Stable neutralizing antibody levels 6 months after mild and severe COVID-19 episodes

Background Understanding mid-term kinetics of immunity to SARS-CoV-2 is the cornerstone for public health control of the pandemic and vaccine development. However, current evidence is rather based on limited measurements, losing sight of the temporal pattern of these changes. Methods We conducted a longitudinal analysis on a prospective cohort of COVID-19 patients followed up for >6 months. Neutralizing activity was evaluated using HIV reporter pseudoviruses expressing SARS-CoV-2 S protein. IgG antibody titer was evaluated by ELISA against the S2 subunit, the receptor binding domain (RBD), and the nucleoprotein (NP). Statistical analyses were carried out using mixed-effects models. Findings We found that individuals with mild or asymptomatic infection experienced an insignificant decay in neutralizing activity, which persisted 6 months after symptom onset or diagnosis. Hospitalized individuals showed higher neutralizing titers, which decreased following a 2-phase pattern, with an initial rapid decline that significantly slowed after day 80. Despite this initial decay, neutralizing activity at 6 months remained higher among hospitalized individuals compared to mild symptomatic. The slow decline in neutralizing activity at mid-term contrasted with the steep slope of anti-RBD, S2, or NP antibody titers, all of them showing a constant decline over the follow-up period. Conclusions Our results reinforce the hypothesis that the quality of the neutralizing immune response against SARS-CoV-2 evolves over the post-convalescent stage. Funding This study was funded by 10.13039/501100016387Grifols, the Departament de Salut of the Generalitat de Catalunya (grant nos. SLD016 to J.B. and SLD015 to J.C.), the Spanish Health Institute Carlos III (grant nos. PI17/01518 and PI18/01332 to J.C.), CERCA Programme/Generalitat de Catalunya2017 SGR 252, and the crowdfunding initiatives #joemcorono, BonPreu/Esclat, and Correos. The funders had no role in the study design, the data collection and analysis, the decision to publish, or the preparation of the manuscript. E.P. was supported by a doctoral grant from the National Agency for Research and Development of Chile (ANID; 72180406). C.A.-N. was supported by a doctoral grant from Generalitat de Catalunya and Fons Social Europeu (FI). S.P.-Y. was supported by 10.13039/501100011850Fundación Canaria Doctor Manuel Morales and 10.13039/100015528Universidad de La Laguna.
Graphical Abstract
Context and significance Assessing the durability of neutralizing responses against SARS-CoV-2 is crucial to predict the level of protection in post-convalescent COVID-19 patients. We monitored for >6 months a cohort of 210 SARS-CoV-2-infected individuals with a wide range of symptoms (from asymptomatic infection to severe disease). Our results indicate that neutralizing antibodies are stable for at least 6 months after infection. However, individuals with mild or asymptomatic infection developed lower titers of neutralizing antibodies and could be at higher risk of reinfection. Despite the maintenance of neutralizing antibodies, total antibody titers slowly but gradually declined over time without apparent stabilization. This observation requires further analysis to evaluate the potential role of viral persistence or viral re-exposure in maintaining neutralization titers.
Pradenas et al. describe the kinetics of neutralizing antibodies against SARS-CoV-2 and demonstrate their association with clinical severity and their stability for at least 6 months, despite constant decay of IgG titers. These findings help us to understand the mid-term immune response and the impact on herd immunity.