Publications
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Liu Z, Alexander JL, Eng KY, et al., 2024, Antibody responses to influenza vaccination are diminished in patients with inflammatory bowel disease on infliximab or tofacitinib, Journal of Crohn's and Colitis, Vol: 18, Pages: 560-569, ISSN: 1873-9946
Background and aims:We sought to determine whether six commonly used immunosuppressive regimens were associated with lower antibody responses after seasonal influenza vaccination in patients with IBD.Methods:We conducted a prospective study including 213 IBD patients and 53 healthy controls; 165 who had received seasonal influenza vaccine and 101 who had not. IBD medications included infliximab, thiopurines, infliximab and thiopurine combination therapy, ustekinumab, vedolizumab or tofacitinib. The primary outcome was antibody responses against influenza/A H3N2 and A/H1N1, compared to controls, adjusting for age, prior vaccination and interval between vaccination and sampling.Results:Lower antibody responses against influenza A/H3N2 were observed in patients on infliximab (Geometric Mean Ratio 0.35 [95% CI 0.20-0.60], p=0.0002), combination of infliximab and thiopurine therapy (0.46 [0.27-0.79], p=0.0050) and tofacitinib (0.28 [0.14-0.57], p=0.0005) compared to controls. Lower antibody responses against A/H1N1 were observed in patients on infliximab (0.29 [0.15-0.56], p=0.0003), combination of infliximab and thiopurine therapy (0.34 [0.17-0.66], p=0.0016), thiopurine monotherapy (0.46 [0.24-0.87], p=0.017) and tofacitinib (0.23 [0.10-0.56], p=0.0013). Ustekinumab and vedolizumab were not associated with reduced antibody responses against A/H3N2 or A/H1N1. Vaccination in the previous year was associated with higher antibody responses to A/H3N2. Vaccine-induced anti-SARS-CoV-2 antibody concentration weakly correlated with antibodies against H3N2 (r=0.27; p=0.0004) and H1N1 (r=0.33; p<0.0001).Conclusions:Vaccination in both the 2020-2021 and 2021-2022 seasons was associated with significantly higher antibody responses to influenza/A than no vaccination or vaccination in 2021-2022 alone. Infliximab and tofacitinib are associated with lower binding antibody responses to Influenza/A, similar to COVID-19 vaccine-induced antibody responses. Funding:Financial support was
Negash M, Chanyalew M, Girma T, et al., 2024, Evidence for immune activation in pathogenesis of the HLA class II associated disease, podoconiosis., Nat Commun, Vol: 15
Available evidences suggest that podoconiosis is triggered by long term exposure of bare feet to volcanic red clay soil particles. Previous genome-wide studies in Ethiopia showed association between the HLA class II region and disease susceptibility. However, functional relationships between the soil trigger, immunogenetic risk factors and the immunological basis of the disease are uncharted. Therefore, we aimed to characterise the immune profile and gene expression of podoconiosis patients relative to endemic healthy controls. Peripheral blood immunophenotyping of T cells indicated podoconiosis patients had significantly higher CD4 and CD8 T cell surface HLA-DR expression compared to healthy controls while CD62L expression was significantly lower. The levels of the activation markers CD40 and CD86 were significantly higher on monocytes and dendritic cell subsets in patients compared to the controls. RNA sequencing gene expression data indicated higher transcript levels for activation, scavenger receptors, and apoptosis markers while levels were lower for histones, T cell receptors, variable, and constant immunoglobulin chain in podoconiosis patients compared to healthy controls. Our finding provides evidence that podoconiosis is associated with high levels of immune activation and inflammation with over-expression of genes within the pro-inflammatory axis. This offers further support to a working hypothesis of podoconiosis as soil particle-driven, HLA-associated disease of immunopathogenic aetiology.
Altmann DM, Boyton RJ, 2024, Arming up against Omicron subvariants., Cell Host Microbe, Vol: 32, Pages: 147-148
The rapid evolution of COVID-19 Omicron variants is driven by evasion of neutralizing antibodies. Breakthrough infections are common, even in highly vaccinated populations, making it vital to understand immune cross-protective repertoires to variants. Two studies in this issue show that the primed T cell repertoire comprises strong cross-recognition of current variants.
Abhishek A, Peckham N, Pade C, et al., 2024, Effect of a 2-week interruption in methotrexate treatment on COVID-19 vaccine response in people with immune-mediated inflammatory diseases (VROOM study): a randomised, open label, superiority trial., Lancet Rheumatol, Vol: 6, Pages: e92-e104
BACKGROUND: Methotrexate is the first-line treatment for immune-mediated inflammatory diseases and reduces vaccine-induced immunity. We evaluated if a 2-week interruption of methotrexate treatment immediately after COVID-19 booster vaccination improved antibody response against the S1 receptor binding domain (S1-RBD) of the SARS-CoV-2 spike protein and live SARS-CoV-2 neutralisation compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases. METHOD: We did a multicentre, open-label, parallel-group, randomised, superiority trial in secondary-care rheumatology and dermatology clinics in 26 hospitals in the UK. Adults (aged ≥18 years) with immune-mediated inflammatory diseases taking methotrexate (≤25 mg per week) for at least 3 months, who had received two primary vaccine doses from the UK COVID-19 vaccination programme were eligible. Participants were randomly assigned (1:1) using a centralised validated computer program, to temporarily suspend methotrexate treatment for 2 weeks immediately after COVID-19 booster vaccination or continue treatment as usual. The primary outcome was S1-RBD antibody titres 4 weeks after COVID-19 booster vaccination and was assessed masked to group assignment. All randomly assigned patients were included in primary and safety analyses. This trial is registered with ISRCTN, ISRCTN11442263; following a pre-planned interim analysis, recruitment was stopped early. FINDING: Between Sept 30, 2021, and March 7, 2022, we screened 685 individuals, of whom 383 were randomly assigned: to either suspend methotrexate (n=191; mean age 58·8 years [SD 12·5], 118 [62%] women and 73 [38%] men) or to continue methotrexate (n=192; mean age 59·3 years [11·9], 117 [61%] women and 75 [39%] men). At 4 weeks, the geometric mean S1-RBD antibody titre was 25 413 U/mL (95% CI 22 227-29 056) in the suspend methotrexate group and 12 326 U/mL (10 538-14 418) in
Altmann DM, Whettlock EM, Liu S, et al., 2023, The immunology of long COVID (vol 23, 618, 2023), NATURE REVIEWS IMMUNOLOGY, Vol: 23, Pages: 697-697, ISSN: 1474-1733
Liu Z, Alexander J, Le K, et al., 2023, Neutralising antibody responses against SARS-CoV-2 Omicron BA.4/5 and wild-type virus in patients with inflammatory bowel disease following three doses of COVID-19 vaccine (VIP): a prospective, multicentre, cohort study, EClinicalMedicine, Vol: 64, ISSN: 2589-5370
BackgroundPatients with inflammatory bowel disease (IBD) receiving anti-TNF and JAK-inhibitor therapy have attenuated responses to COVID-19 vaccination. We aimed to determine how IBD treatments affect neutralising antibody responses against the Omicron BA.4/5 variant.MethodsIn this multicentre cohort study, we prospectively recruited 340 adults (69 healthy controls and 271 IBD) at nine UK hospitals between May 28, 2021 and March 29, 2022. The IBD study population was established (>12 weeks therapy) on either thiopurine (n = 63), infliximab (n = 45), thiopurine and infliximab combination therapy (n = 48), ustekinumab (n = 45), vedolizumab (n = 46) or tofacitinib (n = 24). Patients were excluded if they were being treated with any other immunosuppressive therapies. Participants had two doses of either ChAdOx1 nCoV-19 or BNT162b2 vaccines, followed by a third dose of either BNT162b2 or mRNA1273. Pseudo-neutralisation assays against SARS-CoV-2 wild-type and BA.4/5 were performed. The half maximal inhibitory concentration (NT50) of participant sera was calculated. The primary outcome was anti-SARS-CoV-2 neutralising response against wild-type virus and Omicron BA.4/5 variant after the second and third doses of anti-SARS-CoV-2 vaccine, stratified by immunosuppressive therapy, adjusting for prior infection, vaccine type, age, and interval between vaccination and blood collection. This study is registered with ISRCTN (No. 13495664).FindingsBoth heterologous (first two doses adenovirus vaccine, third dose mRNA vaccine) and homologous (three doses mRNA vaccine) vaccination strategies significantly increased neutralising titres against both wild-type SARS-CoV-2 virus and the Omicron BA.4/5 variant in healthy participants and patients with IBD. Antibody titres against BA.4/5 were significantly lower than antibodies against wild-type virus in both healthy participants and patients with IBD (p < 0.0001). Multivariable models demonstrated that neutralising antibodies against
Salgado BB, Barbosa ARC, Arcanjo AR, et al., 2023, Hybrid immunity results in enhanced and more sustained antibody responses after the second Sinovac-Coronavac dose in a Brazilian cohort: DETECTCoV-19 cohort, Viruses, Vol: 15, ISSN: 1999-4915
We measured anti-SARS-CoV-2 antibody responses before and after CoronaVac (inactivated) vaccination in a case-control study performed in CoronaVac-immunized individuals participating in a longitudinal prospective study of adults in Manaus (DETECTCoV-19). Antibody responses were measured by standard serological immunoassays. Peak anti-S-RBD and neutralizing RBD-ACE2 blocking antibody responses after two doses of CoronaVac vaccine were similar in vaccine breakthrough cases (n = 9) and matched controls (n = 45). Individuals with hybrid immunity resulting from prior SARS-CoV-2 infection followed by vaccination (n = 22) had elevated levels of anti-N, anti-S-RBD and RBD-ACE2 blocking antibodies after the second vaccine dose compared to infection-naïve individuals (n = 48). Post-vaccination SARS-CoV-2-specific antibody responses rapidly waned in infection-naïve individuals. Antibody responses wane after vaccination, making individuals susceptible to infection by SARS-CoV-2 variants. These findings support the need for booster doses after primary vaccination. Population antibody serosurveys provide critical information toward implementing optimal timing of booster doses.
Altmann DM, Boyton RJ, 2023, Outsourcing covid-19 vaccination to the private sector will increase health inequalities, BMJ: British Medical Journal, Vol: 382, Pages: 2012-2012, ISSN: 0959-535X
Altmann DM, Reynolds CJ, Joy G, et al., 2023, Persistent symptoms after COVID-19 are not associated with differential SARS-CoV-2 antibody or T cell immunity, Nature Communications, Vol: 14, Pages: 1-9, ISSN: 2041-1723
Among the unknowns in decoding the pathogenesis of SARS-CoV-2 persistent symptoms in Long Covid is whether there is a contributory role of abnormal immunity during acute infection. It has been proposed that Long Covid is a consequence of either an excessive or inadequate initial immune response. Here, we analyze SARS-CoV-2 humoral and cellular immunity in 86 healthcare workers with laboratory confirmed mild or asymptomatic SARS-CoV-2 infection during the first wave. Symptom questionnaires allow stratification into those with persistent symptoms and those without for comparison. During the period up to 18-weeks post-infection, we observe no difference in antibody responses to spike RBD or nucleoprotein, virus neutralization, or T cell responses. Also, there is no difference in the profile of antibody waning. Analysis at 1-year, after two vaccine doses, comparing those with persistent symptoms to those without, again shows similar SARS-CoV-2 immunity. Thus, quantitative differences in these measured parameters of SARS-CoV-2 adaptive immunity following mild or asymptomatic acute infection are unlikely to have contributed to Long Covid causality. ClinicalTrials.gov (NCT04318314).
da Silva Duarte G, Jones AD, de Goes Cavalcanti LP, et al., 2023, Multicenter study of the natural history and therapeutic responses of patients with chikungunya, focusing on acute and chronic musculoskeletal manifestations - a study protocol from the clinical and applied research in Chikungunya (REPLICK network), BMC Infectious Diseases, Vol: 23, Pages: 1-12, ISSN: 1471-2334
BACKGROUND: Chikungunya is associated with high morbidity and the natural history of symptomatic infection has been divided into three phases (acute, post-acute, and chronic) according to the duration of musculoskeletal symptoms. Although this classification has been designed to help guide therapeutic decisions, it does not encompass the complexity of the clinical expression of the disease and does not assist in the evaluation of the prognosis of severity nor chronic disease. Thus, the current challenge is to identify and diagnose musculoskeletal disorders and to provide the optimal treatment in order to prevent perpetuation or progression to a potentially destructive disease course. METHODS: The study is the first product of the Clinical and Applied Research Network in Chikungunya (REPLICK). This is a prospective, outpatient department-based, multicenter cohort study in Brazil. Four work packages were defined: i. Clinical research; ii) Translational Science - comprising immunology and virology streams; iii) Epidemiology and Economics; iv) Therapeutic Response and clinical trials design. Scheduled appointments on days 21 (D21) ± 7 after enrollment, D90 ± 15, D120 ± 30, D180 ± 30; D360 ± 30; D720 ± 60, and D1080 ± 60 days. On these visits a panel of blood tests are collected in addition to the clinical report forms to obtain data on socio-demographic, medical history, physical examination and questionnaires devoted to the evaluation of musculoskeletal manifestations and overall health are performed. Participants are asked to consent for their specimens to be maintained in a biobank. Aliquots of blood, serum, saliva, PAXgene, and when clinically indicated to be examined, synovial fluid, are stored at -80° C. The study protocol was submitted and approved to the National IRB and local IRB at each study site. DISCUSSI
Altmann DM, Whettlock EM, Liu S, et al., 2023, The immunology of long COVID, Nature Reviews Immunology, ISSN: 1474-1733
Long COVID is the patient-coined term for the disease entity whereby persistent symptoms ensue in a significant proportion of those who have had COVID-19, whether asymptomatic, mild or severe. Estimated numbers vary but the assumption is that, of all those who had COVID-19 globally, at least 10% have long COVID. The disease burden spans from mild symptoms to profound disability, the scale making this a huge, new health-care challenge. Long COVID will likely be stratified into several more or less discrete entities with potentially distinct pathogenic pathways. The evolving symptom list is extensive, multi-organ, multisystem and relapsing-remitting, including fatigue, breathlessness, neurocognitive effects and dysautonomia. A range of radiological abnormalities in the olfactory bulb, brain, heart, lung and other sites have been observed in individuals with long COVID. Some body sites indicate the presence of microclots; these and other blood markers of hypercoagulation implicate a likely role of endothelial activation and clotting abnormalities. Diverse auto-antibody (AAB) specificities have been found, as yet without a clear consensus or correlation with symptom clusters. There is support for a role of persistent SARS-CoV-2 reservoirs and/or an effect of Epstein-Barr virus reactivation, and evidence from immune subset changes for broad immune perturbation. Thus, the current picture is one of convergence towards a map of an immunopathogenic aetiology of long COVID, though as yet with insufficient data for a mechanistic synthesis or to fully inform therapeutic pathways.
Boyton RJ, Altmann DM, 2023, Imprinted hybrid immunity against XBB reinfection, Lancet Infectious Diseases, Vol: 23, Pages: 764-765, ISSN: 1473-3099
Milighetti M, Peng Y, Tan C, et al., 2023, Large clones of pre-existing T cells drive early immunity against SARS-COV-2 and LCMV infection, iScience, Vol: 26, Pages: 1-20, ISSN: 2589-0042
T cell responses precede antibody and may provide early control of infection. We analyzed the clonal basis of this rapid response following SARS-COV-2 infection. We applied T cell receptor (TCR) sequencing to define the trajectories of individual T cell clones immediately. In SARS-COV-2 PCR+ individuals, a wave of TCRs strongly but transiently expand, frequently peaking the same week as the first positive PCR test. These expanding TCR CDR3s were enriched for sequences functionally annotated as SARS-COV-2 specific. Epitopes recognized by the expanding TCRs were highly conserved between SARS-COV-2 strains but not with circulating human coronaviruses. Many expanding CDR3s were present at high frequency in pre-pandemic repertoires. Early response TCRs specific for lymphocytic choriomeningitis virus epitopes were also found at high frequency in the preinfection naive repertoire. High-frequency naive precursors may allow the T cell response to respond rapidly during the crucial early phases of acute viral infection.
Liu Z, Alexander J, Le K, et al., 2023, Neutralising antibody responses against SARS-CoV-2 Omicron BA.4/5 and wild-type strain in patients with IBD after three doses of COVID-19 vaccine, Annual Meeting of the British-Society-of-Gastroenterology (BSG), Publisher: BMJ PUBLISHING GROUP, Pages: A89-A90, ISSN: 0017-5749
Boyton RJ, Altmann DM, 2023, Redirected vaccine imprinting by co-administration of COVID-19 and influenza vaccines, The Lancet Regional Health. Europe, Vol: 29, ISSN: 2666-7762
Le K, Zhou X, Alexander J, et al., 2023, Neutralising antibody potency against SARS-CoV-2 wild-type and Omicron BA.1 and BA.4/5 variants in infliximab and vedolizumab treated patients with Inflammatory Bowel Disease after three doses of COVID-19 vaccine: a prospective multicentre cohort study, Publisher: OXFORD UNIV PRESS, Pages: I32-I34, ISSN: 1873-9946
Liu Z, Alexander J, LIN K, et al., 2023, Infliximab and tofacitinib attenuate neutralizing antibody responses against SARS-CoV-2 ancestral and Omicron variants in IBD patients following 3 doses of COVID-19 vaccine, Gastroenterology, Vol: 164, Pages: 300-303.e3, ISSN: 0016-5085
Liu Z, Le K, Zhou X, et al., 2023, Neutralising antibody potency against SARS-CoV-2 wild-type and Omicron BA.1 and BA.4/5 variants in infliximab and vedolizumab treated patients with inflammatory bowel disease after three doses of COVID-19 vaccine: a prospective multicentre cohort study (CLARITY), The Lancet Gastroenterology & Hepatology, Vol: 8, Pages: 145-156, ISSN: 2468-1253
Background:Anti-tumour necrosis factor (TNF) drugs such as infliximab are associated with attenuated antibody responses after COVID-19 vaccination. It is unknown how infliximab impacts vaccine-induced serological responses against highly transmissible Omicron variants, which possess the ability to evade host immunity and are now the dominating variants causing current waves of infection. Methods:CLARITY IBD is a prospective, multicentre, observational cohort study investigating the impact of infliximab and vedolizumab on SARS-CoV-2 infection and vaccination in patients with inflammatory bowel disease (IBD). In the current work, the primary outcome was neutralising antibody responses against SARS-CoV-2 wild-type and Omicron BA.1 and BA.4/5 variants after three doses of COVID-19 vaccination in 1288 patients with IBD without prior COVID-19 infection, who were established on either infliximab (n=871) or vedolizumab (n=417). Cox proportional hazards models were constructed to investigate the risk of breakthrough infection in relation to neutralising antibody titres.Findings:Following three doses of COVID-19 vaccine, neutralising titre NT50 (half-inhibitory neutralising titre) was significantly diminished in patients treated with infliximab as compared to patients treated with vedolizumab, against wild-type (geometric mean [95% CI], 1990 [1781, 2223] vs 3212 [2780, 3712], p<0·0001), BA.1 (95·46 [82·80, 110·0] vs 599·1 [492·6, 728·6], p<0·0001) and BA.4/5 (30·73 [26·26, 35·96] vs 212·2 [177·0, 254·4], p<0·0001) variants. Breakthrough infection was significantly more frequent in patients treated with infliximab (13·66% [11·49%, 16·16%], 119/871) compared to patients treated with vedolizumab (6·95% [4·79%, 9·95%], 29/417, p=0·0004). Cox proportional hazards models of time to breakthrough infection after the third d
Liu Z, Alexander J, Le K, et al., 2023, P535 COVID-19 vaccine-induced neutralising antibody responses against SARS-CoV-2 Omicron BA.4/5 are diminished in patients with inflammatory bowel disease on anti-TNF or JAK-inhibitor therapy, Journal of Crohn's and Colitis, Vol: 17, Pages: i664-i664, ISSN: 1873-9946
BackgroundPatients with Inflammatory bowel disease (IBD) receiving anti-TNF or JAK-inhibitor therapy have attenuated responses to COVID-19 vaccination. We aimed to determine how IBD treatments affect neutralising antibody responses against the currently dominant Omicron BA.4/5 variants.MethodsWe prospectively recruited 329 adults (68 healthy controls (HC) and 261 IBD) who had received three doses of COVID-19 vaccine at nine UK centres. The IBD population was established (>12 weeks therapy) on either thiopurine (n=60), infliximab (IFX) (n=43), thiopurine & IFX combination (n=46), ustekinumab (n=43), vedolizumab (n=46) or tofacitinib (n=23). Pseudoneutralisation assays were performed and the half maximal inhibitory concentration (NT50) of participant sera was calculated. The primary outcome was anti-SARS-CoV-2 neutralising response against wild-type (WT) virus and the BA.4/5 variant after the second and third doses of anti-SARS-CoV-2 vaccine, stratified by immunosuppressive therapy, adjusting for prior infection, ethnicity, vaccine type and age.ResultsHeterologous (two doses adenovirus vaccine, third dose mRNA vaccine) and homologous (three doses mRNA vaccine) vaccination strategies significantly increased neutralising titres against both WT SARS-CoV-2 virus and the BA.4/5 variants in HCs and IBD (fig 1). Antibody titres against BA.4/5 were significantly lower than antibodies against WT virus in both groups (Geometric Mean Ratio (GMR) [95% CI], 0.11 [0.09, 0.15], P<0.0001 in healthy participants; GMR 0.07 [0.06, 0.08], P<0.0001 in IBD patients). Multivariable models showed that neutralising antibodies against BA.4/5 after three doses of vaccine were significantly lower in IBD patients on IFX (GMR 0.44 [0.20, 0.97], P=0.042), IFX and thiopurine combination (GMR 0.34 [0.15, 0.77], P=0.0098) or tofacitinib (GMR 0.37 [0.15, 0.92], P=0.032), but not in patients on thiopurine monotherapy, ustekinumab or vedolizumab. Breakthrough infection was associated with lo
Kennedy NA, Janjua M, Chanchlani N, et al., 2023, Vaccine escape, increased breakthrough and reinfection in infliximab-treated patients with IBD during the Omicron wave of the SARS-CoV-2 pandemic, Gut, Vol: 72, Pages: 295-305, ISSN: 0017-5749
Objective Antitumour necrosis factor (TNF) drugs impair serological responses following SARS-CoV-2 vaccination. We sought to assess if a third dose of a messenger RNA (mRNA)-based vaccine substantially boosted anti-SARS-CoV-2 antibody responses and protective immunity in infliximab-treated patients with IBD.Design Third dose vaccine induced anti-SARS-CoV-2 spike (anti-S) receptor-binding domain (RBD) antibody responses, breakthrough SARS-CoV-2 infection, reinfection and persistent oropharyngeal carriage in patients with IBD treated with infliximab were compared with a reference cohort treated with vedolizumab from the impaCt of bioLogic therApy on saRs-cov-2 Infection and immuniTY (CLARITY) IBD study.Results Geometric mean (SD) anti-S RBD antibody concentrations increased in both groups following a third dose of an mRNA-based vaccine. However, concentrations were lower in patients treated with infliximab than vedolizumab, irrespective of whether their first two primary vaccine doses were ChAdOx1 nCoV-19 (1856 U/mL (5.2) vs 10 728 U/mL (3.1), p<0.0001) or BNT162b2 vaccines (2164 U/mL (4.1) vs 15 116 U/mL (3.4), p<0.0001). However, no differences in anti-S RBD antibody concentrations were seen following third and fourth doses of an mRNA-based vaccine, irrespective of the combination of primary vaccinations received. Post-third dose, anti-S RBD antibody half-life estimates were shorter in infliximab-treated than vedolizumab-treated patients (37.0 days (95% CI 35.6 to 38.6) vs 52.0 days (95% CI 49.0 to 55.4), p<0.0001).Compared with vedolizumab-treated, infliximab-treated patients were more likely to experience SARS-CoV-2 breakthrough infection (HR 2.23 (95% CI 1.46 to 3.38), p=0.00018) and reinfection (HR 2.10 (95% CI 1.31 to 3.35), p=0.0019), but this effect was uncoupled from third vaccine dose anti-S RBD antibody concentrations. Reinfection occurred predominantly during the Omicron wave and was predicted by SARS-CoV-2 antinucleocapsid concentr
Milojkovic D, Reynolds CJ, Sandoval DM, et al., 2023, COVID-19 vaccine boosted immunity against Omicron in chronic myeloid leukemia patients treated with tyrosine kinase inhibitors, LEUKEMIA, Vol: 37, Pages: 244-247, ISSN: 0887-6924
Captur G, Moon JC, Topriceanu C-C, et al., 2022, Plasma proteomic signature predicts who will get persistent symptoms following SARS-CoV-2 infection, EBioMedicine, Vol: 85, Pages: 1-14, ISSN: 2352-3964
BACKGROUND: The majority of those infected by ancestral Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) during the UK first wave (starting March 2020) did not require hospitalisation. Most had a short-lived mild or asymptomatic infection, while others had symptoms that persisted for weeks or months. We hypothesized that the plasma proteome at the time of first infection would reflect differences in the inflammatory response that linked to symptom severity and duration. METHODS: We performed a nested longitudinal case-control study and targeted analysis of the plasma proteome of 156 healthcare workers (HCW) with and without lab confirmed SARS-CoV-2 infection. Targeted proteomic multiple-reaction monitoring analysis of 91 pre-selected proteins was undertaken in uninfected healthcare workers at baseline, and in infected healthcare workers serially, from 1 week prior to 6 weeks after their first confirmed SARS-CoV-2 infection. Symptom severity and antibody responses were also tracked. Questionnaires at 6 and 12 months collected data on persistent symptoms. FINDINGS: Within this cohort (median age 39 years, interquartile range 30-47 years), 54 healthcare workers (44% male) had PCR or antibody confirmed infection, with the remaining 102 (38% male) serving as uninfected controls. Following the first confirmed SARS-CoV-2 infection, perturbation of the plasma proteome persisted for up to 6 weeks, tracking symptom severity and antibody responses. Differentially abundant proteins were mostly coordinated around lipid, atherosclerosis and cholesterol metabolism pathways, complement and coagulation cascades, autophagy, and lysosomal function. The proteomic profile at the time of seroconversion associated with persistent symptoms out to 12 months. Data are available via ProteomeXchange with identifier PXD036590. INTERPRETATION: Our findings show that non-severe SARS-CoV-2 infection perturbs the plasma proteome for at least 6 weeks. The plasma proteomic signature at th
Alexander J, Liu Z, Munoz Sandoval D, et al., 2022, COVID-19 vaccine-induced antibody and T cell responses in immunosuppressed patients with inflammatory bowel disease after the third vaccine dose: a multicentre, prospective, case-control study, The Lancet Gastroenterology & Hepatology, Vol: 7, Pages: 1005-1015, ISSN: 2468-1253
Background:COVID-19 vaccine-induced antibody responses are reduced in patients with inflammatory bowel disease (IBD) taking anti-TNF or tofacitinib after two vaccine doses. We sought to determine whether immunosuppressive treatments were associated with reduced antibody and T cell responses after a third vaccine dose.Methods:352 adults (72 healthy controls and 280 IBD) were sampled 28-49 days after a third dose of SARS-CoV-2 vaccine. IBD medications studied included thiopurines (n=65), infliximab (n=46), thiopurine/infliximab combination therapy (n=49), ustekinumab (n=44), vedolizumab (n=50) or tofacitinib (n=26). SARS-CoV-2 spike antibody binding and T cell responses were measured. Findings:Geometric mean [geometric SD] anti-S1 RBD antibody concentrations increased in all groups following a third dose, but were significantly lower in patients treated with infliximab (2736.8 U/mL [4.3]; P<0.0001), infliximab and thiopurine combination (1818.3 U/mL [6.7]; P<0.0001) and tofacitinib (8071.5 U/mL [3.1]; P=0.0018) compared to controls (16774.2 U/ml [2.6]). There were no significant differences in anti-S1 RBD antibody concentrations between control subjects and thiopurine (12019.7 U/mL [2.2]; P=0.099), ustekinumab (11089.3 U/mL [2.8]; P=0.060), nor vedolizumab treated patients (13564.9 U/mL [2.4]; P=0.27). In multivariable modelling, lower anti-S1 RBD antibody concentrations were independently associated with infliximab (Geometric mean ratio 0.15, 95% CI 0.11-0.21, P<0.0001), tofacitinib (0.52, 95% CI 0.31-0.87, P=0.012) and thiopurine (0.69, 95% CI 0.51-0.95, P=0.021), but not with ustekinumab (0.64, 95% CI 0.39-1.06, P=0.083), or vedolizumab (0.84, 95% CI 0.54-1.30, P=0.43). Previous SARS-CoV-2 infection (1.58, 95% CI 1.22-2.05, P=0.00056) and older age (0.88, 95% CI 0.80-0.97, P=0.0073) were independently associated with higher and lower anti-S1 antibody concentrations respectively. Antigen specific T cell responses were similar in all groups, except for reci
de Morais Batista F, Puga MAM, da Silva PV, et al., 2022, Serum biomarkers associated with SARS-CoV-2 severity, Scientific Reports, Vol: 12, ISSN: 2045-2322
Immunity with SARS-CoV-2 infection during the acute phase is not sufficiently well understood to differentiate mild from severe cases and identify prognostic markers. We evaluated the immune response profile using a total of 71 biomarkers in sera from patients with SARS-CoV-2 infection, confirmed by RT-PCR and controls. We correlated biological marker levels with negative control (C) asymptomatic (A), nonhospitalized (mild cases-M), and hospitalized (severe cases-S) groups. Among angiogenesis markers, we identified biomarkers that were more frequently elevated in severe cases when compared to the other groups (C, A, and M). Among cardiovascular diseases, there were biomarkers with differences between the groups, with D-dimer, GDF-15, and sICAM-1 higher in the S group. The levels of the biomarkers Myoglobin and P-Selectin were lower among patients in group M compared to those in groups S and A. Important differences in cytokines and chemokines according to the clinical course were identified. Severe cases presented altered levels when compared to group C. This study helps to characterize biological markers related to angiogenesis, growth factors, heart disease, and cytokine/chemokine production in individuals infected with SARS-CoV-2, offering prognostic signatures and a basis for understanding the biological factors in disease severity.
Ascough S, Ingram RJ, Chu KKY, et al., 2022, Impact of HLA polymorphism on the immune response to bacillus anthracis protective antigen in vaccination versus natural infection, Vaccines, Vol: 10, Pages: 1-17, ISSN: 2076-393X
The causative agent of anthrax, Bacillus anthracis, evades the host immune response and establishes infection through the production of binary exotoxins composed of Protective Antigen (PA) and one of two subunits, lethal factor (LF) or edema factor (EF). The majority of vaccination strategies have focused upon the antibody response to the PA subunit. We have used a panel of humanised HLA class II transgenic mouse strains to define HLA-DR-restricted and HLA-DQ-restricted CD4+ T cell responses to the immunodominant epitopes of PA. This was correlated with the binding affinities of epitopes to HLA class II molecules, as well as the responses of two human cohorts: individuals vaccinated with the Anthrax Vaccine Precipitated (AVP) vaccine (which contains PA and trace amounts of LF), and patients recovering from cutaneous anthrax infections. The infected and vaccinated cohorts expressing different HLA types were found to make CD4+ T cell responses to multiple and diverse epitopes of PA. The effects of HLA polymorphism were explored using transgenic mouse lines, which demonstrated differential susceptibility, indicating that HLA-DR1 and HLA-DQ8 alleles conferred protective immunity relative to HLA-DR15, HLA-DR4 and HLA-DQ6. The HLA transgenics enabled a reductionist approach, allowing us to better define CD4+ T cell epitopes. Appreciating the effects of HLA polymorphism on the variability of responses to natural infection and vaccination is vital in planning protective strategies against anthrax.
Doykov I, Baldwin T, Spiewak J, et al., 2022, Quantitative, multiplexed, targeted proteomics for ascertaining variant specific SARS-CoV-2 antibody response, Cell Reports Methods, Vol: 2, Pages: 1-15, ISSN: 2667-2375
Determining the protection an individual has to SARS-CoV-2 variants of concern (VoC) is crucial for future immune surveillance, vaccine development and understanding the changing immune response. We devised a more informative assay to current ELISA based serology using multiplexed, baited, targeted-proteomics for direct detection of multiple proteins in the SARS-CoV-2 anti-spike antibody immunocomplex. Serum from individuals collected after infection, or first and second dose vaccination demonstrate this approach shows concordance with existing serology and neutralisation. Our assays show altered responses of both immunoglobulins and complement to the Alpha (B.1.1.7), Beta (B.1.351) and Delta (B.1.617.1) VoC. and a reduced response to Omicron (B1.1.1529). We were able to identify individuals who had prior infection, and observed that C1q is closely associated with IgG1 (r>0.82) and may better reflect neutralisation to VoC. Analysing additional immunoproteins beyond IgG, provides important information about our understanding of the response to infection and vaccination.
Abhishek A, Boyton RJ, Peckham N, et al., 2022, Effect of a 2-week interruption in methotrexate treatment versus continued treatment on COVID-19 booster vaccine immunity in adults with inflammatory conditions (VROOM study): a randomised, open label, superiority trial, The Lancet Respiratory Medicine, Vol: 10, Pages: 840-850, ISSN: 2213-2600
BACKGROUND: Immunosuppressive treatments inhibit vaccine-induced immunity against SARS-CoV-2. We evaluated whether a 2-week interruption of methotrexate treatment immediately after the COVID-19 vaccine booster improved antibody responses against the S1 receptor-binding domain (S1-RBD) of the SARS-CoV-2 spike protein compared with uninterrupted treatment in patients with immune-mediated inflammatory diseases. METHODS: We did an open-label, prospective, two-arm, parallel-group, multicentre, randomised, controlled, superiority trial in 26 hospitals in the UK. We recruited adults from rheumatology and dermatology clinics who had been diagnosed with an immune-mediated inflammatory disease (eg, rheumatoid arthritis, psoriasis with or without arthritis, axial spondyloarthritis, atopic dermatitis, polymyalgia rheumatica, and systemic lupus erythematosus) and who were taking low-dose weekly methotrexate (≤25 mg per week) for at least 3 months. Participants also had to have received two primary vaccine doses from the UK COVID-19 vaccination programme. We randomly assigned the participants (1:1), using a centralised validated computer randomisation program, to suspend methotrexate treatment for 2 weeks immediately after their COVID-19 booster (suspend methotrexate group) or to continue treatment as usual (continue methotrexate group). Participants, investigators, clinical research staff, and data analysts were unmasked, while researchers doing the laboratory analyses were masked to group assignment. The primary outcome was S1-RBD antibody titres 4 weeks after receiving the COVID-19 booster vaccine dose, assessed in the intention-to-treat population. This trial is registered with ISRCT, ISRCTN11442263; following the pre-planned interim analysis, recruitment was stopped early. FINDINGS: Between Sept 30, 2021 and March 3, 2022, we recruited 340 participants, of whom 254 were included in the interim analysis and had been randomly assigned to one of the two groups: 127 in the co
Alexander JL, Liu Z, Mūnoz Sandoval D, et al., 2022, COVID-19 vaccine-induced antibody and T cell responses in immunosuppressed patients with inflammatory bowel disease after the third vaccine dose, Publisher: SSRN
Background: COVID-19 vaccine-induced antibody responses are reduced in patients with inflammatory bowel disease (IBD) taking infliximab or tofacitinib after two vaccine doses. We sought to determine whether immunosuppressive treatments were associated with reduced antibody and T cell responses after a third vaccine dose. Methods: 352 adults (72 healthy controls and 280 IBD) from the prospectively recruited study cohort were sampled 28-49 days after a third dose of SARS-CoV-2 vaccine. IBD medications studied included thiopurines (n=65), infliximab (n=46), thiopurine/infliximab combination therapy (n=49), ustekinumab (n=44), vedolizumab (n=50) or tofacitinib (n=26). SARS-CoV-2 spike antibody binding and T cell responses were measured. Findings: Geometric mean [geometric SD] anti-S1 RBD antibody concentrations increased in all study groups following a third dose of vaccine, but were significantly lower in patients treated with infliximab (2736.8 U/mL [4.3]; P<0.0001), infliximab and thiopurine combination (1818.3 U/mL [6.7]; P<0.0001) and tofacitinib (8071.5 U/mL [3.1]; P=0.0018) compared to controls (16774.2 U/ml [2.6]). There were no significant differences in anti-S1 RBD antibody concentrations between control subjects and thiopurine (12019.7 U/mL [2.2]; P=0.099), ustekinumab (11089.3 U/mL [2.8]; P=0.060), nor vedolizumab treated patients (13564.9 U/mL [2.4]; P=0.27). In multivariable modelling, lower anti-S1 RBD antibody concentrations were independently associated with infliximab (Geometric mean ratio 0.15, 95% CI 0.11-0.21, P<0.0001), tofacitinib (0.52, 95% CI 0.31-0.87, P=0.012) and thiopurine (0.69, 95% CI 0.51-0.95, P=0.021), but not with ustekinumab (0.64, 95% CI 0.39-1.06, P=0.083), or vedolizumab (0.84, 95% CI 0.54-1.30, P=0.43). Previous SARS-CoV-2 infection (1.58, 95% CI 1.22-2.05, P=0.00056) and older age (0.88, 95% CI 0.80-0.97, P=0.0073) were independently associated with higher and lower anti-S1 antibody concentrations respectively. However
Reynolds CJ, Pade C, Gibbons JM, et al., 2022, Immune boosting by B.1.1.529 (Omicron) depends on previous SARS-CoV-2 exposure, Science, Vol: 377, Pages: 1-13, ISSN: 0036-8075
INTRODUCTIONB.1.1.529 (Omicron) and its subvariants pose new challenges for control of the COVID-19 pandemic. Although vaccinated populations are relatively protected from severe disease and death, countries with high vaccine uptake are experiencing substantial caseloads with breakthrough infection and frequent reinfection.RATIONALEWe analyzed cross-protective immunity against B.1.1.529 (Omicron) in triple-vaccinated health care workers (HCWs) with different immune-imprinted histories of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection during the ancestral Wuhan Hu-1, B.1.1.7 (Alpha), and B.1.617.2 (Delta) waves and after infection during the B.1.1.529 (Omicron) wave in previously infection-naïve individuals and those with hybrid immunity, to investigate whether B.1.1.529 (Omicron) infection could further boost adaptive immunity. Spike subunit 1 (S1) receptor binding domain (RBD) and whole spike binding, live virus neutralizing antibody (nAb) potency, memory B cell (MBC) frequency, and T cell responses against peptide pools and naturally processed antigen were assessed.RESULTSB and T cell recognition and nAb potency were boosted against previous variants of concern (VOCs) in triple-vaccinated HCWs, but this enhanced immunity was attenuated against B.1.1.529 (Omicron) itself. Furthermore, immune imprinting after B.1.1.7 (Alpha) infection resulted in reduced durability of antibody binding against B.1.1.529 (Omicron), and S1 RBD and whole spike VOC binding correlated poorly with live virus nAb potency. Half of triple-vaccinated HCWs showed no T cell response to B.1.1.529 (Omicron) S1 processed antigen, and all showed reduced responses to the B.1.1.529 (Omicron) peptide pool, irrespective of SARS-CoV-2 infection history. Mapping T cell immunity in class II human leukocyte antigen transgenics showed that individual spike mutations could result in loss or gain of T cell epitope recognition, with changes to T cell effector and regulatory programs
Abhishek A, Boyton RJ, McKnight A, et al., 2022, Effects of temporarily suspending low- dose methotrexate treatment for 2 weeks after SARS-CoV-2 vaccine booster on vaccine response in immunosuppressed adults with inflammatory conditions: protocol for a multicentre randomised controlled trial and nested mechanistic substudy (Vaccine Response On/Off Methotrexate (VROOM) study), BMJ Open, Vol: 12, ISSN: 2044-6055
Introduction It is unknown if a temporary break in long-term immune-suppressive treatment after vaccination against COVID-19 improves vaccine response. The objective of this study was to evaluate if a 2-week interruption in low-dose weekly methotrexate treatment after SARS-CoV-2 vaccine boosters enhances the immune response compared with continuing treatment in adults with autoimmune inflammatory conditions.Methods and analysis An open-label, pragmatic, prospective, parallel group, randomised controlled superiority trial with internal feasibility assessment and nested mechanistic substudy will be conducted in rheumatology and dermatology clinics in approximately 25 UK hospitals. The sample size is 560, randomised 1:1 to intervention and usual care arms. The main outcome measure is anti-spike receptor-binding domain (RBD) antibody level, collected at prebooster (baseline), 4 weeks (primary outcome) and 12 weeks (secondary outcome) post booster vaccination. Other secondary outcome measures are patient global assessments of disease activity, disease flares and their treatment, EuroQol 5- dimention 5-level (EQ-5D-5L), self-reported adherence with advice to interrupt or continue methotrexate, neutralising antibody titre against SARS-CoV-2 (mechanistic substudy) and oral methotrexate biochemical adherence (mechanistic substudy). Analysis of B-cell memory and T-cell responses at baseline and weeks 4 and 12 will be investigated subject to obtaining additional funding. The principal analysis will be performed on the groups as randomised (ie, intention to treat). The difference between the study arms in anti-spike RBD antibody level will be estimated using mixed effects model, allowing for repeated measures clustered within participants. The models will be adjusted for randomisation factors and prior SARS-CoV-2 infection status.Ethics and dissemination This study was approved by the Leeds West Research Ethics Committee and Health Research Authority (REC reference: 21/HRA/3483
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