Researchers investigate the influence of past coronavirus disease 2019 (COVID-19) vaccination on immune responses during a breakthrough infection with the severe acute respiratory syndrome coronavirus 2 in a recent study published on the bioRxiv* preprint server (SARS-CoV-2).
What is the efficacy of 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 was found to wane several months after immunization.
Additional messenger ribonucleic acid (mRNA) vaccination dosages were subsequently approved to improve antibody titers and strengthen protection against clinical disease. During a breakthrough infection, spike-specific T-cells proliferate and memory CD8 T-cells can be engaged, although the dynamics of memory B- and T-cell activation in connection to antibody production are unknown.
Concerning the research
The current investigation examines the kinetics of SARS-CoV-2 spike-specific cellular and humoral recall responses in vaccinated persons in response to SARS-CoV-2 breakthrough infections.
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, to determine the dynamics of recall responses primed by vaccination during SARS-CoV-2 breakthrough infection.
The ratio of neutralizing antibodies in BA.1.1 was compared to that targeting the SARS-CoV-2 D614G strain in order to determine whether Omicron breakthrough infection resulted in an antibody response that particularly targeted that variant strain.
To evaluate the response of plasmablasts during SARS-CoV-2 breakthrough infection, a panel of protein tetramer probes was used. These probes were used to assess the 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 such as spike-2 (S2), N-terminal domain (NTD), and receptor binding domain (RBD), and RBD variants from BA.1, BA.4/5, and Delta.
The study’s findings
RBD-binding antibodies were found in all patients prior to SARS-CoV-2 infection. However, antibody titers were nearly five-fold lower than peak titers recorded two weeks after receiving the third mRNA vaccination dosage.
RBD-binding antibody titers were steady for the first week of breakthrough infections, then increased two-fold between days seven and fifteen. Antibody binding titers against the Omicron and D614G spike RBDs grew to a similar level, showing that Omicron infection resulted in the development of circulating antibodies that bind to both the wildtype strain and subsequent viral variations.
Similar results were found for neutralizing antibody titers in response to the SARS-CoV-2 spike protein wild-type D614G strain. Booster immunization elevated D614G neutralizing antibody titers about eightfold by day 15.
However, following breakthrough infection, D614G neutralizing antibody levels increased 2.4-fold by the fifteenth post-infection day, with another minor increase on day 45.
Similarly, during the first week of breakthrough infection, there was no discernible increase in neutralizing titers in response to the Omicron BA.1.1 subvariant. By the second week, BA.1.1 neutralizing antibodies had risen faster than D614G and had increased 7.8-fold by day 15.
When compared to D614G, the neutralizing efficacy of the BA.1.1 antibody response improved considerably from less than 25% before infection to 50% by day 15. This neutralization ratio did not alter during the first week of infection.
Despite the fact that the fold change for BA.1.1 neutralizing antibodies was greater than that for D614G, the scientists noted that the absolute boost in neutralizing antibodies was the same for both variants. As a result, antibodies produced in response to a breakthrough infection were able to efficiently neutralize both BA.1.1 and D614G. Despite this, preferential synthesis of BA.1.1-neutralizing antibodies resulted in a significant increase in neutralizing potency.
B-cell frequencies identifying the full-length spike protein or specific spike domains were stable over the first week of breakthrough infection. During the early stages of infection, nucleocapsid-specific memory B-cells were virtually undetectable in the majority of patients.
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The frequency of nucleocapsid- and spike-specific memory B-cells increased throughout the second week of infection, while nucleocapsid-specific memory B-cells were about 80-fold lower on day 15.
S2-specific B-cells did not grow significantly after a breakthrough infection among memory B-cells specific to the spike protein. By day one, the frequency of B-cells that bind NTDs and RBDs grew significantly, particularly those that interacted with BA.1 and BA.5 RBDs.
Conclusions
Prior vaccination resulted in a coordinated SARS-CoV-2 spike-specific recall response, which was characterized by higher neutralizing antibodies and activated memory B-cell levels when compared to uninfected individuals. The current study emphasized the importance of memory B- and T-cells during recall immunological responses in patients with mildly symptomatic breakthrough infections, shedding information on the processes underlying vaccine-induced immunity.
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*Important Note: Because bioRxiv publishes preliminary scientific papers that have not been peer-reviewed, they should not be regarded as conclusive, should not guide clinical practice/health-related behavior, and should not be treated as established information.
