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Does the duration between SARS-CoV-2 infection and vaccination affect immunity?

In a recent study posted to the medRxiv* preprint server, researchers at Oregon Health & Science University assessed the impact of the duration between coronavirus disease 2019 (COVID-19) infection and vaccination on immunity against infection.

As the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections continues, long-term immunity against COVID-19 has become more critical. Global public health concerns have been exacerbated by the continuous emergence of novel SARS-CoV-2 variants with higher transmissibility and infectivity than preceding variants. Extensive investigation is needed to understand various aspects of SARS-CoV-2 immunity, such as the temporal profile, especially between infection and repeated vaccination.

Study: The time between vaccination and infection impacts immunity against SARS-CoV-2 variants. Image Credit: Ja_inter / Shutterstock

About the study

In the present study, researchers assessed the effect of combined COVID-19 infection and vaccination or hybrid immunity and its associated timing on the quantity and quality of antibodies elicited.

The team recruited ten individuals from December 2020 to March 2021 who tested COVID-19 positive via polymerase chain reaction (PCR) before being vaccinated. Blood samples were collected prior to and after a two-dose BNT162b2 vaccination. Additionally, 20 gender- and age-matched individuals with no self-reported history of previous COVID-19 infection were recruited, and their blood samples were collected before and after vaccination. Furthermore, serum-neutralizing titers were estimated and compared for these two cohorts via a live virus focus reduction neutralization test (FRNT).

An additional cohort was recruited comprising 23 vaccinated individuals who did and did not exhibit hybrid immunity because of prior COVID-19 infection along with 23 subjects with vaccine breakthrough infections. Serological samples were obtained less than 60 days after either vaccination or breakthrough infection confirmed by PCR. Additionally, the team estimated spike-specific antibody levels for this cohort via enzyme-linked immunosorbent assay (ELISA).

The hybrid immune group included subjects diagnosed with SARS-CoV-2 infection almost 40 to 404 days after vaccination and subjects vaccinated 35 to 283 days after COVID-19 diagnosis. The team characterized the association between neutralizing titers and antibody levels using age, gender, exposure interval, and the time that passed between the last exposure and sample collection. The cohort was further subdivided into 100-day exposure interval bins.    


The study results found that serum-neutralizing titers rose for the previously infected as well as the naive cohorts before and after COVID-19 vaccination. The titers were also notably higher among individuals with a history of prior infection compared to those vaccinated against all strains, such as the original SARS-CoV-2 (WA1) and variants like Alpha, Beta, and Gamma variants of concern (VOCs). This indicated that hybrid immunity resulting from both natural infection and vaccination might lead to elevated neutralizing serum antibody titers.

ELISA performed on the larger cohort showed that total antigen-specific antibody proportions elevated by 3.6-fold due to hybrid immunity than after only vaccination. Class-specific ELISA revealed that this phenomenon was due to the 3.7-fold increase in immunoglobulin (Ig)-G levels and a 3.2-fold increase in IgA levels. IgM levels displayed no such variation between the two groups. Total antibody levels also increased with hybrid immunity against the SARS-CoV-2 spike (s) protein by 3.1-fold.

The team also noted that neutralizing antibody titers against SARS-CoV-2 and all the variants tested increased in the group having hybrid immunity compared to the cohort that was only vaccinated. The neutralizing titers increased by 8.4-fold, 12.5-fold, 22.7-fold, 9.6-fold, 19-fold, and 13.3-fold against WA1, Alpha, Beta, Delta, Omicron BA.1, and Omicron BA.2, respectively. The highest increase was noted against Beta and Omicron BA.1 and BA.2 subvariants.   

In the hybrid immune group, neutralizing antibody titers and antibody levels were notably associated with exposure interval. The most significant correlations were observed for SARS-CoV-2 spike-specific antibody levels and neutralization of WA1, Alpha, Delta, Beta, and Omicron BA.1 and BA.2. Additionally, the extent of elevation noted by the team varied between different variants. By day 400, the neutralizing titers rose by 5.3-fold against WA1, 4.8-fold against Alpha, 11.5-fold against Beta, 11.2-fold against Delta, 17.6-fold against Omicron BA.1, and 14.3-fold against Omicron BA.2. Between the 35 to 100 and 300 to 404-day exposure interval cohorts, the neutralizing titers increased against WA1 by 4.2-fold, Alpha by 4.1-fold, Beta by 9.6-fold, Delta by 7.1-fold, Omicron BA.1 by 12.5-fold, and Omicron BA.2 by 10.7-fold.


The study findings showed that individuals having hybrid immunity exhibited robust SARS-CoV-2 neutralizing antibody responses against all variants, including the SARS-CoV-2 Omicron BA.2 sublineage. The team also found remarkably enhanced neutralizing titers when the vaccination-infections time intervals were longer at up to 400 days. These findings suggested that anti-SARS-CoV-2 antibody responses undergo continual maturation after the primary exposure to the virus via either infection or vaccination for a minimum of 400 days since the last exposure to the antigen. The researchers believe these findings may extend to COVID-19 booster vaccine doses, which could elicit higher protection against infection when administered after longer intervals.

*Important notice

medRxiv 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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