After vaccination with an mRNA-based vaccine, individuals with no history of SARS-CoV-2 infection were found to have increased plasma neutralizing activity; however, they may not produce as potent of antibodies compared with vaccinated convalescent individuals. These findings were published in Nature.

A total of 30 patients with no history of SARS-CoV-2 infection who had received either the Moderna (n=8) or Pfizer BioNTech (n=24) COVID-19 vaccine were enrolled and matched with individuals who had recovered from a previous SARS-CoV-2 infection (convalescent group). At 2.5 weeks after the first vaccine dose and 35.5 days and 5 months after the second dose, patients with no prior SARS-CoV-2 infection were assessed for antibody responses. Patients in the convalescent group were assessed for antibody responses at 38.5 days and 5 months after vaccination.

Among patients included in the study, the median was 34.5 (range, 23-78) years and 53% were men.

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Between the first and second doses of vaccine, plasma immunoglobulin (Ig)G responses to the receptor binding domain (RBD) of the SARS-CoV-2 virus were significantly increased (P <.0001); however, a 4.3-fold decrease was observed at month 5 (P <.0001).

After stratification by infection status, patients with no history of SARS-CoV-2 infection tended to have variable neutralizing activity, with a mean half-maximal neutralizing titer of 171.

Compared with patients in the convalescent group, those with no history SARS-CoV-2 infection had a 4.9- and 3.6-fold increase in neutralizing titers at 1.3 and 5 months after receiving the second vaccine dose (P <.0001), respectively.

The researchers assessed memory B cells via flow cytometry for RBD expression of the wild-type (WT) virus and 3 SARS-CoV-2 variants of concern. After the first vaccine dose, memory B cells for the WT virus were detected among all vaccinated patients, which increased at month 5. Of note, IgM-expressing memory B cells were found in 23% of blood sample specimens after the first vaccine dose but were nearly absent after the second dose. A similar pattern was observed for RBD-specific plasmablasts.

A total of 458 antibodies were tested for neutralizing capacity, 94% of which bound to the WT virus. The researchers observed that the neutralizing capacity increased between the first and second vaccine doses, mostly due to memory B cells. After the second vaccine dose, there was no improvement in the neutralizing capacity of monoclonal antibodies among patients with no history of infection (P >.99). Among patients in the convalescent group who received the second vaccine dose, memory B cell antibodies persisted up to 1 year (P =.003).

A minority of antibodies (19%) obtained from patients with no history of SARS-CoV-2 infection had potency against mutant combinations compared with 59% of antibodies among those in the convalescent group (P <.0001). For the Delta variant specifically, the vaccinated and convalescent antibodies had potencies of 21% and 69% (P =.007), respectively.

This study was limited by its small sample size and the imbalance between vaccine types.

The researchers found that mRNA-based COVID 19 vaccines conferred similar plasma neutralizing activity among patients with no history of SARS-CoV-2 vs those in the convalescent group. “Given the current rapid emergence of SARS-CoV-2 variants, boosting to prevent infection would likely be needed on a time scale of months,” the researchers concluded.

Disclosure: One author declared affiliations with industry. Please see the original reference for a full list of disclosures.


Cho A, Muecksch F, Schaefer-Babajew D, et al. Anti-SARS-CoV-2 receptor binding domain antibody evolution after mRNA vaccination. Nature. Published online October 7, 2021. doi:10.1038/s41586-021-04060-7