COVID-19 vaccination elicits broader antibody response to SARS-CoV-2 spike than infection

A collaborative study published on the preprint server bioRxiv* demonstrates that antibodies generated in response to messenger ribonucleic acid (mRNA)-based coronavirus disease 2019 (COVID-19) vaccination target more epitopes across the viral spike protein as compared to that targeted by infection-induced antibodies.

Study: Comprehensive characterization of the antibody responses to SARS-CoV-2 Spike protein after infection and/or vaccination. Image Credit: Kateryna Kon /


The combination of mass vaccination with non-pharmaceutical control measures like mask-wearing and physical distancing is the best possible way to bring an end to the COVID-19 pandemic. Multiple potential vaccines are currently rolling out in many countries across the globe. In the United States, more than 50% of the adult population have already been vaccinated mostly by either of the two mRNA-based COVID-19 vaccines, BNT162b2 (Pfizer/BioNTech) and mRNA-1273 (Moderna).

Several studies have highlighted the potency of these vaccines in preventing the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, severe disease, and mortality. However, it is still uncertain whether these vaccines can retain their antiviral efficacy against newly emerging variants of SARS-CoV-2.  

Studies on endemic coronaviruses have shown that continuous evolution of the spike protein through mutations can facilitate the virus escape from neutralizing antibodies induced by natural infection. Similarly, some recent studies have shown that the SARS-CoV-2 Delta variant can induce breakthrough infections in fully vaccinated individuals, thus highlighting the possibility of emerging escape mutations. Routine monitoring of vaccine efficacy is thus important to better manage the pandemic.

In the current study, the scientists have characterized the dynamics of antibody response induced by mRNA COVID-19 vaccination or natural SARS-CoV-2 infection.

Study design

The scientists used phage peptide libraries and deep mutational scanning (phage-DMS) to identify spike-specific epitopes and escape sites for antibodies induced by vaccination, infection, or both. To identify potential escape mutations within the epitope regions, antibody binding of wild-type peptides was compared to that of mutated peptides.

Epitope profiling

The analysis was conducted using serum samples obtained from mRNA-1273-vaccinated, BNT162b2-vaccinated, or SARS-CoV-2-infected individuals, as well as, from vaccinated individuals with a history of COVID-19.

The findings revealed that the most commonly targeted epitopes across the study population include N-terminal and C-terminal domains (NTD and CTD, respectively) in the spike S1 subunit, as well as fusion peptide and heptad-repeat regions in the spike S2 subunit.

More specifically, fusion peptide and heptad-repeat regions appear to be the most frequently targeted epitopes in mildly infected, unvaccinated individuals. In contrast, antibodies generated in response to vaccination or severe infection target all four epitopes identified. Interestingly, antibodies obtained from infection- and vaccination-naïve individuals showed occasional cross-reactivity to fusion peptide and heptad-repeat regions, thereby indicating that these epitopes are conserved between SARS-CoV-2 and endemic coronaviruses.

Antibodies generated in response to mild infection showed significantly higher binding to the fusion peptide. In contrast, vaccination- or severe infection-induced antibodies showed significantly higher binding to NTD, CTD, and heptad-repeat regions.

The study did not observe any significant impact of age, vaccine dosage, vaccine type, and timepoint since the last vaccination/symptom onset on the epitope binding efficiency of antibodies.

Sites of escape within epitopes  


The analysis of spike-specific mutations responsible for antibody escape revealed that the majority of vaccine-induced antibodies are highly sensitive to mutations located at the extreme C-terminal portion of the NTD and the region located between NTD and spike receptor-binding domain (RBD).

The N-terminal portion of the CTD was identified as the most dominant epitope for vaccine-induced antibodies. Within this epitope, two sites were identified as potential escape sites in most of the samples.

The unique escape profile induced by vaccination across individuals appeared to change over time.

Fusion peptide

Antibodies induced by both infection and vaccination showed sensitivity to four sites within the fusion peptide epitope. However, in infected individuals, no change in escape profile was observed after vaccination.

In infection-naïve individuals, vaccination-induced distinct escape profiles within the fusion peptide epitope.

Heptad-repeat regions

Distinct escape profiles were identified within the heptad-repeat region epitope in previously infected, unvaccinated individuals. In contrast, a unique escape profile was identified in vaccinated individuals with or without previous infection.

Study significance

The current study identifies four major epitopes outside the spike RBD that are targeted by vaccination- and severe infection-induced antibodies. However, antibodies induced by mild infection targets only two of these epitopes. This indicates that COVID-19 vaccination induces a comparatively broader antibody response than natural infection.

*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.

Journal reference:
Dr. Sanchari Sinha Dutta

Written by

Dr. Sanchari Sinha Dutta

Dr. Sanchari Sinha Dutta is a science communicator who believes in spreading the power of science in every corner of the world. She has a Bachelor of Science (B.Sc.) degree and a Master's of Science (M.Sc.) in biology and human physiology. Following her Master's degree, Sanchari went on to study a Ph.D. in human physiology. She has authored more than 10 original research articles, all of which have been published in world renowned international journals.


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  1. Holger Lundstrom Holger Lundstrom Austria says:

    If the unvaccinated individuals did not have antibodies that bind to the S1 subunit, but the vaccinated individuals had such antibodies, then there is only one possible conclusion to this finding: during an infection with SARS-CoV-2, binding epitopes of the S1 subunit are not exposed. Clearly, if the S1 subunit were exposed during natural infection, antibodies would have been developed against this subunit by people with natural immunity.

    In effect, the study documents that a part of the antibodies produced as a result of vaccination are artificial and produce no additional value during an infection with the virus. They are, in essence, completely useless.

The opinions expressed here are the views of the writer and do not necessarily reflect the views and opinions of News Medical.
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