Immune responses after SARS-CoV-2 infection and/or vaccination

From the start of the COVID-19 pandemic, it was clear that studying immune responses after SARS-CoV-2 infection and later on, after vaccination, was of outmost importance in battling the pandemic. To understand immunological responses and their potential durability and robustness was key when planning and predicting the course of the pandemic, although the virus was continuously evolving. The overarching aim of the studies in this thesis was to investigate immune responses after SARS-CoV-2 infection and/or vaccination through the longitudinal blood and mucosal sampling from healthcare workers and COVID-19 patients in the ongoing and observational COVID-19 Immunity (COMMUNITY) study taking place at Danderyd Hospital, Stockholm, Sweden.

In study I, we included 2149 healthcare workers and determined the seroprevalence of SARS-CoV-2 antibodies in an early phase of the pandemic. We found a high seroprevalence (19%) compared to society in general at the time. We also reported symptoms and occupational exposure in relation to seroprevalence. We found that symptoms most associated with seroprevalence were anosmia and ageusia and a strong association between seroprevalence and patient contact exposure, implying an occupational risk for SARS-CoV-2 infection among healthcare workers.

In study II we investigated immune responses 8 months post infection in 370 healthcare workers and 51 hospitalized COVID-19 patients. We demonstrated a robust and long-lasting humoral and cellular response. We also studied the risk of reinfection by a three month PCR screening study of 252 seropositive and 48 seronegative participants. The results indicated that the risk of reinfection was substantially lower among healthcare workers who had experienced a previous SARS-CoV-2 infection.

In study III we investigated immune responses after a single dose of ChAdOx1 nCoV-19 vaccine in 82 healthcare workers with previous SARS-CoV-2 infection and compared them with 65 SARS-CoV-2 naïve participants that received two doses of the BNT162b2 mRNA vaccine. Our findings showed similar or higher responses in the group with hybrid immunity (infection followed by vaccination) despite having received a single dose, opening up for the possibility for a single dose vaccine regimen for previously infected individuals.

In study IV we proceeded to investigate long term humoral and cellular immune responses after hybrid immunization. Using longitudinally collected samples from 514 healthcare workers, both SARS-CoV-2 naïve and recovered, across different vaccine platforms and regimens, we found unanimously enhanced vaccine responses among those who had SARS-CoV-2 infection prior vaccination.

Finally, in study V we investigated the protective role of mucosal anti-spike IgA against Omicron infection in 338 triple-vaccinated healthcare workers. Participants with highest levels of mucosal anti-spike IgA were primarily individuals with prior SARS-CoV-2 infection. Additionally, we determined that those with highest levels of mucosal anti-spike IgA had a significantly lower risk of breakthrough infection compared to those with lower levels.

Taken together, these studies emphasize important aspects of SARS-CoV-2 infection and immune responses, which have been pivotal in addressing the challenges and developing strategies in the battle against the COVID-19 pandemic.

List of scientific papers

I. Rudberg AS*, Havervall S*, Månberg A, Jernbom Falk A, Aguilera K, Ng H, Gabrielsson L, Salomonsson AC, Hanke L, Murrell B, McInerney G, Olofsson J, Andersson E, Hellström C, Bayati S, Bergström S, Pin E, Sjöberg R, Tegel H, Hedhammar M, Phillipson M, Nilsson P, Hober S, Thålin C. SARS-CoV-2 exposure, symptoms and seroprevalence in healthcare workers in Sweden. Nature communications. 2020 11;1 5064-. *Contributed equally
https://doi.org/10.1038/s41467-020-18848-0

II. Havervall S*, Ng H*, Falk AJ*, Greilert-Norin N, Manberg A, Marking U, Lauren I, Gabrielsson L, Salomonsson AC, Aguilera K, Kihlgren M, Mansson M, Rosell A, Hellström C, Andersson E, Olofsson J, Skoglund L, Yousef J, Pin E, Lord M, Åberg M, Hedhammar M, Tegel H, Dönnes P, Phillipson M, Nilsson P, Klingström J, Mangsbo S, Hober S, Thålin C. Robust humoral and cellular immune responses and low risk for reinfection at least 8 months following asymptomatic to mild COVID19. Journal of Internal Medicine. 2022 291;1 72-80. *Contributed equally
https://doi.org/10.1111/joim.13387

III. Havervall S*, Marking U*, Greilert-Norin N, Ng H, Gordon M, Salomonsson AC, Hellström C, Pin E, Blom K, Mangsbo S, Phillipson M, Klingström J, Hober S, Nilsson P, Åberg M, Thålin C. Antibody responses after a single dose of ChAdOx1 nCoV-19 vaccine in healthcare workers previously infected with SARS-CoV-2. EBioMedicine. 2021 70; 103523-. *Contributed equally
https://doi.org/10.1016/j.ebiom.2021.103523

IV. Havervall S, Marking U, Greilert-Norin N, Gordon M, Ng H, Christ W, Phillipson M, Nilsson P, Hober S, Blom K, Klingström J, Mangsbo S, Åberg M, Thålin C. Impact of SARS-CoV-2 infection on vaccine-induced immune responses over time. Clinical & translational immunology. 2022 11;4 e1388-.
https://doi.org/10.1002/cti2.1388

V. Havervall S*, Marking U*, Svensson J, Greilert-Norin N, Bacchus P, Nilsson P, Hober S, Gordon M, Blom K, Klingström J, Åberg M, SmedSörensen A, Thålin C. Anti-Spike Mucosal IgA Protection against SARS-CoV-2 Omicron Infection. The New England journal of medicine. 2022 387;14 1333-1336. *Contributed equally
https://doi.org/10.1056/NEJMc2209651