Study: Anamnestic Humoral Correlates of Immunity Across SARS-CoV-2 Variants of Concern. Image Credit: Corona Borealis Studio / Shutterstock

Correlates of anamnestic humoral immunity in SARS-CoV-2 variants of care

A recent work posted on the bioRxiv* preprint server assessed the indicators of anamnestic humoral immunity in the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of care (VOCs).

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

Background

The decline of vaccine-provided immunity and the induction of neutralizing antibody-resistant SARS-CoV-2 VOCs, such as the B.1.612 (Delta) and B.1.529 (Omicron), resulted in a rapid increase in the transmission of 2019 CoV disease (COVID-19) worldwide, regardless of the impressive vaccine effectiveness seen in phase III SARS-CoV-2 vaccine experiments. However, the incidence of serious illness and mortality did not increase simultaneously, indicating that other post-transmission inhibitory immune responses help clear and control COVID-19 once it has occurred.

Immune correlates may play a mechanical role in protective immunity. However, they can also indicate replacements for other immunological systems that are essential for the control of pathogens. Immune correlates to SARS-CoV-2 are usually determined at maximal immunogenicity after vaccination. Nevertheless, immune responses that specifically increase during the anamnestic response after infection can provide extensive and mechanistic details regarding the immune pathways of protection. Furthermore, it is unknown whether anamnestic correlates are shared by the SARS-CoV-2 VOCs, such as the Delta and more distant Omicron VOCs.

About the study

In the present study, the researchers thoroughly evaluated the humoral immune response in COVID-19 vaccinated people who had recently acquired Omicron or Delta-VOC infections to characterize the anamnestic markers of immunity among SARS-CoV-2 VOCs.

There is a significant association between non-neutralizing antibody effector patterns and the natural resolution of severe COVID-19. In light of this connection, the team performed systems serology on the sera of 37 and 23 subjects who had completed their SARS-CoV-2 vaccination series and had a registered breakthrough infection of the Delta or Omicron VOCs, respectively, for one week and two, respectively. up to three weeks after infection. They sought to identify the specific humoral properties associated with resolving infection.

Furthermore, the authors assessed the multiple-fold increase in the concentrations of immunoglobulin G1 (IgG1) in subdomains of the SARS-CoV-2 spike (S) protein, VOCs and common human CoVs (HCoVs). This was to compare the degree of anamnestic expansion between S domains during the breakthrough instances. They used partial least squares discriminant analysis (PLS-DA) of 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 individuals.

Breakthrough cases were distributed among people who received one of the two COVID-19 messenger ribonucleic acid (mRNA) vaccinations (mRNA-1273 (Moderna) or BNT162b2 (Pfizer)). This was to see if they produced an identical anamnestic response. In addition, the team mapped the increasing breakthrough response to infection between peptides expressing the S. cover antigen‘s S2 domain to determine whether S2-specific responses targeted different regions of S2.

Results

The study results indicated that after the Omicron and Delta breakthrough infections, a limited transient SARS-CoV-2 N-terminal domain (NTD) and receptor binding domain (RBD) specific immune enhancement was seen. On the contrary, one week after breakthrough infection, opsonophagocytic S-specific antibody responses showed a marked immunodominant expansion, mainly targeting the conserved SARS-CoV-2 S2 domain.

​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​ (A) Fold changes in IgG1 binding of the subdomains of Spike (NTD in black, RBD in blue, and S2 in red) for vaccinated Delta breakthrough cases < 1 week or 2-3 weeks after breakthrough.  (B) Same as A, but for vaccinated Omicron breakthrough cases.  (C) Fold Changes in IgG1 Binding of the Whole Spikes of VoC in Delta Breakthrough Cases.  (D) Same as C, but for Omicron breakthrough cases.  (E) Fold changes in IgG1 binding from the peak of common CoV peaks in Delta breakthrough infections at < 1 week or 2-3 weeks after breakthrough.  SARS-CoV-2 nucleocapsid (N) is used as a control for infection.  (F) Same as C, but for Omicron breakthroughs.  * = p < 0.05 and ** = p < 0,01 voor alle panelen.Preserved areas of Spike are selectively expanded in breakthrough cases. (A) Fold changes in IgG1 binding of the subdomains of Spike (NTD in black, RBD in blue, and S2 in red) for vaccinated Delta breakthrough cases < 1 week or 2-3 weeks after breakthrough. (B) Same as A, but for vaccinated Omicron breakthrough cases. (C) Fold Changes in IgG1 Binding of the Whole Spikes of VoC in Delta Breakthrough Cases. (D) Same as C, but for Omicron breakthrough cases. (E) Fold changes in IgG1 binding from the peak of common CoV peaks in Delta breakthrough infections at < 1 week or 2-3 weeks after breakthrough. SARS-CoV-2 nucleocapsid (N) is used as a control for infection. (F) Same as C, but for Omicron breakthroughs. * = p < 0.05 and ** = p < 0.01 for all panels.

This S2-specific functional humoral response, which primarily targets common CoVs and numerous SARS-CoV-2 VOCs, continued to develop for two to three weeks after both Omicron and Delta breakthrough infections. These responses drastically targeted the fusion peptide 2 (FP2) and heptad repeat 1 (HR1), and both FP2 and HR1 were linked to faster viral clearance rates.

A marked anamnestic rise in early S2 FP2- and HR1-specific IgM antibodies utilizing monocyte phagocytosis was responsible for most of the S-specific expansion. Furthermore, in both Omicron and Delta breakthrough infections, a more mature S2 HR1- and FP2-specific IgG fraction-crystallizable receptor (FcR) confirming the recruitment response of neutrophils was observed. These data suggested an unexpected and crucial role for S2-specific functional humoral immunity as important anamnestic markers of immunity in SARS-CoV-2 VOCs. This inference was inconsistent with the immunodominant vaccine-induced response to the RBD.

The authors noted discrepancies in the anamnestic reflex after vaccination with Pfizer and Moderna. They found an increased progress in anamnestic immunity in Pfizer vaccinees and a functional increase in Moderna vaccines. Nevertheless, both breakthrough traits led to an extension of immunity specific to the S2 domain.

The variations in vaccination data may be related to the differences in actual efficacy between the vaccine platforms. Indeed, the Moderna vaccinees showed reduced breakthrough infections, possibly linked to the increased functional humoral immunity and IgA concentrations, likely conferring a remarkably robust defense against SARS-CoV-2 infection at the mucosal barrier. Nevertheless, the increase in S2-specific immunity after both vaccinations targeting HR1 and FP2 may be related to their accessible sites on the S protein.

conclusions

The present study evaluated the post-COVID-19 immunological patterns emerging in breakthrough infections, with a specific focus on determining whether the kinetics of breakthrough markers of immunity were constant among the SARS-CoV-2 VOCs. The study results showed a rapid expansion of FcR attachment and opsonophagocytic humoral immune responses in the Omicron and Delta VOC breakthrough cases, with a coherent priority for the expansion of the S protein S2 subdomain centered on the FP2 and HR1, which followed with augmented SARS-coV-2 clearance.

Taken together, the present study indicates that the control of SARS-CoV-2 infection among VOCs was highly dependent on highly conserved, effective S2-specific responses. The current work suggests that humoral response associated with viral attenuation could drive next-generation COVID-19 vaccine amplification techniques to provide comprehensive protection against future SARS-CoV-2 VOCs.

*Important announcement

bioRxiv 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.

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