22 research outputs found
T cell immunity induced by SARS-CoV-2 and flavivirus vaccination
No full textEmerging 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.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.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.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.List of scientific papersI. Blixt, L *. , Wullimann, D *. , 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.https://doi.org/10.3324/haematol.2021.280300II. Blixt, L., Gao, Y *. , Wullimann, D *. , 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.https://doi.org/10.1182/blood.2022016815III. Humbert, M., Olofsson, A., Wullimann, D., 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. https://doi.org/10.1073/pnas.2220320120IV. Wullimann, D., 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.https://doi.org/10.1371/journal.pntd.0012693</p
Discovery of candidate biomarkers for purification of atrial and ventricular cardiomyocytes derived from human pluripotent stemcells : Version 2
No full textAtlas of early zebrafish brain development : a tool for molecular neurogenetics /
No full textThis book remains the only neuroanatomical expression atlas of important genetic and immunohistochemical markers of this vertebrate model system. It represents a key reference and interpretation matrix for analyzing expression domains of genes involved in Zebrafish brain development and neurogenesis, and serves as a continuing milestone in this research area. This updated volume provides in-situ hybridized and immunostained preparations of complete series of brain sections, revealing markers of the fundamental stages in the life history of neuronal cells in very high quality preparations and photographic plates. Specific additions to this edition include documentation on the distribution of neurons expressing GABA, dopamine and serotonin, material on the basal ganglia, hypothalamus, and the caudal, segmented part of the diencephalon, new theories on the early organization of the telencephalon and thalamus, and integration of a comparative perspective on the mid- and hindbrain.Includes list of abbreviations, bibliographical references (pages 27-237), and index.This book remains the only neuroanatomical expression atlas of important genetic and immunohistochemical markers of this vertebrate model system. It represents a key reference and interpretation matrix for analyzing expression domains of genes involved in Zebrafish brain development and neurogenesis, and serves as a continuing milestone in this research area. This updated volume provides in-situ hybridized and immunostained preparations of complete series of brain sections, revealing markers of the fundamental stages in the life history of neuronal cells in very high quality preparations and photographic plates. Specific additions to this edition include documentation on the distribution of neurons expressing GABA, dopamine and serotonin, material on the basal ganglia, hypothalamus, and the caudal, segmented part of the diencephalon, new theories on the early organization of the telencephalon and thalamus, and integration of a comparative perspective on the mid- and hindbrain.Print version record.Elsevie
Circadian rhythmicity and light sensitivity of the zebrafish brain
No full textLight is important for entraining circadian rhythms, which regulate a wide range of biological processes. Zebrafish have directly light responsive tissues (Whitmore et al 2000) and are thus a useful vertebrate model for circadian rhythmicity and light sensitivity. Recent studies show the pineal regulates locomotor rhythms (Li et al 2012). However, there are many unresolved questions concerning the neurobiological basis of the zebrafish clock, such as whether neuronal pacemakers, which drive rhythms in other tissues, are present throughout the brain. In this study, per3-luc zebrafish confirm that both central and peripheral tissues are directly light sensitive and have endogenous circadian rhythmicity. Chromogenic in situ hybridization reveals localised expression of several core zebrafish clock genes, a rhythmic gene, per3, and two light responsive genes, cry1a and per2. Adult brain nuclei with expression include the suprachiasmatic nucleus, periventricular grey zone of the optic tectum, and granular cells of the rhombencephalon. Pilot experiments using high-resolution spatial recording of per3-luc brain slices show some of these regions can display robust rhythmicity in DD. Some of the cells expressing clock genes are neurons, and therefore neurons were further investigated. C-fos, a marker for neuronal activity in mammalian photoreceptors, is upregulated in at least four different responses to light in zebrafish, in different brain nuclei. This suggests the brain contains several types of photosensitive cells, which respond to different lighting conditions. Zebrafish larvae exhibit developmental changes in spatial circadian gene expression of per3 and light induction of c-fos. Finally, the photopigment group of opsins were investigated for their potential role in light entrainment. Exorh was prominent solely in the pineal. Rgr1 was found in numerous nuclei, many of which had shown expression of cry1a, per2 and per3. Overall, this thesis shows that the zebrafish brain is not uniformly light sensitive. Localised regions in the zebrafish brain with strong rhythmicity and light sensitivity are neuronal pacemaker candidates
Functional SARS-CoV-2 cross-reactive CD4+ T cells established in early childhood decline with age.
No full textPre-existing SARS-CoV-2-reactive T cells have been identified in SARS-CoV-2-unexposed individuals, potentially modulating COVID-19 and vaccination outcomes. Here, we provide evidence that functional cross-reactive memory CD4+ T cell immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is established in early childhood, mirroring early seroconversion with seasonal human coronavirus OC43. Humoral and cellular immune responses against OC43 and SARS-CoV-2 were assessed in SARS-CoV-2-unexposed children (paired samples at age two and six) and adults (age 26 to 83). Pre-existing SARS-CoV-2-reactive CD4+ T cell responses targeting spike, nucleocapsid, and membrane were closely linked to the frequency of OC43-specific memory CD4+ T cells in childhood. The functional quality of the cross-reactive memory CD4+ T cell responses targeting SARS-CoV-2 spike, but not nucleocapsid, paralleled OC43-specific T cell responses. OC43-specific antibodies were prevalent already at age two. However, they did not increase further with age, contrasting with the antibody magnitudes against HKU1 (β-coronavirus), 229E and NL63 (α-coronaviruses), rhinovirus, Epstein-Barr virus (EBV), and influenza virus, which increased after age two. The quality of the memory CD4+ T cell responses peaked at age six and subsequently declined with age, with diminished expression of interferon (IFN)-γ, interleukin (IL)-2, tumor necrosis factor (TNF), and CD38 in late adulthood. Age-dependent qualitative differences in the pre-existing SARS-CoV-2-reactive T cell responses may reflect the ability of the host to control coronavirus infections and respond to vaccination
Immunodeficiency syndromes differentially impact the functional profile of SARS-CoV-2-specific T cells elicited by mRNA vaccination
No full textMany immunocompromised patients mount suboptimal humoral immunity after SARS-CoV-2 mRNA vaccination. Here, we assessed the single-cell profile of SARS-CoV-2-specific T cells post-mRNA vaccination in healthy individuals and patients with various forms of immunodeficiencies. Impaired vaccine-induced cell-mediated immunity was observed in many immunocompromised patients, particularly in solid-organ transplant and chronic lymphocytic leukemia patients. Notably, individuals with an inherited lack of mature B cells, i.e., X-linked agammaglobulinemia (XLA) displayed highly functional spike-specific T cell responses. Single-cell RNA-sequencing further revealed that mRNA vaccination induced a broad functional spectrum of spike-specific CD4(+) and CD8(+) T cells in healthy individuals and patients with XLA. These responses were founded on polyclonal repertoires of CD4(+) T cells and robust expansions of oligoclonal effector-memory CD45RA(+) CD8(+) T cells with stem-like characteristics. Collectively, our data provide the functional continuum of SARS-CoV-2-specific T cell responses post-mRNA vaccination, highlighting that cell-mediated immunity is of variable functional quality across immunodeficiency syndromes
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
No full textRobust T Cell Immunity in Convalescent Individuals with Asymptomatic or Mild COVID-19
No full textSARS-CoV-2-specific memory T cells will likely prove critical for long-term immune protection against COVID-19. Here, we systematically mapped the functional and phenotypic landscape of SARS-CoV-2-specific T cell responses in unexposed individuals, exposed family members, and individuals with acute or convalescent COVID-19. Acute-phase SARS-CoV-2-specific T cells displayed a highly activated cytotoxic phenotype that correlated with various clinical markers of disease severity, whereas convalescent-phase SARS-CoV-2-specific T cells were polyfunctional and displayed a stem-like memory phenotype. Importantly, SARS-CoV-2-specific T cells were detectable in antibody-seronegative exposed family members and convalescent individuals with a history of asymptomatic and mild COVID-19. Our collective dataset shows that SARS-CoV-2 elicits broadly directed and functionally replete memory T cell responses, suggesting that natural exposure or infection may prevent recurrent episodes of severe COVID-19
Local and Systemic Immunity During Five Vaccinations Against SARS-CoV-2 in Zanubrutinib-Treated Patients With Chronic Lymphocytic Leukemia
No full textBackground: Patients with chronic lymphocytic leukemia (CLL) are vulnerable to coronavirus disease 2019 (COVID-19) and are at risk of inferior response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination, especially if treated with the first-generation Bruton’s tyrosine kinase inhibitor (BTKi) ibrutinib. We aimed to evaluate the impact of the third-generation BTKi, zanubrutinib, on systemic and mucosal response to SARS-CoV-2 vaccination. Methods: Nine patients with CLL with ongoing zanubrutinib therapy were included and donated blood and saliva during SARS-CoV-2 vaccination, before vaccine doses 3 and 5 and 2 - 3 weeks after doses 3, 4, and 5. Ibrutinib-treated control patients (n = 7) and healthy aged-matched controls (n = 7) gave blood 2 - 3 weeks after vaccine dose 5. We quantified reactivity and neutralization capacity of SARS-CoV-2-specific IgG and IgA antibodies (Abs) in both serum and saliva, and reactivity of T cells activated with viral peptides. Results: Both zanubrutinib- and ibrutinib-treated patients had significantly, up to 1,000-fold, lower total spike-specific Ab levels after dose 5 compared to healthy controls (P < 0.01). Spike-IgG levels in serum from zanubrutinib-treated patients correlated well to neutralization capacity (r = 0.68; P < 0.0001) and were thus functional. Mucosal immunity (specific IgA in serum and saliva) was practically absent in zanubrutinib-treated patients even after five vaccine doses, whereas healthy controls had significantly higher levels (tested in serum after vaccine dose 5) (P < 0.05). In contrast, T-cell reactivity against SARS-CoV-2 peptides was equally high in zanubrutinib- and ibrutinib-treated patients as in healthy control donors. Conclusions: In our small cohort of zanubrutinib-treated CLL patients, we conclude that up to five doses of SARS-CoV-2 vaccination induced no detectable IgA mucosal immunity, which likely will impair the primary barrier defence against the infection. Systemic IgG responses were also impaired, whereas T-cell responses were normal. Further and larger studies are needed to evaluate the impact of these findings on disease protection.In the publication, Mikael Åberg i misspelled as Mikael Aberg</p
