Men's Health

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


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

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

How effective are COVID-19 vaccines?

In early 2021, the COVID-19 vaccination rate rose significantly, which had considerable changes for the trajectory of the pandemic. Nevertheless, the protection conferred by vaccine-induced antibodies were found to wane several months after immunization.

Additional messenger ribonucleic acid (mRNA) vaccine doses were subsequently approved to increase antibody titers and strengthen protection against symptomatic illness. While spike-specific T-cells proliferate and memory CD8 T-cells can be activated during a 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 assess the kinetics of SARS-CoV-2 spike-specific cellular and humoral recall responses in response to SARS-CoV-2 breakthrough infections in vaccinated individuals.

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

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

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

Study findings

Prior to SARS-CoV-2 breakthrough infection, RBD-binding antibodies were detected in all patients. However, antibody titers were almost five-fold lower as compared to peak titers reported two weeks following receipt of the third mRNA vaccine dose.

During breakthrough infections, RBD-binding antibody titers remained stable for the first week, then rose two-fold between days seven and 15. Antibody binding titers against the Omicron and D614G spike RBDs also increased to a similar extent, thus indicating that Omicron infection elicited the generation of circulating antibodies that continue to bind to the wildtype strain, as well as newer viral variants.

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

However, during breakthrough infection, D614G neutralizing antibody levels did not rise throughout the first week but rose by 2.4-fold by the fifteenth-day post-infection, with another small increase on 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 the second week, BA.1.1 neutralizing antibodies rose more rapidly than D614G and continued to increase by 7.8-fold on day 15.

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

Even though the fold change reported for BA.1.1 neutralizing antibodies was more than that of D614G, the team noted that the absolute boost in neutralizing antibodies was the same for both variants. Thus, the antibodies generated in response to a 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, B-cell frequencies detecting the full-length spike protein or certain spike domains remained consistent. Nucleocapsid-specific memory B-cells were practically undetectable in most patients during the initial time points of infection.

Nucleocapsid- and spike-specific memory B-cells rose throughout the second week of infection, while the frequency of nucleocapsid-specific memory B-cells was almost 80-fold lower on day 15.

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


As compared to uninfected individuals, prior vaccination generated a coordinated SARS-CoV-2 spike-specific recall response, which was characterized by increased neutralizing antibody and activated memory B-cell levels. The current study highlighted the significance of memory B- and T-cells during recall immunological responses in patients with moderately symptomatic breakthrough infections, thus 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 regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

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