Background The burden and duration of persistent symptoms after non-severe COVID-19 remains uncertain. This study aimed to assess post-infection symptom trajectories in home-isolated COVID-19 cases compared to age- and time-period matched seronegative controls, and investigate immunological correlates of long COVID. Methods A prospective case-control study conducted between February 28th and April 4th 2020 included home-isolated COVID-19 cases followed for 12 (n = 233) to 18 (n = 149) months, and 189 age-matched SARS-CoV-2 naive controls. We collected clinical data at baseline, 6, 12 and 18 months post-infection, and blood samples at 2, 4, 6 and 12 months for analysis of SARS-CoV-2 specific humoral and cellular responses. Results Overall, 46% (108/233) had persisting symptoms 12 months after COVID-19. Compared to controls, adult cases had a high risk of fatigue (27% excess risk, gender and comorbidity adjusted odds ratio [aOR] 5.86, 95% confidence interval [CI]3.27-10.5), memory problems (21% excess risk, aOR 7.42, CI 3.51-15.67), concentration problems (20% excess risk, aOR 8.88, CI 3.88-20.35), and dyspnea (10% excess risk, aOR 2.66, CI 1.22-5.79). The prevalence of memory problems increased overall from 6 to 18 months (excess risk 11.5%, CI 1.5, 21.5, p = 0.024) and among women (excess risk 18.7%, CI 4.4, 32.9, p = 0.010). Longitudinal spike IgG was significantly associated with dyspnea at 12 months. The spike-specific clonal CD4 + TCRβ depth was significantly associated with both dyspnea and number of symptoms at 12 months. Conclusions This study documents a high burden of persisting symptoms after mild COVID-19, and suggest that infection induced SARS-CoV-2 specific immune responses may influence long-term symptoms.

Background Neutralizing antibodies are important for protection against the pandemic SARS-CoV-2 virus, and long-term memory responses determine the risk of re-infection or boosting after vaccination. T-cellular responses are considered important for partial protection against novel variants of concern. Methods A prospective cohort of hospitalized (n = 14) and community (n = 38) patients with rt-PCR confirmed SARS-CoV-2 infection were recruited. Blood samples and clinical data were collected when diagnosed and at 6 months. Serum samples were analyzed for SARS-CoV-2-spike specific antibodies using ELISA (IgG, IgA, IgM), pseudotype neutralization and microneutralization assays. Peripheral blood mononuclear cells were investigated for virus-specific T-cell responses in the interferon-γ and interleukin-2 fluorescent-linked immunosorbent spot (FluroSpot) assay. Results We found durable SARS-CoV-2 spike- and internal protein specific T-cellular responses in patients with persistent antibodies at 6 months. Significantly higher IL-2 and IFN-γ secreting T-cell responses as well as SARS-CoV-2 specific IgG and neutralizing antibodies were detected in hospitalized compared to community patients. The immune response was impacted by age, gender, comorbidity and severity of illness, reflecting clinical observations. Conclusions SARS-CoV-2 specific T-cellular and antibody responses persisted for 6 months post confirmed infection. In previously infected patients, re-exposure or vaccination will boost long-term immunity, possibly providing protection against re-infection with variant viruses.

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Background Evaluation of susceptibility to emerging SARS-CoV-2 variants of concern (VOC) requires rapid screening tests for neutralising antibodies which provide protection. Methods Firstly, we developed a receptor-binding domain-specific haemagglutination test (HAT) to Wuhan and VOC (alpha, beta, gamma and delta) and compared to pseudotype, microneutralisation and virus neutralisation assays in 835 convalescent sera. Secondly, we investigated the antibody response using the HAT after two doses of mRNA (BNT162b2) vaccination. Sera were collected at baseline, three weeks after the first and second vaccinations from older (80–99 years, n = 89) and younger adults (23–77 years, n = 310) and compared to convalescent sera from naturally infected individuals (1–89 years, n = 307). Results Here we show that HAT antibodies highly correlated with neutralising antibodies (R = 0.72–0.88) in convalescent sera. Home-dwelling older individuals have significantly lower antibodies to the Wuhan strain after one and two doses of BNT162b2 vaccine than younger adult vaccinees and naturally infected individuals. Moverover, a second vaccine dose boosts and broadens the antibody repertoire to VOC in naïve, not previously infected older and younger adults. Most (72–76%) older adults respond after two vaccinations to alpha and delta, but only 58–62% to beta and gamma, compared to 96–97% of younger vaccinees and 68–76% of infected individuals. Previously infected older individuals have, similarly to younger adults, high antibody titres after one vaccination. Conclusions Overall, HAT provides a surrogate marker for neutralising antibodies, which can be used as a simple inexpensive, rapid test. HAT can be rapidly adaptable to emerging VOC for large-scale evaluation of potentially decreasing vaccine effectiveness.