Abstract Immune responses in people with multiple sclerosis (pwMS) on 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 antibody responses after vaccination. Evaluation of cellular responses after vaccination is therefore of particular importance in these populations. In this study, we analysed CD4 and CD8 T cell functional responses to SARS-CoV-2 spike peptides in healthy controls and pwMS on five different DMTs by flow cytometry. Although pwMS on anti-CD20 and S1PR therapies had low antibody responses after both 2 and 3 vaccine doses, T cell responses in pwMS on anti-CD20 therapies were preserved after a third vaccination, even when additional anti-CD20 treatment was administered between vaccine doses 2 and 3. PwMS taking S1PR modulators 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 antibody responses vaccination can generate immune responses in pwMS.
Abstract Cytokine-induced memory-like (CIML) NK cells generated in response to proinflammatory cytokines in vitro and in vivo can also be generated by vaccination, exhibiting heightened responses to cytokine stimulation months after their initial induction. Our previous study demonstrated that in vitro human NK cell responses to inactivated influenza virus were also indirectly augmented by very low doses of IL-15, which increased induction of myeloid cell–derived cytokine secretion. These findings led us to hypothesize that IL-15 stimulation could reveal a similar effect for active influenza vaccination and influence CIML NK cell effector functions. In this study, 51 healthy adults were vaccinated with seasonal influenza vaccine, and PBMC were collected before and up to 30 d after vaccination. Myeloid and lymphoid cell cytokine secretion was measured after in vitro PBMC restimulation with low-dose IL-15, alone or in combination with inactivated H3N2 virus; the associated NK cell response was assessed by flow cytometry. PBMC collected 30 d postvaccination showed heightened cytokine production in response to IL-15 compared with PBMC collected at baseline; these responses were further enhanced when IL-15 was combined with H3N2. NK cell activation in response to IL-15 alone (CD25) and H3N2 plus IL-15 (CD25 and IFN-γ) was enhanced postvaccination. We also observed proliferation of less-differentiated NK cells with downregulation of cytokine receptors as early as 3 d after vaccination, suggesting cytokine stimulation in vivo. We conclude that vaccination-induced “training” of accessory cells combines with the generation of CIML NK cells to enhance the overall NK cell response postvaccination.
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 following 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 21 healthy controls were included. In both IBD and arthritis patients, 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. IBD patients had a comparable quantity (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. Arthritis patients had lower frequency, but comparable quality, of responding T cells to controls and IBD patients. Breakthrough infection increased spike-specific CD8 T cell quality and T cell responses against non-spike peptides. Interpretation: IBD patients 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 and breadth of T cell responses. Our results indicate that IBD patients on TNFi treatment may follow the same COVID-19 vaccine recommendations as the healthy population in future. Funding: South-Eastern Norway Regional Health Authority, Coalition for Epidemic Preparedness Innovations (CEPI), Norwegian Institute of Public Health, Akershus University Hospital, Diakonhjemmet Hospital.Declaration of Interest: KHB reports funding from Akershus University Hospital and speaker bureaus for Janssen-Cilag. TKK reports grants from AbbVie, BMS, Galapagos, Novartis, Pfizer, UCB, speakers’ bureaus from Grünenthal, Janssen, Sandoz, consultant fees from AbbVie, Gilead, Janssen, Novartis, Pfizer, Sandoz, UCB, and participation on advisory board for AbbVie. JJ reports grants from Boehringer-Ingelheim, speakers bureaus from AbbVie/Abbott, Bristol-Myers, Squibb, Galapagos, Gilead, Janssen, Pfizer, Roche, Sandoz, Takeda, consultant fees from AbbVie/Abbott, Pfizer, and participation in advisory board for AbbVie/Abbott, Bristol-Myers Squibb, Galapagos, Gilead, Janssen, Pfizer, Roche, Sandoz, Takeda. LAM reports funding from KG Jebsen foundation, support for infrastructure and biobanking from the university of Oslo and Oslo University Hospital, grants from the Coalition of Epidemic Preparedness Innovations (CEPI), speakers bureaus from Incyte, Janssen, and expert testimony for Norwegian Medicines Agency. EAH reports speakers’ bureaus from Pfizer, UCB, Novartis, and consulting fees from Abbvie, Pfizer, Eli Lilly. GG reports speaker bureaus from AbbVie/Abbott, Galapagos, Pfizer, UCB, participation in advisory board from AstraZeneca, Janssen, Moderna, Seqirus. and consulting fees from The Norwegian System of Patient Injury Compensation. JTV reports grant from CEPI. FLJ reports funding from South-East Health Authorities in Norway, CEPI and Oslo University Hospital. GLG reports speakers’ bureaus from AbbVie/Abbott, Galapagos, Pfizer, UCB, and participation in advisory board from AbbVie/Abbott, Galapagos, Pfizer, UCB, Novartis. KKJ reports speakers’ bureaus from Bristol-Myers Squibb and Janssen, and participation in advisory board for AstraZeneca and IPSEN. SWS reports participation in advisory board for AstraZeneca. ASW, HSØ, SB, GS, IFK, IJ, UCN, ABK, IEC, SEJ, KPL, AC, ATT, JS, SAP, HK, and SM report nothing to disclose.Ethical Approval: The study was approved by the Norwegian Regional Committees for Medical and Health Research Ethics (reference numbers 235424 and 135924). Written informed consent was obtained from all the patients.
The SARS-CoV-2 Omicron variant has more than 15 mutations in the receptor binding domain of the Spike protein enabling increased transmissibility and viral escape from antibodies in vaccinated individuals. It is unclear how vaccine immunity protects against Omicron infection. Here we show that vaccinated participants at a super-spreader event have robust recall response of humoral and pre-existing cellular immunity induced by the vaccines, and an emergent de novo T cell response to non-Spike antigens. Individuals with Omicron SARS-CoV-2 breakthrough infections have significantly increased activated SARS-CoV-2 wild type Spike-specific cytotoxic T cells, activated follicular helper (T
Abstract The new SARS-CoV-2 variant of concern (VOC) Omicron has more than 30 mutations in the receptor binding domain (RBD) of the Spike protein enabling viral escape from antibodies in vaccinated individuals and increased transmissibility 1-6 . It is unclear how vaccine immunity protects against Omicron infection. Here we show that vaccinated participants at a superspreader event had robust recall response of humoral and pre-existing cellular immunity induced by the vaccines, and an emergent de novo T cell response to non-Spike antigens. We compared cases from a Christmas party where 81 of 110 (74%) developed Omicron breakthrough COVID-19 7 , with Delta breakthrough cases and vaccinated non-infected controls. Omicron cases had significantly increased activated SARS-CoV-2 wild type Spike-specific (vaccine) cytotoxic T cells, activated follicular helper (T FH ) cells, functional T cell responses, boosted humoral responses, activated anti-Spike plasmablasts and anti-RBD memory B cells compared to controls. Omicron cases had significantly increased de novo memory T cell responses to non-Spike viral antigens compared to Delta breakthrough cases demonstrating development of broad immunity. The rapid release of Spike and RBD-specific IgG + B cell plasmablasts and memory B cells into circulation suggested affinity maturation of antibodies and that concerted T and B cell immunity may provide durable broad immunity.
Abstract Heterogeneity in vaccine response, particularly in vulnerable populations like the elderly, represents a significant public health challenge. We conducted an in-depth examination of immune cell profiles before and after SARS-CoV-2 vaccination utilizing mass cytometry in a cohort of healthy Norwegian seniors (65–80 years). We have demonstrated that higher pre-vaccination frequencies of CD27+IgD− class-switched memory B cells and subsets of CD27−CD24+CD38+ transitional B cells were associated with a robust vaccine response. Post-vaccination, high responders exhibited increased frequencies of IFN-γ+CD4+ T cells with antigen recall and a concurrent decrease in TH17 cell subset frequencies compared to low responders. The presence of a γδ T cell subset displaying polyfunctional cytokine responses was also associated with better vaccine response in the elderly. This comprehensive analysis sheds light on inherent differences in immune cell frequencies and functions that should offer insights for targeted vaccination strategies in older populations.
Abstract Heterogeneity in vaccine response, particularly in vulnerable populations like the elderly, represents a significant public health challenge. We conducted an in-depth examination of immune cell profiles before and after SARS-CoV-2 vaccination utilizing mass cytometry in a cohort of healthy Norwegian seniors (65–80 years). We have demonstrated that higher pre-vaccination frequencies of CD27 + IgD - class-switched memory B cells and subsets of CD27 - CD24 + CD38 + transitional B cells were associated with a robust vaccine response. Post-vaccination, high responders exhibited increased frequencies of IFN-γ + CD4 + T cells with antigen recall and a concurrent decrease in CCR6(+) T H cell subset frequencies compared to low responders. The presence of a γδ T cell subset displaying polyfunctional cytokine responses was also associated with better vaccine response in the elderly. This in-depth profiling sheds light on inherent differences in immune cell frequencies and functions that may offer insights for targeted vaccination strategies in older populations.
Pneumococcal conjugate vaccine (PCV) efficacy is lower for noninvasive pneumonia than invasive disease. In this study, participants were immunized with 13-valent PCV (PCV13) or hepatitis A vaccine (control). Bronchoalveolar lavage samples were taken between 2 and 6 months and serum at 4 and 7 weeks postvaccination. In the lung, anti-capsular immunoglobulin G (IgG) levels were higher in the PCV13 group compared to controls for all serotypes, except 3 and 6B. Systemically, IgG levels were elevated in the PCV13 group at 4 weeks for all serotypes, except serotype 3. IgG in bronchoalveolar lavage and serum positively correlated for nearly all serotypes. PCV13 shows poor immunogenicity to serotype 3, implying lack of protective efficacy. Clinical Trials Registration. ISRCTN 45340436.
Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition with unknown aetiology, unclear pathophysiology and with no diagnostic test or biomarker available. Many patients report their ME/CFS began after an acute infection, and subsequent increased frequency of infections, such as colds or influenza, is common. These factors imply an altered immunological status exists in ME/CFS, in at least a proportion of patients, yet previous studies of peripheral immunity have been discrepant and inconclusive. The UK ME/CFS Biobank, which has collected blood samples from nearly 300 clinically-confirmed ME/CFS patients, enables large-scale studies of immunological function in phenotypically well-characterised participants. In this study, herpes virus serological status and T cell, B cell, NK cell and monocyte populations were investigated in 251 ME/CFS patients, including 54 who were severely affected, and compared with those from 107 healthy participants and with 46 patients with Multiple Sclerosis. There were no differences in seroprevalence for six human herpes viruses between ME/CFS and healthy controls, although seroprevalence for the Epstein-Barr virus was higher in multiple sclerosis patients. Contrary to previous reports, no significant differences were observed in NK cell numbers, subtype proportions or in vitro responsiveness between ME/CFS patients and healthy control participants. In contrast, the T cell compartment was altered in ME/CFS, with reduced proportions of effector memory CD8+ T cells and of intermediately differentiated CD8+ T cells in ME/CFS. Conversely, there was a significantly increased proportion of mucosal associated invariant T cells (MAIT) cells, especially in severely affected ME/CFS patients. These abnormalities demonstrate that an altered immunological state does exist in ME/CFS, particularly in severely affected people. This may simply reflect ongoing or recent infection, or may indicate future increased susceptibility to infection. Longitudinal studies of ME/CFS patients are needed to help to determine cause and effect and thus any potential benefits of immuno-modulatory treatments for ME/CFS.
Studies to develop cell-based therapies for cancer and other diseases have consistently shown that purified human natural killer (NK) cells secrete cytokines and kill target cells after in vitro culture with high concentrations of cytokines. However, these assays poorly reflect the conditions that are likely to prevail in vivo in the early stages of an infection and have been carried out in a wide variety of experimental systems, which has led to contradictions within the literature. We have conducted a detailed kinetic and dose-response analysis of human NK cell responses to low concentrations of IL-12, IL-15, IL-18, IL-21 and IFN-alpha, alone and in combination, and their potential to synergise with IL-2. We find that very low concentrations of both innate and adaptive common gamma chain cytokines synergise with equally low concentrations of IL-18 to drive rapid and potent NK cell CD25 and IFN-gamma expression; IL-18 and IL-2 reciprocally sustain CD25 and IL-18R alpha expression in a positive feedback loop; and IL-18 synergises with FcgRIII (CD16) signalling to augment antibody-dependent cellular cytotoxicity. These data indicate that NK cells can be rapidly activated by very low doses of innate cytokines and that the common gamma chain cytokines have overlapping but distinct functions in combination with IL-18. Importantly, synergy between multiple signalling pathways leading to rapid NK cell activation at very low cytokine concentrations has been overlooked in prior studies focusing on single cytokines or simple combinations. Moreover, although the precise common gamma chain cytokines available during primary and secondary infections may differ, their synergy with both IL-18 and antigen-antibody immune complexes underscores their contribution to NK cell activation during innate and adaptive responses.
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