Differential decline of SARS‐CoV‐2‐specific antibody levels, innate and adaptive immune cells, and shift of Th1/inflammatory to Th2 serum cytokine levels long after first COVID‐19

• Published in: Allergy (Copenhagen) Vol. 79; no. 9; pp. 2482 - 2501
• Main Authors: Kratzer, Bernhard, Gattinger, Pia, Trapin, Doris, Ettel, Paul, Körmöczi, Ulrike, Rottal, Arno, Stieger, Robert B., Sehgal, Al Nasar Ahmed, Feichter, Melanie, Borochova, Kristina, Tulaeva, Inna, Grabmeier‐Pfistershammer, Katharina, Tauber, Peter A., Perkmann, Thomas, Fae, Ingrid, Wenda, Sabine, Kundi, Michael, Fischer, Gottfried F., Valenta, Rudolf, Pickl, Winfried F.
• Format: Journal Article
• Language: English
• Published: Denmark Blackwell Publishing Ltd 01.09.2024
• Subjects: Adaptive Immunity - immunology; Adult; Aged; Antibodies; Antibodies, Viral - blood; Antibodies, Viral - immunology; Blood flow; CD19 antigen; CD19+CD27+ B memory cells; CD27 antigen; CD3 antigen; CD45RA antigen; CD56 antigen; Complications; Coronavirus Nucleocapsid Proteins - immunology; COVID-19; COVID-19 - blood; COVID-19 - immunology; Cytokines; Cytokines - blood; Effector cells; Female; Flow cytometry; Humans; Immune response (humoral); Immunity, Innate; Immunoglobulin D; Immunological memory; Infections; L-selectin; Leukocytes (granulocytic); leukopenia; Longitudinal Studies; long‐term effect; Lymphocytes B; Lymphocytes T; Male; Memory cells; Middle Aged; Monocytes; Morbidity; Natural killer cells; Nucleocapsids; recent thymic emigrants; SARS-CoV-2 - immunology; SARS‐CoV‐2; Severe acute respiratory syndrome coronavirus 2; specific antibody decline; Spike Glycoprotein, Coronavirus - immunology; Th1 Cells - immunology; Th1 Cells - metabolism; Th1/Th2 cytokine shift; Th2 Cells - immunology; Thymus; Vaccination; CD19+CD27+ B memory cells; leukopenia; specific antibody decline; COVID‐19; Th1/Th2 cytokine shift; SARS‐CoV‐2; long‐term effect; recent thymic emigrants
• ISSN: 0105-4538; 1398-9995; 1398-9995
• DOI: 10.1111/all.16210

Background SARS‐CoV‐2 has triggered a pandemic and contributes to long‐lasting morbidity. Several studies have investigated immediate cellular and humoral immune responses during acute infection. However, little is known about long‐term effects of COVID‐19 on the immune system. Methods We performed a longitudinal investigation of cellular and humoral immune parameters in 106 non‐vaccinated subjects ten weeks (10 w) and ten months (10 m) after their first SARS‐CoV‐2 infection. Peripheral blood immune cells were analyzed by multiparametric flow cytometry, serum cytokines were examined by multiplex technology. Antibodies specific for the Spike protein (S), the receptor‐binding domain (RBD) and the nucleocapsid protein (NC) were determined. All parameters measured 10 w and 10 m after infection were compared with those of a matched, noninfected control group (n = 98). Results Whole blood flow cytometric analyses revealed that 10 m after COVID‐19, convalescent patients compared to controls had reduced absolute granulocyte, monocyte, and lymphocyte counts, involving T, B, and NK cells, in particular CD3+CD45RA+CD62L+CD31+ recent thymic emigrant T cells and non‐class‐switched CD19+IgD+CD27+ memory B cells. Cellular changes were associated with a reversal from Th1‐ to Th2‐dominated serum cytokine patterns. Strong declines of NC‐ and S‐specific antibody levels were associated with younger age (by 10.3 years, p < .01) and fewer CD3−CD56+ NK and CD19+CD27+ B memory cells. Changes of T‐cell subsets at 10 m such as normalization of effector and Treg numbers, decline of RTE, and increase of central memory T cell numbers were independent of antibody decline pattern. Conclusions COVID‐19 causes long‐term reduction of innate and adaptive immune cells which is associated with a Th2 serum cytokine profile. This may provide an immunological mechanism for long‐term sequelae after COVID‐19. COVID‐19 leads to a sustained reduction of immune cells of the myeloid and lymphoid cell lineages even 10 months after the first infection. Ten months after the first infection, S‐ and RBD‐specific IgG responses declined below the detection limit in almost 18% and in more than 80% in subjects, respectively. Anti‐NC antibodies remained positive in all subjects 10 m after the first infection. A shift towards a Th2 cytokine pattern in serum accompanied by an inversion of the IFN‐γ/IL‐4‐ratio was found between the time point 10 weeks and 10 months after infection.Abbreviations: CD, cluster of differentiation; COVID‐19, coronavirus disease 2019; IL, interleukin; IFN, interferon; NC, nucleocapsid protein; NK, natural killer; RBD, receptor binding domain; RTE, recent thymic emigrants; S, spike protein; SARS‐CoV‐2, severe acute respiratory syndrome coronavirus 2.