Long-term study of COVID reveals limits of immunity

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Long-term study of COVID reveals limits of immunity

In a recent article published in medRxiv preprint* server, researchers assessed the duration of humoral immune responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and their kinetics after initial infection and vaccination against coronavirus disease 2019 (COVID-19). In addition, they determined SARS-CoV-2 re-infection rates and assessed correlates of protection against SARS-CoV-2 infection.

survey: Kinetics and durability of humoral responses to SARS-CoV-2 infection and vaccination. Image credit: Dotted Yeti / Shutterstock.com

*Important message: medRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, guide clinical practice/health-related behavior, or be treated as established information.


In March 2020, New York City became the epicenter of the COVID-19 pandemic in the United States, with an exponential increase in severe cases of COVID-19 that overwhelmed the health care system and led to numerous deaths. Given the acute shortage of personal protective equipment (PPE) at the beginning of the pandemic, the risk of infection is highest among healthcare workers.

Short-term studies evaluating limited data points after peak immune responses to SARS-CoV-2 infection have shown that immunity induced by messenger ribonucleic acid (mRNA)-based COVID-19 vaccines rapidly wanes. Furthermore, the emergence of new SARS-CoV-2 variants has reduced the effectiveness of these vaccines against symptomatic disease.

Information on the kinetics of antibody responses, including persistence and longevity, elicited in response to COVID-19 mRNA vaccination following infection, primary immunization, booster vaccination, and breakthrough infections is still lacking.

About the research

The Protection Associated with Rapid Immunity to SARS-CoV-2 (PARIS) study was conducted in New York between April 2020 and April 2023. Here, more than 8,000 biopsies were analyzed in addition to longitudinal data from 501 adults, most of who are healthcare workers working in the Mount Sinai Health System.

The mean age of the study cohort was 41 years at enrolment, 67% of whom were female. All study participants provided data, blood and saliva samples at all study visits.

The interval between study visits was two to four weeks from baseline to week eight. This interval is then increased to four to eight weeks after week eight.

Weekly until that visits also occurred after vaccination and other immune events, such as SARS-CoV-2 infection and re-infection. An in-house enzyme-linked immunosorbent assay (ELISA) was used to measure antibodies against the SARS-CoV-2 spike (S) glycoprotein.

Survey results

All 501 participants in PARIS received between two and six doses of the COVID-19 vaccine. Of the study cohort, 93% received mRNA vaccines, of which 342 and 111 individuals received two doses of BNT162b2 and mRNA-1273 vaccines, respectively. The remaining 36 participants received Ad26.COV2.S or AZD1222 vaccines.

Of the 465 participants in PARIS who received a primary vaccination, 366 received a booster vaccination, 97 of whom subsequently received a second booster dose. Fifteen study participants received a third booster dose, while only one individual received a fourth booster dose. Of the 27 recipients of two monovalent boosters, 14 chose bivalent booster vaccination.

After primary vaccination, plasmablast-derived serum antibodies immediately reach a high peak; however, this antibody response began to wane within two weeks. These antibodies represent the 28-34 day half-life of the short-lived component of the PARIS model; however, some antibodies, such as immunoglobulin G1 (IgG1), have a half-life of about four weeks.

In the pre-Omicron era, no breakthrough infections were reported in the hybrid immunity group for 11 months. In comparison, during the Omicron era, given the strong immune evasion capabilities and highly infectious nature of this variant, most of the study participants experienced breakthrough infections.

The hybrid immune group remained significantly more protected than previously naïve individuals. Indeed, among previously untreated individuals who developed breakthrough infections after vaccination, the breakthrough infection elicited similar antibody responses as the booster dose.

Among individuals who received two or three booster doses, breakthrough infection did not elicit serum antibody responses as strongly as vaccination. This may be due to strong preexisting immunity limiting virus replication in these individuals; therefore, exposure to lower levels of antigen elicits a lower immune response.

The PARIS cohort tolerated SARS-CoV-2 mRNA vaccines well, with about 67% of the cohort experiencing mild to moderate side effects. Local and systemic adverse reactions are common in individuals with hybrid immunity. This observation is clinically relevant because reactogenicity can increase vaccine hesitancy and decrease its absorption.


The current longitudinal study followed individuals from the start of the pandemic for up to three years. This allowed the researchers to perform a comprehensive analysis of the long-term kinetics of antibody responses after primary and booster vaccination and breakthrough infections.

The kinetics of antibody decline is slower after booster vaccination; however, antibody titers stabilized increasingly after each booster dose. Primary vaccination against COVID-19 in previously infected individuals elicited antibody titers of approximately 20,000 area under the curve (AUC); however, total antibody titers peaked at about 10,000 AUC. This apparent ceiling effect gradually decreased with repeated exposure to SARS-CoV-2 and booster vaccinations.

Among the groups of initially infected and initially untreated individuals, booster vaccination acted as a leveler. Specifically, vaccinated individuals with prior infection had higher peak antibody titers than individuals who were naïve prior to the primary vaccination series.

Age and vaccine type also affect long-term antibody titers. For example, in naïve individuals prior to infection, mRNA-1273 induced about 1.3-fold higher antibody titers than BNT162b2.

*Important message: medRxiv publishes preliminary scientific reports that are not peer-reviewed and therefore should not be considered conclusive, guide clinical practice/health-related behavior, or be treated as established information.

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