) Same as C, but for Omicron breakthroughs.  * = p < 0.05, and ** = p < 0,01 pour tous les panels.Conserved regions of Spike are selectively extended in breakthrough cases. (A) Fold changes in IgG1 binding of Spike subdomains (NTD in black, RBD in blue, and S2 in red) for Delta breakthrough cases vaccinated at

This functional S2-specific humoral response, which primarily targets common CoVs and many SARS-CoV-2 COVs, continued to develop for two to three weeks after the breakthroughs of Omicron and Delta. These reactions focused drastically on fusion peptide 2 (FP2) and repeat heptad 1 (HR1), and FP2 and HR1 were linked to faster viral clearance rates.

A distinct anamnestic increase in early S2-specific IgM antibodies FP2 and HR1 exploiting monocyte phagocytosis was responsible for most of the S-specific expansion. Recruitment of neutrophils attached to the crystallizable receptor (FcR) to the S2-specific IgG fraction HR1 and more mature FP2 was observed. These data suggest an unexpected and crucial role for S2-specific functional humoral immunity as important anamnestic markers of immunity across SARS-CoV-2 COVs. This inference was contrary to the reaction elicited by the immunodominant RBD vaccine.

The authors noted deviations in the anamnestic reflex post-Pfizer and Moderna vaccination. They found a large-scale improvement in anamnestic immunity in Pfizer vaccinees and a functional increase in Moderna vaccinees. Nevertheless, both breakthrough features led to an expansion of S2 domain-specific immunity.

Variations in vaccination data could be associated with differences in actual efficacy between vaccine platforms. Indeed, Moderna vaccinees demonstrated a decrease in breakthrough infections, possibly related to elevated functional humoral immunity and IgA concentrations, likely conferring a particularly robust defense against SARS-CoV-2 infection in the level of the mucous barrier. Yet, the increase in S2-specific immunity after both vaccinations targeting HR1 and FP2 might be related to their accessible sites on protein S.


Current research assessed the post-COVID-19 immunological patterns that emerged in breakthrough infections with particular emphasis on determining whether the kinetics of breakthrough markers of immunity were consistent among SARS-CoV-2 COVs. Study results showed rapid expansion of FcR attachment and opsonophagocytic humoral immune responses in breakthrough Omicron and Delta VOC cases, with a consistent priority for expansion of the S protein S2 subdomain centered on FP2 and HR1, which followed with increased SARS. coV-2 clearance.

Taken together, the present study indicates that control of SARS-CoV-2 infection among COVs was critically dependent on highly conserved and efficient S2-specific responses. Current work implies that the humoral response linked to viral attenuation could guide next-generation COVID-19 vaccine stimulation techniques to provide broad protection against future SARS-CoV-2 COVs.

*Important Notice

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

Journal reference:

  • Anamnestic humoral correlates of immunity across SARS-CoV-2 variants of concern; Ryan McNamara, Jenny S Maron, Harry L Bertera, Julie Boucau, Vicky Roy, Amy K. Barczak, The Positive Study Staff, Nicholas Franko, Jonathan Z Li, Jason S McLellan, Mark Siedner, Jacob E Lemieux, Helen Chu, Galit Alter, bioRxiv preprint 2022, DOI: https://doi.org/10.1101/2022.06.19.496718, https://www.biorxiv.org/content/10.1101/2022.06.19.496718v1