In late February, in a blog about a suspected COVID-19 reinfection in Japan, I mentioned an inconvenient 2016 study (see EID Journal: Antibody Response & Disease Severity In HCW MERS Survivors) that found limited, and short-lived antibody titers among a small cohort of mild MERS-CoV survivors.
Six weeks later, in COVID-19: From Here To Immunity, we revisited that study and several others following an opinion piece published in the New York Times by Dr. Marc Lipsitch that went over the still slim and sometimes conflicting evidence for acquired immunity from COVID-19 infection.
Since then, we've seen a number of reports and studies suggesting that infection with SARS-CoV-2 may not provide everyone with a robust and long-lasting immunity to the virus.
This has ramifications not only for individual post-infection immunity, but potentially also for the effectiveness and duration of protection from any vaccine.
Since August, we've started to see a smattering of laboratory confirmed reinfection cases (see C.I.D.: Another SARS-CoV-2 Reinfection Report - 2 HCWs From India), and over the summer we've seen a steady stream of studies showing waning antibodies in recovered COVID cases.
Last July (see Kings College: Longitudinal Evaluation & Decline of Antibody Responses in SARS-CoV-2 infection), researchers reported that `the magnitude of the nAb response is dependent upon the disease severity', pretty much in alignment with the 2016 MERS Study mentioned at the top of this blog.
They also found a significant percentage of mild cases saw their nAb titers drop to near baseline within 60 days post-infection.
While concerning, it should be noted that nAb titers aren't the only measure of potential post-infection immunity, as the role of T-Cells and other elements of the innate immune system in fighting this virus remain poorly understood.
Two months post infection 100% of patients with pneumonia and 71% with asymptomatic infection had positive ELISA results. At five months, only 57.1% of asymptomatic had a positive ELISA, and one of the more subtle pneumonia cases was no longer positive by ELISA.
When taken along with past studies, this report raises adds to concerns that naturally acquired immunity against SARS-CoV-2 might not be long-lasting.
Volume 27, Number 1—January 2021
Pyoeng Gyun Choe1, Chang Kyung Kang1, Hyeon Jeong Suh, Jongtak Jung, Kyoung-Ho Song, Ji Hwan Bang, Eu Suk Kim, Hong Bin Kim, Sang Won Park, Nam Joong Kim, Wan Beom ParkComments to Author , and Myoung-don OhComments to Author
Author affiliation: Seoul National University College of Medicine, Seoul, South Korea
We investigated the kinetics of severe acute respiratory syndrome coronavirus 2 neutralizing antibodies in 7 asymptomatic persons and 11 patients with pneumonia. The geometric mean titer of neutralizing antibodies declined from 219.4 at 2 months to 143.7 at 5 months after infection, indicating a waning antibody response.
Neutralizing antibodies develop in asymptomatic persons with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection; however, the initial immune response is not as strong as in patients with more severe disease (1,2). We investigated the kinetics of SARS-CoV-2 neutralizing antibodies during the 5 months after infection in asymptomatic persons and patients with pneumonia caused by SARS-CoV-2.
We studied 7 persons infected with SARS-CoV-2 who were isolated in a community treatment center operated by Seoul National University (SNU) Hospital in Daegu, South Korea (3). Comprehensive monitoring confirmed that these 7 patients were asymptomatic (4). We also evaluated 11 SARS-CoV-2–positive patients with pneumonia at the Biocontainment Unit in the SNU Hospital and SNU Bundang Hospital. We classified each case of pneumonia as subtle (i.e., infiltrations observed only on computed tomography) or apparent (i.e., infiltrations observed on plain chest radiograph) (Appendix). All patients provided informed consent.
We evaluated the antibody responses at 2 and 5 months after infection, as reported (1). We semiquantitatively measured IgG against SARS-CoV-2 using ELISA (Euroimmun, https://www.euroimmun.comExternal Link) with the recombinant S1 domain of the SARS-CoV-2 spike protein as the antigen. We interpreted the optical density ratio (sample/calibrator) as negative (<0.8), borderline (>0.8 to <1.1), or positive (>1.1), according to the manufacturer’s recommendations. We also conducted neutralization assays as previously described (5) using BetaCoV/Korea/SNU01/2020 virus (6) and 2-fold serially diluted plasma samples (2–4,096-fold). We recorded the highest dilution of plasma that showed inhibition activity of SARS-CoV-2 as the neutralizing antibody titer. We considered a >4-fold reduction in antibody titer to be a waning response. The Institutional Review Boards of Seoul National University Hospital approved the study (IRB no. H-2004-158-1118).
Two months after infection, 11 (100%) patients with pneumonia and 5 (71%) with asymptomatic infection had positive ELISA results. Five months after infection, 5 (100.0%) patients with apparent pneumonia, 5 (83.3%) with subtle pneumonia, and 4 (57.1%) with asymptomatic infection had positive ELISA results. The mean ELISA optical density decreased significantly from 2 to 5 months after infection (4.93 at 2 months vs. 4.09 at 5 months; p = 0.01).
Two months after infection, all patients had neutralizing antibodies. Antibody titers correlated with disease severity; the geometric mean titer was 105 among symptomatic persons, 161 among patients with subtle pneumonia, and 891 among patients with apparent pneumonia. Five months after infection, all patients still had neutralizing antibodies, but the geometric mean titer decreased significantly (219.4 at 2 months vs. 143.7 at 5 months; p = 0.03). In the linear regression model, the decline was significantly associated with the antibody levels at 2 months as measured by ELISA (r = 0.536, p = 0.02) and the neutralization assay (r = 0.563, p = 0.02) (Appendix Figure).
The waning neutralizing antibody response occurred in 2 (40%) of 5 patients with apparent pneumonia and 2 (33%) of 6 with subtle pneumonia, but none of the asymptomatic persons (Figure).
Determining the longevity of humoral immunity to SARS-CoV-2 is essential to predicting herd immunity to coronavirus disease. Among patients with severe acute respiratory syndrome coronavirus, which is closely related to SARS-CoV-2, a total of 90% maintained IgG for 2 years and 50% for 3 years (7). However, humoral immunity to common human coronavirus is short-lived; antibodies against seasonal coronaviruses return to baseline levels by 52 weeks after infection, enabling homologous reinfections (8). A recent study showed that the antibody titers of patients with mild coronavirus disease declined more quickly than did those of patients with severe acute respiratory syndrome (9).
Our findings demonstrate waning humoral immunity in patients with SARS-CoV-2 infection. We documented the decline of neutralizing antibody titers in asymptomatic and symptomatic patients. In this study, the initial neutralizing antibody reaction appeared to correlate with the severity of the disease. However, patients with pneumonia were considerably older than asymptomatic persons, and increasing age is associated with a stronger neutralizing antibody response (10). In this study, neutralizing antibody titer decreased more in symptomatic than asymptomatic patients. Our study reinforces the concern that naturally acquired humoral immunity against SARS-CoV-2 might not be long-lasting.
Dr. Choe is a clinical scientist at Seoul National University Hospital. His research interests focus on preventing healthcare-associated infection and responding to emerging infectious diseases.