Longitudinal cohort study of primary healthcare workers reveals long-lasting SARS-CoV-2 humoral immunity in the absence of vaccination

In a recent study published in BMC Medicine, researchers performed a longitudinal cohort study to assess the levels of immunoglobulins M (IgM), G (IgG), and A (IgA) against the spike and nucleocapsid proteins of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 247 primary health care workers in Barcelona, Spain across 616 days from the onset of the coronavirus disease 2019 (COVID-19) pandemic.

Background

Despite the impetus to develop vaccines and vaccinate the global population against SARS-CoV-2, a significant portion of the world’s population are still unvaccinated and protected largely by antibody responses to an initial SARS-CoV-2 infection. Studies have shown that the antibody responses to SARS-CoV-2 infections are active for up to one year in the body after recovery.

The humoral immune responses to COVID-19 largely comprise immunoglobulins specific to the viral antigens, such as spike and nucleocapsid proteins. In the initial stages of the infection, IgM and IgA dominate the immune response, while IgM and IgG are responsible for most of the neutralizing activity.

Waning humoral immunity and the emergence of immune-evading SARS-CoV-2 variants can increase the susceptibility to reinfections. Furthermore, many studies have found strong correlations between comorbidities and the severity of COVID-19, but the effect of comorbidities on the antibody levels from previous infections has not been investigated.

Understanding the persistence of SARS-CoV-2 infection-induced immunity and the variation in antibody levels due to comorbidities is essential for developing treatment and prevention strategies against emerging SARS-CoV-2 variants.

About the study

The longitudinal cohort study included 247 COVID-19-positive healthcare workers in Barcelona, Spain; samples were collected at different time points between March 2020 and November 2021. Rapid diagnostic tests and quantitative reverse transcription polymerase chain reaction (qRT-PCR) tests were used to detect SARS-CoV-2 infections in symptomatic participants or healthcare workers who had been in contact with COVID-19 patients.

The effect of a wide range of comorbidities such as diabetes mellitus, chronic obstructive pulmonary disease, cardiovascular diseases, autoimmune diseases, cancer, and many more on the antibody responses to SARS-CoV-2 infections was analyzed.

Antibody responses were quantified based on the IgG, IgA, and IgM levels against SARS-CoV-2 spike protein, subunit S2, nucleocapsid protein, receptor binding domain (RBD), and the C-terminal region. Linear mixed models were used to model the change in antibody levels over time.

Including the baseline tests, nine samples were collected from each individual throughout the study. Additionally, the first and last three samples were measured for antibodies against the RBD of the Alpha, Beta, Gamma, and Omicron SARS-CoV-2 variants. The frequency of reinfections was also determined.

Results

The results reported that while a significant but gradual decline was noted in antibody levels over time, the seropositivity against the five SARS-CoV-2 proteins cumulatively remained above 90% during the study period. The seropositivity in the unvaccinated subset was 95.65%. The highest seropositivity was for IgA and IgG (95.65% for both), with mainly anti-spike protein and anti-RBD responses for IgG and anti-spike responses for IgA and lower for IgM (47.83%), which were primarily anti-RBD responses.

The Alpha and Delta variant RBDs elicited similar IgG seropositivity as the original Wuhan-Hu-1 strain, but the seropositivity values were lower for the Beta and Gamma variants.

The reinfection rate in the unvaccinated frontline healthcare workers was 3.23%, while in recovered COVID-19 patients, it was between 0 and 20%. The cumulative reinfection rate was as low as 0.65%. On average, the reinfected individuals were 43.9 ± 9.5 years old, and 62.5% had at least one comorbidity. Among the reinfected cases, 85.7% experienced similar symptoms as the first infection, while the rest had milder symptoms. None of the reinfections were more severe than the original infection.

Correlation analyses between antibody levels and comorbidities, clinical manifestations, and baseline characteristics closest to the time of infection and just before vaccination revealed that fever, anosmia, and dysgeusia were associated with higher antibody levels, as was hypertension. Hospitalization was associated with sustained high levels of IgG, indicating that the severity of COVID-19 did not decrease the memory B cell or plasma cell stability.

Conclusions

Overall, the results indicated that anti-SARS-CoV-2 antibodies persist in the body for close to 1.7 years after infection. Unvaccinated individuals exhibited greater than 90% seropositivity for more than 20 months after COVID-19.

High IgG levels appeared to protect individuals against reinfections with the wildtype strain and Alpha variant in the absence of vaccinations. Hybrid immunity from vaccinations and previous infections displayed the highest protection against SARS-CoV-2 reinfections.

Written by

Dr. Chinta Sidharthan

Chinta Sidharthan is a writer based in Bangalore, India. Her academic background is in evolutionary biology and genetics, and she has extensive experience in scientific research, teaching, science writing, and herpetology. Chinta holds a Ph.D. in evolutionary biology from the Indian Institute of Science and is passionate about science education, writing, animals, wildlife, and conservation. For her doctoral research, she explored the origins and diversification of blindsnakes in India, as a part of which she did extensive fieldwork in the jungles of southern India. She has received the Canadian Governor General’s bronze medal and Bangalore University gold medal for academic excellence and published her research in high-impact journals.