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• Robertson, Anna Hayman; Wolf, Asia-Sophia Fumika Michaela; Fossum, Even; Solum, Guri; Bhandari, Sabin & Vikse, Elisabeth Lea [Show all 12 contributors for this article] (2026). Long-lasting cross-reactive and polyfunctional SARS-CoV-2 T cell responses in seniors are maintained after repeated vaccination and infections. Vaccine. ISSN 0264-410X. 80, p. 1–12. doi: 10.1016/j.vaccine.2026.128511. Full text in Research Archive
• Mukherjee, Ratnadeep; Eggesbø, Linn Margrethe; Wolf, Asia-Sophia Fumika Michaela; Kjønstad, Ingrid Fadum; Solum, Guri & Ravussin, Anthony [Show all 13 contributors for this article] (2024). Mass cytometry reveals cellular correlates of immune response heterogeneity to SARS-CoV-2 vaccination in the elderly. npj Vaccines. 9(1). doi: 10.1038/s41541-024-01028-2. Full text in Research Archive
• Wolf, Asia-Sophia Fumika Michaela; Hammersbøen, Kristin Reine; Ørbo, Hilde Sofie Sager; Bhandari, Sabin; Solum, Guri & Kjønstad, Ingrid Fadum [Show all 30 contributors for this article] (2024). T cell responses to repeated SARS-CoV-2 vaccination and breakthrough infections in patients on TNF inhibitor treatment: a prospective cohort study. EBioMedicine. 108. doi: 10.1016/j.ebiom.2024.105317. Full text in Research Archive Show summary

  Background Understanding cellular responses to SARS-CoV-2 immunisations is important for informing vaccine recommendations in patients with inflammatory bowel disease (IBD) and other vulnerable patients on immunosuppressive therapies. This study investigated the magnitude and quality of T cell responses after multiple SARS-CoV-2 vaccine doses and COVID-19 breakthrough infection. Methods This prospective, observational study included patients with IBD and arthritis on tumour necrosis factor inhibitors (TNFi) receiving up to four SARS-CoV-2 vaccine doses. T cell responses to SARS-CoV-2 peptides were measured by flow cytometry before and 2–4 weeks after vaccinations and breakthrough infection to assess the frequency and polyfunctionality of responding cells, along with receptor-binding domain (anti-RBD) antibodies. Findings Between March 2, 2021, and December 20, 2022, 143 patients (118 IBD, 25 arthritis) and 73 healthy controls were included. In patients with either IBD or arthritis, humoral immunity was attenuated compared to healthy controls (median anti-RBD levels 3391 vs. 6280 BAU/ml, p = 0.008) after three SARS-CoV-2 vaccine doses. Patients with IBD had comparable quantities (median CD4 0.11% vs. 0.11%, p = 0.26, CD8 0.031% vs. 0.047%, p = 0.33) and quality (polyfunctionality score: 0.403 vs. 0.371, p = 0.39; 0.105 vs. 0.101, p = 0.87) of spike-specific T cells to healthy controls. Patients with arthritis had lower frequencies but comparable quality of responding T cells to controls. Breakthrough infection increased spike-specific CD8 T cell quality and T cell responses against non-spike peptides. Interpretation Patients with IBD on TNFi have T cell responses comparable to healthy controls despite attenuated humoral responses following three vaccine doses. Repeated vaccination and breakthrough infection increased the quality of T cell responses. Our study adds evidence that, in the absence of other risk factors, this group may in future be able to follow the general recommendations for COVID-19 vaccines.

• Ørbo, Hilde Sofie Sager; Kasahara, Taissa de Matos; Wolf, Asia-Sophia Fumika Michaela; Bjørlykke, Kristin Hammersbøen; Sexton, Joseph & Jyssum, Ingrid [Show all 24 contributors for this article] (2024). Humoral and cellular responses to a fifth bivalent SARS-CoV-2 vaccine dose in patients with immune-mediated inflammatory diseases on tumour necrosis factor inhibitors: a prospective cohort study. The Lancet Regional Health - Europe. 48. doi: 10.1016/j.lanepe.2024.101121. Full text in Research Archive Show summary

  Background As most people now have established hybrid immunity, the need for regular, updated SARS-CoV-2 vaccine boosters in patients with immune-mediated inflammatory diseases (IMIDs) is unclear. The study aim was to assess humoral and cellular immunogenicity of a fifth bivalent vaccine dose in patients with IMID on tumour necrosis factor inhibitors (TNFi). Methods In the longitudinal, observational Nor-vaC study, we assessed anti-spike and neutralising antibodies against Wuhan, Omicron BA.1 and BA.4, as well as frequency and polyfunctionality of responding T cells, following a fourth monovalent and a fifth bivalent (BA.1 or BA.4/5) vaccine dose in patients with or without hybrid immunity using TNFi. Findings Between December 17, 2021, and June 20, 2023, 456 infection-naïve patients with IMIDs using TNFi received a fourth vaccine dose and were otherwise eligible for inclusion. A total of 373/456 (82%) received a fifth vaccine dose, of these 190/373 (51%) had hybrid immunity defined as having had COVID-19 between the fourth and fifth dose. In patients with hybrid immunity, the fifth dose did not induce improved humoral responses compared to infection, neither with BA.1 (median anti-spike antibody concentrations 23,244 IU/ml (IQR 15,138–45,233) vs 36,341 IU/ml (11,887–53,710), p = 0.52) nor BA.4/5 (31,693 IU/ml (15,176–54,186), p = 0.30). Comparison of neutralising antibodies yielded similar results. In infection-naïve patients, a fifth BA.4/5 vaccine, but not the BA.1, induced slightly higher humoral responses (18,890 IU/ml (6494–50,211)) compared to the fourth dose (7304 IU/ml (3245–17,260), p < 0.0001). CD8 T cell responses remained stable following a fourth dose (median frequency of spike-specific cells 0.039% (IQR 0.010–0.14)), infection (0.058% (0.026–0.17)) and a fifth dose (0.058% (0.013–0.20). Interpretation In patients on TNFi with hybrid immunity, there was no immunological benefit of an updated fifth SARS-CoV-2 booster dose. Stable CD8 cellular responses following four doses indicate established protective immunity. Patients whose only risk factor is TNFi may in future follow vaccine recommendations for the general population.

• Ravussin, Anthony; Robertson, Anna Hayman; Wolf, Asia-Sophia Fumika Michaela; Blix, Kristine; Kjønstad, Ingrid Fadum & Solum, Guri [Show all 13 contributors for this article] (2023). Determinants of humoral and cellular immune responses to three doses of mRNA SARS-CoV-2 vaccines in older adults: a longitudinal cohort study. The Lancet Healthy Longevity. 4(5), p. e188–e199. doi: 10.1016/S2666-7568(23)00055-7. Full text in Research Archive Show summary

  Background Older age is associated with poorer outcomes to COVID-19 infection. The Norwegian Institute of Public Health established a longitudinal cohort of adults aged 65–80 years to study the effects of the COVID-19 pandemic. Here we describe the characteristics of the cohort in general, and specifically the immune responses at baseline and after primary and booster vaccination in a subset of longitudinal blood samples, and the epidemiological factors affecting these responses. Methods 4551 participants were recruited, with humoral (n=299) and cellular (n=90) responses measured before vaccination and after two and three vaccine doses. Information on general health, infections, and vaccinations were obtained from questionnaires and national health registries. Findings Half of the participants had a chronic condition. 849 (18·7%) of 4551 were prefrail and 184 (4%) of 4551 were frail. 483 (10·6%) of 4551 had general activity limitations (scored with the Global Activity Limitation Index). After dose two, 295 (98·7%) of 299 participants were seropositive for anti-receptor binding domain IgG, and 210 (100%) of 210 participants after dose three. Spike-specific CD4 and CD8 T cell responses showed high heterogeneity after vaccination and responded to the alpha (B.1.1.7), delta (B.1.617.2), and omicron (B.1.1.529 or BA.1) variants of concern. Cellular responses to seasonal coronaviruses increased after SARS-CoV-2 vaccination. Heterologous prime boosting with mRNA vaccines was associated with the highest antibody (p=0·019) and CD4 T cell responses (p=0·003), and hypertension with lower antibody levels after three doses (p=0·04). Interpretation Most older adults, including those with comorbidities, generated good serological and cellular responses after two vaccine doses. Responses further improved after three doses, particularly after heterologous boosting. Vaccination also generated cross-reactive T cells against variants of concern and seasonal coronaviruses. Frailty was not associated with impaired immune responses, but hypertension might indicate reduced responsiveness to vaccines even after three doses. Individual differences identified through longitudinal sampling enables better prediction of the variability of vaccine responses, which can help guide future policy on the need for subsequent doses and their timing.

• Wolf, Asia-Sophia Fumika Michaela; Ravussin, Anthony; König, Marton; Øverås, Mathias Herstad; Solum, Guri & Kjønstad, Ingrid Fadum [Show all 18 contributors for this article] (2023). T cell responses to SARS-CoV-2 vaccination differ by disease-modifying therapy for multiple sclerosis. JCI Insight. 8(12), p. 1–14. doi: 10.1172/jci.insight.165111. Full text in Research Archive Show summary

  Immune responses in people with multiple sclerosis (pwMS) receiving disease-modifying therapies (DMTs) have been of significant interest throughout the COVID-19 pandemic. Lymphocyte-targeting immunotherapies, including anti-CD20 treatments and sphingosine-1-phosphate receptor (S1PR) modulators, attenuate Ab responses after vaccination. Evaluation of cellular responses after vaccination, therefore, is of particular importance in these populations. In this study, we used flow cytometry to analyze CD4 and CD8 T cell functional responses to SARS-CoV-2 spike peptides in healthy control study participants and pwMS receiving 5 different DMTs. Although pwMS receiving rituximab and fingolimod therapies had low Ab responses after both 2 and 3 vaccine doses, T cell responses in pwMS taking rituximab were preserved after a third vaccination, even when an additional dose of rituximab was administered between vaccine doses 2 and 3. PwMS taking fingolimod had low detectable T cell responses in peripheral blood. CD4 and CD8 T cell responses to SARS-CoV-2 variants of concern Delta and Omicron were lower than to the ancestral Wuhan-Hu-1 variant. Our results indicate the importance of assessing both cellular and humoral responses after vaccination and suggest that, even in the absence of robust Ab responses, vaccination can generate immune responses in pwMS.

• Malecki, Jedrzej Mieczyslaw; Willemen, Hanneke L.D.M.; Pinto, Rita; Ho, Angela Yeuan Yen; Moen, Anders & Kjønstad, Ingrid Fadum [Show all 10 contributors for this article] (2018). Lysine methylation by the mitochondrial methyltransferase FAM173B optimizes the function of mitochondrial ATP synthase. Journal of Biological Chemistry. ISSN 0021-9258. 294(4), p. 1128–1141. doi: 10.1074/jbc.RA118.005473. Full text in Research Archive Show summary

  Lysine methylation is an important post-translational modification that is also present on mitochondrial proteins, but the mitochondrial lysine-specific methyltransferases (KMTs) responsible for modification are in most cases unknown. Here, we set out to determine the function of human family with sequence similarity 173 member B (FAM173B), a mitochondrial methyltransferase (MTase) reported to promote chronic pain. Using bioinformatics analyses and biochemical assays, we found that FAM173B contains an atypical, noncleavable mitochondrial targeting sequence responsible for its localization to mitochondria. Interestingly, CRISPR/Cas9-mediated KO of FAM173B in mammalian cells abrogated trimethylation of Lys-43 in ATP synthase c-subunit (ATPSc), a modification previously reported as ubiquitous among metazoans. ATPSc methylation was restored by complementing the KO cells with enzymatically active human FAM173B or with a putative FAM173B orthologue from the nematode Caenorhabditis elegans. Interestingly, lack of Lys-43 methylation caused aberrant incorporation of ATPSc into the ATP synthase complex and resulted in decreased ATP-generating ability of the complex, as well as decreased mitochondrial respiration. In summary, we have identified FAM173B as the long-sought KMT responsible for methylation of ATPSc, a key protein in cellular ATP production, and have demonstrated functional significance of ATPSc methylation. We suggest renaming FAM173B to ATPSc-KMT (gene name ATPSCKMT).

• Bugge, Marit; Bergstrøm, Bjarte; Eide, Oda K.; Solli, Helene; Kjønstad, Ingrid Fadum & Stenvik, Jørgen [Show all 8 contributors for this article] (2017). Surface Toll-Like Receptor 3 Expression in Metastatic Intestinal Epithelial Cells induces Selective Cytokine Production and Promotes Invasiveness. Journal of Biological Chemistry. ISSN 0021-9258. 292(37), p. 15408–15425. doi: 10.1074/jbc.M117.784090. Full text in Research Archive Show summary

  Toll-like receptors (TLR)s are innate immune receptors for microbial molecules and also sense damage-associated molecular patterns released from host cells. Double-stranded RNA and the synthetic analog polyinosinic:polycytidylic acid (Poly(I:C)) bind and activate TLR3. This leads to recruitment of the adaptor molecule TRIF (Toll-IL-1-resistance (TIR) domain-containing adaptor-inducing interferon β (IFNβ)), and downstream activation of the transcription factors nuclear factor κB (NF-κB) and interferon regulatory factor 3 (IRF-3), classically inducing IFNβ production. In this study we report that metastatic intestinal epithelial cells (IEC)s express TLR3, in contrast to non-metastatic IECs, and that TLR3 activation promotes the invasive properties of these cells. The metastatic IECs also induced CXCL10 in a TLR3- TRIF- IRF3- dependent manner in response to Poly(I:C) addition, but failed to produce IFNβ. This was in contrast to healthy and non-metastatic IECs which did not respond to Poly(I:C) stimulation. The endosomal transporter protein UNC93B1 and endolysosomal acidification was required for Poly(I:C) induced CXCL10 production, underscoring the role of endosomes in TLR3 activation. TLR3- induced CXCL10 was, however, triggered by immobilized ligand, was only modestly affected by inhibition of endocytosis, and could be blocked with an anti-TLR3 antibody, indicating that TLR3 still can signal from the cell surface of these cells. Plasma membrane fractions of metastatic IECs furthermore contained both full-length and cleaved TLR3. Our results imply that metastatic IECs express surface TLR3, allowing it to sense extracellular stimuli, which triggers chemokine responses, and promotes invasiveness in these cells. Altered TLR3 expression and localization may have implications for disease progression.

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• Bugge, Marit; EIde, Oda Kamilla; Solli, Helene; Kjønstad, Ingrid Fadum; Stenvik, Jørgen & Bergstrøm, Bjarte [Show all 8 contributors for this article] (2018). SURFACE TOLL-LIKE RECEPTOR 3 EXPRESSION IN METASTATIC INTESTINAL EPITHELIAL CELLS INDUCES INFLAMMATORY CYTOKINE PRODUCTION AND PROMOTES INVASIVENESS. Full text in Research Archive
• Bugge, Marit; Bergstrøm, Bjarte Aune; Eide, Oda K.; Solli, Helene; Kjønstad, Ingrid Fadum & Stenvik, Jørgen [Show all 8 contributors for this article] (2017). Surface Toll-Like Receptor 3 Expression in Metastatic Intestinal Epithelial Cells induces Inflammatory Cytokine Production and Promotes Invasiveness. Full text in Research Archive
• Nilsen, Nadra J.; Espevik, Terje; Gjerdingen, Thea Johannne; Bugge, Marit & Kjønstad, Ingrid Fadum (2015). A TOLL-LIKE RECEPTOR 7/8 LIGAND SECRETED BY MYELOMA CELLS INDUCES PRIMARY BONE MARROW STROMAL CELLS TO PRODUCE CYTOKINES THAT PROMOTE MYELOMA SURVIVAL. Full text in Research Archive
• Almaas, Eivind; Lale, Rahmi; Andersen, Maria; Moghaddam, Shiva; Stormo, Ellen & Adl, Patricia [Show all 7 contributors for this article] (2014). Syntetisk biologi. [TV]. Schrödingers Katt . Full text in Research Archive

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