B cell responses to human flavivirus vaccination and SARS-CoV-2 infection

Viral infections pose a major threat to global heath. As specific antiviral treatments are lacking against many human viruses, vaccination is the most effective medical intervention to prevent severe disease and death. Delineating the immune events following viral vaccination and infection can help in the design of new vaccines and therapeutics. The aims of this thesis were to characterize human B cell responses following yellow fever virus (YFV) vaccination (Paper I), following concomitant vaccination with YFV and the Tick-borne encephalitis virus (TBEV) vaccine or Japanese encephalitis virus (JEV) vaccine (Paper II), and during acute and convalescent SARS-CoV-2 infection (Papers III and IV).

In Paper I, healthy volunteers were vaccinated with the YFV vaccine and blood samples were taken at up to five time points afterwards to characterize the magnitude, kinetics, and specificity of the humoral immune response. Activation in the Th1-polarized circulating T follicular helper cell population was observed 7 days following vaccination, coinciding with increased germinal center activity as measured by serum CXCL13 levels. Peak YFV-E specific plasmablast expansion was observed at day 14 following vaccination. Additionally, the frequencies of IgG+ plasmablasts at day 14 correlated with day 90 neutralizing antibody (nAb) titer magnitude, suggesting that plasmablasts may be used as an early marker indicating later protective immunity. YFV-E specific memory B cells were also detectable at day 28 and 90 as well as protective titers of nAbs. These findings provide insights into immune events that lead to the development of B cell immunity following YFV vaccination.

In Paper II, we investigated the feasibility and effectiveness of concomitant vaccination with YFV vaccines and either TBEV or JEV vaccines. 145 healthy volunteers were recruited into a prospective open label, non-randomized clinical trial and received either YFV, TBEV, or JEV vaccines only or YFV vaccine with either TBEV or JEV vaccines. Blood and serum samples were taken at baseline and up to ten timepoint following vaccination. The development of virus-specific nAbs was not affected by concomitant vaccination when comparing the vaccine cohorts. Importantly adverse events were mild and not affected by concomitant vaccination suggesting that the vaccination strategy should be considered effective and safe.

In Papers III and IV, early immune events and ultimately immune memory was investigated in COVID-19 patients during and after hospitalization. Increased germinal center activity with a Th1-polarized circulating T follicular helper cell activation was observed that coincided with SARS-CoV-2-specific expanded antibody secreting cells during acute COVID-19. The majority of patients also had detectable levels of nAbs during acute disease. In Paper IV, SARS-CoV-2-specific nAb titers persisted in patients at 5- and 9-months post infection as well as virus-specific polyfunctional memory T cells and memory B cells regardless of COVID-19 severity during hospitalization. Together, the findings in this thesis contribute to our understanding of humoral responses to different types of flavivirus vaccines as well as infection with SARS-CoV-2.

List of scientific papers

I. Sandberg JT, Ols S, Löfling M, Varnaitė R, Lindgren G, Nilsson O, Rombo L, Kalén M, Loré K, Blom K, and Ljunggren HG. Activation and Kinetics of Circulating T Follicular Helper Cells, Specific Plasmablast Response and Development of Neutralizing Antibodies Following Yellow Fever Virus Vaccination. Journal of Immunology. 2021, 207 (4), pp. 1033-1043.
https://doi.org/10.4049/jimmunol.2001381

II. Sandberg JT, Löfling M, Varnaitė R, Emgård J, Al-Tawil N, Lindquist L, Gredmark-Russ S, Klingström J, Loré K, Blom K, and Ljunggren HG. Safety and immunological responses of concomitant vaccination with flavivirus vaccines: results from an open label non-randomized clinical trial. [Manuscript]

III. Varnaitė R, Garcia M, Glans H*, Maleki KT*, Sandberg JT*, Tynell J, Christ W, Lagerqvist N, Asgeirsson H, Ljunggren HG, 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. Journal of Immunology. 2020, 205 (9), pp. 2437-2446. *Authors contributed equally.
https://doi.org/10.4049/jimmunol.2000717

IV. Sandberg JT*, Varnaitė R*, Christ W, Chen P, Muvva JR, Maleki KT, Garcia 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 HG, Blom K, Gredmark-Russ S, and The Karolinska COVID-19 Study Group. SARS-CoV-2-specific humoral and cellular immunity persists through 9 months irrespective of COVID-19 severity at hospitalization. Clinical & Translational Immunology. 2021, 10: e1306. *Joint first authors.
https://doi.org/10.1002/cti2.1306