Adaptive immune responses to tick-borne encephalitis virus and SARS-CoV-2

Tick-borne encephalitis virus (TBEV) and SARS-CoV-2 are two unrelated viruses that currently cause substantially different public health burdens and distinct pathologies in humans. TBEV infection leads to neurological symptoms of varying severity, while SARS-CoV-2 primarily targets the respiratory tract. The aims of this thesis were to estimate the relative level of mortality due to TBE in Sweden (Paper I) and to describe the human adaptive immune responses to TBE vaccination (Paper II), TBEV infection (Paper III), and SARS-CoV-2 infection (Papers IV-V).

In Paper I, we measured the standardized mortality ratio (SMR) in TBE patients and found that, compared to a matched control population, TBE patients experience around a four-times higher mortality within 90 days after the diagnosis. Considering that TBE is a vaccinepreventable disease, this finding highlights the need for increased vaccination efforts for people at risk of exposure to TBEV.

In Paper II, we assessed memory T cell responses throughout the primary immunization schedule with TBE (three doses within one year). We observed a heterogenous magnitude of memory CD4+ T cell response in the TBE vaccinated individuals, with the highest magnitude after the 2nd dose. Compared to TBE patients, TBE vaccinees had fewer polyfunctional memory CD4+ T cells and lower IFN-g responses. This study suggests that the TBE vaccine elicits a lower quality of CD4+ T cell memory compared to TBE infection and highlights the need for the development of improved TBE vaccines.

In Paper III, we assessed the antibody-secreting cell (ASC) responses and TBEV-specific antibody levels in TBE patients at varying timepoints after hospitalization. ASC expansion is typically a hallmark of early B cell responses during acute infections. Compared to dengue patients, who served as a control cohort in this study, low frequencies of ASCs were detected in TBE patients at all four sampling timepoints (i.e., <7, 7-13, 14-30 and >30 days after hospitalization). In addition, all TBE patients had detectable TBEV-specific IgM and IgG antibody levels throughout the course of the study. These findings indicate that the early B cell response may take place even earlier during TBE, likely before hospitalization.

In Papers IV and V, we investigated germinal center activity, ASC responses and antibody levels during the acute SARS-CoV-2 infection in hospitalized COVID-19 patients. We observed an increased germinal center activity and ASC expansion in COVID-19 patients. In Paper V, we subsequently detected polyfunctional memory T cell and memory B cell responses in previously hospitalized recovered COVID-19 patients at 5 and 9 months after symptom onset. This finding indicates that immunological memory to SARS-CoV-2 persists for at least up to 9 months regardless of COVID-19 severity at hospitalization. In conclusion, this thesis contributes to the understanding of TBEV and SARS-CoV-2 infections, particularly in relation to the adaptive human immune responses to these viruses.

List of scientific papers

I. Varnaitė R, Gredmark-Russ S and Klingström J. Mortality in tick-borne encephalitis and other reportable zoonotic infectious diseases in Sweden. [Manuscript]

II. Varnaitė R, Blom K, Lampen MH, Vene S, Thunberg S, Lindquist L, Ljunggren H-G, Rombo L, Askling HH and Gredmark-Russ S. Magnitude and functional profile of the human CD4+ T cell response throughout primary immunization with tick-borne encephalitis virus vaccine. 2020. The Journal of Immunology. 204(4): 914-922.
https://doi.org/10.4049/jimmunol.1901115

III. Varnaitė R, Mayola Danés N, Asgeirsson H, Ljunggren H-G, Blom K and Gredmark-Russ S. Characterization of human B cell responses and specific antibody levels in tick-borne encephalitis patients. [Manuscript]

IV. Varnaitė R, García M, Glans H, Maleki KT, Sandberg JT, Tynell J, Christ W, Lagerqvist N, Asgeirsson H, Ljunggren H-G, Ahlén G, Frelin L, Sällberg M, Blom K, Klingström J and Gredmark-Russ S. Expansion of SARS-CoV-2– specific antibody-secreting cells and generation of neutralizing antibodies in hospitalized COVID-19 patients. 2020. The Journal of Immunology. 205(9):2437-2446.
https://doi.org/10.4049/jimmunol.2000717

V. Sandberg JT*, Varnaitė R*, Christ W, Chen P, Muvva JR, Maleki KT, García M, Dzidic M, Folkesson E, Skagerberg M, Ahlén G, Frelin L, Sällberg M, Eriksson LI, Rooyackers O, Sönnerborg A, Buggert M, Björkström NK, Aleman S, Strålin K, Klingström J, Ljunggren H-G, Blom K, Gredmark-Russ S & The Karolinska COVID-19 Study Group. SARS-CoV-2-specific humoral and cellular immunity persists through 9 months irrespective of COVID-19 severity at hospitalisation. 2021. Clinical & Translational Immunology. 10(7):e1306. *Contributed equally.
https://doi.org/10.1002/cti2.1306