T cell immunity induced by SARS-CoV-2 and flavivirus vaccination

<p dir="ltr">Emerging viruses is a continued threat to global public health and vaccines is the most effective medical intervention to reduce viral infectious disease. This thesis contains clinical studies that were conducted to better understand T cell responses to vaccination against SARS-CoV-2 and flaviviruses. Multiple vaccine platforms have been studied, including mRNA-based vaccines against COVID-19 and live attenuated or inactivated whole flavivirus vaccines. This thesis presents studies in the chronological order they were conducted, with Papers I-III focusing on SARS-CoV-2 and Paper IV on flaviviruses.</p><p dir="ltr">In Paper I, we studied the T cell response in patients with CLL after primary vaccination with the mRNA BNT162b2 vaccine. Using an IFN-y ELISpot assay, we longitudinally assessed an increased T cell response after two doses of mRNA BNT162b2. Compared to healthy individuals the T cell response was lower, indicating that a booster dose may be important to reach higher protective levels. In Paper II, a cohort of patients with CLL with hybrid immunity was studied to measure the adaptive immune response. Spike- and nucleocapsid-specific antibodies were measured in serum and saliva, and T cell responses were evaluated using an IFN-y ELISpot assay and AIM assay. A robust antibody response in serum and saliva, as well as in the T-cell compartment, was observed after three doses of mRNA vaccination in a hybrid setting of CLL patients. In Paper III, we studied the relationship between SARS-CoV-2 and HCoV-OC43 T cells in unexposed individuals to better understand pre-existing immunity to SARS-CoV-2. We mapped and identified several T cell epitopes in spike, nucleocapsid and membrane regions of SARS-CoV-2 and OC43 using a FluroSpot assay.</p><p dir="ltr">In Paper IV, we longitudinally assessed the T cell response in a clinical cohort of healthy participants co-administrated with YFV vaccine and either TBEV or JEV vaccines. Using an AIM assay, we measured the frequency of activated CD4+ and CD8+ T cells specific for envelope (E), capsid (C) and non-structural (NS) 5 proteins. We detected robust T cell responses after flavivirus vaccination that was primarily directed against envelope. Comparing single vaccinated individuals with concomitant vaccinated participants revealed strikingly similar results. Across all vaccine cohorts, limited cross-reactivity between different flaviviruses, including Zika peptides, was observed. Detectable cross-reactive responses were more prominent for CD8+ T cells. In conclusion, this study demonstrates that co-vaccination elicits responses comparable to single administration and importantly, does not diminish the virus-specific T cell response.</p><p dir="ltr">The clinical studies in this thesis have expanded our understanding of T cells in the viral vaccine response. These findings offer valuable insights into the immune mechanisms induced by infection with and vaccination against emerging viruses.</p><h3>List of scientific papers</h3><p dir="ltr">I. Blixt, L *. , <b>Wullimann, D</b> *. , Aleman, S., Lundin, J., Chen, P., Gao, Y., Cuapio, A., Akber, M., Lange, J., Rivera-Ballesteros, O., Buggert, M., Ljunggren, H. G., Hansson, L., & Österborg, A. (2022). T-cell immune responses following vaccination with mRNA BNT162b2 against SARS-CoV-2 in patients with chronic lymphocytic leukemia: results from a prospective open-label clinical trial. Haematologica, 107(4), 1000-1003. *Joint first authors.<br><a href="https://doi.org/10.3324/haematol.2021.280300" rel="noreferrer" target="_blank">https://doi.org/10.3324/haematol.2021.280300</a><br><br></p><p dir="ltr">II. Blixt, L., Gao, Y *. , <b>Wullimann, D</b> *. , Murén Ingelman-Sundberg, H., Muschiol, S., Healy, K., Bogdanovic, G., Pin, E., Nilsson, P., Kjellander, C., Grifoni, A., Sette, A., Sällberg Chen, M., Ljunggren, H. G., Buggert, M., Hansson, L., & Österborg, A. (2022). Hybrid immunity in immunocompromised patients with CLL after SARS-CoV-2 infection followed by booster mRNA vaccination. Blood, 140(22), 2403-2407. * Authors contributed equally.<br><a href="https://doi.org/10.1182/blood.2022016815" rel="noreferrer" target="_blank">https://doi.org/10.1182/blood.2022016815<br><br></a></p><p dir="ltr">III. Humbert, M., Olofsson, A., <b>Wullimann, D.</b>, Niessl, J., Hodcroft, E. B., Cai, C., Gao, Y., Sohlberg, E., Dyrdak, R., Mikaeloff, F., Neogi, U., Albert, J., Malmberg, K. J., Lund-Johansen, F., Aleman, S., Björkhem- Bergman, L., Jenmalm, M. C., Ljunggren, H. G., Buggert, M., & Karlsson, A. C. (2023). Functional SARS-CoV-2 cross-reactive CD4+ T cells established in early childhood decline with age. Proceedings of the National Academy of Sciences of the United States of America, 120(12), e2220320120. <br><a href="https://doi.org/10.1073/pnas.2220320120" rel="noreferrer" target="_blank">https://doi.org/10.1073/pnas.2220320120<br><br></a></p><p dir="ltr">IV. <b>Wullimann, D.</b>, Sandberg, J. T., Akber, M., Löfling, M., Gredmark-Russ, S., Michaëlsson, J., Buggert, M., Blom, K., & Ljunggren, H. G. (2025). Antigen-specific T cell responses following single and co- administration of tick-borne encephalitis, Japanese encephalitis, and yellow fever virus vaccines: Results from an open-label, non- randomized clinical trial-cohort. PLoS neglected tropical diseases, 19(2), e0012693.<br><a href="https://doi.org/10.1371/journal.pntd.0012693" rel="noreferrer" target="_blank">https://doi.org/10.1371/journal.pntd.0012693</a></p>