One Year after Mild COVID-19: The Majority of Patients Maintain Specific Immunity, But One in Four Still Suffer from Long-Term Symptoms

Abstract

After COVID-19, some patients develop long-term symptoms. Whether such symptoms correlate with immune responses, and how long immunity persists, is not yet clear. This study focused on mild COVID-19 and investigated correlations of immunity with persistent symptoms and immune longevity. Persistent complications, including headache, concentration difficulties and loss of smell/taste, were reported by 51 of 83 (61%) participants and decreased over time to 28% one year after COVID-19. Specific IgA and IgG antibodies were detectable in 78% and 66% of participants, respectively, at a 12-month follow-up. Median antibody levels decreased by approximately 50% within the first 6 months but remained stable up to 12 months. Neutralizing antibodies could be found in 50% of participants; specific INFgamma-producing T-cells were present in two thirds one year after COVID-19. Activation-induced marker assays identified specific T-helper cells and central memory T-cells in 80% of participants at a 12-month follow-up. In correlative analyses, older age and a longer duration of the acute phase of COVID-19 were associated with higher humoral and T-cell responses. A weak correlation between long-term loss of taste/smell and low IgA levels was found at early time points. These data indicate a long-lasting immunological memory against SARS-CoV-2 after mild COVID-19.

Keywords: COVID-19; SARS-CoV-2; cellular immunity; humoral immunity; persistent symptoms.

Figure 1

Flow cytometric gating strategy of AIM assay to identify specific T-helper cells (THC), and central memory T-cell (Tcm) and effector memory T-cell (Tem) subsets from a participant included in the study: (A) lymphocytes (Gate P1) were gated using forward and side scatter; (B) gated on P1: THC (Gate P2) were defined by co-expression of CD3 and CD4; (D) gated on P2: specific THC (Gate P3) were analyzed as CD25 high/CD134 high double-positive cell population after stimulation with SARS-CoV-2; (C) borders of Gate P3 were defined by means of unstimulated THC population; (F) gated on P3: specific THC were further divided into Tcm and Tem; (E) borders between Tcm, Tem and naïve T-cells were defined by unstimulated THC.

Figure 2

Consort diagram for this prospective study.

Figure 3

(A) Frequency of symptoms in patients after mild COVID-19 lasting at least 1, 3, 6 and 12 months, respectively, given in percentage. Correlation matrix displaying the co-occurrence of long-term symptoms for at least 1 (B), 3 (C), 6 (D) and 12 (E) months after COVID-19. Color intensity and the size of the circle are proportional to the correlation coefficients.

Figure 4

Course of IgA/IgG antibody level (A,B) and specific T-cells (C,D) over time. Black lines in boxplots represent median values. * p < 0.001 significant value. At 12-months measurement points, only non-vaccinated participants were considered.

Figure 5

Correlation analyses of humoral and cellular immunity assays in non-vaccinated participants at 12-months follow-up: (A) IgG value vs. IgA value; (B) titer of Nab vs. IgA value; (C) titer of Nab vs. IgG value; (D) INFg⁺ T-cells vs. specific THC; (E) IgG value vs. specific THC; (F) titer of Nab vs. specific THC; Nab, neutralizing antibody; THC, T-helper cells; SI, stimulation index.