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1.
In Vivo ; 37(1):70-78, 2023.
Article in English | EMBASE | ID: covidwho-2204978

ABSTRACT

Background/Aim: The manifestation and severity of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections show a clear correlation to the age of a patient. The younger a person, the less likely the infection results in significant illness. To explore the immunological characteristics behind this phenomenon, we studied the course of SARS-CoV-2 infections in 11 households, including 8 children and 6 infants/neonates of women who got infected with SARS-CoV-2 during pregnancy. Material(s) and Method(s): We investigated the immune responses of peripheral blood mononuclear cells (PBMCs), umbilical cord blood mononuclear cells (UCBCs), and T cells against spike and nucleocapsid antigens of SARS-COV-2 by flow cytometry and cytokine secretion assays. Result(s): Upon peptide stimulation, UCBC from neonates showed a strongly reduced IFN-gamma production, as well as lower levels of IL-5, IL-13, and TNF-alpha alongside with decreased frequencies of surface CD137/PD-1 co-expressing CD4+ and CD+8 T cells compared with adult PBMCs. The PBMC response of older children instead was characterized by elevated frequencies of IFN-gamma+ CD4+ T cells, but significantly lower levels of multiple cytokines (IL-5, IL-6, IL-9, IL-10, IL-17A, and TNF-alpha) and a marked shift of the CD4+/CD8+ T-cell ratio towards CD8+ T cells in comparison to adults. Conclusion(s): The increased severity of SARS-CoV-2 infections in adults could result from the strong cytokine production and lower potential to immunomodulate the excessive inflammation, while the limited IFN-gamma production of responding T cells in infants/neonates and the additional higher frequencies of CD8+ T cells in older children may provide advantages during the course of a SARS-CoV-2 infection. Copyright © 2023 International Institute of Anticancer Research. All rights reserved.

2.
Frontiers in Immunology ; 13 (no pagination), 2022.
Article in English | EMBASE | ID: covidwho-2198890

ABSTRACT

Background: The mRNA vaccines help protect from COVID-19 severity, however multiple sclerosis (MS) disease modifying therapies (DMTs) might affect the development of humoral and T-cell specific response to vaccination. Method(s): The aim of the study was to evaluate humoral and specific T-cell response, as well as B-cell activation and survival factors, in people with MS (pwMS) under DMTs before (T0) and after two months (T1) from the third dose of vaccine, comparing the obtained findings to healthy donors (HD). All possible combinations of intracellular IFNgamma, IL2 and TNFalpha T-cell production were evaluated, and T-cells were labelled "responding T-cells", those cells that produced at least one of the three cytokines of interest, and "triple positive T-cells", those cells that produced simultaneously all the three cytokines. Result(s): The cross-sectional evaluation showed no significant differences in anti-S antibody titers between pwMS and HD at both time-points. In pwMS, lower percentages of responding T-cells at T0 (CD4: p=0.0165;CD8: p=0.0022) and triple positive T-cells at both time-points compared to HD were observed (at T0, CD4: p=0.0007 and CD8: p=0.0703;at T1, CD4: p=0.0422 and CD8: p=0.0535). At T0, pwMS showed higher plasma levels of APRIL, BAFF and CD40L compared to HD (p<0.0001, p<0.0001 and p<0.0001, respectively) and at T1, plasma levels of BAFF were still higher in pwMS compared to HD (p=0.0022). According to DMTs, at both T0 and T1, lower anti-S antibody titers in the depleting/sequestering-out compared to the enriching-in pwMS subgroup were found (p=0.0410 and p=0.0047, respectively) as well as lower percentages of responding CD4+ T-cells (CD4: p=0.0394 and p=0.0004, respectively). Moreover, the depleting/sequestering-out subgroup showed higher percentages of IFNgamma-IL2-TNFalpha+ T-cells at both time-points, compared to the enriching-in subgroup in which a more heterogeneous cytokine profile was observed (at T0 CD4: p=0.0187;at T0 and T1 CD8: p =0.0007 and p =0.0077, respectively). Conclusion(s): In pwMS, humoral and T-cell response to vaccination seems to be influenced by the different DMTs. pwMS under depleting/sequestering-out treatment can mount cellular responses even in the presence of a low positive humoral response, although the cellular response seems qualitatively inferior compared to HD. An understanding of T-cell quality dynamic is needed to determine the best vaccination strategy and in general the capability of immune response in pwMS under different DMT. Copyright © 2022 Dominelli, Zingaropoli, Tartaglia, Tortellini, Guardiani, Perri, Pasculli, Ciccone, Malimpensa, Baione, Napoli, Gaeta, Lichtner, Conte, Mastroianni and Ciardi.

3.
Frontiers in Immunology ; 13 (no pagination), 2022.
Article in English | EMBASE | ID: covidwho-2198881

ABSTRACT

Introduction: Despite numerous efforts to describe COVID-19's immunological landscape, there is still a gap in our understanding of the virus's infections after-effects, especially in the recovered patients. This would be important to understand as we now have huge number of global populations infected by the SARS-CoV-2 as well as variables inclusive of VOCs, reinfections, and vaccination breakthroughs. Furthermore, single-cell transcriptome alone is often insufficient to understand the complex human host immune landscape underlying differential disease severity and clinical outcome. Method(s): By combining single-cell multi-omics (Whole Transcriptome Analysis plus Antibody-seq) and machine learning-based analysis, we aim to better understand the functional aspects of cellular and immunological heterogeneity in the COVID-19 positive, recovered and the healthy individuals. Result(s): Based on single-cell transcriptome and surface marker study of 163,197 cells (124,726 cells after data QC) from the 33 individuals (healthy=4, COVID-19 positive=16, and COVID-19 recovered=13), we observed a reduced MHC Class-I-mediated antigen presentation and dysregulated MHC Class-II-mediated antigen presentation in the COVID-19 patients, with restoration of the process in the recovered individuals. B-cell maturation process was also impaired in the positive and the recovered individuals. Importantly, we discovered that a subset of the naive T-cells from the healthy individuals were absent from the recovered individuals, suggesting a post-infection inflammatory stage. Both COVID-19 positive patients and the recovered individuals exhibited a CD40-CD40LG-mediated inflammatory response in the monocytes and T-cell subsets. T-cells, NK-cells, and monocyte-mediated elevation of immunological, stress and antiviral responses were also seen in the COVID-19 positive and the recovered individuals, along with an abnormal T-cell activation, inflammatory response, and faster cellular transition of T cell subtypes in the COVID-19 patients. Importantly, above immune findings were used for a Bayesian network model, which significantly revealed FOS, CXCL8, IL1beta, CST3, PSAP, CD45 and CD74 as COVID-19 severity predictors. Discussion(s): In conclusion, COVID-19 recovered individuals exhibited a hyper-activated inflammatory response with the loss of B cell maturation, suggesting an impeded post-infection stage, necessitating further research to delineate the dynamic immune response associated with the COVID-19. To our knowledge this is first multi-omic study trying to understand the differential and dynamic immune response underlying the sample subtypes. Copyright © 2022 Chattopadhyay, Khare, Kumar, Mishra, Anand, Maurya, Gupta, Sahni, Gupta, Wadhwa, Yadav, Devi, Tardalkar, Joshi, Sethi and Pandey.

4.
Frontiers in Immunology ; 13 (no pagination), 2022.
Article in English | EMBASE | ID: covidwho-2198878

ABSTRACT

Background: Long-term immunity to SARS-CoV-2 infection, including neutralizing antibodies and T cell-mediated immunity, is required in a very large majority of the population in order to reduce ongoing disease burden. Method(s): We have investigated the association between memory CD4 and CD8 T cells and levels of neutralizing antibodies in convalescent COVID-19 subjects. Finding(s): Higher titres of convalescent neutralizing antibodies were associated with significantly higher levels of RBD-specific CD4 T cells, including specific memory cells that proliferated vigorously in vitro. Conversely, up to half of convalescent individuals had low neutralizing antibody titres together with a lack of receptor binding domain (RBD)-specific memory CD4 T cells. These low antibody subjects had other, non-RBD, spike-specific CD4 T cells, but with more of an inhibitory Foxp3+ and CTLA-4+ cell phenotype, in contrast to the effector T-bet+, cytotoxic granzymes+ and perforin+ cells seen in RBD-specific memory CD4 T cells from high antibody subjects. Single cell transcriptomics of antigen-specific CD4+ T cells from high antibody subjects similarly revealed heterogenous RBD-specific CD4+ T cells that comprised central memory, transitional memory and Tregs, as well as cytotoxic clusters containing diverse TCR repertoires, in individuals with high antibody levels. However, vaccination of low antibody convalescent individuals led to a slight but significant improvement in RBD-specific memory CD4 T cells and increased neutralizing antibody titres. Interpretation(s): Our results suggest that targeting CD4 T cell epitopes proximal to and within the RBD-region should be prioritized in booster vaccines. Copyright © 2022 Phetsouphanh, Khoo, Jackson, Klemm, Howe, Aggarwal, Akerman, Milogiannakis, Stella, Rouet, Schofield, Faulks, Law, Danwilai, Starr, Munier, Christ, Singh, Croucher, Brilot-Turville, Turville, Phan, Dore, Darley, Cunningham, Matthews, Kelleher and Zaunders.

5.
Virology Journal ; 19(1) (no pagination), 2022.
Article in English | EMBASE | ID: covidwho-2196349

ABSTRACT

Background: Adaptive immune response has been thought to play a key role in SARS-CoV-2 infection. The role of B cells, CD4+T, and CD8+T cells are different in vaccine-induced immune response, thus it is imperative to explore the functions and kinetics of adaptive immune response. We collected blood samples from unvaccinated and vaccinated individuals. To assess the mechanisms contributing to protective immunity of CoronaVac vaccines, we mapped the kinetics and durability of humoral and cellular immune responses after primary and boost vaccination with CoronaVac vaccine in different timepoints. Material(s) and Method(s): We separate PBMC and plasma from blood samples. The differentiation and function of RBD-spcific CD4+T and CD8+T cells were analyzed by flow cytometry and ELISA. Antibodies response was analyzed by ELISA. ELISPOT analysis was perfomed to detected the RBD-spcific memory B cells. CBA analysis was performed to detected the cytokine immune profiles. Graphpad prism 8 and Origin 2021 were used for statistical analysis. Result(s): Vaccine-induced CD4+T cell responses to RBD were more prominent than CD8+T cell responses, and characterized by a predominant Th1 and weak Th17 helper response. CoronaVac vaccine triggered predominant IgG1 antibody response and effectively recalled specific antibodies to RBD protein after booster vaccination. Robust antigen-specific memory B cells were detected (p < 0.0001) following booster vaccination and maintained at 6 months (p < 0.0001) following primary vaccination. Vaccine-induced CD4+T cells correlated with CD8+T cells (r = 0.7147, 0.3258, p < 0.0001, p = 0.04), memory B cell responses (r = 0.7083, p < 0.0001), and IgG and IgA (r = 0.6168, 0.5519, p = 0.0006, 0.003) after vaccination. In addition, vaccine induced a broader and complex cytokine pattern in plasma at early stage. Conclusion(s): Taken together, these results highlight the potential role of B cell and T cell responses in vaccine-induced long-term immunity. Copyright © 2022, The Author(s).

6.
Open Forum Infectious Diseases ; 9(Supplement 2):S770-S771, 2022.
Article in English | EMBASE | ID: covidwho-2189959

ABSTRACT

Background. We studied immunological response against SARS-CoV-2 after two doses of vaccine in health care workers (HCW) at our Infectious Disease Unit Methods. We enrolled prospectively HCW without (group A) and with previous infection (group B). We collected peripheral blood at baseline (before the BNT162b2 vaccine), T1 (before the 2nd dose), T2 and T6 (after 1 and 6 months after of 2nd dose). The activation induced cell marker assay (AIM) was performed with CD4 and CD8 Spike peptide megapools (MPs). We evaluated the Stimulation Index (SI) as AIM+ stimulated cells/negative control (positive response SI >= 2). Quantitative antibodies (Abs) to Spike-1 protein (S) and to nucleocapside protein (N) were detected with an electrochemiluminescence immunoassay. We tested at T6 the responses to alpha, beta, gamma, delta and epsilon variants MPs.We used the linear mixed model with random intercept adjusted for age and sex to compare specific times to T0. To assess differences over time between groups the interaction with time was tested. Results. In group A 13/22 (59%) were female vs 5/7 (71%) group B, the mean age 40 vs 38 years, respectively. For CD4+ Spike the overall rate of change over time was significant at T1 (p=0.038) and at T2 (p< 0.001) vs T0 with a decreasing at T6 (p not significant) [Figure 1] with a trend of higher response in group A. In group B the CD8 + Spike reactivity increased at T1(p=0.037) and at T6 (p=0.005) vs T0. The interaction between SI and time was statistically significant at T1 (p=0.033);T2 (p= 0.046) and T6 (p=0.035) (mean values in group B higher than A). For overall population, the anti-S Abs significantly increased at T1 vs T0, T2 vs T0 and at T6 vs T0 [Figure 2A]. The group B at T6 retained a higher anti S response but the rate of change significantly differs between the two group (overall interaction: p< 0.001) [Figure 2B]. At T6 in both groups we found a high CD4+ T cells response to epsilon variant, even if not detected as circulant virus. Conclusion. The humoral response was persistent and increased in previous infected subjects. The CD4+T cells response after vaccination retained a response in uninfected subject, with an increasing trend and with a response to non-circulating variants. The vaccine could help the CD8+ T cells reactivity specific for Spike peptides.

7.
Open Forum Infectious Diseases ; 9(Supplement 2):S763, 2022.
Article in English | EMBASE | ID: covidwho-2189942

ABSTRACT

Background. COVID-19 (C-19) vaccines have demonstrated effectiveness in reducing SARS-CoV-2 related morbidity/mortality. The duration of protection in the general population is showing a waning immunity over time. Variable antibody responses to C-19 vaccines have been shown in persons living with HIV. We followed the anti-SARS-CoV-2 receptor biding domain (RBD) antibody titers, after 2 and 3 (booster) C-19 vaccinations, in US Veterans living with HIV (USVLH). Methods. Retrospective chart review of USVLH who had received C-19 vaccinations at Northport VAMC. Testing was done with the © Beckman Coulter enzyme immunoassay measuring total IgG antibody to the RBD, a critical target of neutralizing antibodies within the spike protein encoded in the mRNA vaccines. Titers were drawn after the 2nd and 3rd doses C-19 vaccines in variable timing. Demographic data, CD4+ T cell counts nadir and current, HIV viral load, comorbid conditions were reviewed. Results. We analyzed the SARS CoV-2 RBD IgG titers in 50 vaccinated USVLH. The median age is 65 years (range 36-75). 50% were Black, Caucasian 40%, Hispanic 10%. Risk factor for HIV infection, Heterosexual 52%, IVDU 18%, MSM 26%, needle stick 2%, blood transfusion 2%. The median CD4 nadir was 200/muL (5- 600), median current CD4 656 (174-1529). All USVLH were on HAART, 92% on INSTI-based therapy. 45 had undetectable HIV viral load (< 20), 5 had viremia from 22 to 563 copies. Medical conditions: diabetes 30%, CAD 18%, HTN 60%, COPD 8%, HLD 66%, smokers 18%. Six USV had C-19 prior to vaccination, and six had C-19 after vaccination with median 102 days (90-148) from last vaccine dose. Vaccines given: Janssen in 3 USVLH: Moderna (MOD)- 2 doses: 4;MOD-3 doses:5;Pfizer (PFZ)-2: 6;PFZ-3: 32. IgG titers decrease with time after 2nd vaccine dose and increase after booster dose. IgG titers checked after 2nd dose median days 120 (11-392) {titers: median 4.63 S/CO [0.17 - 53.66]}, 91 days (5-181) after 3rd dose {titers: median 16.22 [1.15-73.92]}. Titers were higher in MOD-2 vs. PFZ-2, median 25.7 vs. 4.63, P: 0.039, MOD-3 vs. PFZ-3 33.89 vs. 15.5, P: 0.117. No death due to C-19 was seen. SARS-CoV-2 RBD IgG titers in US Veterans living with HIV after 2nd dose of COVID vaccine. COVID-19 VACCINATED IN US VETERANS LIVING WITH HIV N=50 Conclusion. In a cohort of USVLH, well controlled on HAART, C-19 vaccinations produced a serologic response that decayed over time and increased after booster dose. MOD vaccine may have achieved higher titers than PFZ.

8.
Open Forum Infectious Diseases ; 9(Supplement 2):S92, 2022.
Article in English | EMBASE | ID: covidwho-2189540

ABSTRACT

Background. Despite higher prevalence of cognitive disorders in people with human immunodeficiency virus (PWH) and dementia being a risk factor for COVID-19 mortality, the association between dementia and adverse outcomes in PWH with COVID-19 has not been well established. Methods. This was a matched case-control study (1:10) of patients with and without HIV at an academic institution with documented SARS-CoV-2 polymerase chain reaction (PCR) positivity from March 2020-March 2021. Data were extracted from the electronic health record data registry. PWH were matched to people without HIV (PWoH) by age, sex, race, and zip code. The primary exposures were dementia (identified using International Classification of Diseases, Tenth Revision codes) and cognitive concerns, defined as documentation of possible cognitive impairment up to 12 months prior to COVID-19 diagnosis and ascertained using a semi-automated natural language processing annotation tool. VACS 2.0 Index (including age, sex, body mass index, CD4+ T-cell count and HIV-1 RNA) was calculated. Logistic regression models assessed the effect of dementia and cognitive concerns on the odds of death (OR [95% confidence interval]), adjusted for VACS 2.0 Index. Results. Sixty-four (0.45%) PWH were identified among 14129 patients with COVID-19 and were matched to 463 PWoH. Among PWH, 59% were virally suppressed, and 14% had CD4< 200 cells/muL. Compared to 463 matched PWoH, PWH had higher prevalence of dementia (16% vs. 6%, p=0.01) and cognitive concerns (22% vs. 16%, p=0.04). Death was more frequent in PWH (17% vs. 6%, p< 0.01) and at younger ages (58 vs. 66 years, p=0.03). Cognitive concerns (2.5 [1.1-5.9], p=0.03) and dementia (3.4 [1.3-8.1], p=0.01) were significantly associated with increased adjusted odds of death in the overall group. Among PWH, cognitive concerns (7.2 [1.1-48], p=0.04) and dementia (6.0 [0.8-43.8], p=0.08) remained associated with mortality. Conclusion. Dementia and cognitive concerns were associated with mortality among PWH with COVID-19. The magnitude of the effect of cognitive impairment on COVID-19 outcomes may be greater in HIV, and additional studies with larger cohorts will help to assess this association further. Assessment of cognitive status is an important component to care for aging PWH in the COVID-19 era.

9.
Indian Journal of Hematology and Blood Transfusion ; 38(Supplement 1):S90, 2022.
Article in English | EMBASE | ID: covidwho-2175130

ABSTRACT

Introduction: The second wave of COVID-19 in India was followed by large number of mucormycosis cases. Indiscriminate use of immunosuppressive drugs, underlying diseases like diabetes cancers, or autoimmune diseases was thought to be the cause. However, the mortality was not as high as that seen in non-COVID mucormycosis. Aims & Objectives: To study the detailed characteristics of T-cells for evaluating the underlying differences in the T-cell immune dysfunction in post-COVID and non-COVID mucor patients. Material(s) and Method(s): The study included histopathologically confirmed cases of mucor (13 post-COVID, 13 non-COVID) and 15 healthy individuals (HI). Expression of T-cell activation (CD44, HLADR, CD69, CD38) and exhaustion (CTLA, PD-1, LAG-3 and TIM-3) markers was evaluated by flow cytometry. Result(s): All cases showed significant depletion of T-cells compared to HI. Both post-COVID and non-COVID groups showed increased activation and exhaustion as compared to HI. Non-COVID mucor group showed significant activation of CD4 + T cells for HLADR and CD38 ((P = 0.025, P = 0.054) and marked T-cell exhaustion in form of co-expression of PD-1 and LAG-3 on both CD4 + and CD8 + T cells in comparison to post-COVID patients (P = 0.002, P = 0.001). Additionally, co-expression of PD-1 & CTLA and LAG-3 & TIM-3 on CD8 + T cells was statistically significant in non- COVID mucor patients ((P = 0.031, P = 0.003). Conclusion(s): Immunosuppression in non-COVID mucor showed pronounced exhaustion of T-cells in comparison to post-COVID mucor cases implicating T-cell immune dysfunction is much more severe in non-COVID mucor which are in a state of continuous activation followed by extreme exhaustion leading to poorer outcome.

10.
Journal for ImmunoTherapy of Cancer ; 10(Supplement 2):A958, 2022.
Article in English | EMBASE | ID: covidwho-2161949

ABSTRACT

Background The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant has demonstrated high transmissibility and possesses several spike protein mutations that allow for evasion of previously established immunity.1 mRNA vaccines against the spike protein of the ancestral strain of the virus have been reported to induce robust T cell immunity against the omicron variant when examined in healthy individuals. 2 However, the effectiveness of the booster vaccine doses in late-stage lung cancer patients undergoing active anti-PD-1/ PD-L1 agent immunotherapy has yet to be investigated.3 Methods To address this question, we assessed both CD8+ and CD4+ T cell responses using a modified activationinduced marker (AIM) assay that was performed on peripheral blood mononuclear cells (PBMCs), which was coupled with high dimension spectral flow cytometry analyses. The PBMCs were obtained using cryopreserved blood samples collected from The COVID-19 Vaccine Study of Infections and Immune REspoNse (SIIREN) trial, and a total of 51 patient samples (20 non-cancer patients and 31 lung cancer patients) were assessed. Results Our observations included that booster vaccines induced CD8+ T cell response in both non-cancer subjects and lung cancer patients against ancestral strain and omicron variant, while only marginal induction or trend was detected for CD4+ T cells in normal subjects. Pertinent results also consisted of identification of distinct subpopulation dynamics involving varying degrees of differentiation of antigen-specific CD8+ and CD4+ T cells in lung cancer patients compared to non-cancer subjects, thus demonstrating evidence of dysfunction. Another noteworthy finding included the observation of sex biased T cell responses with female lung cancer patients demonstrating more efficient antigen-specific T cell responses compared to males. Conclusions We conclude that lung cancer patients in our study cohort have substantial qualitative deviation in their T cell response to mRNA vaccine from the normal individuals. This altered response may be a consequence of altered T cell differentiation states, resulting in the high degree of heterogeneity of AIM+ T cells identified in booster vaccinated individuals. Moreover, the dampened T cell response to omicron in cancer patients could implicate that less protection was established by vaccination for lung cancer patients, especially given that humoral response is also reduced in cancer patients.4 This further highlights the need for heightened protective measures for cancer patients to minimize the risk of breakthrough infection with the omicron and other future variants of SARS-CoV-2.5.

11.
Annals of Neurology ; 92(Supplement 29):S201-S202, 2022.
Article in English | EMBASE | ID: covidwho-2127558

ABSTRACT

Introduction: IC14 (atibuclimab) is a monoclonal anti-CD14 antibody that may target T-regulatory (T-reg) cell function. A previous phase 1 trial of 10 participants with amyotrophic lateral sclerosis (ALS) demonstrated initial safety of IC14 for a single cycle of treatment. We provided longterm treatment with IC14 to 17 individuals with ALS via an expanded access protocol (EAP) and documented target engagement, safety, and disease endpoints. Method(s): Participants received intravenous IC14 every two weeks. Consistent with FDA guidelines, participants were ineligible for clinical trials and the EAP was inclusive of a broad population. Participants unable to travel to MGH due to the COVID-19 pandemic or disease progression, were transitioned to infusions in-home or local clinics. Blood samples for hematology, chemistry, and coagulation were collected to monitor safety. The Amyotrophic Lateral Sclerosis Functional Rating Scale-Revised (ALSFRS-R) was administered monthly to track disease progression. Respiratory function was measured through slow vital capacity tests -data for this is limited due to the COVID-19 pandemic. Whole blood and serum were collected to determine monocyte CD14 receptor occupancy (RO), soluble CD14, and antidrug antibodies (ADA). Ex vivo T regulatory functional assays were performed with five participants. Result(s): Participants received IC14 for up to 103 weeks (average: 30.1 weeks, range: 1-103 weeks). Treatmentemergent adverse events were uncommon, mild, and self-limited. There were 18 serious adverse events (SAEs) which were related to disease progression and unrelated (17) or likely unrelated (1) to IC14. Three participants died due to disease progression. Most participants achieved >80% monocyte mCD14 RO on a 14-day dosing schedule, although one individual required more frequent dosing (every 10 days) to achieve >80% RO. ADA were detected in only one participant and were transient, low titer, and non-neutralizing. Tregs were isolated from the available longitudinal samples and assayed for suppression of CD4 T cell proliferation and cytokine production versus baseline T-reg activity. Conclusion(s): IC14 administration to ALS patients was safe and well tolerated in this EAP, with no significant changes in laboratory tests and no drug-related SAEs. Measuring RO guided dosing frequency. Preliminary data suggest IC14 enhanced T-reg activity. Additional placebo-controlled trials are required to determine the efficacy of IC14 in ALS.

12.
Multiple Sclerosis Journal ; 28(3 Supplement):626-627, 2022.
Article in English | EMBASE | ID: covidwho-2138902

ABSTRACT

Introduction: Immunosuppressed patients may not mount an adequate immune response to 2 doses of SARS-CoV-2 mRNA vaccine and are eligible to receive a 3rddose. There is limited knowledge about T cell responses specifically in patients with multiple sclerosis (MS) who receive 3 doses of vaccine. Objectives & Aims: To assess the SARS-CoV-2 spike antibody responses and T cell responses in MS patients on high efficacy immunotherapies and healthy controls (HC) who received 2 and 3 doses of SARS-CoV-2 mRNA vaccines. Method(s): This is a study of patients with MS, aged 18-65, on fingolimod (FIN) and ocrelizumab (OCR) for at least 3 months prior to 1stmRNA SARS-CoV-2 vaccine dose (BNT162b2 or mRNA- 1273) and a cohort of HC. Blood samples were collected after 2nd(2- vax) and 3rd(3-vax) dose of mRNA vaccine. The proportion of patients and HC who exhibited seroconversion, demonstrating serum SARS-CoV-2 spike antibody levels >0.4 U/ml,was determined. T cell responses were examined in a subgroup of patients with MS and HC after 2-vax and 3-vax by flow cytometry. Result(s): The proportion of patients who seroconverted after 2-vax was 8/33 (24.2%) in the OCR group, 5/7 (71.4%) in the FIN group, and 29/29 (100%) in the HC group (Fisher's exact test,P=5.7*10-11). After 3-vax, 9/21 (40.9%) patients in the OCR group seroconverted as compared to 19/21 (90.5%) in the FIN group, and 7/7 (100%) in the HC group (Fisher's exact test for difference,P=0.0003). There was SARS-CoV-2 peptide reactive CD4+ and CD8+ T cell activation across all 3 groups (OCR 2-vax n=10, FIN 2-vax n=6, HC 2-vax n=8, OCR 3-vax n=9, FIN 3-vax n=10, HC 3-vax n=5) as compared to unstimulated condition after 2-vax and 3-vax (Mixed effects analysis,P<0.0001). There was an increase in the percentage of SARS-CoV-2 peptide reactive CD4+ T cells in HC and OCR group but not in FINgroupafter 2-vax and 3-vax. There was anincrease in the percentage ofIFNgammaandTNFalphaproducing CD4+ and CD8+ T cells in FIN group as compared to HC and OCR group after 2-vax and 3-vax.TNFalphaproducing central memory CD4+ T cells were increased in OCR group after 2-vax andIFNgammaandTNFalphaproducing effector memory and terminally differentiated effector memory CD4+ T cells were increased in FIN group after 2-vax and 3-vax as compared to HC. Conclusion(s): MS patients on ocrelizumab and fingolimod had decreased spike antibody responses, but preserved T cell responses compared to HCs after SARS-CoV-2 mRNA vaccination.

13.
Multiple Sclerosis Journal ; 28(3 Supplement):644-645, 2022.
Article in English | EMBASE | ID: covidwho-2138880

ABSTRACT

Background: Immunosuppressive therapies may impact immune response to COVID-19 vaccines in persons with multiple sclerosis (pwMS). Accordingly, effects of vaccination in pwMS treated with disease-modifying therapies (DMTs) need further elucidation. Aim(s): To investigate COVID-19 BNT162b2 vaccine effect concerning antibody seroconversion, T cells-associated cytokines production and immunophenotype assessment in pwMS under three different DMTs: cladribine, fingolimod, ocrelizumab. Method(s): Enzyme immunoassay test was used for anti-spike IgG detection in 98 DMTs-treated pwMS completing first vaccination cycle. In a subset of patients (n=47), serum T cells-associated cytokines (GrB, IFN-gamma and TNF-alpha) were quantified using an automatic ELISA (ELLA) and blood immunophenotype was assessed by flow cytometry. ANCOVA followed by post hoc tukey's test was used to compare anti-spike IgG response in the different DMTs, Student's paired t-test was used to evaluate differences between pre- and post-vaccination in pairwise samples and Pearson's correlation was applied to evaluate association between spike-specific IgG antibody titer and lymphocytes count. Result(s): More pwMS treated with ocrelizumab (63%) lacked anti-spike IgG compared to patients treated with cladribine (14%) and fingolimod (20%) (p<0.001). When present, the anti-spike IgG titer in the ocrelizumab group was lower than in cladribine- (p<0.001) and in fingolimod-treated pwMS (p=0.003). No significant differences in lymphocytes count and T-cell associated cytokines were observed in cladribine- and in fingolimod-treated pwMS, while in pwMS on ocrelizumab a significant increase in GrB serum levels (p=0.021) and a trend of increased CD4+ T cells count were observed after vaccination. Specifically considering non-seroconverted ocrelizumab-treated pwMS, a significant increase of GrB serum levels (p=0.008) and of CD4+ T lymphocytes count (p=0.040) was foundafter vaccination and a negative correlation was observed between anti-spike IgG production and CD4+T cells count (rho=-0.452, p=0.014). Conclusion(s): Our data confirmed differences in spike-specific antibodies among different DMTs and provided evidence of T-cell immunity preservation and activations after BNT162b2 vaccination in ocrelizumab-treated pwMS, specifically in pwMS patients lacking anti-spike IgG, suggesting a protective T-cell response that might explain why the ongoing treatment with ocrelizumab is not associated with a higher risk of COVID-19 infection.

14.
Multiple Sclerosis Journal ; 28(3 Supplement):879, 2022.
Article in English | EMBASE | ID: covidwho-2138827

ABSTRACT

Introduction: In Argentina, multiple sclerosis patients (MSp) are vaccinated against SARS-CoV-2 using different formulations upon availability, including viral vector/inactivated virus/mRNA vaccines, at distinct times between doses. The real-world effectiveness of these unique vaccination schedules is scarce, so asthe efficacy to mount an appropriate immune response even more in MSp under treatment (DMTs) Aims: To analyze the presence of reactive CD4+ and CD8+ T cells for SARS-CoV-2, IgG and IgM anti-Spike and anti-RBD, in MSp after receiving a 3rd vaccine dose Methods: 27 MSp and 9 healthy controls (HC) were included in this study. SARS-CoV-2-reactive T cells were analysed with a T Cell Analysis Kit from Miltenyi as described by the manufacturer. In brief, peripheral blood mononuclear cells (PBMCs) were cultured with a pool of lyophilized peptides, consisting of 15-mer sequences with 11 amino acids overlap, covering the complete protein coding sequence (aa 5-1273) of the surface or Spike glycoprotein (S) of SAR-CoV-2 and controls. After stimulation, the cells were stained with the live/dead marker, washed, fixed, permeabilized and stained for lineage and activation markers as well as cytokines. Cells were analysed using a flow cytometer. Doublets, debris, and dead cells as well as CD14+ and CD20+ cells were excluded. Cells were pregated on CD3 as well as CD4 and CD8. For reactive CD4 T cells CD154 and TNF-alpha were assessed on CD4+ T cells while TNF-alpha and IFN-gamma in CD8+ T cells Results: IgG antibodies (Ab) against S and RBD were found in all analysed HC, while in 22 and 20 out of a total of 27 MSp. Levels of IgG against S were lower in MSp vs HC. IgM levels against RBD were found in all HC and MSp, but 8 MSp had low levels of those Ab.There were no differences between HC and MSp in the % of reactive CD4+ T cells to S (p= 0.151). However, we found a lower % of reactive CD8+ T cells in MSp than HC (p= 0.026). Actually, CD8+ T cells were not detected in 4 out of 5 MSp treated with Fingolimod (FTY) but were present in all patients treated with monoclonal Ab, IFN or DMF. Furthermore, MSp treated with FTY had lower values of reactive CD4+ T cells and IgG anti-RBD than patients receiving other DMTs Conclusion(s): Most MSp vaccinated against SARS-CoV-2 present some humoral and cellular response to SARS-CoV-2. This humoral and cellular response would be lower in MSp treated with FTY.

15.
Multiple Sclerosis Journal ; 28(3 Supplement):776, 2022.
Article in English | EMBASE | ID: covidwho-2138820

ABSTRACT

Introduction: Infection with the SARS-CoV-2 coronavirus can lead to a wide range of acute and also chronic disease manifestations. The rapidly developed vaccinations are highly effective in preventing severe disease courses and have been proven safe. Both natural infection and, to a much lower extent, the mRNAbased vaccinations can be accompanied by transient autoimmune phenomena or onset of autoimmune diseases. Objective(s): We report here two cases of multiple sclerosis (MS) with clinical and new radiological signs beginning in close temporal relation to spike (S) protein mRNA-based vaccinations. Aim(s): To establish that the onset of MS in these two cases is very likely caused by CD4+ T cell clones that cross-recognize SARSCoV- 2 S protein-derived peptides and peptides derived from myelin proteins, which have previously been implicated in MS. Method(s): Spike specific CD4+ T cells from peripheral blood and CD4+ T cells from CSF sample were isolated and expanded for autoantigen screening test. A list of well-known MS-related autoantigens including immunodominant peptides and isoforms from MBP, MOG, PLP, RASGRP2, TSTA3 peptides were included to assess T cell reactivity. CD4+ CFSElow fraction were sorted after stimulate with positive autoantigen pools or SARSCov- 2 Spike protein, followed by expansion and testing with autoantigen peptides and Spike protein. Supernatant from cell culture were further analyzed for IFN-gamma secretion. Result(s): Self-reactive T cells were detected from Spike specific T cell population in both patients. CD4+ T from CSF also showed reactivity to MBP, MOG, PLP peptide pools. Finally, we found proinflammatory T cell clones that recognize both Spike protein and immunodominant MBP peptides and MOG peptides, which have previously been implicated in MS. Conclusion(s): Detailed studies of both peripheral blood- and CSFderived CD4+ T cells show that the onset of MS in these two cases is very likely caused by CD4+ T cell clones that cross-recognize SARS-CoV-2 S protein-derived peptides and peptides derived from myelin proteins, which have previously been implicated in MS.

16.
American Journal of Transplantation ; 22(Supplement 3):1059, 2022.
Article in English | EMBASE | ID: covidwho-2063485

ABSTRACT

Purpose: The purpose of this study was to evaluate long term humoral and cellular immunity generated following SARS-CoV-2 infection in solid organ transplant recipients (SOTR). Method(s): Patients included had an active graft of an organ transplant as an adult, a positive polymerase chain reaction nasopharyngeal swab for SARS-CoV-2 after transplant, and had not received convalescent plasma, vaccination, or monoclonal antibody for SARS-CoV-2. Whole blood was obtained 6 months (+/- 1 month) after infection. Serology measured IgG and IgM titer to the SARS-CoV-2 spike protein receptor binding domain, reported as signal/ cut-off ratio (s/co). CD4+ and CD8+ T-cell reactivity was measured by Activation Induced Marker assays following stimulation of peripheral blood mononuclear cells with SARS-CoV-2 peptide pools encompassing the SARS-CoV-2 spike protein. Result(s): Of 25 subjects, 19 (76.0%) were hospitalized, 4 (16.0%) developed hypoxia, but none required mechanical ventilation. Biopsy-proven graft rejection occurred in 3 (12.0%), but none had graft loss. At 6 months, 8 (16%) had persistent symptoms and 2 (4.0%) were re-infected within one year. In the immunity study, 22 (88.0%) had reactive IgG testing and 11 (44.0%) had reactive IgM testing. Median IgG titer was 3.68 s/co (range 0.19-36.44) and IgM titer was 0.79 s/co (range 0.02-16.41). Virus-specific CD4+ T-cell reactivity was noted in 23 (92%), but only 10 (40.0%) had reactive CD8+ T-cell testing. Moderate correlation was observed between IgG and IgM titer (r=.51, p= 0.009) and between IgG titer and percent virus-specific CD4+ T-cells (r=.46, p=0.02). CD8+ T-cell reactivity was correlated with greater illness severity (p=0.043). Use of Tacrolimus, mycophenolate, or corticosteroids at time of infection was not associated with T-cell or antibody reactivity. Conclusion(s): In summary, this cohort of SOTR evaluated six months after noncritical COVID-19 illness demonstrated robust IgG and CD4+ T-cell responses, and CD8+ T-cell reactivity was correlated with higher disease severity.

17.
American Journal of Transplantation ; 22(Supplement 3):1066, 2022.
Article in English | EMBASE | ID: covidwho-2063484

ABSTRACT

Purpose: The purpose of this study was to study our cohort of adult solid organ transplant recipients who had been infected with SARS-CoV-2 to describe the incidence density of SARS-CoV-2 re-infection, as well as the clinical features and convalescent immunity profile. Method(s): Incidence density was calculated as the total cases of re-infection divided by total days after initial diagnosis with active graft. We included those with initial infection diagnosed by polymerase chain reaction before or after transplantation, and cycle threshold values were obtained when possible. Two recipients had immunity evaluated in the weeks prior to re-infection, by measuring IgG antibody titer to the SARS-CoV-2 receptor binding domain and virus-specific CD4+ and CD8+ T-cell reactivity following stimulation with SARS-CoV-2 peptide pools and using activation induced marker assays. Result(s): Out of 210 infected recipients, 5 (2.4%) developed re-infection, including two that had received full mRNA vaccination, but none developed hypoxia. The incidence density was 9.4 (95% confidence interval 3.9-22.6) cases/100,000 patient days. Two cases of re-infection had participated in our immunity study and had convalescent immunity data from a blood draw approximately six months after initial infection and prior to re-infection. Both mounted virus specific CD4 T cell responses prior to re-infection (1.19% and 0.28% of total CD4 T cells) and both had reactive IgG testing (1.30 and 4.99 signal/cut off ratio). Conclusion(s): This suggests that SOT recipients infected with SARS-CoV-2 remain at high risk for re-infection even after generating reactive cellular and humoral immune responses.

18.
American Journal of Transplantation ; 22(Supplement 3):638, 2022.
Article in English | EMBASE | ID: covidwho-2063446

ABSTRACT

Purpose: Prior studies suggest that two doses of mRNA vaccine in SOTR may result in lower antibody and T-cell responses relative to levels seen following natural SARS-CoV-2 infection. In this study, we evaluated whether three doses of mRNA-1273 vaccine result in immune responses more comparable to, or greater than, natural infection. Method(s): Serum was collected 4-6 weeks from symptom onset in n=74 SOTR recovered from SARS-CoV-2 infection, and in n=60 SOTR receiving a third dose of mRNA-1273. Disease severity in the infection cohort ranged from mild to severe, but no deaths were reported. Vaccinated SOTR all had negative anti-nucleoprotein antibody results to confirm absence of infection. SARS-CoV-2 serology was assessed using an anti-spike (S) receptor binding domain (RBD) immunoassay (Roche). Neutralizing antibodies (nAb) were assessed using a commercial surrogate virus neutralization test (SVNT) targeting wildtype (WT), alpha, beta and delta strains (GenScript). A subset of participants underwent spike-specific T-cell testing (infection n=50, three doses n=34). PBMCs were stimulated overnight with overlapping peptides and frequencies of S-specific polyfunctional CD4+ and CD8+ T-cells (expressing IFN-gamma and IL-2) were measured by intracellular cytokine staining. Mann Whitney U, and Chi-square tests were used for statistical comparisons;significance was defined at p<0.05. Result(s): Anti-S RBD antibodies in SOTR recovered from infection were similar to levels in those receiving three doses of mRNA-1273 (median U/mL [IQR]: 73.5 [14.9-240.1] vs. 313.8 [313.8-2191.0];p=0.17). Relative to SOTR recovered from infection, the proportion of SOTR positive for nAb after three doses of vaccine was significantly lower. This was true for WT (93.2% vs. 60.0%, p<0.0001) and all variants tested - alpha: 90.5% vs. 56.7%, p<0.0001;beta: 67.6% vs. 50%, p=0.039;and delta: 85.1% vs. 55%, p=0.0001. Spike-specific polyfunctional CD4+ T-cell frequencies were similar between infection and three doses of vaccine (median cell frequency [IQR]: 241.7 [50-539.7] vs. 432.4 [50-1226];p>0.05). Spike-specific polyfunctional CD8+ T-cells were uncommonly detected following infection or vaccination. Vaccinated participants were significantly older than infected SOTR (p<0.001), and some differences in type of transplant were found between groups. However, sex and type of immunosuppressive medications were similar between infected and vaccinated SOTR cohorts (p>0.05). Conclusion(s): Three doses of mRNA vaccine may be required to optimize binding antibody, and to a lesser extent, CD4+ T-cell immunity, to levels similar to natural infection. However, nAb responses to wild-type virus and variants of concern were highest in SOTR recovered from infection when compared to vaccinated patients. These data provide further evidence of impaired SARS-CoV-2 vaccine responses in SOTR.

19.
American Journal of Transplantation ; 22(Supplement 3):441-442, 2022.
Article in English | EMBASE | ID: covidwho-2063342

ABSTRACT

Purpose: Correlates of protection for SARS-CoV-2 vaccines are not well-established in kidney transplant recipients(KTRs). Studies have highlighted the importance of neutralizing antibodies(Abs), however data suggests T cell responses may play a secondary role in preventing reinfection. We performed a longitudinal assessment of immunogenicity, T and B cell response in KTRs following SARS-CoV-2 vaccination. Method(s): KTRs eligible for SARS-CoV-2 vaccination from 3/12/21 were enrolled. Baseline and weekly blood samples were collected for routine lab, SARS-CoV-2 spike protein Ab titers and cellular phenotyping for 12 weeks. Ab response was defined as a 10-fold increase in total binding IgG titers. To determine if T cell responses were induced by vaccination, we considered the proportion of activated non-naive CD4+ and CD8+ T cells post-vaccination. Result(s): 49 KTRs were enrolled ( Demographics -Table 1). 10 patients (20.4%) mounted an Ab response following vaccination. A history of COVID-19 was associated with an increased likelihood of developing an Ab response (OR: 18.3, 95% CI 3.2, 105.0, p=0.0005). For non-naive CD8+ T cells, a subset co-expressing CD38+Ki67+ was induced 1 week after the 1st immunization in some SARS-CoV- 2-naiive patients (P=0.12 versus P=0.14 for SARS-CoV-2-experienced adults, Fig 1A/B). For non-naive CD4+ T cells, induction of a subset co-expressing CD38+Ki67+ was observed at 1 week after the 1st immunization for SARS-CoV-2-naive participants (P = 0.09 for SARS-CoV-2-naive, P=0.03 for SARS-CoV-2-experienced adults, Fig 1C/D). For CD8+ and CD4+ T cells, dose 2 stimulated weak induction of the CD38+Ki67+ subset in the SARS-CoV-2-naive patients only (Fig 1A-D). Conclusion(s): Quantitative Ab responses were strongly associated with prior SARS-CoV-2 infection. Activated CD4+ and CD8+ T cell responses were evident in most patients irrespective of history of COVID-19. Further studies are needed to determine whether these activated CD4+ and CD8+ T cell responses were antigenspecific or confer immunity. (Table Presented).

20.
Chest ; 162(4):A605-A606, 2022.
Article in English | EMBASE | ID: covidwho-2060646

ABSTRACT

SESSION TITLE: Chest Infections in Immunocompromised Patients Case Posters SESSION TYPE: Case Report Posters PRESENTED ON: 10/17/2022 12:15 pm - 01:15 pm INTRODUCTION: Pneumocystis pneumonia (PCP) is a life-threatening opportunistic infection caused by Pneumocystis jirovecii. HIV-negative patients with PCP are primarily individuals receiving immunosuppressive therapy for other disease processes. In rare instances, PCP could be an initial manifestation of underlying defected or suppressed cell-mediated immunity that needs to be diagnosed to prevent morbidity and mortality. CASE PRESENTATION: 75-year-old female with a history of hypertension and hypothyroidism presented to the emergency department for evaluation of cough, fever, and shortness of breath gradually worsening over the last few weeks. She received outpatient treatment with no improvement. She was vaccinated against covid-19. On presentation, the temperature was 103F, heart rate was 108 bpm, blood pressure was 163/93 mm Hg, and oxygen saturation was 86% on room air. Hemogram showed leukocytosis with left shift with elevated inflammatory markers. Chest X-ray revealed bilateral ground glass opacities. She was started on broad-spectrum antibiotics, but symptoms worsened over the next few days. CT chest showed diffuse bilateral ground glass opacities with prominent interstitial markings. BAL obtained from bilateral upper lobes was lymphocyte predominant with pneumocystis jirovecii diagnosed on Gomori methenamine silver (GMS) staining. She was started on PCP-directed antibiotics with intravenous glucocorticoids, and workup for an underlying immunodeficiency was started. Subsequent BATS biopsy revealed diffuse organizing alveolar damage, with possible associated acute interstitial pneumonia pattern. This could be a rare manifestation of PCP or a primary presentation in the appropriate clinical setting. Autoimmune panel, leukemia, and lymphoma panel came back negative. AFB smear, HIV, EBV, CMV, HTLV I/II also returned negative. The lymphocyte subset panel revealed a CD4 count of 205 and a subsequent count a few days later of 64 with decreased total IgG. The patient was treated with high dose steroids for an extended period along with treatment for PCP however continued to decline clinically. The patient and family eventually decided to pursue comfort care. DISCUSSION: The predisposition to PCP in patients is primarily due to a decrease in cell-mediated immunity regardless of HIV infection. In our patient, the etiology of idiopathic CD4+ T cell lymphocytopenia cannot be determined due to the lack of serial laboratory data measurement. One of the proposed etiologies of ICL is systemic persistent immune activation in the setting of exogenous mRNA, the current technology that is being widely used for vaccine development. CONCLUSIONS: In this era of biotechnology, with advancements in immunosuppressive therapy and mRNA-based vaccines, increased awareness around the potential immune system activation and potential downstream complications needs to be further highlighted to raise awareness among physicians. Reference #1: Li, Y., Ghannoum, M., Deng, C., Gao, Y., Zhu, H., Yu, X., & Lavergne, V. (2017). Pneumocystis pneumonia in patients with inflammatory or autoimmune diseases: usefulness of lymphocyte subtyping. International Journal of Infectious Diseases, 57, 108-115. Reference #2: Pardi, N., Hogan, M. J., Porter, F. W., & Weissman, D. (2018). mRNA vaccines - a new era in vaccinology. Nature reviews. Drug discovery, 17(4), 261–279. https://doi.org/10.1038/nrd.2017.243 Reference #3: Vijayakumar, S., Viswanathan, S., & Aghoram, R. (2020). Idiopathic CD4 Lymphocytopenia: Current Insights. ImmunoTargets and therapy, 9, 79–93. https://doi.org/10.2147/ITT.S214139 DISCLOSURES: No relevant relationships by Santhosh Gheevarghese John No relevant relationships by Konstantin Golubykh No relevant relationships by Iuliia Kovalenko No relevant relationships by Maidah Malik No relevant relationships by Hafiz Muhammad Siddique Qurashi No relevant relationships by Taj Rahman No rel vant relationships by Tabinda Saleem

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