In a recent observational study published in the journal Immunity, researchers from the United States of America investigated the longevity of antibody responses to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and vaccination. They found that the humoral responses to SARS-CoV-2 infection and vaccination were long-lasting and biphasic, with an initial decline followed by stabilization after seven to nine months.

Study: SARS-CoV-2-infection- and vaccine-induced antibody responses are long lasting with an initial waning phase followed by a stabilization phase. Kateryna Kon / Shutterstock

Background

The COVID-19 pandemic, which began four years ago, prompted the rapid development of messenger RNA (mRNA) vaccines, including the BNT162b2 and mRNA-1273, helping save millions of lives. However, emerging variants of SARS-CoV-2 and the waning immunity against them pose challenges. Although mRNA-based vaccine-induced immunity is perceived to decline rapidly, this perception is based on limited data, primarily from short-term studies.

Amidst the exponential rise of SARS-CoV-2 cases in March 2020, the New York metropolitan area faced a crisis, with essential healthcare workers at a high infection risk. In response, a specific and sensitive SARS-CoV-2 enzyme-linked immunosorbent assay (ELISA) was developed, and the Protection Associated with Rapid Immunity to SARS-CoV-2 (PARIS) study was launched. This initiative tracked antibody responses, reinfection rates, and immunity factors in healthcare workers, offering vital insights into pandemic dynamics. Researchers in the present study utilized data from the PARIS study, one of the most comprehensive investigations on SARS-CoV-2 immunity longevity, and analyzed the humoral responses to SARS-CoV-2 infection and vaccination.

About the study

The PARIS study was an observational, longitudinal study conducted from April 2020 to March 2023 and enrolled 501 healthcare workers. Their mean age was 41 years, and 67% of them were female. Weekly saliva samples and bi-weekly blood samples were collected for the first two months. Nasopharyngeal/ante-near swabs were taken for respiratory symptoms or after vaccination. About 38% of participants showed baseline SARS-CoV-2-spike-binding immunoglobulin G (IgG) antibodies. A total of 93% of participants were vaccinated– 0.2% received four mRNA boosters, 2.6% had three boosters, 16.6% had two boosters, and 53.7% had one booster. Approximately 21.3% of the participants chose not to receive boosters.

The study utilized REDCap for monthly surveys on general health and SARS-CoV-2 risk, focusing on side effects after mRNA vaccinations and booster doses. Data from 228 participants were analyzed, and severity scoring was conducted, revealing reported incidence and severity trends across doses and subgroups.

Antibody titers in serum were assessed using enzyme-linked immunosorbent assay (ELISA) and optical density at 490 nm (OD₄₉₀). Statistical and quantitative analysis involved the use of the Wilcoxon test, Mann-Whitney U test, log-rank test, unweighted pair group method with arithmetic mean (UPGMA) clustering, antibody kinetic modeling including nonlinear mixed-effects (NLME) models, and demographic factor assessment in post-vaccine and post-boost models.

Results and discussion

While 38% of the participants had detectable spike-binding IgG antibodies at baseline, 62% were seronegative at the first visit. Vaccination-naïve individuals exhibited low antibody titers after the first mRNA vaccine dose, with a substantial increase after the second dose. However, individuals with pre-existing immunity reached higher and faster peak titers, maintaining over threefold higher responses after primary immunization.

Seven to nine months post-primary vaccination, antibody titers were found to achieve a steady state. Individuals with hybrid immunity maintained higher and more stable titers compared to naïve recipients, indicating the induction of long-lasting serum antibodies. Furthermore, vaccine type and age were found to affect the antibody titers in participants without hybrid immunity modestly. As per the study, the administration of booster doses elevated the threshold at which long-term serum antibody responses reached a stable state.

A total of 225 SARS-CoV-2 infections were observed in the study period, predominantly occurring after immunization, with breakthrough infections more prevalent during the Omicron wave. In individuals with vaccine-only immunity, breakthrough infections acted as equivalent boosts to antibody responses, while in those with hybrid immunity, vaccination had a more robust boosting effect compared to a second infection.

Participants with pre-existing immunity experienced more side effects after the first vaccine dose, with overall reactogenicity decreasing after subsequent doses. Booster doses induced fewer systemic side effects than the second dose in naïve participants, while those with hybrid immunity had a different pattern, showing slightly increased side effects with booster doses.

However, the study is limited by the inability to analyze mucosal immune responses, the lack of measuring neutralizing antibodies or antibodies to specific epitopes, and the lack of assessment of later variant spikes or nucleoprotein.

Conclusion

In conclusion, the present study provides evidence that antibody responses to SARS-CoV-2 mRNA vaccination exhibit a classical biphasic decay, transitioning from rapid waning to stabilization. The findings emphasize the prolonged protection provided by hybrid immunity against several variants and the potential booster-like effect of breakthrough infections in enhancing immunity.