Cellular Immune Responses In Patients Research Articles

Abstract PO5-02-05: Assessing Vaccine-Mediated Cellular Immune Responses in Patients Receiving Combined Vaccine and Chemotherapy Treatment

Abstract Background: We showed recently that immunizing breast cancer patients with the P10s-PADRE vaccine in combination with chemotherapy activates both humoral and cellular immune responses. Induction of specific antibody response was easily determined by measuring anti-P10s antibodies, however, we observed increase in serum interferon-gamma (IFNg) and tumor necrosis factor-alpha (TNFα) as well as activation of Natural Killer (NK) and T-cells, accurate assessing of which proved complicated due to the non-specific impact of chemotherapy. This study was undertaken to further distinguish the vaccine-induced cellular immune responses from the immune effects induced by chemotherapy, and to evaluate their potential contributions to anti-tumor activity. Methods: Peripheral blood mononuclear cells (PBMCs) from twenty-five subjects who received a combination of P10s-PADRE and standard-of-care chemotherapy were utilized for gene expression analysis and various immune assays. PBMC samples collected before and after treatment were subjected to flow cytometry and ELISpot assays, as well as bulk and single-cell RNA sequencing analyses. For functional assays PBMCs were stimulated with P10s, P10s-PADRE, anti-CD3/CD28, and tumor cell lysates. Differential gene expression analysis, gene set analysis, Hiearchical Clustering, and principal component analysis were performed. Results: Non-specific (anti-CD3/CD28) and specific (peptide, cancer cells) stimulation of PBMCs significantly activated immune cells in post-immune samples compared to pre-immune samples as measured by cytokine secretion, with IFNg being the dominant cytokine secreted. Flow cytometry showed activation of both natural killer and CD8+ cells measured by a significant increase in CD69 expression. These data plus detection of Ab response suggests induction of both humoral and cellular immune responses. However, bulk RNA-seq performed on 24 patients indicate a dramatic reduction of B, T, and NK cells in the post-immune samples. Deconvolution reanalysis of the bulk sequencing data together with complementary scRNA-seq analysis of PBMCs of select subjects supports vaccine-mediated activation of both CD8+ and NK cells and suggests NK cells as a source of detected serum increase in IFNg and TNFα. Conclusions: The P10s-PADRE vaccine elicits substantial and quantifiable cellular and humoral immune responses, despite the deleterious effects of chemotherapy on effector immune cells involved. The evidence indicates that the activation of both CD8+ and NK cells is facilitated by the vaccine. It is probable that the NK cells are the primary contributors of IFNγ and TNFα. These findings carry considerable implications for the structuring of advanced phase trials and the potential application of the vaccine in treating other forms of malignancies. Citation Format: Donald Johann, Fariba Jousheghany, Emily Blitz, Bernice Nounamo, Sam Makhoul, Eric Siegel, Thomas Kieber-Emmons, Behjatolah Monzavi-Karbassi. Assessing Vaccine-Mediated Cellular Immune Responses in Patients Receiving Combined Vaccine and Chemotherapy Treatment [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr PO5-02-05.

Clinical effectiveness of coronavirus disease 2019 vaccination in patients with multiple sclerosis stratified by disease-modifying treatment.

Coronavirus disease 2019 (COVID-19) vaccination has been associated with a dampened humoral and/or cellular immune response in patients with multiple sclerosis (MS) who were concurrently on disease-modifying treatment (DMT) with B-cell depleting agents or sphingosine-1-phosphate receptor modulators (S1PRMs). Our main goal was to investigate the impact of these DMT classes on the clinical effectiveness of COVID-19 vaccination. Since March 2020, demographics and clinical data of patients with MS who developed COVID-19 have been collected at the Belgian National MS Centre in Melsbroek. Patients were considered to be 'protected by vaccination' if they were (i) fully vaccinated and (ii) tested positive for COVID-19 in the period ranging from 14 days to 6 months after the last administered vaccine. On 19 December 2022, 418 COVID-19 cases were retrospectively identified in 389 individual patients. Hospitalization and mortality rates resulting from the infection were 10.8% and 2.4%, respectively. Being 'unprotected by vaccination' was significantly associated with a worse COVID-19 outcome (i.e., hospitalization and/or death) in the total cohort (N = 418, odds ratio [OR] 3.96), in patients on ongoing DMT other than anti-CD20 agents or S1PRMs (N = 123, OR 31.75) and in patients without DMT (N = 182, OR 5.60), but not in those receiving anti-CD20 agents (N = 91, OR 0.39); the S1PRMs subgroup was considered too small (22 infections) for any meaningful analysis. Coronavirus disease 2019 vaccination protects against severe infection in patients with MS but it was not possible to confirm this effect in those on DMT with B-cell depleting agents.

(1067) - Longitudinal Dynamics of SARS-CoV-2 Specific Humoral and Cellular Immune Responses in Patients on Waiting List and After Lung Transplantation

(1067) - Longitudinal Dynamics of SARS-CoV-2 Specific Humoral and Cellular Immune Responses in Patients on Waiting List and After Lung Transplantation

Immunogenicity of COVID-19 vaccines in patients with cirrhosis: A meta-analysis

ABSTRACT The immunogenicity of COVID-19 vaccines in patients with liver cirrhosis remains largely unknown. The purpose of this meta-analysis was to investigate the immunogenicity of COVID-19 vaccines in patients with cirrhosis and compare the humoral and cellular immune responses following complete COVID-19 vaccination between cirrhosis patients and healthy controls. A systematic literature search was conducted in PubMed, EMBASE, and Web of Science from 1 January 2020 to 22 August 2023. Sixteen studies with 2127 cirrhosis patients were included. The pooled seroconversion rate in patients with cirrhosis following complete COVID-19 vaccination was 92.4% (95% CI, 86.2%–96%, I 2 = 90%) with significant between-study heterogeneity. Moreover, COVID-19 vaccination elicited a higher humoral immune response in patients of compensated cirrhosis as compared with decompensated cirrhosis (RR = 1.069, 95% CI, 1.011–1.131, I 2 = 17%, p = .019). Additionally, 10 studies were included for comparison analysis of seroconversion rate between cirrhosis patients and healthy controls. The results showed that the seroconversion rate in patients with cirrhosis was slightly lower compared with healthy controls (RR = 0.972, 95% CI, 0.955–0.989, I 2 = 66%, p = .001). Meanwhile, the pooled RR of cellular immune response rate for cirrhosis patients vs. healthy controls was 0.678 (95% CI, 0.563–0.817, I 2 = 0, p < .0001). Our meta-analysis demonstrated that COVID-19 vaccination elicited diminished humoral and cellular immune responses in patients of cirrhosis. Patients with cirrhosis particularly decompensated cirrhosis who have completed full-doses of COVID-19 vaccination should receive continuous attention and preemptive measures.

Humoral and cellular immune response in patients of liver cirrhosis and immunocompetent recipient of ChAdOx1nCoV-19 Vaccine (Covishield)

Despite the effectiveness of COVID-19 vaccination in reducing the severity of the disease, the demand for booster is increasing in vulnerable populations like elderly and immunocompromised individuals especially with each new wave of COVID-19 in different countries. There is limited data on the sustained immunity against COVID-19 in patients with liver cirrhosis. The study was aimed to compare the T cell and humoral immune response after 1 year of ChAdOx1nCoV-19 Vaccine in patients with liver cirrhosis and healthy health care workers (HCW). This was a prospective observational study including 36 HCW, 19 liver cirrhosis patients and 10 unvaccinated individuals. Anti-SARS-CoV-2S antibody, neutralizing antibody and memory T cell subsets were evaluated by ELISA and flow cytometry, respectively, in all three groups after 1 year of initial vaccination. Compared to HCW and unvaccinated individuals, liver cirrhosis patients had significantly depleted T cells, although CD4:CD8 + T cell ratio was normal. Both cirrhotic patients and HCW developed memory T cell subset [effector memory RA (P = 0.141, P < 0.001), effector memory (P < 0.001, P < 0.001), central memory (P < 0.001, P < 0.01), stem cell memory (P = 0.009, P = 0.08) and naïve (P < 0.001, P = 0.02)] compared to unvaccinated unexposed individuals of CD4 + T and CD8 + T, respectively. However, among HCW and cirrhotic group no difference was noted on central memory and stem cell memory cells on T cells. Patients with liver cirrhosis developed comparable memory T cells after vaccination which can evoke sustainable immune response on reinfection. Therefore, additional vaccine doses may not be necessary for cirrhosis patients.

Cellular Mechanisms Associated with Suboptimal Immune Responses to Sars-Cov-2 Bivalent Booster Vaccination in Patients with Multiple Myeloma

Background: In response to the ever-evolving challenges posed by the antigenically diverse Omicron variants, the deployment of bivalent mRNA booster vaccines encompassing both the ancestral (WA1) and Omicron BA.5 spike components was initiated in fall of 2022. The real-world impact of these bivalent vaccines is largely unknown in patients with Multiple Myeloma (MM). We characterize the humoral and cellular immune responses in patients with MM before and after receiving the bivalent booster implementing cutting edge methodologies to identify patterns associated with continuing vulnerability in the current post-pandemic era. Methods: We studied the humoral and cellular immune responses before and after bivalent booster immunization in 48 MM patients. Spike binding IgG antibody levels were measured by SARS-CoV-2 spike binding ELISA and neutralization capacity was assessed by a SARS-CoV-2 multi-cycle microneutralization assay. We measured spike specific T cell function using the QuantiFERON SARS-CoV-2 (Qiagen) assay as well as flow cytometry-based T cell assays quantifying interferon-gamma (IFNg) production. In a subset of 38 patients, immune profiling was performed using high-dimensional flow cytometry. The frequencies of dendritic cells (DCs), B cells, Natural Killer (NK) cells and T follicular helper cells (TFH) were compared between responders and non-responders. Results: The serological effect of the bivalent vaccination in MM patients is nuanced with the overall cohort not demonstrating a significant increase post bivalent vaccination (median 196 AU/mL prior to bivalent to median 276 post bivalent p=0.11). The lack of antibody response was driven by patients undergoing anti-CD38 and anti-BCMA antibody therapy as compared to MM patients undergoing other therapies who demonstrated a significant increase in antibody levels post vaccination (p=0.021). Patients on anti-CD38 and anti-BCMA antibody therapy also did not significantly increase neutralizing capacity to WA1 (p=0.42) or BA.5 omicron strain (p=0.48) while MM patients on other therapies benefitted significantly, as illustrated by the increased neutralizing capacity of WA1 (p=0.024) and BA.5 (p=0.0055 Figure 1A). In addition to quantifying antibody responses, we profiled T cell responses using our published flow cytometry method using WA1 anti-S peptides as well as the QuantiFERON SARS-CoV-2 RUO assay (Qiagen). Spike reactive T cell responses significantly correlated with anti-Spike IgG levels in MM patients (r 2=0.49, p&amp;lt;0.001), WA1 neutralizing ID50 (R 2 = 0.6, p&amp;lt;0.01) and BA.5 neutralizing ID50 (R 2= 0.54, p=0.01) reinforcing the fact that T cell compensation is lacking in MM patients. We separated the lowest quantile (patients with Anti-S IgG &amp;lt;156 AU/mL) to delineate suboptimal producing patients compared to the remaining MM anti-S producing patients. Non-responders exhibited deficiencies in immune populations involved in robust antibody production including lower frequency of CD1c+ DCs (p=0.02 Figure 1B), B Cells (p&amp;lt;0.01 Figure 1B) and circulating CXCR3-CCR4+TFH cells (p&amp;lt;0.01 Figure 1B). Furthermore, immature NK cells were the predominant population in non-responders, while responders had more cytotoxic mature NK phenotype (p&amp;lt;0.01 Figure 1B) after bivalent vaccination. Conclusions: Our study highlights the varying immune responses observed in MM patients after receiving bivalent COVID-19 vaccination. Specifically, a subgroup of MM patients undergoing anti-CD38 and anti-BCMA therapy experience impairments in immune cells such DCs, B cells, NK cells and TFH cells, leading to an inability to generate adequate antibody and T cell responses to vaccinations. Our results indicate that the QuantiFERON SARS-CoV-2 assay could be deployed for clinical use bridging the need for suitable laboratory tests to measure SARS-CoV-2 specific T cell responses. Ongoing research will further investigate whether the compromised immune machinery and diminished T cell activity identified in this study can serve as discriminators for identifying MM patients at high risk of infectious complications stemming from anti-BCMA therapies. Such insights will aid in developing targeted strategies to address these challenges and improve patient outcomes.

Cellular mechanisms associated with sub-optimal immune responses to SARS-CoV-2 bivalent booster vaccination in patients with Multiple Myeloma

The real-world impact of bivalent vaccines for wild type (WA.1) and Omicron variant (BA.5) is largely unknown in immunocompromised patients with Multiple Myeloma (MM). We characterize the humoral and cellular immune responses in patients with MM before and after receiving the bivalent booster, including neutralizing assays to identify patterns associated with continuing vulnerability to current variants (XBB1.16, EG5) in the current post-pandemic era. We studied the humoral and cellular immune responses before and after bivalent booster immunization in 48MM patients. Spike binding IgG antibody levels were measured by SARS-CoV-2 spike binding ELISA and neutralization capacity was assessed by a SARS-CoV-2 multi-cycle microneutralization assays to assess inhibition of live virus. We measured spike specific T-cell function using the QuantiFERON SARS-CoV-2 (Qiagen) assay as well as flow-cytometry based T-cell. In a subset of 38 patients, high-dimensional flow cytometry was performed to identify immune cell subsets associated with lack of humoral antibodies. We find that bivalent vaccination provides significant boost in protection to the omicron variant in our MM patients, in a treatment specific manner. MM patients remain vulnerable to newer variants with mutations in the spike portion. Anti-CD38 and anti-BCMA therapies affect the immune machinery needed to produce antibodies. Our study highlights varying immune responses observed in MM patients after receiving bivalent COVID-19 vaccination. Specifically, a subgroup of MM patients undergoing anti-CD38 and anti-BCMA therapy experience impairment in immune cells such DCs, B cells, NK cells and TFH cells, leading to an inability to generate adequate humoral and cellular responses to vaccination. National Cancer Institute (National Institutes of Health), National Institute of Allergy and Infectious Diseases (National Institutes of Health), NCI Serological Sciences Network for COVID-19 (SeroNet) and The Icahn School of Medicine at Mount Sinai.

T-cell immunity status of children with combined infection with SARS-CoV-2 and human herpesviruses

There is an opinion that COVID-19 may be the cause of the reactivation of herpesviruses. Purpose. To study the state of the cellular link of adaptive immunity in the combined course of herpesvirus infections and COVID-19, to describe the clinical and laboratory characteristics of such conditions. Material and methods. In 2022–2023 a cross-sectional study was conducted. 71 patients aged from 1 month to 16 years were selected. Inclusion criteria: presence of signs of acute respiratory disease associated with SARS-CoV-2 and/or mononucleosis-like syndrome associated with active herpesvirus infection. All patients underwent a standard laboratory examination, determined by nosology, and an additional assessment of the cellular link of adaptive immunity (CD3+, CD4+, CD8+, CD3+HLA-DR+, CD3- CD16+CD56+ and CD20+) on a flow cytometer using monoclonal antibodies. Results and conclusion. The clinical pattern of the combined course of herpesvirus infection and SARS-CoV-2 differs little from monoinfections. Only at the first encounter with the Epstein-Barr virus, lymphoproliferative syndrome and hepatomegaly were more often recorded (p&lt;0.05). Comparing the nature of the cellular immune response in patients with COVID-19 and herpesvirus infection, we observed pronounced differences. In patients with primary herpesvirus infection, the T-cell immune response was an order of magnitude higher than in acute COVID-19, herpesvirus reactivation, and co-infection, and this was true for all studied lymphocyte subpopulations. With SARS-CoV-2, a decrease in the total number of T-lymphocytes, T-helpers, and cytotoxic lymphocytes was observed. This condition, of course, cannot be called immunosuppression, but some parallel is clearly traced. And even with the combined course of SARS-CoV-2 and herpesvirus infection, the absolute values of T-cell immunity indicators do not reach the same indicators in patients without COVID-19. It is likely that this reason underlies the phenomenon of reactivation of persistent herpesviruses in patients infected with SARS-CoV-2.

Immunogenicity after two and three doses of mRNA vaccine in patients with cancer treated with exclusive radiotherapy.

Data on immunoresponse after SARS-CoV-2 vaccines for patients treated with exclusive radiotherapy (RT) are scarce. Since RT may affect the immune system, we conducted the MORA trial (Antibody response and cell-mediated immunity of MOderna mRNA-1273 vaccine in patients treated with RAdiotherapy). Data regarding humoral and cellular immune response of patients treated with RT were prospectively collected after the second and third dose of mRNA vaccines. Ninety-two patients were enrolled. With a median of 147days after the second dose, the median SARS-CoV-2 IgG titer was 300 BAU/mL: six patients were seronegative (Spike IgG titer≤40 BAU/mL), whereas 24, 46 and 16 were poor responders (Spike IgG titer:41-200 BAU/mL), responders (Spike IgG titer:201-800 BAU/mL) and ultraresponders (Spike IgG titer>800 BAU/mL), respectively. Among seronegative patients, two patients were negative also for cell mediated response, as tested with IFN-γ release Assay (IGRA) test. With a median of 85days after the third dose, the median SARS-CoV-2 IgG titer was 1632 BAU/mL in 81 patients: only two patients were seronegative, whereas 16 and 63 patients were responders and ultraresponders, respectively. Among the 2 persistently seronegative patients, IGRA test was negative in one who had previously received anti-CD20 therapy. Documented paucisymptomatic (n=3) or asymptomatic (n=4) infection occurred after the third dose, during the Omicron wave. In patients treated with exclusive RT, even during the Omicron breakthrough, robust humoral response and clinical protection from severe SARS-CoV-2 disease were achievable with three doses of mRNA vaccine.

Comparative characteristics of the cellular immune response to SARS-CoV-2 during infection and post-vaccination

An important area of research concerns monitoring of immune response features in patients with SARS-CoV-2 infection as well as their analysis, as compared with characteristics of vaccine-mediated protection, in order to specify the determinants of cellular immune response. The aim of our work was to compare the state of cellular immune response in patients who underwent COVID-19, and in persons vaccinated with a peptide vaccine preparation. The study involved volunteers who suffered with COVID-19 of varying severity (n = 30), as well as persons who completed the full course of vaccination with the peptide vaccine (n = 27). For comparison, we took blood specimens from the volunteers before vaccination. Immunophenotyping of leukocytes was performed by the Lyse/No-Wash procedure (BD Bioscience, USA), and Cyto-Stat monoclonal antibodies (CD45-FITC, CD4-PE, CD8-ECD, CD3-PC5), CD45RA-PC7, CD45RO-PE (Beckman Coulter, USA), and analyzed with a DakoCytomation flow cytometer (Denmark). Determination of intracellular IFNγ (CD4+IFNγ+) was performed with the standard technique. Cytokine production was determined using reagent kits for detection of IFNγ, TNFα, IL-4, IL-8, IL-10 (Vector-Best JSC, Russia) with automatic enzyme immunoassay analyzer LAZURIT (Dynex Technologies, USA). As based on the results obtained, we have shown that cellular immunity was developed after vaccination and infection with COVID-19. However, the most pronounced immune response was recorded in the COVID-19 reconvalescents, i.e., more than 60% of these patients showed an increased number of CD4+T-memory helper cells (8.7 (0.5-12.1) % versus 0.3 (0.1-0.5) % in the comparison group, p &lt; 0.05) as well as proportion of CD4+IFNγ+T lymphocytes (4.2 (1.8-4.3) % versus 0.4 (0-0.8) % in the comparison group, p &lt; 0.05). Moreover, we revealed an increased functional reserve of cells in terms of TNFα, IL-8, IL-10 production. One month after vaccination of volunteers with the peptide-based preparation, the total pool of memory T lymphocytes was apparently dominated by CD8+T memory cells (CD45+CD8+CD45RA-CD45RO+). A significant increase was found in the average levels of CD4+IFNγ+ activated cells (8.2-fold), as well as in values of ConA-induced IL-4 production (3.3 (1.1-4.5) pg/mL, and 2.8 (1.7-3.9) pg/mL, respectively versus 1.3 (0.1-2.4) pg/mL in the control group, p &lt; 0.05). The data obtained are in accordance with information available in the literature concerning development of cellular immune responses to SARS-CoV-2, which results from a past illness, or measures for the specific prevention of COVID-19. Further search for cellular correlates of protection against a new coronavirus infection will allow us to revise the current vaccination strategy and develop an optimal approach to COVID-19 prevention.

Humoral and cellular immune response to second and third severe acute respiratory syndrome coronavirus 2 mRNA vaccine in patients with plasma cell dyscrasia.

The recently developed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mRNA vaccine has a short history of use and further information is needed regarding its efficacy, especially in immunocompromised conditions, such as plasma cell dyscrasia (PCD). We retrospectively measured serum SARS-CoV-2 antibodies against the spike protein (S-IgG) after the second and third mRNA vaccine doses (doses 2 and 3, respectively) in 109 patients with PCD. We evaluated the proportion of patients with an adequate humoral response (defined as S-IgG titers ≥300 antibody units/mL). Although active anti-myeloma treatments prior to vaccination had a significantly negative impact on adequate humoral response, specific drug subclasses including immunomodulatory drugs, proteasome inhibitors, and monoclonal antibodies were not negatively associated, except for B-cell maturation antigen-targeted therapy. Dose 3 (booster vaccination) led to significantly higher S-IgG titers and more patients acquired an adequate humoral response. Furthermore, evaluation of vaccine-induced cellular immune response in patients using T-spot Discovery SARS-CoV-2 kit, revealed an enhanced cellular immune response after Dose 3. This study highlighted the significance of booster SARS-CoV-2 mRNA vaccination in patients with PCD with respect to humoral and cellular immunity. Moreover, this study highlighted the potential impact of certain drug subclasses on vaccine-induced humoral immune response.

Compromised T-cell immunity in patients with spinal cord injury and its relationship with injury characteristics.

The aim of this study was to investigate in vivo and in vitro cellular immune responses in patients with chronic (spinal cord injury; SCI), determine the effects of autonomic dysfunction on cellular immune response, and determine the effect of completeness of the injury at different levels on cellular immune response. Forty-nine patients (42 males, 7 females; mean age: 35.5±13.4 years; range, 18 to 68 years) with chronic (time since injury >6 months) traumatic SCI were included in this cross sectional study between March 2013 and December 2013. Patients were allocated into two groups: Group 1, patients with an injury at T7 or below, and Group 2, patients with an injury at T6 or above. All patients in Group 2 had a history of autonomic dysreflexia and orthostatic hypotension. Intradermal skin tests were applied to the participants to reveal delayed T-cell responses. The percentages of cluster of differentiation (CD)3+ T cells and CD3+ T cells expressing CD69 and CD25 were analyzed by flow cytometry for the detection of activated T cells including all T-cell subsets. When patients with complete injuries were compared, the CD45+ cell percentage was found to be significantly higher in patients in Group 2. Patients with an incomplete SCI had increased skin response to candida antigens compared to complete SCI patients. Incomplete SCI patients also had higher percentages of lymphocytes and CD3+CD25+ and CD3+CD69+ T cells compared to patients with complete SCI. T-cell activity is impaired in chronic SCI patients with higher levels of injury, and the completeness of injury and autonomic dysfunction gain prominence as compromising factors in T-cell immunity.

Humoral and cellular immune response in patients with hematological disorders after two doses of BNT162b2 mRNA COVID-19 vaccine: A single-center prospective observational study (NCT05074706).

Hematological patients at higher risk of severe COVID‐19 were excluded from the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) vaccine trials. In this single‐center observational prospective study (NCT05074706), we evaluate immune response in the hematological patients followed at the Hematological Division of San Gerardo Hospital, Monza (Italy) deemed to be severely immunosuppressed after vaccination with two doses of the BNT162b2 vaccine. Anti‐SARS‐CoV‐2 immunoglobulin G titers above the cutoff value of 33.8 BAU/ml were detected in 303 (80.2%) out of the 378 patients enrolled. Patients with lymphoproliferative disorders had a significant lower probability of immunization (43.2% vs. 88.4%, p < 0.001). Patients treated with anti‐CD20 showed a significantly lower probability of immunization compared to all other treatments (21.4%, p < 0.0001). Among 69 patients who failed seroconversion, 15 patients (22.7%) showed a positive T‐cell response. Patients previously treated with anti‐CD20 were 2.4 times more likely to test positive for T‐cell responses (p = 0.014). Within a follow‐up of 9 months from the second COVID‐19 vaccination, symptomatic SARS‐CoV‐2 infections were reported by 20 patients (5.3%) and four of them required hospitalization. Successful serological or T‐cell‐mediated immunization conferred protection from symptomatic COVID‐19. Patients treated with anti‐CD20 who were not seroconverted after vaccination might still be protected from COVID‐19 due to the T‐cell immune response.

SARS-CoV-2 mRNA vaccinations fail to elicit humoral and cellular immune responses in patients with multiple sclerosis receiving fingolimod

BackgroundSARS-CoV-2 mRNA vaccination of healthy individuals is highly immunogenic and protective against severe COVID-19. However, there are limited data on how disease-modifying therapies (DMTs) alter SARS-CoV-2 mRNA vaccine immunogenicity in...

Immunogenicity of CAR-T Cell Therapeutics: Evidence, Mechanism and Mitigation.

Chimeric antigen receptor T cell (CAR-T) therapy demonstrated remarkable success in long-term remission of cancers and other autoimmune diseases. Currently, six products (Kymriah, Yescarta, Tecartus, Breyanzi, Abecma, and Carvykti) are approved by the US-FDA for treatment of a few hematological malignancies. All the six products are autologous CAR-T cell therapies, where delivery of CAR, which comprises of scFv (single-chain variable fragment) derived from monoclonal antibodies for tumor target antigen recognition is through a lentiviral vector. Although available CAR-T therapies yielded impressive response rates in a large number of patients in comparison to conventional treatment strategies, there are potential challenges in the field which limit their efficacy. One of the major challenges is the induction of humoral and/or cellular immune response in patients elicited due to scFv domain of CAR construct, which is of non-human origin in majority of the commercially available products. Generation of anti-CAR antibodies may lead to the clearance of the therapeutic CAR-T cells, increasing the likelihood of tumor relapse and lower the CAR-T cells efficacy upon reinfusion. These immune responses influence CAR-T cell expansion and persistence, that might affect the overall clinical response. In this review, we will discuss the impact of immunogenicity of the CAR transgene on treatment outcomes. Finally, this review will highlight the mitigation strategies to limit the immunogenic potential of CARs and improve the therapeutic outcome.

Immune responses of patients without cancer recurrence after a cancer vaccine over a long term.

The present study aimed to clarify the humoral and cellular immune responses of patients with cancer who experienced no recurrence over a long term after receiving a cancer vaccine. The immune kinetics were investigated in response to a personalized peptide vaccination (PPV) among 44 Japanese patients without an active tumor at entry to the vaccination: Lung adenocarcinoma (n=11); colon (n=18); and breast cancer (n=15) (9, 10, 12, 8 and 5 patients with stage I, II, III and IV recurrences, respectively). The patients' immunoglobulin G (IgG) and cytotoxic T lymphocyte (CTL) activities were measured using a multiplexed Luminex assay and an interferon-γ release assay, respectively. There were no severe adverse events related to the PPV other than a grade III injection site reaction. A potent boost in IgG or CTL at the end of the 1st vaccination cycle was observed in 77% of the patients (n=84). The IgG levels were sustained throughout the follow-up period, whereas the CTL levels declined and were transient. A total of 37 of the 44 patients (84%) had no recurrence, with a median follow-up of 67.6 months (interquartile range, 45.6-82.8 months). Overall, the PPV induced long-term humoral immunity with transient cellular immunity in the majority of patients with cancer without an active tumor at their entry to the PPV.

MO836: Patients Receiving Haemodialysis Maintain Sars-Cov-2 Immunity Comparable With Healthy Individuals: A Prospective Cohort Study

Abstract BACKGROUND AND AIMS Patients with end-stage kidney disease receiving maintenance haemodialysis (HD) are at increased risk for mortality after infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) compared with the general population. However, it is currently unknown whether the long-term SARS-CoV-2 humoral and cellular immune responses in patients receiving HD are comparable to individuals with normal kidney function. We aimed to investigate the 6-month kinetics of SARS-CoV-2 IgG antibody and specific T-cell levels in patients receiving HD compared with those in healthy individuals. METHOD The prospective cohort study included 24 patients treated with maintenance HD and 27 healthy controls with confirmed history of coronavirus disease (COVID-19). Nobody of them received vaccination before and during the study period. In all participants, the levels of specific IgG were quantified at three timepoints: 10, 18 and 26 weeks from disease onset. In a subgroup of patients, specific CD4+ and CD8+ T-lymphocyte responses were evaluated using IGRA test. RESULTS The incidence of COVID-19-related symptoms did not differ between the groups, except for the loss of smell, which occurred much more frequently among healthy subjects (70% versus 30.4% in HD group, P = 0.01). The seropositivity rate declined in healthy subjects over time and was 85% and 70.4% at weeks 18 and 26, respectively. All HD patients remained seropositive over the study period. Seropositivity rate at week 26 was greater among patients receiving HD: RR = 1.4 [95% confidence interval (95% CI): 1.17–1.94] (reciprocal of RR = 0.7, 95% CI: 0.52–0.86), P = 0.0064. In both groups, IgG levels decreased from week 10 to week 26, but antibodies vanished more rapidly in controls than in HD group (ANOVA P = 0.0012)—Figure 1. The magnitude of T-cell response was significantly lower in controls than in HD patients at weeks 10 (P = 0.019) and 26 (P = 0.0098) after COVID-19 diagnosis, but not at week 18—Figure 2. CONCLUSION Compared with healthy adults, patients receiving HD maintain significant long-term humoral and cellular immune responses following natural COVID-19. SARS-CoV-2 IgG antibodies did not decline more rapidly in patients receiving HD than in healthy controls over 6-months period.

Cellular Immune Response in Patients Immunized with Three Vaccine Doses of Different Vaccination Schemes Authorized by the Chilean Ministry of Health in January 2022.

In December 2019, a case of atypical pneumonia was reported in Wuhan, China. It was named COVID-19 and caused by SARS-CoV-2. In a few months, scientific groups around the world developed vaccines to reduce the disease’s severity. The objective was to evaluate the humoral and cellular immune response post immunization with three different vaccination schedules administered in Chile until January 2022. Sixty volunteers were recruited with a three-dose schedule, who had no history of infection nor close contact with a positive patient. IgG against the spike antigenic domain was detected, and the neutralization capacity against two groups of variants, Original/Alpha and Beta/Gamma, was also measured. Finally, the cellular response with interferon release was measured through IGRA. Results showed that there were significant differences in the neutralizing antibodies for the original and alpha variant when comparing three Comirnaty doses with Coronavac and Vaxzevria. A high number of reactive subjects against the different SARS-CoV-2 variants, alpha, gamma, and delta, were observed, with no significant differences between any of the three schemes, confirming the existence of a cellular immune response against SARS-CoV-2. In conclusion, the three vaccine schemes generated a cellular immune response in these volunteers.

Impact of disease-modifying therapies on humoral and cellular immune-responses following SARS-CoV-2 vaccination in MS patients.

The impact of distinct disease‐modifying therapies (DMTs) on severe acute respiratory syndrome‐coronavirus 2 (SARS‐CoV‐2) vaccination efficacy in patients with multiple sclerosis (MS) is still enigmatic. In this prospective comparative study, we investigated humoral and cellular immune‐responses in patients with MS receiving interferon beta, natalizumab, and ocrelizumab pre‐vaccination and 6 weeks post second SARS‐CoV‐2 vaccination. Healthy individuals and interferon beta‐treated patients generated robust humoral and cellular immune‐responses. Although humoral immune responses were diminished in ocrelizumab‐treated patients, cellular immune‐responses were reduced in natalizumab‐treated patients. Thus, both humoral and cellular immune responses should be closely monitored in patients on DMTs. Whereas patients with a poor cellular immune‐response may benefit from additional vaccination cycles, patients with a diminished humoral immune‐response may benefit from a treatment with SARS‐CoV‐2 antibodies in case of an infection.

SARS-CoV-2 Humoral and Cellular Immune Responses of Patients With HIV After Vaccination With BNT162b2 mRNA COVID-19 Vaccine in the Tel-Aviv Medical Center.

BackgroundLittle is known about vaccine efficacy and sustainability among people with HIV (PWH). We estimated humoral and cellular immune responses postvaccination with BNT162b2 mRNA coronavirus disease 2019 (COVID-19) vaccine among PWH in Tel-Aviv Medical Center.MethodsThe vaccine humoral response was evaluated by measuring immunoglobulin G (IgG) titers of antispike receptor-binding domain antibodies (anti-RBD IgG). Cellular response was assessed by stimulating donor peripheral blood mononuclear cells with pooled complete S-peptide mix.ResultsOne hundred thirty-six PWH who completed 2 doses of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine were tested for anti-RBD IgG and compared with 61 vaccinated health care workers (HCWs). The antibody titers were similar between the groups (median, 118 BAU/mL for PWH and 101.4 BAU/mL for HCWs; P = .231), although the mean time from second vaccine was 4.5 months in PWH and 6.7 months in HCWs (P < .0001). Longer time from second vaccine dose was associated with decreased antibody level, as were CD4 counts <300 cells/µL compared with higher CD4 counts (25.1 BAU/mL vs 119.3 BAU/mL, respectively; P = .047). There was no difference in cellular immune response between vaccinated PWH, convalescent unvaccinated PWH, and vaccinated HCWs.ConclusionsThe humoral immune response of PWH was comparable to that of HCWs after BNT162b2 mRNA vaccination. Cellular immune response did not differ between vaccinated PWH, convalescent PWH, and vaccinated HCWs. PWH with CD4 counts <300 cells/µL (n = 9) had lower antibody titers compared with patients with counts >300 cells/µL (n = 127).