Impaired Cellular Immunity Research Articles

Risk Factors for Impaired Cellular or Humoral Immunity after Three Doses of SARS-CoV-2 Vaccine in Healthy and Immunocompromised Individuals.

Background: We aimed to identify the risk factors for impaired cellular and humoral immunity after three doses of the SARS-CoV-2 vaccine. Methods: Six months after the third vaccine dose, T-cell immunity was evaluated using interferon-gamma release assays (IGRAs) in 60 healthy and 139 immunocompromised (IC) individuals, including patients with hematologic malignancy (HM), solid malignancy (SM), rheumatic disease (RD), and kidney transplantation (KT). Neutralizing antibody titers were measured using the plaque reduction neutralization test (PRNT) and surrogate virus neutralization test (sVNT). Results: T-cell immunity results showed that the percentages of IGRA-positive results using wild-type/alpha spike protein (SP) and beta/gamma SP were 85% (51/60) and 75% (45/60), respectively, in healthy individuals and 45.6% (62/136) and 40.4% (55/136), respectively, in IC individuals. IC with SM or KT showed a high percentage of IGRA-negative results. The underlying disease poses a risk for impaired cellular immune response to wild-type SP. The risk was low when all doses were administered as mRNA vaccines. The risk factors for an impaired cellular immune response to beta/gamma SP were underlying disease and monocyte%. In the sVNT using wild-type SP, 12 of 191 (6.3%) individuals tested negative. In the PRNT of 46 random samples, 6 (13%) individuals tested negative for the wild-type virus, and 19 (41.3%) tested negative with omicrons. KT poses a risk for an impaired humoral immune response. Conclusions: Underlying disease poses a risk for impaired cellular immune response after the third dose of the SARS-CoV-2 vaccine; KT poses a risk for impaired humoral immune response, emphasizing the requirement of precautions in patients.

Secreted phospholipase PLA2G2E contributes to regulation of T cell immune response against influenza virus infection.

The involvement of secreted phospholipase A2s in respiratory diseases, such as asthma and respiratory viral infections, is well-established. However, the specific role of secreted phospholipase A2 group IIE (PLA2G2E) during influenza virus infection remains unexplored. Here, we investigated the role of PLA2G2E during H1N1 influenza virus infection using a targeted mouse model lacking Pla2g2e gene (Pla2g2e-/-). Our findings demonstrated that Pla2g2e-/- mice had significantly lower survival rates and higher viral loads in lungs compared to wild-type mice following influenza virus infection. While Pla2g2e-/- mice displayed comparable innate and humoral immune responses to influenza virus challenge, the animals showed impaired influenza-specific cellular immunity and reduced T cell-mediated cytotoxicity. This indicates that PLA2G2E is involved in regulating specific T cell responses during influenza virus infection. Furthermore, transgenic mice expressing the human PLA2G2E gene exhibited resistance to influenza virus infection along with enhanced influenza-specific cellular immunity and T cell-mediated cytotoxicity. Pla2g2e deficiency resulted in perturbation of lipid mediators in the lung and T cells, potentially contributing to its impact on the anti-influenza immune response. Taken together, these findings suggest that targeting PLA2G2E could hold potential as a therapeutic strategy for managing influenza virus infections.IMPORTANCEThe influenza virus is a highly transmissible respiratory pathogen that continues to pose a significant public health concern. It effectively evades humoral immune protection conferred by vaccines and natural infection due to its continuous viral evolution through the genetic processes of antigenic drift and shift. Recognition of conserved non-mutable viral epitopes by T cells may provide broad immunity against influenza virus. In this study, we have demonstrated that phospholipase A2 group IIE (PLA2G2E) plays a crucial role in protecting against influenza virus infection through the regulation of T cell responses, while not affecting innate and humoral immune responses. Targeting PLA2G2E could therefore represent a potential therapeutic strategy for managing influenza virus infection.

Post Transplant Cyclophosphamide (PTCY) in Peripheral Blood Stem Cell Transplant Results in Successful Engraftment and Substantially Low Frequency of Chronic Graft Versus Host Disease (GvHD), without Impaired Cellular Immune Reconstitution

The Post-Transplant Cyclophosphamide (PTCY) approach was first studied in the haploidentical transplant setting, and it resulted in high percentages of engraftment and reduced frequency of acute and mainly chronic GvHD as well as non-relapsed mortality. PTCY is now increasingly being used in HLA-partially and fully matched unrelated, as well as matched related donors. The aim of this study was to investigate the impact of PTCY on the incidence of chronic GvHD, disease relapse and infections because of possible cellular immune impairment. Fifty-one consecutive patients who underwent allogeneic hematopoietic stem cell transplant from an unrelated donor were studied. PTCΥ was administered on days +3 and +4 post-transplant at a dose of 50 mg/kg/day. Additional GvHD prophylaxis included tacrolimus and mycophenolate mofetil starting on day +5. In patients with no evidence of GvHD, immunosuppression was gradually tapered, and eventually stopped by day +90. We evaluated the safety and efficacy of PTCY, focusing on toxicity, engraftment, aGvHD and cGvHD frequency, relapse, non-relapse mortality, survival and immune reconstitution. We performed 51 unrelated donor transplants with PTCY from January 2021 to May 2023 in patients with a median age of 52 (18-69) years. The indication for transplant was AML/MDS (n=36), NHL/CLL, (n=2), pMF (n=2), CML (n=2) και ALL (n=9). Disease risk index (DRI) was intermediate for most patients (34/51), 7 had low and 10 had high DRI. Thirty-seven patients received myeloablative conditioning and 14 reduced-intensity. Overall, three patients were transplanted from a matched sibling, 36 from an 8/8 matched unrelated donor and 12 from an 7/8 HLA-matched unrelated donor. All patients received a peripheral blood graft with a median CD34+ cell dose of 6.97×10e6/kg (3.27-15.82). The most common toxicities observed were mucositis (n=34), diarrhea (n=40), vomit (n=12), liver toxicity (n=3) and acute kidney injury (n=4) - which in all cases were grade Ι-ΙΙ. Engraftment, defined as neutrophils >500/μl, was achieved in 46 cases in a median of 16 (13-27) days. Three patients died before day +28 due to NRM and two additional patients with myelofibrosis and MDS respectively had primary graft failure. The cumulative incidence of aGvHD, grade ΙΙ-IV at 100 days was 46.7% (95%CI: 34.1-63.8). However, aGvHD, grade ΙΙΙ-IV was only 3.9% (95%CI: 1.0-15.5). The cumulative incidence of cGvHD at 18 months was 13,4% (95%CI: 5.8-31.0), with only one case of extensive cGvHD. In a median follow-up of 14.5 (1-28) months, disease free (DFS) was 76,8% (95%CI: 65.5-90.0) at 18 months and overall survival (OS) was 76.3% (95%CI: 64.9-89.8) and 71.6% (95%CI: 58.6-88.3) respectively. There was no statistically significant difference in survival rates for patients who received an HLA mismatched and those who received an HLA-matched unrelated-donor transplant. cGvHD-Relapse-Free Survival was 63.5% (95%CI: 50.3-80.1). Two patients died of their disease and non-relapse mortality was 19.1%. Specifically, 6 patients died of Infections, 1 due to primary graft failure, 1 due to heart failure, and 1 due to Idiopathic Pulmonary Syndrome. Immune reconstitution at month 6 was 420 cells/ul (20-2225) and 179 (13-594) for CD8 and CD4 respectively. At month 12 CD8 and CD4 were 552 (55-3002) and 364 (60-787). 31 viral infections were documented in 28 patients (Respiratory viruses n=13, BKV n=11, CMV n=7). In regard with opportunistic infections, 2 patients had fungal infections and 1 patient atypical mycobacterium. We used PTCY for GvHD prophylaxis in mismatched, full-matched unrelated and matched sibling donor transplants with peripheral blood stem cell graft. This approach was well tolerated. Engraftment was documented in most patients, with a low incidence of grade III-IV aGvHD. Importantly cGvHD, which is the most important barrier in unrelated donor transplant, was substantially low with this method. Cellular immune reconstitution was adequate for CD8 but somewhat impaired for CD4. However, the incidence of viral and opportunistic infections was not increased. Overall, there are implications that PTCY may revert the negative impact of HLA mismatch on the outcomes of unrelated donor transplantation, while it is also a viable option for MUD and MSD transplant.

COVID-19 Vaccine Acceptance/Hesitancy and Influence on Infection in Patients with Multiple Myeloma: A National-Wide Multicenter Survey in China

Background Patients with multiple myeloma (MM) are immunocompromised due to impaired humoral and cellular immunity in addition to immunosuppressive therapy. The situation and protective effects of severe coronavirus disease 2019 (COVID-19) vaccination in MM patients are not clarified. The study aimed to explore the reasons of COVID-19 vaccine hesitancy and its influence on severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) infection in MM patients during COVID-19 Omicron BA.4/5 subvariant outbreak in China. Methods An anonymous online questionnaire designed by our team was distributed to MM patients national-wide from December 26, 2022, to April 20, 2023. Then content of questionnaire included the contents of disease status, vaccination and SARS-COV-2 infection. Results A total of 508 valid questionnaires from 30 provinces were collected all over China. The vaccination rate of COVID-19 in MM patients was only 34.1% (n=173). The overall infection rate was 57.2%. Multivariate analysis showed that demographic characteristics were not factors affecting vaccination, while those accomplishing autologous stem cell transplantation (ASCT) presented a lower vaccination rate (20.2% vs. 48.4%, P<0.001). In the survey of vaccine acceptance/hesitancy, voluntary choice (49%), concerns to COVID-19 infection (35.1%), and trust of vaccine efficacy (26.5%) were the three main reasons for receiving vaccines. Physicians' suggestion (52.0%), conflicts of MM treatment (37.8%) and concerns about MM progression (31.3%) were the top three reasons for vaccine hesitancy. Adverse events (AEs) after vaccination were mainly myalgia or joint pain, fatigue and erythema or swelling at the site of injection. No MM disease-related adverse effects were reported. Among 104 vaccinated MM patients with SARS-COV-2 infection, the median time since last vaccines to infections was 304 days (range 4-593). The infection rates between the vaccinated population (n=173) versus non-vaccinated ones (n=335) were 60.1% vs. 55.8% respectively (P=0.35). In subgroup analyses, the infection rates in vaccinated patients were lower than those in unvaccinated ones including the elderly (49.3% vs. 55.2%), obese patients (BMI≥28) (50% vs. 63.3%), and R/RMM population (42.2% vs. 66.7%, P=0.005). The proportion of hospitalized patients due to SARS-COV-2 infection in vaccinated group was significantly lower than that in unvaccinated group (4.8% vs.12.3%, P=0.038). Conclusions Vaccine hesitation is common in Chinese MM patients although inactivated COVID-19 vaccine only causes mild AEs. Lower infection rate in MM patients is probably due to strict self-quarantine. COVID-19 vaccination is not translated into less SARS-COV-2 infections, but does protect the elderly, obese or R/RMM patients from severe infections. Clinicians are suggested to encourage MM patients to receive COVID-19 vaccines for the sake of reducing severe infections and related mortality. Keywords Questionnaire; Multiple Myeloma; vaccination; SARS-COV-2; outbreak infection

Highly Active Cytotoxic CD4 + T Cells Targeting EBV Oncoproteins with Enhanced In Vivo Anti-Tumor and Self-Renewal Properties

Background: Epstein-Barr virus (EBV), a human gamma herpesvirus primarily of B-cell tropism that infects more than 90% of humans during childhood, establishing a lifelong latent persistence after the initial immune clearance. Alterations in the immune surveillance in subjects with impaired cellular immunity can lead to viral reactivation and uncontrolled B cell lymphoproliferation manifesting as post-transplant lymphoproliferative disease (PTLD) and malignant transformation into B-cell lymphomas and some epithelial tumors. Adoptive transfer of virus-specific cytotoxic T cells targeting viral oncoproteins of EBV (EBV-CTLs) may lead to rapid reconstitution of T cell immune surveillance and may efficiently control PTLD and some EBV-driven lymphomas. However, success of this approach has been hampered by suboptimal/variable potency of donor-derived EBV-CTLs and possibly their terminally differentiated/exhausted phenotype associated with limited in vivo persistence and activity, especially when targeting elusive Latency 1-associated diseases. We hypothesized that that EBV-specific CD4 + T cells differentiated using novel pro-inflammatory conditions might efficiently target viral oncoproteins concurrently retaining highly desirable stem-cell like properties required for successful eradication of tumor cells in vivo. Methods: In this study, we developed a method for generating novel and highly potent CD4 + cytotoxic T cells (CD4 +-CTLs) simultaneously targeting EBNA1, LMP1, and LMP2A. Peripheral blood mononuclear cells (PBMCs) were isolated from healthy donors, and either total T cells or CD4 +T cells were purified. These cells were then stimulated with PBMCs loaded with overlapping peptide libraries spanning LMP1, LMP2A, and EBNA1 antigens, either under neutral conditions (IL2 and IL-7) or in the presence of pro-inflammatory (type 1/17) cytokines ex vivo for 12-14 days. The phenotypes, reactivity, and cytotoxic capability of these CD4 +-CTLs against autologous EBV-Lymphoblastoid cell lines (LCLs) were assessed in vitro and in vivo upon adoptive transfer into tumor-bearing NSG mice. Results: In comparison to EBV-CTLs generated from unselected PBMCs (standard conditions), purified CD4 + expanded in the presence of pro-inflammatory cytokines exhibited significantly higher frequency of antigen specific T cells with a marked skewing towards EBNA1 antigen, and displaying marked polyfunctionality, concurrently secreting tumor necrosis factor-α (TNF-α), interferon-γ (IFN-γ), and inducible granzyme B (GzmB), while maintaining interleukin-2 (IL-2) secretion capacity. Antigen-reactive CD4 +-CTLs induced in pro-inflammatory conditions retained a significant population with central memory (T CM) phenotype (CCR7 hi, CD27 hi), while those expanded in neutral conditions predominantly displayed an effector memory (T EM) phenotype. These CD4 +-CTLs demonstrated enhanced cytotoxicity against autologous EBV-LCLs and superior proliferative capacity in vitro upon secondary stimulation, whereas standard EBV-CTLs proliferated poorly. In the LCL-injected NSG mice, CD4 +-CTLs exhibited superior self-renewal and long-term persistence, resulting in a significant reduction/eradication of established LCL burden when compared to standard EBV-CTLs. Conclusion: Ex vivo priming with EBV antigens in the presence of pro-inflammatory cytokines reliably induces EBV-reactive CD4 +-CTLs with markedly enhanced antigen-specificity, polyfunctionality, cytotoxic potential, preserved stemness, proliferative capacity, and superior in vivo persistence and anti-tumor activity . These findings hold significant promise for developing improved adoptive immunotherapies to target EBV-associated diseases, especially of Latency-I origin and may be generalized as a strategy for targeting other viral oncoproteins expressed by human cancers. Figure 1: EBV-CD4 + CTLs generated under pro-inflammatory conditions display superior reactivity, persistence, and anti-tumor activity in vivo: (A.) The percentage of CD4 +Th cells primed with LMP1/2 and EBNA1 and expanded under indicated conditions producing TNF-α, IFN-γ, IL-2 and GZMB upon antigenic restimulation (n=29). (B.) Frequency of EBV-LCLs (CD23 +) and CD3 + cells detected in spleens on Day 26 post adoptive transfer of standard and pro-inflammatory EBV-CD4 + CTLs(n=4 per group).

Генетична верифікація автозапального синдрому, спричиненого гетерозиготною мутацією в гені SOCS1, що маскувався під гемобластоз. Клінічний випадок

Familial autoinflammatory syndrome with or without immunodeficiency (AISIMD), caused by a heterozygous mutation in the SOCS1 gene on chromosome 16p13, is characterized by the appearance of various autoimmune signs usually in the first decades of life, although later onset has been reported. Typical features of AISIMD include autoimmune cytopenia, thrombocytopenia, hemolytic anemia and lymphadenopathy, possible alterations in cellular immunity, and hypogammaglobulinemia. Purpose - to present a combination of clinical, imaging and laboratory signs in a nine-year-old patient with autoinflammatory syndrome and mild immunodeficiency caused by a heterozygous mutation in the SOCS1 gene; to emphasise the importance of genetic tests for definitive diagnosis. Clinical case. Features of diagnosis of autoinflammatory syndrome caused by heterozygous mutation in the SOCS1 gene in a 9-year-old boy are described. The disease was manifested in the laboratory by leukopenia with neutropenia, monocytosis, thrombocytopenia, an increase in markers of inflammation - C-reactive protein (CRP) and erythrocyte sedimentation rate (ESR), impaired cellular immunity (inverse CD4/CD8 ratio, reduced number of NK cells (CD3-CD16+CD56+), decrease in CD19, increase in the per cent of double-negative T-lymphocytes (Neg. In T- Double LF (CD3+CD4-CD8-); clinical: hyperthermia, recurrent aphthous stomatitis, irritable bowel syndrome, progressive generalized lymphoproliferative syndrome. Differential diagnosis with hemoblastosis was carried out, which was denied. Subsequently the presence of an ulcer in the ileum and mucinous metaplasia in the covering epithelium gave grounds to diagnose an inflammatory bowel disease: Crohn's disease with damage to the terminal part of the small intestine. Verification of the final diagnosis of an autoinflammatory syndrome caused by a heterozygous mutation in the SOCS1 gene took place using genome sequencing. The research was carried out in accordance with the principles of the Helsinki Declaration. The informed consent of the patient was obtained for conducting the studies. No conflict of interests was declared by the authors.

Exploration and improvement of QuantiFERON-TB assay in patients with indeterminate results in clinical practice: A head-to-head study

BackgroundWe implemented the QuantiFERON-TB Gold In-Tube (QFT-GIT) based on peripheral blood mononuclear cells (QFT-PBMCs) and QFT Gold Plus (QFT-Plus) in patients with indeterminate results, and use Mit-Nil value to identify false negatives and impaired cellular immunity. MethodsOne hundred seventy-one out of 2480 patients who had a QFT-GIT test were prospectively recruited and classified as high Nil (n = 35), low Mit (n = 75) and control (n = 61) cohorts. Head-to-head comparisons, i.e., QFT-PBMCs vs. QFT-GIT in high Nil cohort, QFT-Plus vs. QFT-GIT in low Mit cohort, and QFT-PBMCs vs. QFT-GIT in controls, were performed. Lymphocyte subsets counts were conducted in low Mit and control cohorts. ResultsA significant reduction of positive rate only occurred in Mit-Nil < 6 IU/ml (p < 0.001). QFT-PBMCs yielded 100 % valid results and had a significant Nil decline in high Nil cohort (0.98 ± 1.06 vs. 9.55 ± 0.64 IU/ml, p < 0.0001), while correlated well with QFT-GIT for qualitative (Cohen’s k = 0.93) and quantitative (TB–Ag [R2 = 0.91] and Mit [R2 = 0.94]) analyses. QFT-Plus produced 61.3 % valid results and had a significant Mit increase in low Mit cohort (0.82 ± 0.95 vs. 0.17 ± 0.11 IU/ml, p < 0.0001). Mit-Nil value significantly correlated with lymphocyte subsets counts (R:0.49–0.56, p < 0.0001), separately corresponding to thresholds of 4.26, 5.33, 5.55 and 5.81 IU/ml for predicting decreased total lymphocyte, T lymphocyte, CD4+ and CD8+ cells. ConclusionsQFT that replacing whole blood with PBMCs should be recommended to handle high Nil samples, and QFT-Plus can declined the frequency of low Mit results. In addition, Mit-Nil < 6 and 5.81 IU/ml are potential thresholds to identify the risk of false negatives and impaired cellular immunity, respectively.

The role of vitamin A in non-ruminant immunology

Vitamin A (retinol) is an essential micronutrient with a crucial role in the immune system of non-ruminant animals, such as swine and poultry. It includes three chemical compounds with distinct properties and functions in the body: retinol, retinal, and retinoic acid. In monogastric feed, vitamin A is primarily present in the form of retinyl esters. The metabolism of dietary vitamin A esters involves their conversion to retinol, which is then transported to different tissues and cells for further metabolism into active forms such as retinoic acid. These active forms of vitamin A have been found to play a crucial role in regulating both innate and adaptive immune responses. Specifically, they are involved in the differentiation, proliferation, and function of immune cells such as T and B lymphocytes, as well as dendritic cells. Vitamin A deficiency can lead to impaired cellular immunity, reduced antibody production, and consequently an increased susceptibility to infections. In swine and poultry, hypovitaminosis A can also affect gut-associated lymphoid tissues, leading to gut-related health problems and compromised growth performance. On the other hand, vitamin A supplementation has been shown to have immunomodulatory effects on non-ruminant immune responses. By administering or supplementing retinol, immune cell proliferation, antibody production, and cytokine secretion can be enhanced, which can ultimately result in improved immune function and disease resistance. Therefore, vitamin A has potential applications as an immuno-micronutrient for improving health and preventing diseases in swine and poultry. However, the optimal dosage and timing of vitamin A supplementation need to be carefully determined based on the specific requirements of different non-ruminant species and their production stages. Overall, a better understanding of the role of vitamin A in non-ruminant nutritional immunology could have significant implications for animal health and productivity and could inform the development of effective dietary strategies to optimize immune function and prevent diseases in swine and domestic fowl. This review paper aims to offer valuable insights into the role of vitamin A in the nutritional immunology of non-ruminants while also emphasizing the current gaps in knowledge and potential areas for further research.

Response to COVID-19 Vaccination Post-CAR T Therapy in Patients With Non-Hodgkin Lymphoma and Multiple Myeloma.

COVID-19 adversely affects individuals with cancer. Several studies have found that seroconversion rates among patients with hematologic malignancies are suboptimal when compared to patients without cancer. Patients with non-Hodgkin lymphoma (NHL) and multiple myeloma (MM) are immunocompromised due to impaired humoral and cellular immunity in addition to prescribed immunosuppressive therapy. Chimeric antigen receptor T-cell (CAR T) therapy is now widely used for NHL and MM, but little is known about seroconversion rates after COVID-19 vaccination among these populations. We evaluated SARS-CoV-2 spike-binding IgG antibody levels following COVID-19 vaccination among NHL and MM CAR T therapy recipients. Out of 104 CAR T infusions, 19 patients developed known COVID-19 infection post-CAR T. We tested 17 patients that received CAR T for antibody spike titers post COVID-19 vaccination, only 29 % (n=5) were able to mount a clinically relevant antibody response (>250 IU/mL).

РОЛЬ ИММУННОГО МЕХАНИЗМА В РАЗВИТИИ ДИСФУНКЦИИ ЭНДОТЕЛИЯ И АПОПТОЗА У БЕРЕМЕННЫХ ЖЕНЩИН С ТЯЖЕЛЫМИ ОСЛОЖНЕНИЯМИ

In order to identify the role of cellular and humoral immunity, nonspecific resistance, cytokine spec-trum in the development of endothelial dysfunction and apoptosis in the pathogenesis of obstetric complications, 40 women with severe pregnancy complications and critical conditions associated with thrombotic micro angiopathy and 30 patients with physiologically occurring pregnancy were exam-ined. The assessment of cellular elements of peripheral blood, indicators of cellular and humoral im-munity, the level of cytokines, a disintegrin and metalloprotease with thrombospondin-1-like domains, member 13 (ADAMTS – 13), Willebrand factor, apoptosis-inducing factor, CD95, progesterone and the number of endotheliocytes is given.&#x0D; The conducted study indicates the failure of the functional state of both innate and acquired immunity in women with complicated pregnancy. The leading role in the development of endothelial dysfunction and the mechanism of apoptosis in pregnant women with severe complications and criti-cal cases associated with thrombotic microangiopathy belongs to an insufficient reserve of nonspecific resistance, impaired cellular and humoral immunity with low background progesterone level and high cytokine activity

Delayed CD4 +T-cell response in older adults is associated with reduced immunogenicity and reactogenicity after COVID-19 mRNA vaccination

Abstract While the newly developed COVID-19 mRNA vaccines are highly effective, characteristics of the immune response after the vaccination and its association with the adverse effects, especially for an older population, remain elusive. In this study, we recruited a total of 216 SARS-CoV-2-naïve healthy donors of various ages (23–81 years) who received two doses of the BNT162b2 vaccine and assessed age-associated differences in vaccine-induced T-cell responses and adverse effects over 3 months. We observed that older adults (≥65 years) had fewer vaccine-induced Spike-specific CD4 +T cells, including CXCR3 +cTfh and Th1 cells, after the first dose, which correlated with their lower peak IgG levels and fewer systemic adverse effects after the second dose, compared with younger adults. Moreover, Spike-specific Th1 cells in older adults expressed higher levels of PD-1, a negative regulator of T-cell activation, which was associated with low Spike-specific CD8 +T-cell response. These data indicated that delayed induction of CD4 +T-cell response in older adults is linked to impaired humoral and cellular immunity and reduced systemic reactogenicity. Therefore, enhancing CD4 +T-cell response following the first dose is key to improving vaccine efficacy in older adults. This work was supported by the Japan Agency for Medical Research and Development (grant numbers JP21gm5010005, JP20fk0108454, and JP223fa627009; Y.H.), iPS Cell Research Fund (Y.H.), the COVID-19 Private Fund to the Shinya Yamanaka Laboratory, CiRA, Kyoto University (Y.H.), Japanese Ministry of Education, Culture, Sports, Science and Technology (MEXT)/Japan Society for the Promotion of Science (grant number 19K23862; N.J.), Kansai Economic Federation (KANKEIREN; Y.H.), Sumitomo-Mitsui Trust Bank Fund for Covid-19 Research, Kyoto University (Y.H.), and Takeda Science Foundation (Y.H.).

Insufficient epitope specific T cell clones is responsible for impaired cellular immunity to inactivated SARS-CoV-2 vaccine in the elderly

Abstract Aging is a critical risk factor for SARS-CoV-2 vaccine efficacy. Although low humoral immunity in the elderly was observed in mRNA and recombinant protein vaccination, the immune responses to inactivated vaccine in the elderly, and the underlying mechanisms of differences to young, if any, are still unclear. Here, we studied a cohort of 121 young (18–30 years old) and 48 old (60–85 years old) donors vaccinated with inactivated SARS-CoV-2 and demonstrate that the neutralizing antibody response is slower in the elderly, but eventually reached the similar level to day 7 post-vaccination in young. We identified a range of epitopes targeted by CD8 T cells that were underrepresented in immune responses in the old group, especially when measured with tetramers derived from the 13 major SARS-CoV-2 variants. Comparison of the transcriptomes of B, CD4 and CD8 T cells from pre- and post-vaccinated young and elderly revealed genes potentially responsible for low immune responses in elderly, functionally related to antigen processing and presentation. We further built an epitope specific TCR repertoire database using single-cell RNA and TCR sequencing. Statistical and machine-learning based analyses demonstrated that SARS-CoV-2 epitope specific CD8 T cell clones were significantly lower in the old than young, and failed to be boosted after vaccination in elderly. Comparison of BCRs and TCRs from pre- and post-vaccinated young and elderly individuals revealed inadequate receptor repertoire size and diversity might be responsible for low immune response in the elderly. Together, the altered immune cell function and the attenuated antigen specific TCR repertoire were responsible for the impaired CD8 T cell immune response in the elderly. This work was supported by grants from the National Key Research and Development Program of China (2018YFC2002003 to G.C., 2021YFC2009400 to G.Z.), the Natural Science Foundation of China (U1801285 and 92169102 to G.C., 81971301 and 32050410285 to O.J.L., 82201954 to Z.R.)

Cellular immunity in COVID-19 and other infections in Common variable immunodeficiency.

COVID-19 has shed light on the role of cellular immunity in the absence of humoral response in different patient groups. Common variable immunodeficiency (CVID) is characterized by impaired humoral immunity but also an underlying T-cell dysregulation. The impact of T-cell dysregulation on cellular immunity in CVID is not clear, and this review summarizes available literature on cellular immunity in CVID with a particular focus on COVID-19. Overall mortality of COVID-19 in CVID is difficult to assess, but seems not significantly elevated, and risk factors for severe disease mirrors that of the general population, including lymphopenia. Most CVID patients have a significant T-cell response to COVID-19 disease with possible cross-reactivity to endemic coronaviruses. Several studies find a significant but impaired cellular response to basal COVID-19 mRNA vaccination that is independent of an antibody response. CVID patients with infection only have better cellular responses to vaccine in one study, but there is no clear association to T-cell dysregulation. Cellular response wane over time but responds to a third booster dose of vaccine. Opportunistic infection as a sign of impaired cellular immunity in CVID is rare but is related to the definition of the disease. CVID patients have a cellular response to influenza vaccine that in most studies is comparable to healthy controls, and annual vaccination against seasonal influenza should be recommended. More research is required to clarify the effect of vaccines in CVID with the most immediate issue being when to booster the COVID-19 vaccine.

Nationwide Laboratory Surveillance of Progressive Multifocal Leukoencephalopathy in Japan: Fiscal Years 2011-2020.

Progressive multifocal leukoencephalopathy (PML) is a devastating demyelinating disease caused by JC virus (JCV), predominantly affecting patients with impaired cellular immunity. PML is a non-reportable disease with a few exceptions, making national surveillance difficult. In Japan, polymerase chain reaction (PCR) testing for JCV in the cerebrospinal fluid (CSF) is performed at the National Institute of Infectious Diseases to support PML diagnosis. To clarify the overall profile of PML in Japan, patient data provided at the time of CSF-JCV testing over 10 years (FY2011-2020) were analyzed. PCR testing for 1537 new suspected PML cases was conducted, and 288 (18.7%) patients tested positive for CSF-JCV. An analysis of the clinical information on all individuals tested revealed characteristics of PML cases, including the geographic distribution, age and sex patterns, and CSF-JCV-positivity rates among the study subjects for each type of underlying condition. During the last five years of the study period, a surveillance system utilizing ultrasensitive PCR testing and widespread clinical attention to PML led to the detection of CSF-JCV in the earlier stages of the disease. The results of this study will provide valuable information not only for PML diagnosis, but also for the treatment of PML-predisposing conditions.

Insufficient epitope-specific T cell clones are responsible for impaired cellular immunity to inactivated SARS-CoV-2 vaccine in older adults

Aging is a critical risk factor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine efficacy. The immune responses to inactivated vaccine for older adults, and the underlying mechanisms of potential differences to young adults, are still unclear. Here we show that neutralizing antibody production by older adults took a longer time to reach similar levels in young adults after inactivated SARS-CoV-2 vaccination. We screened SARS-CoV-2 variant strains for epitopes that stimulate specific CD8 T cell response, and older adults exhibited weaker CD8 T-cell-mediated responses to these epitopes. Comparison of lymphocyte transcriptomes from pre-vaccinated and post-vaccinated donors suggested that the older adults had impaired antigen processing and presentation capability. Single-cell sequencing revealed that older adults had less T cell clone expansion specific to SARS-CoV-2, likely due to inadequate immune receptor repertoire size and diversity. Our study provides mechanistic insights for weaker response to inactivated vaccine by older adults and suggests the need for further vaccination optimization for the old population.

Symptomatic COVID-19 in Pregnancy: Hospital Cohort Data between May 2020 and April 2021, Risk Factors and Medicolegal Implications.

Pregnancy does not appear to increase susceptibility to SARS-CoV-2 infection, but some physiological changes, such as the reduction of residual functional volumes, elevation of the diaphragm, and impaired cellular immunity, may increase the risk of severe disease and result in a higher risk of complications. The article's primary objective is to evaluate the factors associated with symptomatic COVID-19 disease in pregnancy. The secondary objective is to describe maternal and neonatal outcomes and cases of vertical transmission of the infection. All pregnant women hospitalized with SARS-CoV2 infection were included in a prospective study in the UOC of Obstetrics and Gynecology, AOOR Villa Sofia-Cervello, Palermo, between May 2020 and April 2021. The patients who requested the termination of the pregnancy according to Law 194/78 were excluded. We included 165 pregnancies with a total number of 134 deliveries. Overall, 88.5% of the patients were asymptomatic at the time of admission and 11.5% were symptomatic. Of them, 1.8% of the patients required hospital admission in the intensive care unit. Symptoms occurrences were positively associated with the increase in maternal BMI (OR 1.17; p = 0.002), the prematurity (OR 4.71; p = 0.022), and at a lower birth weight (OR 0.99; p = 0.007). One infant tested positive for SARS-CoV2 nasopharyngeal swab; 11.4% of newborns had IgG anti SARS-CoV2 at birth; IgM was positive in 2.4% of newborns. There was no difference statistically significant difference in the vertical transmission of the infection among the group of symptomatic pregnant women and that of asymptomatic pregnant women.

Prolonged experimental CD4+ T-cell depletion does not cause disease progression in SIV-infected African green monkeys

CD4+ T-cell depletion is a hallmark of HIV infection, leading to impairment of cellular immunity and opportunistic infections, but its contribution to SIV/HIV-associated gut dysfunction is unknown. Chronically SIV-infected African Green Monkeys (AGMs) partially recover mucosal CD4+ T-cells, maintain gut integrity and do not progress to AIDS. Here we assess the impact of prolonged, antibody-mediated CD4 + T-cell depletion on gut integrity and natural history of SIV infection in AGMs. All circulating CD4+ T-cells and >90% of mucosal CD4+ T-cells are depleted. Plasma viral loads and cell-associated viral RNA in tissues are lower in CD4+-cell-depleted animals. CD4+-cell-depleted AGMs maintain gut integrity, control immune activation and do not progress to AIDS. We thus conclude that CD4+ T-cell depletion is not a determinant of SIV-related gut dysfunction, when gastrointestinal tract epithelial damage and inflammation are absent, suggesting that disease progression and resistance to AIDS are independent of CD4+ T-cell restoration in SIVagm-infected AGMs.

Impaired Cellular and Antibody immunity after COVID-19 in Chronically Immunosuppressed Transplant Recipients.

Assessment of cellular immunity to the SARS-CoV-2 coronavirus is of great interest in chronically immunosuppressed transplant recipients (Tr), who are predisposed to infections and vaccination failures. We evaluated CD154-expressing T-cells induced by spike (S) antigenic peptides in 204 subjects-103 COVID-19 patients and 101 healthy unexposed subjects. S-reactive CD154+T-cell frequencies were a) higher in 42 healthy unexposed Tr who were sampled pre-pandemic, compared with healthy NT (p=0.02), b) lower in Tr COVID-19 patients compared with healthy Tr (p<0.0001) and were accompanied by lower S-reactive B-cell frequencies (p<0.05), c) lower in Tr with severe COVID-19 (p<0.0001), or COVID-19 requiring hospitalization (p<0.05), compared with healthy Tr. Among Tr with COVID-19, cytomegalovirus co-infection occurred in 34%; further, incidence of anti-receptor-binding-domain IgG (p=0.011) was lower compared with NT COVID-19 patients. Healthy unexposed Tr exhibit pre-existing T-cell immunity to SARS-CoV-2. COVID-19 impairs anti-S T-cell and antibody and predisposes to CMV co-infection in transplant recipients.

Cryptococcal Immune Reconstitution Inflammatory Syndrome: From Clinical Studies to Animal Experiments.

Cryptococcus neoformans is an encapsulated pathogenic fungus that initially infects the lung but can migrate to the central nervous system (CNS), resulting in meningoencephalitis. The organism causes the CNS infection primarily in immunocompromised individuals including HIV/AIDS patients, but also, rarely, in immunocompetent individuals. In HIV/AIDS patients, limited inflammation in the CNS, due to impaired cellular immunity, cannot efficiently clear a C. neoformans infection. Antiretroviral therapy (ART) can rapidly restore cellular immunity in HIV/AIDS patients. Paradoxically, ART induces an exaggerated inflammatory response, termed immune reconstitution inflammatory syndrome (IRIS), in some HIV/AIDS patients co-infected with C. neoformans. A similar excessive inflammation, referred to as post-infectious inflammatory response syndrome (PIIRS), is also frequently seen in previously healthy individuals suffering from cryptococcal meningoencephalitis. Cryptococcal IRIS and PIIRS are life-threatening complications that kill up to one-third of affected people. In this review, we summarize the inflammatory responses in the CNS during HIV-associated cryptococcal meningoencephalitis. We overview the current understanding of cryptococcal IRIS developed in HIV/AIDS patients and cryptococcal PIIRS occurring in HIV-uninfected individuals. We also describe currently available animal models that closely mimic aspects of cryptococcal IRIS observed in HIV/AIDS patients.

Immunological imprint on peripheral blood in kidney transplant recipients after two doses of SARS-CoV-2 mRNA vaccination in Japan.

The immunological imprint after two doses of severe acute respiratory syndrome–coronavirus 2 (SARS-CoV-2) mRNA vaccination for patients after kidney transplantation (KTx) remain unclear. This study included KTx recipients and volunteer healthy controls (HCs) who received two doses of SARS-CoV-2 mRNA vaccine (Pfizer BioNTech) from January 2021 to December 2021. We analyzed safety within 21 days after each vaccination dose and compared the immune response in peripheral blood mononuclear cells (PBMCs) between the two groups. No graft rejection was observed throughout this study. Adverse events were generally observed within 5 days. The KTx group exhibited a significantly lower degree of symptoms between doses 1 and 2 (P < 0.001). Increases in activated subsets of T and B cells expressing human leukocyte antigen (HLA)-DR and/or CD38 were observed in the HC group after dose 2 (both P < 0.001), with the greatest increases in HLA-DR+CD8+ T cells and CD38+CD19+ B cells (P = 0.042 and P = 0.031, respectively). In addition, PD1+CD8+ T cells—but not PD1+CD4+ T cells—increased significantly in the HC group (P = 0.027). In the KTx group, however, activated HLA-DR+, CD38+, and PD1+ cells remained at baseline levels. Immunoglobulin (Ig)G against SARS-CoV-2 was detected in only four KTx recipients (13.3%) after dose 2 (P < 0.001). Multivariate logistic regression analyses revealed that ΔHLA-DR+CD8+ T cells and ΔCD38+CD19+ B cells were significantly associated with IgG formation (both P = 0.02). SARS-CoV-2 mRNA vaccine generates impaired cellular and humoral immunity for KTx recipients. Results indicate the need for modified vaccination strategies in immunocompromised KTx recipients.