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1.
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.

2.
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.

3.
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.

4.
Neurology ; 93(23 Supplement 2):S52-S53, 2022.
Article in English | EMBASE | ID: covidwho-2196693

ABSTRACT

Objective To assess adaptive immunity to SARS-CoV-2 in anti-CD20 treated individuals with mRNA vaccination. Background Anti-CD20 therapies attenuate humoral responses to vaccines. However, their effect on T cell responses is less clear. We examined B and T cell responses following COVID-19 vaccination in patients receiving anti-CD20 therapy for multiple sclerosis (MS) and other autoimmune inflammatory neurologic diseases (AINDs, e.g., autoimmune encephalitis, stiff person syndrome, etc.). Design/Methods MS and AIND patients on anti-CD20 therapies were prospectively enrolled for longitudinal analysis of antibody and T cell responses after a 3rd COVID-19 vaccination. Serum antibodies against the receptorbinding domain of the S1 spike protein (RBD-S1 IgG), neutralizing antibodies, and SARS-CoV-2 CD8 T cell responses, using activationinduced markers (AIM) and INF-gamma release assays (EUROIMMUN, Germany), were measured at various time points including prevaccination, post initial vaccination series, and 4 and 12 weeks after 3rd dose. Results Thirty-four MS and AIND participants are enrolled. Results for these patients (mean age 52 years-old, 79% female, 21 Pfizer, 13 Moderna) demonstrated attenuated RBD IgG antibody responses. However, a robust CD8 T cell response was observed, following a two-dose series, compared to non-immunosuppressed, age-matched vaccinated controls or unvaccinated with severe SARS-CoV-2 infection (p = 0.01). T cell response was sustained long-term (>12 weeks post 3rd dose) in all 11 anti-CD20 patients analyzed thus far. Collections are completed for all participants at 12 weeks and analysis to be completed by 05/15/22. Further analysis includes correlation of the INF- gamma release assay compared to RBD-CD8 T cell response detected by AIM assay. Conclusions Results suggest that patients treated with anti-CD20 therapy generate a robust CD8 T cell response to SARS-CoV-2 mRNA after three doses but remain with attenuated humoral immune responses. Our observational study will provide important data to guide vaccine management in patients on or anticipating anti-CD20 therapy.

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.
Science ; 371(6528):477, 2021.
Article in English | EMBASE | ID: covidwho-2193389
7.
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.

8.
Open Forum Infectious Diseases ; 9(Supplement 2):S504, 2022.
Article in English | EMBASE | ID: covidwho-2189813

ABSTRACT

Background. Benefit of COVID-19 vaccines is limited by need for freezing, high cost, requirement for multiple boosters, and waning immunity. An unmet need for safe and effective vaccines that can be quickly deployed worldwide during a pandemic exists. A barrier to developing scalable low-cost vaccines is the restricted access to vaccine- or adjuvant-formulations due to protection by intellectual property rights. This limits research to understand their mechanism of action and potential applicability towards vulnerable populations or emerging pathogens. Methods. We studied cellular and molecular mechanisms of action of adjuvant formulations developed for global open access in 4 distinct but complementary in vitro platforms that are human, age-specific, and enable the same individual to serve as control and test condition;generating data on adjuvant-induced responses in vitro that predict activity in vivo. Results. Whole blood assay that models magnitude of innate immune activation and identifies cell types activated showed that liposomal co-formulation of MPL +QS-21 activated monocytes and natural killer cells and induced cytokine production;tissue construct assay that models monocyte extravasation and autonomous differentiation into dendritic cells (DC) showed that only MPL+QS-21 co-formulation promoted CD14+ cells towards DC phenotype;monocyte-derived DC (MoDC) assay that interrogates immune activation type showed that MPL+QS-21 co-formulation in lipid nanoparticles promoted MoDC maturation by increasing CD40, CD86, CCR7 and HLA-DR expression and Th1-polarizing cytokine secretion;and dendritic cell-T cell interface assay that assesses potential of formulations to re-activate SARS-CoV-2 Spike antigen-specific T cells showed that only MPL+QS-21 coformulation enhanced activation of antigen-specific CD4+ and CD8+ T cells. Conclusion. Thus, human in vitro modeling provides new insight into the mechanism of action and synergistic effects of MPL+QS-21, and positions us to study them in vulnerable populations to assess potential age-specific application on vaccine development. Precision vaccinology coupled with global access may enable marked public health progress by accelerating, de-risking, and advancing affordable adjuvanted vaccines to the most vulnerable.

9.
Open Forum Infectious Diseases ; 9(Supplement 2):S465, 2022.
Article in English | EMBASE | ID: covidwho-2189747

ABSTRACT

Background. Data regarding cell-mediated immunological differences in children across COVID-19 clinical spectrum are limited. We prospectively investigated Spike-protein specific cellular immunity in children with symptomatic COVID-19 or MIS-C, by single cell cytokine expression profiling. Methods. PBMCs fromchildrenwithMIS-C, symptomaticCOVID-19 (onemonth after hospitalization) and healthy controls were isolated prospectively. Cell suspensions were divided into two quantitatively equal samples (a negative control-unstimulated and a positive-stimulated).Cells stimulationwas performed usingSARS-CoV-2 Spike antigenic peptidesmix (Peptivator SARS-CoV-2 Prot-S). Cells of each sample were stained with fluorochrome monoclonal antibodies against 8 surface markers (CD3, CD4, CD8, CD14, CD19, CD137, CD197, CD45RA) and 6 intracellular markers (IL-4, IL-2, IL-17, IFN-gamma, TNF-alpha, Granzyme B). Viability was assessed by 7AAD. Stained cell preparations were analysed using 13 colour Flow Cytometry (DX Flex, Beckman Coulter). Flow cytometric analysis was performed using Kaluza 2.1 Software. Results. Sixteen children (4 MIS-C, 8 post-COVID-19 and 4 healthy controls) were included in the study. The mean age (+/-SD) of the participants was 11.22 years (+/-3.48). Children with MIS-C had significantly higher mean (+/-SD) values of CD8+IFN-gamma/million CD3+ [226.68 (134.92) vs 45.43 (57.28);P: 0.033] and median (IQR) of CD8+IFN-gamma/ml [156.38 (184.13) vs 26.34 (82.36);P: 0.033] compared to symptomatic COVID-19 children. Compared to healthy controls, MIS-C patients had significantly higher median (IQR) values of CD4+IL-2/million CD3+ [923.12 (3777.95) vs 97.59 (71.71);P: 0.042] and CD4+IL-2/ml median (IQR) [626.33 (2744.98) vs 169.3 (173.91);P: 0.042]. No other significant differences were observed regarding other immunological markers in 3 study groups. Conclusion. IFN-gamma production by CD8+ T cells is highly expressed in children with MIS-C compared to hospitalized children one month after acute COVID-19 and could consist possible immunological biomarker. Further studies are needed in order to elucidate the pathophysiological basis of these findings.

10.
Open Forum Infectious Diseases ; 9(Supplement 2):S440, 2022.
Article in English | EMBASE | ID: covidwho-2189700

ABSTRACT

Background. Several studies reported an increased rate of indeterminate QuantiFERON-TB Gold Plus (QFT-P) assay results in patients with severe Coronavirus Disease (COVID)-19. Methods. Aim of the study was to longitudinally evaluate QFT-P responses in patients who survived COVID-19, with a previous indeterminate result. Results. We observed 223 patients with an indeterminate QFT-P assay among 949 patients hospitalized because of COVID-19 (23,5%) during 2020 and 2021. 36 patients among those with an indeterminate QFT-P assay were enrolled for reassessing the test. In 12 patients peripheral blood lymphocyte subsets were also reassessed. Considering disease severity, 30 were classified as severe and 6 as non-severe. Median age was 57,5 (interquartile range [IQR]: 49,5-63,8), with a prevalence of male sex (M/F: 24/12);median Charlson Comorbidity Index was 2 (IQR: 1-3). The second QFT-P assay was performed after at least 1 month from the first assay (median time 7 months, IQR: 5-12 months). All QFT-P assays gave a determined result: 2 positive (5.5%) and 34 negatives (94,4%). A statistically significant difference was observed after comparing the laboratory parameters at the time of the first and the second QFT-P assay: the absolute counts of total lymphocyte, total CD3+, CD4+ and CD8+ T-lymphocytes were significantly increased (p< 0.001) while neutrophil absolute counts, neutrophil to lymphocyte (N/L) ratio, D-dimer,fibrinogen, ferritin, C-reactive protein (CRP) were significantly reduced (p< 0.0001). Concerning the QFT-P assay, interferon gamma (INF-gamma) production in the Mitogen-Nil, TB1-Nil and TB2-Nil conditions were significantly increased (p< 0.0001;p=0.0019;p=0.0205, respectively) (Table 1 and Figure 1). Conclusion. Once the acute phase of COVID-19 is resolved, inflammatory markers and peripheral blood leucocyte counts tend to normalize with an effective INF-gamma production after specific and nonspecific stimulation. All the 36 QFT-P showed a determinate result. Moreover, we observed 2 positive QFT-P assay, supporting the importance of retesting patients with indeterminate result to identify latent tuberculosis infection and monitor patients for possible reactivation because of the immunesuppression associated with COVID-19.

11.
Open Forum Infectious Diseases ; 9(Supplement 2):S85-S86, 2022.
Article in English | EMBASE | ID: covidwho-2189538

ABSTRACT

Background. Vaccines aim to induce immune responses that prevent disease. They may also clear chronic infections or reduce tumor progression. Vaccine adjuvants augment immune responses, in general, by providing stimulatory signals. Our focus has been on a different type of adjuvant that enhances vaccine-induced T cell responses by modulating the herpes virus entry mediator (HVEM) pathway. The B and T cell attenuator (BTLA) is expressed on naive T cells and, upon binding to HVEM on antigen presenting cells, dampens signaling through the T cell receptor. HVEM binds with a different domain to the co-stimulator LIGHT. Within a trimolar BTLA-LIGHT/HVEM complex, inhibition prevails. Herpes simplex virus (HSV-1) glycoprotein D (gD) attaches to the BTLA binding site of HVEM and as it has higher binding affinity outcompetes BTLA binding and allows for co-stimulation through LIGHT. This results in enhanced signaling through the T cell receptor and thereby augments and broadens CD8+ T cell responses as we showed with chimpanzee adenovirus (AdC) vector vaccines for several viral antigens. Methods. Immunogenicity in rodents was evaluated following one or two immunizations with AdC vectors expressing antigens of HIV (gag), HPV-16 (E7/6/5), HBV (core & pol), influenza virus (nucleoprotein) and SARS-CoV2 (nucleoprotein), with or without gD. Vaccine-induced CD8+ T cell responses, including their magnitude, functions, duration, and breadth were characterized. Vaccine efficacy was also evaluated. Results. Vaccination with gD-antigen fusion proteins increased CD8+ T cell frequencies to all of the antigens tested (Fig) and improved efficacy. Addition of gD increased stimulation of CD8+ T cells to subdominant epitopes and thereby enhanced breadth of responses. Conclusion. Checkpoint modification of the HVEM pathway with a gD-antigen fusion protein produces potent, prolonged, and broad responses of CD8+ T cells to immunodominant and subdominant epitopes. The latter is especially important for chronic viral infections, where, due to exhaustion of T cells to dominant epitopes therapeutic efficacy of vaccines may rely on expansion of T cells to subdominant epitopes. Clinical studies to evaluate therapeutic vaccination for chronic HBV are planned. (Figure Presented).

12.
Open Forum Infectious Diseases ; 9(Supplement 2):S3-S4, 2022.
Article in English | EMBASE | ID: covidwho-2189491

ABSTRACT

Background. Many individuals infected with SARS-CoV-2 are left with persistent symptoms of COVID-19. Post-acute sequelae of COVID-19 (PASC) can affect quality of life and functionality. The mechanism underlying PASC is unknown but elevated inflammatory markers several months post infection have been found in those with PASC. Methods. Individuals diagnosed with COVID-19 were evaluated longitudinally for PASC and persistent symptoms. CD4+ and CD8+ cellular markers and intracellular cytokines were assessed at each follow-up time point and analyzed by individual PASC symptoms reported. Results. Participants who reported persistent dyspnea, forgetfulness, confusion, and chest pain had significantly higher levels of CD8+Ki67+ cells. Those with dyspnea also had significantly higher levels of CD8+CD38+, CD8+Granzyme B+, and CD8+IL10+ cells. Those who suffered from forgetfulness, chest pain, and joint pain had significantly higher levels of CD4+CD25+ cells. Conclusion. These findings suggest continued CD8+ T cell and CD4+CD25+ T cell activation and response following SARS-CoV-2 infection in patients with PASC. An increase in T regulatory cells suggests an ongoing attempt to control host inflammation in a subset of these patients. These results shed further light on continued immune system activation and chronic inflammation as a link to symptoms in COVID-19 survivors suffering from PASC. (Figure Presented).

13.
Human Gene Therapy Methods ; 33(23-24):A210-A211, 2022.
Article in English | EMBASE | ID: covidwho-2188083

ABSTRACT

Replication deficient (RD) adenoviruses (Ad) are the most widely administered viral vectors, with licensed SARS-CoV-2 vaccines using vectors derived from human Ad type 5 (Ad5) and 26 (Ad26), and chimpanzee Ad ''ChAdOx1''. Ad vectored vaccines generate robust cellular and humoral immunity, against both the transgene-encoded protein and the Ad vector itself. It's unclear how many times a single Ad vector can be readministered before this anti-vector immunity impairs generation of the desired transgene-specific adaptive responses. Antivector immunity also arises from naturally acquired Ad infections. In the absence of anti-Ad5 immunity, Ad5 is a goldstandard vector with robust vaccine immunogenicity, however widespread Ad5 seroprevalence hampers its use as a vector for the global population. We developed novel pseudotyped Ads as RD vectored vaccines encoding SARS-CoV-2 spike protein. These vectors exhibit fiber knob swaps from low seroprevalence Ads grafted onto an Ad5 backbone. We characterised innate immune responses following administration of these vectors in mice, and spikespecific adaptive responses three weeks later. Furthermore, we quantified the effects of anti-vector humoral immunity against these vectors in an in vitro transduction assay using human plasma. The pseudotyped vectors exhibit many desirable vaccine characteristics as the equivalent Ad5 vector, including CD4+ and CD8+ T cell responses against multiple spike epitopes. Importantly, fiber knob pseudotyping can substantially circumvent the direct, humoral, anti-vector immunity induced through Ad exposure in humans. These data indicate the fiber knob plays an important role in anti-vector immunity, and can be manipulated for evasion of such responses without hampering vaccine immunogenicity.

14.
Annals of Oncology ; 33(Supplement 9):S1547-S1548, 2022.
Article in English | EMBASE | ID: covidwho-2176297

ABSTRACT

Background: CAN is a monoclonal antibody that inhibits proinflammatory IL-1beta-driven pathways that may play a role in tumor growth in early-stage NSCLC. Preclinical data suggest targeting IL-1beta could decrease inflammation and immunosuppression in the tumor microenvironment (TME). Method(s): CANOPY-N (NCT03968419) is a phase II, randomized, open-label study of neoadjuvant CAN, PEM or CAN+PEM in resectable NSCLC. Eligibility: Stage IB-IIIA NSCLC;treatment (tx) naive;ECOG PS 0-1;and eligible for planned resection 4-6 weeks after first dose. Pts were randomized 2:2:1 to the tx arms: CAN, CAN+PEM or PEM. CAN and PEM were both given as two 200 mg doses once every 3 weeks. Primary endpoint: major pathological response (MPR) rate based on central review. Key secondary endpoints: overall response rate (ORR), surgical feasibility rate, and safety. Changes in CD8+ T cell, tumor-associated macrophage (TAM) and regulatory T cell (Treg) levels, among others, were assessed in exploratory biomarker analyses. Result(s): 88 pts enrolled across 3 arms: CAN (n=35), CAN+PEM (n=35) and PEM (n=18). 87 pts completed planned neoadjuvant tx. Four pts did not have surgery: 3 due to disease progression (CAN) and 1 to pt decision (CAN+PEM). MPR rates were 2.9% (CAN), 17.1% (CAN+PEM) and 11.1% (PEM). ORRs were 0% (CAN), 8.6% (CAN+PEM) and 11.1% (PEM). Gr >=3 AEs occurred in 37.1%, 28.6% and 22.2% of pts, of which 0%, 11.4% and 11.1% were tx related, in the CAN, CAN+PEM and PEM arms, respectively. Decreases in TAMs and Tregs were seen in CAN arms whereas increases in CD8+ T cells were seen in PEM arms. Modulations were more pronounced with CAN+PEM (Table). [Formula presented] Conclusion(s): CANOPY-N did not meet the primary endpoint of MPR rate, with minimal clinical efficacy and no increase in CD8+ T cells with CAN alone. No new safety signals were seen. IL-1beta inhibition impacted inflammation and immunosuppression in the TME. Clinical trial identification: CACZ885V2201C / NCT03968419. Editorial acknowledgement: Editorial assistance was provided by Ollie Butlin, MSc of Articulate Science Ltd., and was funded by Novartis Pharmaceuticals Corporation. Legal entity responsible for the study: Novartis Pharmaceuticals Corporation. Funding(s): Novartis Pharmaceuticals Corporation. Disclosure: T.S.K. Mok: Financial Interests, Personal, Invited Speaker: AbbVie, ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Daiichi Sankyo, Fishawack Facilitate, InMed Medical Communication, Lunit USA, Inc., Merck Serono, MSD, Roche, MD Health, Medscape/WebMD, PeerVoice, Touch Medical Media, Permanyer SL, Prime Oncology, Research to Practice, Sanofi-Aventis, Takeda, PER, Daz Group, Lucence Health Inc., Janssen Pharmaceutical NV, Jiahui Holdings Co., LiangYiHui Healthcare, Merck Pharmaceuticals HK Ltd, MiRXES, Novartis, OrigiMed Co. Ltd., Pfizer, Shanghai BeBirds Translation & Consulting Co., Ltd., Taiho Pharmaceutical Co., Ltd, AstraZeneca;Financial Interests, Personal, Advisory Board: AbbVie, ACEA Pharma, Alpha Biopharma, Amgen, Amoy Diagnostics, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly, Blueprint Medicines, Berry Oncology, CStone Pharma, Daiichi Sankyo, Fishawack Facilitate, Eisai, Gritstone Oncology, Guardant Health, G1 Therapeutics, Hengrui, Ignyta, IQVIA, Incyte Corporation, Inivata, Janssen, Loxo Oncology, Qiming Dev., Lunit USA, Inc., Merck Serono, MSD, Roche, Mirati Therapeutics, MoreHealth, Novartis, OrigiMed, Puma Tech., Sanofi-Aventis, Takeda, Virtus Medical, Yuhan, Curio Science, Bayer Healthcare Pharmaceuticals Ltd., Covidien LP, C4 Therapeutics, Cirina Ltd., Da Volterrra, F. Hoffmann-La Roche Ltd / Genentech, Gilead Sciences, Lucence Health Inc., Medscape LLC / WebMD, MiRXES, OSE Immunotherapeutics, Pfizer, SFJ Pharmaceutical Ltd., Synergy Research, Tigermed, Vertex Pharmaceuticals, Berry Oncology, D3 Bio Ltd., Lakeshore Biotech;Financial Interests, Personal, Invited Speaker, Former known as Hutchison Chi-Med: HutchMed;F nancial Interests, Personal, Officer, Chairman: ACT Genomics-Sanomics Group;Financial Interests, Personal, Stocks/Shares: Sanomics Ltd., Biolidics Ltd., Aurora Tele-Oncology, AstraZeneca;Financial Interests, Personal, Stocks/Shares, Former known as Hutchison Chi-Med: HutchMed;Financial Interests, Institutional, Funding, For clinical trials performed at CUHK: Merck Serono, AstraZeneca, BMS, MSD, Novartis, Pfizer, Roche, SFJ Pharmaceuticals, XCovery, Takeda, G1 Therapeutics, Clovis Oncology;Non-Financial Interests, Personal, Advisory Role: geneDecode;Non-Financial Interests, Personal, Other, Invited Speaker: AstraZeneca, Aurora Tele-Oncology, Lunit USA, Inc., Sanomics Ltd.;Non-Financial Interests, Personal, Leadership Role, Term ended on 30 June 2022: American Society of Clinical Oncology (ASCO);Non-Financial Interests, Personal, Leadership Role: Asian Thoracic Oncology Research Group (ATORG), Chinese Lung Cancer Research Foundation Limited (CLCRF), Hong Kong Cancer Fund (HKCF), Hong Kong Cancer Therapy Society (HKCTS), St. Stephen's College & Prep. School (Hong Kong);Non-Financial Interests, Personal, Leadership Role, Term ended: Chinese Society of Clinical Oncology (CSCO);Non-Financial Interests, Personal, Leadership Role, Term ended on 30 April 2019: International Association for the Study of Lung Cancer (IASLC). M. Tsuboi: Financial Interests, Personal, Invited Speaker, Lecture: Johnson & Johnson Japan;Financial Interests, Personal, Advisory Board, Lectures, Advisory boards: AstraZeneca KK, Chugai Pharmaceutical CO.,LTD, MSD;Financial Interests, Personal, Invited Speaker, Lectures: Eli Lilly Japan, Bristol Myers Squibb KK, Teijin Pharma, Taiho Pharma, Medtronic Japan, ONO Pharmaceutical CO.,LTD;Financial Interests, Personal, Advisory Board, Advisory boards: Novartis;Financial Interests, Personal, Invited Speaker: Daiichi-Sankyo company limited, MSD, AstraZeneca, Novartis;Financial Interests, Institutional, Research Grant: Beohringer-Ingelheim Japan, MSD, AstraZeneca KK, Ono Pharmaceutical CO.,LTD, Bristol Myers Squibb KK, Novartis;Financial Interests, Institutional, Invited Speaker: Eli Lilly Japan. J.M. Lee: Financial Interests, Personal, Advisory Board: Bristol Myers Squibb, Astrazeneca, Roche/Genentech, Novartis;Financial nterests, Personal, Invited Speaker, LCMC3, LCMC4, NAUTIKA-1: Roche/Genentech;Financial Interests, Personal, Invited Speaker, CANOPY-N, GEOMETRY-1: Novartis. E.S. Kim: Financial Interests, Personal, Other, Consulting/Research: Regeneron, Takeda, Novartis. J. Zhang: Financial Interests, Personal, Advisory Board: AstraZeneca, Bayer, Biodesix, Bristol Myers Squibb, Cardinal Health, Daiichi Sankyo, Hengrui Therapeutics, Eli Lilly, Mirati, Nexus Health, Novartis, Novocure, Sanofi, Takeda Oncology;Financial Interests, Personal, Invited Speaker: AstraZeneca, MJH Life Sciences, Regeneron, Sanofi;Financial Interests, Institutional, Research Grant, PI and Sponsor: AstraZeneca, Biodesix, Nilogen, Genentech;Financial Interests, Institutional, Invited Speaker: Hengrui Therapeutics, Mirati, Novartis, Abbvie, BeiGene, Merck;Financial Interests, Institutional, Research Grant, PI, basic science research: Mirati;Non-Financial Interests, Personal, Member, American Society of Clinical Oncology: ASCO;Non-Financial Interests, Personal, Member, American Association for Cancer Research: AACR;Non-Financial Interests, Personal, Member, International Association for the Study of Lung Cancer: IASLC;Non-Financial Interests, Personal, Member, Chinese American Hematologist and Oncologist Network: CAHON. J. Duan: Financial Interests, Personal, Stocks/Shares: Novartis Pharmaceuticals Corporation. C. Lobetti-Bodoni: Financial Interests, Personal, Full or part-time Employment, Clinical Development Medical Director: Novartis Oncology;Financial Interests, Personal, Stocks/Shares: Novartis Oncology;Other, Personal, Other, My husband is a Roche employer: Roche;Other, Personal, Other, My husband had consultancy in the last two years with these companies: Sanofi and Takeda;Other, Personal, Other, My husband ha honoraria in the last 2 years with these companies: Takeda, Jansenn-Cilag Ltd;Other, Personal, Other, My husband owns stock of this company: Harlock Helatcare Consulting Ltd. J.C. Brase: Financial Interests, Personal, Full or part-time Employment: Novartis;Financial Interests, Personal, Stocks/Shares: Novartis. A. Savchenko: Financial Interests, Personal, Full or part-time Employment: Novartis;Financial Interests, Personal, Stocks/Shares: Novartis. P. Garrido Lopez: Financial Interests, Personal, Advisory Board: Abbvie, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, GlaxoSmithKline, Janssen, Lilly, MSD, Novartis, Pfizer, Roche, Takeda, sanofi;Financial Interests, Personal, Invited Speaker: AstraZeneca, Janssen, MSD, Novartis, Pfizer, Roche, Takeda, Novartis, IO Biotech;Financial Interests, Personal, Advisory Board, Spouse: Boehringer Ingelheim, Gebro, Janssen, Nordic;Financial Interests, Personal, Invited Speaker, Spouse: Boehringer Ingelheim, Janssen;Financial Interests, Personal, Other, Data monitoring committee for a clinical trial in 2020: Novartis;Financial Interests, Personal, Other, Lung Cancer Medical Education TASC Committee 2021: Janssen;Financial Interests, Institutional, Invited Speaker: Novartis, Janssen, AstraZeneca, Pfizer, Blue print, Apollomics, Amgen, Array Biopharma;Financial Interests, Personal, Invited Speaker, study entitled JNJ-372: Janssen;Non-Financial Interests, Personal, Leadership Role, Council member as Women for Oncology Committee ChairFellowship and Award Committee and Press CommitteeFaculty for lung and other thoracic tumours: ESMO;Non-Financial Interests, Personal, Leadership Role, President of the Spanish Federation of Medical Societies (FACME): FACME;Other, Personal, Other, My son is working in the pharma company TEVA as an engineer. I do not have any kind ofrelationship with TEVA: TEVA;Non-Financial Interests, Personal, Leadership Role, Former President of Spanish Medical Oncology SocietyMember of the Spanish National Health Advisory Board: SEOM;Non-Financial Interests, Personal, Leadership Role, Member of the Scientific Committee of the Spanish Against Cancer Research Foundation (aecc) and also Borad member: AECC;Non-Financial Interests, Personal, Leadership Role, IASLC Women in Tho acic Oncology Working Group Member: IASLC. All other authors have declared no conflicts of interest. Copyright © 2022

15.
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.

16.
Neurological Sciences ; 43(Supplement 1):S462-S463, 2022.
Article in English | EMBASE | ID: covidwho-2174295

ABSTRACT

Background: Vaccination campaign to contrast the spread of SARSCoV- 2 has raised the issue of vaccine immunogenicity in frail populations, especially multiple sclerosis (MS) patients on disease modifying therapies (DMTs). Material(s) and Method(s): Before (T0) and after 2 months from booster dose of mRNABNT162b2 vaccine (T1), MS patients under DMTs and healthy donors (HDs) were enrolled. For both T0 and T1, anti-Spike (S) antibody titer as well as IFNg, IL2 and TNFa T cells production upon S peptide libraries stimulation were assessed. According to DMTs mechanism of action, MS patients were stratified into immunosuppressive (such as fingolimod, cladribine, ocrelizumab, and alemtuzumab) and immunomodulating (natalizumab) groups [1]. "Activated" cells were defined as T cells producing any of IFNg or IL2 or TNFa while polyfunctional T cells were defined as those simultaneously producing all 3 cytokines. All possible combinations of intracellular expression of IFNg, IL2, and TNFa in cytokine-producing T cells were evaluated. Result(s): Sixteen MS patients (11 females/5 males, median age [IQR] 41.5 [34.3-48.8] years) and nine HDs (7 females/2 males) were enrolled. An increase of anti-S antibody titers at T1 compared to T0 in bothMSand HDs was seen (1930 [85.75-5895] and 198.5 [80.73-1140] BAU/ml, respectively, p=0.0017;3590 [1575-10850] and 320 [124.1- 662.0], respectively, p=0.0039). Reduced percentage of CD4 and CD8 "activated" and CD4 polyfunctional T cells were observed inMS compared toHDs at T0 (CD4: 1.025 [0.795-1.275] and 1.640 [1.325-2.245], respectively, p=0.0111;CD8 1.0 [0.603-1.328] and 1.65 [1.315-2.360], respectively, p=0.0135;CD4: 0.045 [0.029-0.089] and 0.10 [0.10-0.125], respectively, p=0.0211). Stratifying MS population, only immunomodulating showed an increase in anti-S antibody titers production at T1 (5410 [2655-9893] and 871 [175.3-1360], respectively, p=0.0313), while a reduced production was seen in immunosuppressive compared to immunomodulating and HDs (369.5 [49.8-1975] and 5410 [2655-9893], respectively, p=0.0172;369.5 [49.8-1975] and 3590 [1575-10850], respectively, p=0.0431]. At T0 in immunosuppressive patients a reduced percentage of "activated" CD4 and CD8 T cells was observed when compared to HDs (0.875 [0.658-1.025] and 1.64[1.325-2.245], respectively, p=0.0020;0.91[0.53-1,293] and 1.65[1.315-2.36], respectively, p=0.019). While, at T1 a reduced percentage of CD8 polyfunctional T cells was seen in immunosuppressive patients when compared to HDs (0.036[0.019-0.065] and 0.1[0.048- 0.1291], respectively, p=0.0232). Conclusion(s): Both humoral and T cell specific response to vaccination in MS patients seems to be significantly influenced by different DMTs mechanism. Moreover, a higher percentage of TNFa and a reduced IFNg production was observed, mainly in immunosoppressive group.

17.
Biochimica Clinica ; 46(3):S130, 2022.
Article in English | EMBASE | ID: covidwho-2169554

ABSTRACT

Introduction Cellular immunity is pivotal for SARS-CoV-2 protection, but measurements of cellular-specific response are rarely performed due to costs and technical requirements. Hyris developed a direct Real-Time PCR (dRT-PCR) assay that measures CD4 and CD8 T cells immunoreactive to SARS-CoV-2 Spike protein by targeting CXCL10 mRNA (upregulated in response to IFN-gamma secreted by antigenspecific T Cell). This test uses a modular T cell activation method based on pool of synthetic peptides to stimulate Sspecific T cell, and those able to tolerate amino acid (AA) mutations that characterize new variants. The aim of this study was to evaluate the assay performances. Methods Whole blood (Li-He) of 13 SARS-CoV-2 naive and 116 vaccinated individuals were stimulated with a pool of Speptides (15 AA long) covering whole S protein (Wuhan) and left unstimulated (SCV2 T Activation kit). Whole blood of 78 healthy vaccinated individuals was stimulated with two sets of peptides covering the constant and mutated region of S protein of Omicron BA1.2 (SCV2 Omicron T Activation kit) and left unstimulated. After overnight incubation T cell activation was detected by bKIT dqTACT MS (CXCL10 and ACTIN mRNA) on the HYRIS bCUBE. Results The vaccinated subjects statistically shown level of relative mRNA expression of CXCL10 greater than unvaccinated subjects;109 vaccinated individuals were detected as reactive to stimulation (mean relative expression 0.043) with SARS-CoV-2 S peptides (Sensitivity 94%), while 10 naive were detected as not-reactive (mean expression -0.25) (Specificity 77%). Considering the 129 samples the AUC value of is 90% (CI 82%-98%). 78 samples activated with the constant and mutated region of S of Omicron peptides showed different quantities of T cells response. The 62% of sample assessed resulted reactive (with a ratio between the two stimulations above 15%) despite the AA mutations, showing that AA mutations can affect the magnitude of S T cell response. Conclusions Combining the modular utilization of synthetic peptide pools as activators and the direct measurement of CXCL10 mRNA in whole blood, dRT-PCR method was proven to be a reliable and efficient assay for the measurement of the individual antigen-specific T cells measurement of SARS-CoV-2 cellular immunity.

18.
Biochimica Clinica ; 46(3):S7-S8, 2022.
Article in English | EMBASE | ID: covidwho-2167874

ABSTRACT

Background: Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccination is the standard of care for the prevention of COVID-19 disease, with a positive impact in countries in which vaccination has been promoted. Since the emergence of variants of concern (VOCs) European Medicines Agency (EMA) recommended an extra dose of the COVID-19 vaccines Comirnaty (BioNTech/Pfizer) and Spikevax (Moderna) for patients with severely weakened immune system and booster doses for subjects with normal immune system to ensure a lasting response. Although Vaccination triggers both humoral and cellular immune response, COVID-19 vaccination efficacy is evaluated by measuring antibodies only, whereas adaptative cellular immunity is unexplored. Our aim is to test this new kit QuantiFERON SARS-CoV-2 to evaluate the immune response after three doses of BNT162b vaccine in healthy donors compared to two cohort of fragile patients: Common Variable Immunodeficiency (CVID) patients and Kidney Transplant Recipients (KTR) patients. Method(s): Blood samples were collected from eight health care workers in our department, fourteen CVID patients and eight KTR patients. All the individuals recruited were naive to SARS-COV2 and immunized by three doses of BNT162b vaccine. We examined humoral responses to vaccinations using the LIAISON DIASORIN SARSCOV-2 S1/S2 IgG. Next blood from all participants was subjected to the novel Interferon gamma (INF-gamma) Release Assay (IGRA) from Qiagen, measuring INF-gamma release induced by two proprietary SARS-CoV-2 peptide pools (Ag1 and Ag2) encompassing the spike protein and designed to stimulate CD4+ and CD8+ T cells and induce the releases of INF-gamma. Result(s): Using LIAISON SARS-COV-2 S1/S2 IgG assay from DIASORIN we confirm that in healthy subjects BNT162b third dose had successfully mounted humoral immune response with a S1/S2 IgG mean of 17100 BAU/ml. Conversely, the CVID group and KTR group shown a statistically significant reduction of IGg levels with a mean of 978 BAU/ml and 1029 respectively. Notably seven patients (five CVID and two KTR) presented IGg levels below the cut-off (33,8 BAU/ml). Next, we evaluated the INF-gamma response to SARS-CoV-2 Ag1 and Ag2 founding seven non-reactive subjects (three CVID and four KTR). Surprisingly three of non-reactive patients shown a good humoral response, whereas three patients with a negative humoral immune response shown reactiveness to IGRA assay. Conclusion(s): Assessing cellular immunity for SARSCOV-2 in addition to humoral immunity is important taking into account that cellular immunity plays a pivotal role against the virus and likely its variants. Some patients with weakened immune response have no correlation between humoral and cellular immunity, suggesting that the evaluation of T cell responses could be a more sensitive clinical marker of immunization. In this scenario the evaluation of cellular immunity might be informative for clinicians to identify patients more susceptible to a severe COVID-19 disease.

19.
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.

20.
Journal for ImmunoTherapy of Cancer ; 10(Supplement 2):A1353, 2022.
Article in English | EMBASE | ID: covidwho-2161959

ABSTRACT

Background Clonal hematopoiesis (CH) is an age-related phenomenon characterized by the overrepresentation of blood cells arising from a single, mutant clone and is detectable in 10-20% of individuals over 70.1 CH has now been implicated in a variety of non-hematological disorders, such as cardiovascular diseases and Covid-19 infections, by exacerbating the innate inflammatory response.2-4 However, the impact of CH in solid tumors and response to immune checkpoint blockade (ICB) is unknown. Methods To assess the prevalence and role of CH in patients with solid tumors, we analyzed publicly available data from the MSKCC-IMPACT study.5, 6 To mechanistically study CH in solid tumors, we established an orthotopic model of pancreatic adenocarcinoma (PDAC) in mice with Tet2+/- CH. CH and WT mice were treated with either ICB (aCTLA-4 + aPD-1) or vehicle control. Single-cell (sc-) RNAseq was performed on tumor infiltrating lymphocytes (n=3/group) while remaining mice were observed for disease progression and overall survival (n=10/group). Results Analyzing CH frequencies in a cohort of patients with solid tumors, we observed that the prevalence of CH was approximately 5 times higher in patients with cancer when compared to healthy age-matched controls. Further, patients with detectable CH clones had significantly worse overall survival (figure 1A). In vivo, sc-RNAseq data revealed that myeloid cells present within the pancreatic tumors of mice with Tet2+/- CH were significantly enriched for both type I and type II interferon (IFN) signaling (figure 1B). Further, these IFN+ myeloid cells were ablated after ICB therapy in Tet2+/+ WT mice but persisted in mice with Tet2+/- CH (figure 1C). PDAC tumors from mice with Tet2+/- CH had approximately half the total number of infiltrating CD8 T cells at baseline when compared to those from Tet2+/+ WT mice. Upon ICB treatment, CD8 effector cells only expanded in the tumors from Tet2+/+ WT mice. Functionally, this translated to more rapidly progressing tumors, resistance to ICB, and reduced overall survival in mice with Tet2+/- CH (figure 1D). Conclusions CH is present in upwards of 30% of patients with solid tumors and is associated with significantly worsened prognosis. Modeling PDAC in the presence of Tet2+/- CH in vivo revealed distinct alterations in the tumor microenvironment that ultimately influenced tumor progression and response to ICB. This proposed research bridges the fields of solid tumor immunology and clonal hematopoiesis to address novel mechanisms of immunotherapy resistance that will span cancer type and, ultimately, improve patient care.

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