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The emergence of new SARS-CoV-2 variants, such as the more transmissible Delta and Omicron variants, has raised concerns on efficacy of the COVID-19 vaccines. Here, we examined the waning of antibody responses against different variants following primary and booster vaccination. We found that antibody responses against variants were low following primary vaccination. The antibody response against Omicron was almost non-existent. Efficient boosting of antibody response against all variants, including Omicron, was observed following a third dose. The antibody response against the variants tested was significantly higher at one month following booster vaccination, compared with two months following primary vaccination, for all individuals, including the low antibody responders identified at two months following primary vaccination. The antibody response, for all variants tested, was significantly higher at four months post booster than at five months post primary vaccination, and the proportion of low responders remained low (6-11%). However, there was significant waning of antibody response in more than 95% of individuals at four months, compared to one month following booster. We also observed a robust memory B cell response following booster, which remained higher at four months post booster than prior to booster. However, the memory B cell responses were on the decline for 50% of individuals at four months following booster. Similarly, while the T cell response is sustained, at cohort level, at four months post booster, a substantial proportion of individuals (18.8 – 53.8%) exhibited T cell response at four months post booster that has waned to levels below their corresponding levels before booster. The findings show an efficient induction of immune response against SARS-CoV-2 variants following booster vaccination. However, the induced immunity by the third BNT162b2 vaccine dose was transient. The findings suggest that elderly individuals may require a fourth dose to provide protection against SARS-CoV-2.

Understanding the impact of age on vaccinations is essential for the design and delivery of vaccines against SARS-CoV-2. Here, we present findings from a comprehensive analysis of multiple compartments of the memory immune response in 312 individuals vaccinated with the BNT162b2 SARS-CoV-2 mRNA vaccine. Two vaccine doses induce high antibody and T cell responses in most individuals. However, antibody recognition of the Spike protein of the Delta and Omicron variants is less efficient than that of the ancestral Wuhan strain. Age-stratified analyses identify a group of low antibody responders where individuals ≥60 years are overrepresented. Waning of the antibody and cellular responses is observed in 30% of the vaccinees after 6 months. However, age does not influence the waning of these responses. Taken together, while individuals ≥60 years old take longer to acquire vaccine-induced immunity, they develop more sustained acquired immunity at 6 months post-vaccination. A third dose strongly boosts the low antibody responses in the older individuals against the ancestral Wuhan strain, Delta and Omicron variants.

Severe SARS-CoV-2 infection can trigger uncontrolled innate and adaptive immune responses, which are commonly associated with lymphopenia and increased neutrophil counts. However, whether the immune abnormalities observed in mild to severely infected patients persist into convalescence remains unclear. Herein, comparisons were drawn between the immune responses of COVID-19 infected and convalescent adults. Strikingly, survivors of severe COVID-19 had decreased proportions of NKT and Vδ2 T cells, and increased proportions of low-density neutrophils, IgA+/CD86+/CD123+ non-classical monocytes and hyperactivated HLADR+CD38+ CD8+ T cells, and elevated levels of pro-inflammatory cytokines such as hepatocyte growth factor and vascular endothelial growth factor A, long after virus clearance. Our study suggests potential immune correlates of "long COVID-19", and defines key cells and cytokines that delineate true and quasi-convalescent states. Agency for Science, Technology and Research (A*STAR) National Medical Research Council (NMRC) National Research Foundation (NRF) Published version This work was supported by A*STAR Infectious Diseases Labs and Singapore Immunology Network (SIgN) core research grants, and the A*STAR COVID-19 Research funding (H/20/04/g1/006) provided to SIgN by the Biomedical Research Council (BMRC). Subject recruitment, sample collection and analyses were funded by the National Medical Research Council (NMRC) COVID-19 Research Fund (COVID19RF-001, COVID19-RF007, COVID190RF-060). The SIgN Immunomonitoring Platform is supported by a BMRC IAF 311006 grant and BMRC transition funds #H16/99/b0/011. The SIgN Flow Cytometry and the Multiple Analyte Platforms were supported by a grant from the National Research Foundation, Immunomonitoring Service Platform ISP) (#NRF2017_SISFP09) and the National Research Foundation Singapore (NRF).

Summary Hepatocellular carcinoma (HCC) often develops following chronic hepatitis B virus (HBV) infection and responds poorly to immune checkpoint blockade. Here, we examined the antigen specificities of HCC-infiltrating T cells and their relevance to tumor control. Using highly multiplexed peptide-MHC tetramer staining of unexpanded cells from blood, liver, and tumor tissues from 46 HCC patients, we detected 91 different antigen-specific CD8+ T cell populations targeting HBV, neoantigen, tumor-associated, and disease-unrelated antigens. Parallel high-dimensional analysis delineated five distinct antigen-specific tissue-resident memory T (Trm) cell populations. Intratumoral and intrahepatic HBV-specific T cells were enriched for two Trm cell subsets that were PD-1loTOXlo, despite being clonally expanded. High frequencies of intratumoral terminally exhausted T cells were uncommon. Patients with tumor-infiltrating HBV-specific CD8+ Trm cells exhibited longer-term relapse-free survival. Thus, non-terminally exhausted HBV-specific CD8+ Trm cells show hallmarks of active involvement and effective antitumor response, implying that these cells could be harnessed for therapeutic purposes.

Summary Growing evidence indicates a role for the gut microbiota in modulating anti-tumor treatment efficacy in human cancer. Here we study mucosa-associated invariant T (MAIT) cells to look for evidence of bacterial antigen recognition in human colon, lung, and kidney carcinomas. Using mass cytometry and single-cell mRNA sequencing, we identify a tumor-infiltrating MAIT cell subset expressing CD4 and Foxp3 and observe high expression of CD39 on MAIT cells from colorectal cancer (CRC) only, which we show in vitro to be expressed specifically after TCR stimulation. We further reveal that these cells are phenotypically and functionally exhausted. Sequencing data show high bacterial infiltration in CRC tumors and highlight an enriched species, Fusobacteria nucleatum, with capability to activate MAIT cells in a TCR-dependent way. Our results provide evidence of a MAIT cell response to microbial antigens in CRC and could pave the way for manipulating MAIT cells or the microbiome for cancer therapy., Graphical Abstract, Highlights Comprehensive profiling of tumor-infiltrating MAIT cells in colorectal cancer (CRC) Identification of a tumor-infiltrating MAIT cell subset expressing CD4 and Foxp3 TCR-driven CD39 expression is enriched in tumor-infiltrating MAIT cells CRC-related Fusobacterium nucleatum can activate MAIT cells in a TCR-dependent way, By investigating human colon, lung, and kidney carcinomas, Li et al. propose MAIT cells as part of the missing link between the gut microbiota and tumor biology. This work will open new avenues in cancer therapy by manipulating MAIT cells or MAIT-related bacterial ligands in the context of microbiota-influenced cancers.

Deep-immunophenotyping of the circulatory T cell compartment using mass cytometry and unsupervised clustering analysis, identifies phenotypic and functional differences in patients with atopic dermatitis (AD) and psoriasis, highlighting the stronger systemic component associated with AD.

Various forms of immunotherapy, such as checkpoint blockade immunotherapy, are proving to be effective at restoring T cell-mediated immune responses that can lead to marked and sustained clinical responses, but only in some patients and cancer types

Fruit and vegetables have therapeutic potential as they dampen inflammation, have no known side-effects and as whole foods have prospective additive and synergistic benefits. Th1 (IFN-γ(+) CD4(+))/Th2 (IL-4(+)CD4(+)) T cells play a vital role in mediating inflammatory responses and may be regulated by regulatory T cells (Tregs). Effects of Carica papaya on cells of healthy individuals were determined using flow cytometry methods. Significant down-regulation of IFN-γ(+) CD4(+) (p=0.03, n=13), up-regulation of IL-4(+) CD4(+) (p=0.04, n=13) T cells and up-regulation of CD3(+) CD4(+) CD25(+) CD127(-) (p=0.001, n=15) Tregs were observed after papaya consumption. In vitro cultures showed up-regulation of Tregs in male subjects and was significantly associated with levels of IL-1β in culture supernatants (R(2) =0.608, p=0.04, n=12). Other inflammatory cytokines were significantly suppressed. Papaya consumption may exert an anti-inflammatory response mediated through Tregs and have potential in alleviating inflammatory conditions.

Animal models have highlighted the importance of innate lymphoid cells (ILCs) in multiple immune responses. However, technical limitations have hampered adequate characterization of ILCs in humans. Here, we used mass cytometry including a broad range of surface markers and transcription factors to accurately identify and profile ILCs across healthy and inflamed tissue types. High dimensional analysis allowed for clear phenotypic delineation of ILC2 and ILC3 subsets. We were not able to detect ILC1 cells in any of the tissues assessed, however, we identified intra-epithelial (ie)ILC1-like cells that represent a broader category of NK cells in mucosal and non-mucosal pathological tissues. In addition, we have revealed the expression of phenotypic molecules that have not been previously described for ILCs. Our analysis shows that human ILCs are highly heterogeneous cell types between individuals and tissues. It also provides a global, comprehensive, and detailed description of ILC heterogeneity in humans across patients and tissues.