Prior vaccination improves immune responses during breakthrough SARS-CoV-2 infection

In a recent study published on bioRxiv* preprint server, researchers are evaluating the impact of prior vaccination against coronavirus disease 2019 (COVID-19) on immune responses during a breakthrough infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV -2).

Study: Prior vaccination enhances immune responses during SARS-CoV-2 infection with early activation of memory T cells followed by production of potent neutralizing antibodies. Image Credit: Lightspring / Shutterstock.com

How effective are COVID-19 vaccines?

At the beginning of 2021, the rate of vaccination against COVID-19 increased significantly, which had considerable changes for the trajectory of the pandemic. Nevertheless, the protection conferred by the antibodies induced by the vaccine was found to decline several months after immunization.

Additional doses of messenger ribonucleic acid (mRNA) vaccine were then approved to increase antibody titers and enhance protection against symptomatic disease. While tip-specific T cells proliferate and memory CD8 T cells can be activated during breakthrough infection, the dynamics of memory B and T cell activation in relation to antibody generation remain unknown.

About the study

In the present study, researchers are evaluating the kinetics of SARS-CoV-2 spike-specific cellular and humoral recall responses in response to SARS-CoV-2 infections in vaccinated individuals.

To determine the dynamics of vaccine-primed booster responses during a breakthrough SARS-CoV-2 infection, blood samples were collected from individuals who had received at least three doses of the COVID-19 mRNA vaccine. and reported a subsequent infection in 2022 when the SARS-CoV-2 Omicron variant and its subvariants were the dominant strains circulating in the United States.

In an effort to elucidate whether a breakthrough infection with Omicron led to an antibody response specifically targeting this variant strain, the report of neutralizing antibodies in BA.1.1 was compared to that targeting SARS-CoV-2 strain D614G.

A panel of tetramer protein probes was used to study the response of plasmablasts during SARS-CoV-2 infection. These probes helped in the assessment of antigen-reactivity of peripheral blood-derived B cells, such as those that target SARS-CoV-2 spike and nucleocapsid proteins, as well as spike domains, including spike-2 (S2), N- terminal (NTD) and receptor binding domain (RBD) and RBD variants of BA.1, BA.4/5 and Delta.

Study results

Prior to SARS-CoV-2 infection, RBD-binding antibodies were detected in all patients. However, the antibody titers were almost five times lower than the peak titers reported two weeks after receiving the third dose of mRNA vaccine.

During breakthrough infections, RBD-binding antibody titers remained stable for the first week, then doubled between days seven and 15. Antibody-binding titers against Omicron and D614G spike RBDs also increased to the same extent, thus indicating that infection with Omicron has caused the generation of circulating antibodies which continue to bind to the wild-type strain, as well as new viral variants.

Similar results were obtained for neutralizing antibody titers in response to wild-type SARS-CoV-2 strain D614G spike protein. On day 15, the booster vaccination significantly increased D614G neutralizing antibody titers by almost eightfold.

However, upon breakthrough infection, D614G neutralizing antibody levels did not increase throughout the first week, but increased 2.4-fold by day 15 post-infection, with another small increase at day 45.

Similarly, there was no quantifiable increase in neutralizing titers in response to the Omicron BA.1.1 subvariant during the first week of breakthrough infection. By week two, neutralizing antibodies BA.1.1 increased faster than D614G and continued to increase 7.8-fold on day 15.

The neutralizing potency of the BA.1.1 antibody response compared to that of D614G increased significantly from less than 25% before infection to 50% on day 15. This neutralization rate did not change during the first week of breakthrough infection.

Even though the reported fold change for BA.1.1 neutralizing antibodies was greater than that of D614G, the team noted that the absolute increase in neutralizing antibodies was the same for both variants. Thus, antibodies generated in response to breakthrough infection could effectively neutralize both BA.1.1 and D614G. Nevertheless, the preferential production of BA.1.1 neutralizing antibodies resulted in a considerable increase in neutralizing potency.

During the first week of a breakthrough infection, the frequencies of B cells detecting the full-length spike protein or certain spike domains remained constant. Nucleocapsid-specific memory B cells were virtually undetectable in most patients during the early stages of infection.

Core and spike-specific memory B cells increased throughout the second week of infection, while the frequency of core-specific memory B cells was almost 80-fold lower by day 15.

Among spike protein-specific memory B cells, S2-specific B cells did not increase appreciably during infection breakthrough. Comparatively, the frequency of B cells that bind to NTDs and RBDs increased significantly on day 1, including those that interacted with RBDs BA.1 and BA.5.

conclusion

Compared to uninfected individuals, prior vaccination generated a coordinated SARS-CoV-2 spike-specific recall response, which was characterized by increased neutralizing antibodies and activated memory B cell levels. The present study has highlighted the importance of memory B and T cells during immunological recall responses in patients with mildly symptomatic breakthrough infections, thereby providing more clarity on the mechanisms responsible for vaccine-induced immunity.

*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.