Immunogenicity and safety of inactivated SARS-CoV-2 vaccines in people living with HIV: A longitudinal cohort study.

To clarify the characteristics in immunogenicity and safety of inactivated SARS-Cov-2 vaccines among HIV-infected individuals, a longitudinal cohort study was performed on HIV-infected and HIV-uninfected participants with no history of COVID-19 infection and COVID-19 vaccine inoculation. Participants information and adverse events were collected. Blood samples were collected on the same day before vaccination, 21 days after the first shot, 28 days after the second shot, 6 months after the second vaccination and 14 days after the third dose to test anti-receptor-binding domain IgG antibody, viral load, CD4+, CD8+ T cell count. Our result showed that although HIV-infected adults with low nadir CD4+ T cell count ≤ 350 cells/mm3 generate significantly lower immune response after three shots of vaccine compared with HIV-negative controls, 100% of all the HIV-infected and healthy controls were seroconverted after the third shot. Seroconversion ratio and antibody level of 190 days after two shots of vaccination for HIV-infected with nadir CD4+ T cell count ≤ 350 were significantly lower than that of healthy controls. No significant difference was found in viral load among blood samples collected at each time points. CD4 and CD4/CD8 ratio value were found increased greatly after each shot of inoculation in HIV-infected individuals with nadir CD4+ T cell count ≤ 350. Multiple logistic regression analysis showed that among HIV-infected individuals, PLWH with CD4+ T cell count ≤ 350 were less likely experience seroconversion 21 days after the first shot, and less likely maintained antibody immunity 6 months post 2nd dose. Adverse events after each inoculation were not serious and recovered within 1 week. In conclusion, inactivated COVID-19 vaccine was safe and effective in people living with HIV after three shots of vaccination. HIV-infected individuals with low nadir CD4+ T cell count ≤ 350 was associated with a nonoptimal antibody response. Further vaccination strategies could be developed for those with low CD4+ T cell counts.

A sequential scheme including PTT and 2'3'-cGAMP/CQ-LP reveals the antitumor immune function of PTT through the type I interferon pathway.

Photothermal therapy (PTT) is a promising antitumor treatment that is easy to implement, minimally invasive, and precisely controllable, and evokes strong antitumor immunity. We believe that a thorough elucidation of its underlying antitumor immune mechanisms would contribute to the rational design of combination treatments with other antitumor strategies and consequently potentiate clinical use. In this study, PTT using indocyanine green (ICG) induced STING-dependent type I interferon (IFN) production in macrophages (RAW264.7 and bone marrow-derived macrophages (BMDMs)), as proven by the use of a STING inhibitor (C178), and triggered STING-independent type I IFN generation in tumor cells (CT26 and 4T1), which was inhibited by DNase pretreatment. A novel liposome coloaded with the STING agonist 2'3'-cGAMP (cGAMP) and chloroquine (CQ) was constructed to achieve synergistic effect with PTT, in which CQ increased cGAMP entrapment efficiency and prevented STING degradation after IFN signaling activation. The sequential combination treatment caused a significant increase in tumor cell apoptosis, probably due to interferon stimulating gene products 15 and 54 (ISG15 and ISG 54), and achieved a more striking antitumor inhibition effect in the CT26 tumor model than the 4T1 model, likely due to higher STAT1 expression and consequently more intense IFN signal transduction. In the tumor microenvironment, the combination treatment increased infiltrating CD8+T cells (4-fold) and M1-like TAMs (10-fold), and decreased M-MDSCs (over 2-fold) and M2-like TAMs (over 4-fold). Above all, in-depth exploration of the antitumor mechanism of PTT provides guidance for selecting sensitive tumor models and designing reasonable clinical schemes.

Humoral immune response following the inactivated quadrivalent influenza vaccination among HIV-infected and HIV-uninfected adults.

BACKGROUND: A limited amount of information is available about the immunogenicity of the quadrivalent inactivated influenza vaccine among human immunodeficiency virus (HIV)-infected individuals, especially in low and middle-income countries (LMICs). METHODS: HIV-infected adults and HIV-uninfected adults received a dose of quadrivalent inactivated influenza vaccine including strains of H1N1, H3N2, BV and BY. Enzyme-linked immunosorbent assay (ELISA) and hemagglutination-inhibition assay (HAI) were used to determine IgA, IgG antibody concentration and geometric mean titers (GMT) at day 0 and day 28, respectively. Associated factors contributing to seroconversion or GMT changes were analyzed using simple logistic regression model. RESULTS: A total of 131 HIV-infected and 55 HIV-uninfected subjects were included in the study. In both HIV-infected and uninfected arms, IgG and IgA against influenza A and B all increased significantly at day 28 after receiving QIV (P < 0.001). GMTs of post-vaccination at day 28 showed that HIV-infected persons with CD4 + T cell counts ≤ 350 cells/mm3 were statistically less immunogenic to all strains of QIV than HIV-uninfected ones (P < 0.05). HIV-infected participants with CD4 + T cell counts ≤ 350 cells/mm3 were less likely to achieve seroconversion to QIV (H1N1, BY and BV) than HIV-uninfected individuals at day 28 after vaccination (P < 0.05). Compared with HIV-infected patients with baseline CD4 + T cell counts ≤ 350 cells/mm3, individuals with baseline CD4 + T cell counts > 350 cell/mm3 seemed more likely to generate antibody responses to H1N1 (OR:2.65, 95 %CI: 1.07-6.56) and BY (OR: 3.43, 95 %CI: 1.37-8.63), and showed a higher probability of seroconversion to BY (OR: 3.59, 95 %CI: 1.03-12.48). Compared with nadir CD4 + T cell count ≤ 350 cell/mm3, individuals with nadir CD4 + T cell count > 350 cell/mm3 showed a higher probability of seroconversion to H1N1(OR: 3.15, 95 %CI: 1.14-8.73). CONCLUSION: Influenza vaccination of HIV-infected adults might be effective despite variable antibody responses. HIV-positive populations with CD4 + T cell counts ≤ 350 are less likely to achieve seroconversion. Further vaccination strategies could be developed for those with low CD4 T cell counts.

Potential of extracellular vesicles for early prediction of severity and potential risk stratification in critical inflammatory diseases.

Some acute inflammatory diseases are often exacerbated during or after hospitalization, leading to some severe manifestations like systemic inflammatory response syndrome, multiple organ failure, and high mortality. Early clinical predictors of disease severity are urgently needed to optimize patient management for better prognosis. The existing clinical scoring system and laboratory tests cannot circumvent the problems of low sensitivity and limited specificity. Extracellular vesicles (EVs) are heterogeneous nanosecretory vesicles containing various biomolecules related to immune regulation, inflammation activation, and inflammation-related complications. This review provides an overview of EVs as inflammatory mediators, inflammatory signaling pathway regulators, promoters of inflammatory exacerbation, and markers of severity and prognosis. Currently, although relevant biomarkers are clinically available or are in the preclinical research stage, searching for new markers and detection methods is still warranted, as the problems of low sensitivity/specificity, cumbersome laboratory operation and high cost still plague clinicians. In-depth study of EVs might open a door in the search for novel predictors.

Nanoparticle encapsulated CQ/TAM combination harmonizes with MSCs in arresting progression of severity in AP mice through iNOS (IDO) signaling.

Background: Sever acute pancreatitis (SAP) is a critical disease with high mortality, and lack of clinically available treatments with specificity and effectiveness. Bone marrow derived mesenchymal stem cells (BMSCs) exhibited moderate effect on AP which needs further improvement. Methods: Pancreatic infiltrating lymphocytes were analyzed to demonstrate the intervention of BMSCs on inflammatory cell infiltration of AP. Gene silencing with siRNA and small molecule inhibitor were utilized to determine the key effector molecule of BMSCs on AP. Pharmacological regulation and nanotechnology were introduced to further ameliorate BMSCs action. Results: It was revealed that BMSCs prevent the progression of acute pancreatitis (AP) by reducing recruitment of macrophages, neutrophils and CD4+T cells in the lesion site. The pivotal role of chemokine-iNOS-IDO axis for BMSCs to intervene AP was confirmed. Compared with any single drug, Chloroquine/Tamoxifen combination together with IFN-γ pronouncedly up-regulated the transcription of several MSC immune regulators such as COX-2, PD-L1, HO-1 especially iNOS/IDO. As expected, BMSCs and human umbilical cord mesenchymal stem cells (UMSCs) pretreated with CQ/TAM/IFN-γ exerted enhanced intervention in AP and SAP mice. Moreover, pretreatment with CQ-LPs/TAM-NPs combination not only counteracted MSCs proliferation inhibition induced by free drugs but also enhanced their efficacy. Conclusion: Under the background of rapid progress in MSCs clinical translation, this study focuses on the urgent clinical issue and initiates an original mechanism-based strategy to promote intervention on severity progression of SAP, which promises its clinical translation in future.

Adoptive CD8+T-cell grafted with liposomal immunotherapy drugs to counteract the immune suppressive tumor microenvironment and enhance therapy for melanoma.

The immunosuppressive tumor microenvironment has become a formidable obstacle to the treatment of tumors using adoptive T cell therapy, in particular solid tumors. For the purposes of addressing this issue, effector OT-1 CD8+T cells conjugated with liposomal immune regulators (CD8-T-LP-CpG/CD8-T-LP-BMS-202) were developed. An anionic liposome formulation was employed to avoid T cell aggregation and prevent unfavorable side-effects. The inclusion of EGCG in the LP-CpG formulation facilitated the formation of compact complexes with poly lysine (PLL) and is thus expected to increase the stability. CD8-T-LP-CpG administered with a median dose of CpG (20 µg per mouse) markedly reduced the frequency of tumor infiltrating polymorphonuclear leukocyte myeloid-derived suppressor cells (PMN-MDSCs) (20-folds), M2-like macrophages (8-folds), regulatory T-cells (Treg) (2.7-folds), and consequently increased the frequency of cytotoxic CD8+T cells in tumor-infiltrating lymphocytes (TILs) (2-folds) and splenic effector memory CD8+T cells (3-folds) relative to the phosphate buffered saline (PBS) control group. Furthermore, the absolute number of tumor infiltrating lymphocyte subtypes altered followed a consistent trend. The difference remained significant compared to the OT-1 CD8+T cells and the drug-loaded liposome combination group. According to in vivo imaging of CD8-T-LP-DiD, we assumed that the improvement in regulation of the tumor microenvironment of LP-CpG/LP-BMS-202 was attributed to the enhanced drug transportation to the tumor site aided by tumor-specific OT-1 CD8+T cells. In addition, CD8-T-LP-BMS-202 administered with a low dose of BMS-202 (1.5 mg per kg body weight) exerted a dramatically improved therapeutic effect by reducing the tumor infiltrating PMN-MDSCs and M2-like macrophages and the corresponding promoted cytotoxic CD8+T cell recruitment in the TILs and effector memory CD8+T cells mediated anti-tumor immunity. In summary, immune therapy drugs backpacked onto adoptive T cell therapy provides a feasible strategy to improve the therapeutic effect and could result in future clinical translation.

[Relationship between cellulose synthesis metabolism and lodging resistance in intercropping soybean at seedling stage].

Physical characteristics of stem are closely relative to the crop lodging. Increase of stem strength is conducive to resolve the problem of lodging. Three soybean cultivars with different shade tolerance were planted under maize-soybean intercropping and soybean monocropping, respectively. Physiological and biochemical indices including cellulose, soluble sugar, sucrose, starch contents and enzyme activity were investigated to assess the snapping resistance and lodging resistance of the stems of soybean seedling, and snapping- and lodging-resistance indices were calculated for further verification. Furthermore, relationship analyses between these factors and the lodging of inter-cropped soybean showed that the intercropping soybean lodged seriously, the snapping resistance, lodging resistance index, contents of cellulose, soluble sugar, sucrose, starch and activities of the related enzymes were significantly lower than monocropping soybean at seedling stage. The three soybean cultivars showed different phenotypes in intercropping condition. The snapping-resistant Nandou12 with strong shade-tolerant traits was the most lodging-resistant phenotype, and it also harbored high contents of cellulose, soluble sugar, sucrose, starch and active enzymes. The lodging resistance index, cellulose content of the stems of intercropped soybean seedling were significantly positively correlated with the snapping resistance, and were significantly negatively correlated with the actual lodging percentage. The activities of sucrose phosphate synthase (SPS) , sucrose synthase (SS) and neutral invertase (NI) were positively correlated with sucrose is content, but not the acid invertase (AI). The activities of SPS, NI and SS were positively correlated with cellulose content, but not Al. In a word, the high activities of SPS and SS in the soybean stem were the enzymatic basis to maintain relatively higher cellulose and sucrose content, which is conducive to improve the stem-sfrength and enhance the lodging resistance ability in intercropping condition. Effects of different light conditions on cellulose metabolic mechanism of soybean seedling stems, lodging resistant characteristics of soybean seedlings studied in the corn-soybean intercropping system provided a basis for screening more shade-tolerant soybean variety.