People who use drugs (PWUD) are at a high risk of contracting and developing severe coronavirus disease 2019 (COVID-19) and other infectious diseases due to their lifestyle, comorbidities, and the detrimental effects of opioids on cellular immunity. However, there is limited research on vaccine responses in PWUD, particularly regarding the role that T cells play in the immune response to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we show that before vaccination, PWUD did not exhibit an increased frequency of preexisting cross-reactive T cells to SARS-CoV-2 and that, despite the inhibitory effects that opioids have on T-cell immunity, standard vaccination can elicit robust polyfunctional CD4 + and CD8 + T-cell responses that were similar to those found in controls. Our findings indicate that vaccination stimulates an effective immune response in PWUD and highlight targeted vaccination as an essential public health instrument for the control of COVID-19 and other infectious diseases in this group of high-risk patients.
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 Diagnostic assays currently used to monitor the efficacy of COVID-19 vaccines measure levels of antibodies to the receptor-binding domain of ancestral SARS-CoV-2 (RBDwt). However, the predictive value for protection against new variants of concern (VOCs) has not been firmly established. Here, we used bead-based arrays and flow cytometry to measure binding of antibodies to spike proteins and receptor-binding domains (RBDs) from VOCs in 12,000 sera. Effects of sera on RBD-ACE2 interactions were measured as a proxy for neutralizing antibodies. The samples were obtained from healthy individuals or patients on immunosuppressive therapy who had received two to four doses of COVID-19 vaccines and from COVID-19 convalescents. The results show that anti-RBDwt titers correlate with the levels of binding- and neutralizing antibodies against the Alpha, Beta, Gamma, Delta, Epsilon and Omicron variants. The benefit of multiplexed analysis lies in the ability to measure a wide range of anti-RBD titers using a single dilution of serum for each assay. The reactivity patterns also yield an internal reference for neutralizing activity and binding antibody units per milliliter (BAU/ml). Results obtained with sera from vaccinated healthy individuals and patients confirmed and extended results from previous studies on time-dependent waning of antibody levels and effects of immunosuppressive agents. We conclude that anti-RBDwt titers correlate with levels of neutralizing antibodies against VOCs and propose that our method may be implemented to enhance the precision and throughput of immunomonitoring.
Background: The oral, selective Janus kinase 1/2 inhibitor baricitinib has shown efficacy in mixed populations of hospitalised participants with COVID-19. Bari-SolidAct is the first trial in the investigator-initiated, adaptive platform trial EU-SolidAct, and is a multinational, phase 3, randomised, double-blind, placebo-controlled trial of baricitinib in hospitalised patients with confirmed SARS-CoV-2 infection. We aimed to evaluate the efficacy and safety of baricitinib plus standard of care in hospitalised adults with severe or critical COVID-19.Methods: The study was conducted in 39 clinical sites (hospital wards and intensive care units) across 10 European countries. Participants (aged ≥18 years) hospitalised with laboratory-confirmed SARS-CoV-2 infection and severe or critical illness were randomly assigned in combination with standard of care (1:1) to baricitinib (4 mg) or matching placebo once daily for up to 14 days The primary end point was all-cause mortality within 60 days, and patients were remotely followed up to day 90 for safety and patient related outcome measures. The efficacy and safety analyses were completed in all randomised participants receiving at least one treatment dose of study drug (modified intention to treat population). The trial was stopped for immunocompetent participants before reaching the planned sample size of 1,900 due to external evidence from the Recovery trial indicating survival benefit of baricitinib in the trial population. The Bari-SolidAct trial is registered with ClinicalTrials.gov, NCT04891133.Findings: Between 3 rd June 2021 and 7 th March 2022, 299 patients were screened, 284 randomised, and 275 participants received study drugs (139 baricitinib and 136 placebo). There were 21 deaths in each group, with a proportion of death at day 60 of 15.1% in the baricitinib group and 15.4% in the placebo group (adjusted absolute difference and 95% CI -0·1% [-8·3 to 8·0]). There were no differences between the study groups with regard to changes in viral load, lymphocyte count, neutrophil count, lactate dehydrogenase, D-Dimer, CRP, procalcitonin or ferritin levels. In subgroup analyses, there was a potential interaction between vaccination status and treatment allocation on 60-day mortality. There were 54 serious adverse events in 32 participants (23%) in the baricitinib group and 60 in 34 participants (25%) in the placebo group. In a post-hoc analysis, there was a significant interaction between vaccination status and treatment allocation on serious adverse events (interaction p-value = 0.003), with an increased occurrence of respiratory complications and severe infections in vaccinated participants treated with baricitinib.Interpretation: We found no difference in participants treated with baricitinib for the primary mortality endpoint at day 60. There was a potential interaction between vaccination status and treatment allocation on mortality and occurrence of serious adverse events, although our findings are not conclusive. Real-world data and subgroup analyses according to vaccination status and disease severity in larger trials, are warranted to assess the precise risk/benefit ratio of baricitinib in vaccinated patients with severe/critical COVID-19. Trial Registration: EU-SolidAct/Bari-SolidAct is registered at www.clinicaltrials.gov (NCT04891133) and euclinicaltrials.eu (EU CTIS number 2022-500385-99-00).Funding: European Commission.Declaration of Interest: MT has been member of scientific advisory board for Lilly. MT has been member of scientific advisory board for Lilly. JP reports lecture fees from Gilead; support for attending meetings from Gilead, Eumedica, Merck Sharp & Dohme, outside the submitted work. ARH reports personal fee from Pfizer (2021) for lectures outside the submitted work. MH(it) has received funding for other trials on COVID-19 from the Federal Belgian Center for Knowledge and the joint Université Libre de Bruxelles-Fonds Erasme-COVID-19 projects (2020-21), personal fees from Gilead (2020) and Pfizer (2021) for editing and lectures outside the submitted work, and travel/congress grants from Pfizer (2020, 2021), and Gilead (2022). MJ reports consulting or speakers fees from Baxter, Gilead, CLS Behring, AM-Pharma, Novartis, Fresenius and grant support from Fresenius, Baxter, outside the submitted work. JAP reports fees for lectures and advisory boards from MSD, Pfizer, Astra-Zeneca, Jansen, Gilead, AOP Orphan Pharmaceuticals, Cepheid MB reports an unrestricted grant for Moderna (2022) outside the submitted work. MB reports an unrestricted grant for Moderna (2022) outside the submitted work. KL reports personal fees from Gilead, MSD, Janssen and ViiV Healthcare for advisory boards and lectures outside of the submitted work. JM reports personal fees from Pfizer (2017) for lectures outside the submitted work and travel fees from Pfizer (2022) and Menarini (2021). JCR reports a grant from Hamilton medical (2019-2020) outside the submitted work FLJ reports Helse Sør-Øst grant for developing COVID-19 serology (2020-2021) and Grant from CEPI to monitor responses in patients (2021-2023) DC reports an HIV grant from Janssen (2019-2020), personal fees from Gilead (2020) and Pfizer (2022) for lectures outside the submitted work. All ther authors have nothing to declare. Ethical Approval: The trial was conducted in accordance with ICH E6 (R2) Good Clinical Practice and the ethical principles of the Declaration of Helsinki. Informed consent by the study participant or legally authorised representative was given prior to inclusion in the study. This is an international trial conducted in several European countries, with approval from ethics committees and national competent authority in each country, and in some countries also regional and site specific ethics approvals. The trial was initially submitted through the volunteer harmonized procedure (VHP) in the CTFG system, with first ethical approvals in France and Norway, followed by approval in all other countries in the trial. The trial has been transferred to CTIS and is now accepted under the Clinical Trial Regulation (CTR), euclinicaltrials.eu (EU CTIS number 2022-500385-99-00). EU-SolidAct/Bari-SolidAct is also registered at www.clinicaltrials.gov (NCT04891133).
Abstract Cancer immunotherapy using T cell receptor-engineered T cells (TCR-Ts) represents a promising treatment option. However, technologies for pre-clinical safety assessment are incomplete or inaccessible to most laboratories. Here, TCR-T off-target reactivity was assessed in five steps: (1) Mapping target amino acids necessary for TCR-T recognition, followed by (2) a computational search for, and (3) reactivity screening against, candidate cross-reactive peptides in the human proteome. Natural processing and presentation of recognized peptides was evaluated using (4) short mRNAs, and (5) full-length proteins. TCR-Ts were screened for recognition of unintended HLA alleles, and as proxy for off-target reactivity in vivo, a syngeneic, HLA-A*02:01-transgenic mouse model was used. Validation demonstrated importance of studying recognition of full-length candidate off-targets, and that the clinically applied 1G4 TCR has a hitherto unknown reactivity to unintended HLA alleles, relevant for patient selection. This widely applicable strategy should facilitate evaluation of candidate therapeutic TCRs and inform clinical decision-making.
Abstract The prevalence and predictors of long COVID in young people remain unresolved. We aimed to determine the point prevalence of long COVID in non-hospitalised adolescents and young adults six months after the acute infection, to determine the risk of developing long COVID adjusted for possible confounders, and to explore a broad range of potential risk factors (prespecified outcomes). We conducted a prospective controlled cohort study of 404 SARS-CoV-2-positive and 105 SARS-CoV-2-negative non-hospitalised individuals aged 12–25 years (ClinicalTrial ID: NCT04686734). Data acquisition was completed February 2022. Assessments included pulmonary, cardiac and cognitive functional testing, biomarker analyses, and completion of a questionnaire, and were performed at inclusion (early convalescent stage) and six months follow-up. The WHO case definition of long COVID was applied. The point prevalence of long COVID at six months was 49% and 47% in the SARS-CoV-2-positive and negative group, respectively. SARS-CoV-2-positivity did not predict development of long COVID (relative risk 1.06, 95% CI 0.83 to 1.37). The main predictor was symptom severity at inclusion, which correlated strongly to personality traits. Low physical activity and loneliness were also predictive, while biological markers were not. In conlusion, our study aims were met, and the findings suggest that persistent symptoms were not driven by the infection, but were associated with psychosocial factors.
We read with interest the report from Georgery et al1 addressing the very low immunization rate of 3.8% in kidney transplant recipients (KTRs) 28 d after 1 dose of the BNT162b2 (Pfizer/BioNTech) vaccine. As addressed by the authors, this is markedly lower than what has been reported in other recent publications on mRNA vaccines (BNT162b2, Pfizer/BioNTech; mRNA-1273, Moderna) in this population.2,3 Our findings after 2 doses of BNT162b2 are in line with their observations. We assessed the serological response 25–89 d after the second dose of the BNT162b2 vaccine in 141 KTRs without a known history of COVID-19 infection and negative SARS-CoV-2 anti-nucleocapsid IgG before vaccination. Antibodies to SARS-CoV-2 spike, the receptor-binding domain of spike and nucleocapsid were measured with a multiplexed bead-based flow cytometric assay as previously described.4 The assay was calibrated to the World Health Organization international standard (National Institute for Biological Standards and Control code 20/136) to assess binding antibody units (BAU). Table 1 summarizes the baseline characteristics and findings following the second dose of BNP162b2 vaccine in the 141 KTRs. The median age was 75 (range, 21–91) y, 56% were male individuals. The median time since transplantation was 9.6 y (range, 0.4–47.1), 72% were transplanted >5 y ago. The majority of the recipients were on a combination of calcineurin inhibitor (CNI), mycophenolate (MPA), and prednisolone (n = 105, 74%). On the day of measurement, only 25 patients (18%) had seroconverted with a mean SARS-CoV-2 spike IgG antibody titer of 21 ± 32 BAU/mL (threshold for positive response: 1.0 BAU/mL). Out of these 25 responders, 16 (64%) did not use MPA and only 6 (24%) were treated with triple maintenance immunosuppression with CNI, MPA, and prednisolone. Patients who seroconverted tended to be younger and had been living with a functioning kidney transplant for a longer time (Table 1). The impact of immunosuppression is obvious, but from the present data, it is not possible to differentiate the exact cause of the negative impact on seroconversion. However, treatment with MPA, especially in triple therapy, appears to lower seroconversion rates. TABLE 1. - Baseline characteristics and findings following the second dose of BNP162b2 (Pfizer/BioNTech) vaccine in kidney transplant recipients All (N = 141) POSitive IgG (N = 25) NEGative IgG (N = 116) Missing P (POS vs NEG) Demographics Age (y) 67.4 ± 17.2 59.1 ± 19.7 69.1 ± 16.2 0 0.02 Male sex 79 (56%) 12 (48%) 67 (58%) 0 0.50 Weight (kg) 74.9 ± 15.2 73.3 ± 12.9 75.3 ± 15.7 2 0.50 BMI (kg/m2) 25.2 ± 4.3 25.6 ± 3.8 25.1 ± 4.4 2 0.52 Time since Tx (y) 11.7 ± 9.8 17.1 ± 13.5 10.4 ± 8.4 0 0.01 First Tx 122 (87%) 20 (80%) 102 (88%) 0 0.41 Living donor 55 (39%) 14 (56%) 41 (35%) 0 0.09 Years in RRT 14.1 ± 9.9 21.8 ± 12.5 12.4 ± 8.4 0 0.001 P-creatinine (µmol/L) 136 ± 78 141 ± 120 135 ± 66 1 0.80 Maintenance immunosuppression CNI + MPA + prednisolonea 105 (74%) 6 (24%) 99 (85%) <0.0001 CNI + prednisolone 19 (13%) 12 (48%) 7 (6%) <0.0001 Other combinationsb 17 (12%) 7 (28%) 10 (9%) 0.02 MPA use 115 (82%) 9 (36%) 106 (91%) <0.0001 Data presented as mean ± SD and number (%). Statistical comparison between groups with positive and negative SARS-CoV-2 IgG samples performed with Student’s T test and chi-square tests. Bold values indicate statistical significance.aCNI type; 35 cyclosporine and 70 tacrolimus.bEverolimus + MPA + prednisolone (n = 7), azathioprine + prednisolone (n = 4), cyclosporine + azathioprine + prednisolone (n = 2), belatacept + MPA + prednisolone (n = 2), belatacept + everolimus + prednisolone (n = 1), tacrolimus + MPA (n = 1).BMI, body mass index; CNI, calcineurin inhibitor; IgG, immunoglobulin G; MPA, mycophenolate; RRT, renal replacement therapy; Tx, transplantation. It is well known that KTRs are at increased risk of a severe outcome if infected with SARS-CoV-2, and there is a hope that vaccination will be protective. Short-term safety data on mRNA vaccines in KTRs seems similar to the general population, but the immunogenicity seems to be markedly reduced.5 To date, it has not been proven that low levels of antibodies to spike predict a lack of protection against severe COVID-19. Although KTRs receiving MPA seem to have a reduced vaccine response rate, with the current knowledge, we do not promote reducing or withholding MPA during revaccination. Early results showing an increase in seroconversion after the second vaccine dose have prompted initiatives to administer a third jab. Whether or not this will enhance the immune response remains to be determined. In the meantime, KTRs should be informed to keep their guard up and behave as if they were not vaccinated!
