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1.
J Med Chem ; 65(3): 2558-2570, 2022 02 10.
Article in English | MEDLINE | ID: covidwho-1895561

ABSTRACT

Safe and effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and its variants are the best approach to successfully combat the COVID-19 pandemic. The receptor-binding domain (RBD) of the viral spike protein is a major target to develop candidate vaccines. α-Galactosylceramide (αGalCer), a potent invariant natural killer T cell (iNKT) agonist, was site-specifically conjugated to the N-terminus of the RBD to form an adjuvant-protein conjugate, which was anchored on the liposome surface. This is the first time that an iNKT cell agonist was conjugated to the protein antigen. Compared to the unconjugated RBD/αGalCer mixture, the αGalCer-RBD conjugate induced significantly stronger humoral and cellular responses. The conjugate vaccine also showed effective cross-neutralization to all variants of concern (B.1.1.7/alpha, B.1.351/beta, P.1/gamma, B.1.617.2/delta, and B.1.1.529/omicron). These results suggest that the self-adjuvanting αGalCer-RBD has great potential to be an effective COVID-19 vaccine candidate, and this strategy might be useful for designing various subunit vaccines.


Subject(s)
COVID-19 Vaccines/therapeutic use , COVID-19/therapy , Galactosylceramides/therapeutic use , Peptide Fragments/therapeutic use , SARS-CoV-2/immunology , Vaccines, Conjugate/therapeutic use , Adjuvants, Immunologic/chemistry , Adjuvants, Immunologic/therapeutic use , Animals , Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19 Vaccines/chemistry , COVID-19 Vaccines/immunology , Female , Galactosylceramides/chemistry , Galactosylceramides/immunology , Immunity, Humoral/drug effects , Immunity, Innate/drug effects , Interferon-gamma/metabolism , Liposomes/chemistry , Liposomes/immunology , Liposomes/therapeutic use , Mice, Inbred BALB C , Peptide Fragments/chemistry , Peptide Fragments/immunology , Protein Domains , Spike Glycoprotein, Coronavirus/chemistry , Spike Glycoprotein, Coronavirus/immunology , Spike Glycoprotein, Coronavirus/therapeutic use , Vaccines, Conjugate/chemistry , Vaccines, Conjugate/immunology
2.
Br J Haematol ; 198(4): 668-679, 2022 08.
Article in English | MEDLINE | ID: covidwho-1874397

ABSTRACT

Allogeneic haematopoietic stem cell transplant (HSCT) recipients remain at high risk of adverse outcomes from coronavirus disease 2019 (COVID-19) and emerging variants. The optimal prophylactic vaccine strategy for this cohort is not defined. T cell-mediated immunity is a critical component of graft-versus-tumour effect and in determining vaccine immunogenicity. Using validated anti-spike (S) immunoglobulin G (IgG) and S-specific interferon-gamma enzyme-linked immunospot (IFNγ-ELIspot) assays we analysed response to a two-dose vaccination schedule (either BNT162b2 or ChAdOx1) in 33 HSCT recipients at ≤2 years from transplant, alongside vaccine-matched healthy controls (HCs). After two vaccines, infection-naïve HSCT recipients had a significantly lower rate of seroconversion compared to infection-naïve HCs (25/32 HSCT vs. 39/39 HCs no responders) and had lower S-specific T-cell responses. The HSCT recipients who received BNT162b2 had a higher rate of seroconversion compared to ChAdOx1 (89% vs. 74%) and significantly higher anti-S IgG titres (p = 0.022). S-specific T-cell responses were seen after one vaccine in HCs and HSCT recipients. However, two vaccines enhanced S-specific T-cell responses in HCs but not in the majority of HSCT recipients. These data demonstrate limited immunogenicity of two-dose vaccination strategies in HSCT recipients, bolstering evidence of the need for additional boosters and/or alternative prophylactic measures in this group.


Subject(s)
COVID-19 Vaccines , COVID-19 , Hematopoietic Stem Cell Transplantation , Age Factors , Antibodies, Viral/immunology , BNT162 Vaccine/immunology , BNT162 Vaccine/therapeutic use , Bone Marrow Transplantation/adverse effects , COVID-19/prevention & control , COVID-19/virology , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/immunology , COVID-19 Vaccines/pharmacology , COVID-19 Vaccines/therapeutic use , ChAdOx1 nCoV-19/immunology , ChAdOx1 nCoV-19/therapeutic use , Hematopoietic Stem Cell Transplantation/adverse effects , Humans , Immunity, Cellular/drug effects , Immunity, Cellular/immunology , Immunity, Humoral/drug effects , Immunity, Humoral/immunology , Immunoglobulin G/blood , Immunoglobulin G/immunology , Seroconversion , Transplantation, Homologous/adverse effects , Vaccination/adverse effects
4.
J Clin Invest ; 131(12)2021 06 15.
Article in English | MEDLINE | ID: covidwho-1731387

ABSTRACT

The characterization of the adaptive immune response to COVID-19 vaccination in individuals who recovered from SARS-CoV-2 infection may define current and future clinical practice. To determine the effect of the 2-dose BNT162b2 mRNA COVID-19 vaccination schedule in individuals who recovered from COVID-19 (COVID-19-recovered subjects) compared with naive subjects, we evaluated SARS-CoV-2 Spike-specific T and B cell responses, as well as specific IgA, IgG, IgM, and neutralizing antibodies titers in 22 individuals who received the BNT162b2 mRNA COVID-19 vaccine, 11 of whom had a previous history of SARS-CoV-2 infection. Evaluations were performed before vaccination and then weekly until 7 days after second injection. Data obtained clearly showed that one vaccine dose is sufficient to increase both cellular and humoral immune response in COVID-19-recovered subjects without any additional improvement after the second dose. On the contrary, the second dose proved mandatory in naive subjects to further enhance the immune response. These findings were further confirmed at the serological level in a larger cohort of naive (n = 68) and COVID-19-recovered (n = 29) subjects, tested up to 50 days after vaccination. These results question whether a second vaccine injection in COVID-19-recovered subjects is required, and indicate that millions of vaccine doses may be redirected to naive individuals, thus shortening the time to reach herd immunity.


Subject(s)
Antibodies, Neutralizing , Antibodies, Viral , COVID-19 Vaccines , COVID-19 , Immunity, Humoral/drug effects , Immunologic Memory/drug effects , SARS-CoV-2 , Adult , Aged , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , Antibodies, Viral/blood , Antibodies, Viral/immunology , COVID-19/blood , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , Female , Humans , Male , Middle Aged , SARS-CoV-2/immunology , SARS-CoV-2/metabolism
5.
Int J Mol Sci ; 23(4)2022 Feb 16.
Article in English | MEDLINE | ID: covidwho-1708485

ABSTRACT

Despite the fact that a range of vaccines against COVID-19 have already been created and are used for mass vaccination, the development of effective, safe, technological, and affordable vaccines continues. We have designed a vaccine that combines the recombinant protein and DNA vaccine approaches in a self-assembled particle. The receptor-binding domain (RBD) of the spike protein of SARS-CoV-2 was conjugated to polyglucin:spermidine and mixed with DNA vaccine (pVAXrbd), which led to the formation of particles of combined coronavirus vaccine (CCV-RBD) that contain the DNA vaccine inside and RBD protein on the surface. CCV-RBD particles were characterized with gel filtration, electron microscopy, and biolayer interferometry. To investigate the immunogenicity of the combined vaccine and its components, mice were immunized with the DNA vaccine pVAXrbd or RBD protein as well as CCV-RBD particles. The highest antigen-specific IgG and neutralizing activity were induced by CCV-RBD, and the level of antibodies induced by DNA or RBD alone was significantly lower. The cellular immune response was detected only in the case of DNA or CCV-RBD vaccination. These results demonstrate that a combination of DNA vaccine and RBD protein in one construct synergistically increases the humoral response to RBD protein in mice.


Subject(s)
COVID-19 Vaccines/chemistry , COVID-19 Vaccines/pharmacology , Immunity, Humoral/drug effects , Spike Glycoprotein, Coronavirus/chemistry , Animals , Binding Sites , COVID-19 Vaccines/immunology , Chlorocebus aethiops , Dextrans/chemistry , Female , HEK293 Cells , Humans , Mice, Inbred BALB C , Protein Domains , Recombinant Proteins/chemistry , Recombinant Proteins/genetics , Recombinant Proteins/metabolism , Spermidine/chemistry , Spike Glycoprotein, Coronavirus/genetics , Spike Glycoprotein, Coronavirus/immunology , Vaccines, DNA/genetics , Vaccines, DNA/immunology , Vaccines, DNA/pharmacology , Vero Cells
8.
Front Immunol ; 12: 798276, 2021.
Article in English | MEDLINE | ID: covidwho-1606542

ABSTRACT

Effects of initiation of programmed-death-protein 1 (PD1) blockade during active SARS-CoV-2 infection on antiviral immunity, COVID-19 course, and underlying malignancy are unclear. We report on the management of a male in his early 40s presenting with highly symptomatic metastatic lung cancer and active COVID-19 pneumonia. After treatment initiation with pembrolizumab, carboplatin, and pemetrexed, the respiratory situation initially worsened and high-dose corticosteroids were initiated due to suspected pneumonitis. After improvement and SARS-CoV-2 clearance, anti-cancer treatment was resumed without pembrolizumab. Immunological analyses with comparison to otherwise healthy SARS-CoV-2-infected ambulatory patients revealed a strong humoral immune response with higher levels of SARS-CoV-2-reactive IgG and neutralizing serum activity. Additionally, sustained increase of Tfh as well as activated CD4+ and CD8+ T cells was observed. Sequential CT scans showed regression of tumor lesions and marked improvement of the pulmonary situation, with no signs of pneumonitis after pembrolizumab re-challenge as maintenance. At the latest follow-up, the patient is ambulatory and in ongoing partial remission on pembrolizumab. In conclusion, anti-PD1 initiation during active COVID-19 pneumonia was feasible and cellular and humoral immune responses to SARS-CoV-2 appeared enhanced in our hospitalized patient. However, distinguishing COVID-19-associated changes from anti-PD1-associated immune-related pneumonitis posed a considerable clinical, radiographic, and immunologic challenge.


Subject(s)
Adrenal Cortex Hormones/therapeutic use , COVID-19/drug therapy , Carcinoma, Non-Small-Cell Lung/drug therapy , Immune Checkpoint Inhibitors/therapeutic use , Lung Neoplasms/drug therapy , SARS-CoV-2/drug effects , Adult , CD8-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/immunology , CD8-Positive T-Lymphocytes/virology , COVID-19/complications , COVID-19/immunology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/immunology , Carcinoma, Non-Small-Cell Lung/complications , Carcinoma, Non-Small-Cell Lung/immunology , Humans , Immunity, Humoral/drug effects , Immunity, Humoral/immunology , Lung Neoplasms/complications , Lung Neoplasms/immunology , Male , Neoplasm Metastasis , Pneumonia/immunology , Pneumonia/prevention & control , Pneumonia/virology , SARS-CoV-2/immunology
9.
ESMO Open ; 7(1): 100359, 2022 02.
Article in English | MEDLINE | ID: covidwho-1560850

ABSTRACT

BACKGROUND: The durability of immunogenicity of SARS-CoV-2 vaccination in cancer patients remains to be elucidated. We prospectively evaluated the immunogenicity of the vaccine in triggering both the humoral and the cell-mediated immune response in cancer patients treated with anti-programmed cell death protein 1/programmed death-ligand 1 with or without chemotherapy 6 months after BNT162b2 vaccine. PATIENTS AND METHODS: In the previous study, 88 patients were enrolled, whereas the analyses below refer to the 60 patients still on immunotherapy at the time of the follow-up. According to previous SARS-CoV-2 exposure, patients were classified as SARS-CoV-2-naive (without previous SARS-CoV-2 exposure) and SARS-CoV-2-experienced (with previous SARS-CoV-2 infection). Neutralizing antibody (NT Ab) titer against the B.1.1 strain and total anti-spike immunoglobulin G concentration were quantified in serum samples. The enzyme-linked immunosorbent spot assay was used for quantification of anti-spike interferon-γ (IFN-γ)-producing cells/106 peripheral blood mononuclear cells. Fifty patients (83.0%) were on immunotherapy alone, whereas 10 patients (7%) were on chemo-immunotherapy. We analyzed separately patients on immunotherapy and patients on chemo-immunotherapy. RESULTS: The median T-cell response at 6 months was significantly lower than that measured at 3 weeks after vaccination [50 interquartile range (IQR) 20-118.8 versus 175 IQR 67.5-371.3 IFN-γ-producing cells/106 peripheral blood mononuclear cells; P < 0.0001]. The median reduction of immunoglobulin G concentration was 88% in SARS-CoV-2-naive subjects and 2.1% in SARS-CoV-2-experienced subjects. SARS-CoV-2 NT Ab titer was maintained in SARS-CoV-2-experienced subjects, whereas a significant decrease was observed in SARS-CoV-2-naive subjects (from median 1 : 160, IQR 1 : 40-1 : 640 to median 1 : 20, IQR 1 : 10-1 : 40; P < 0.0001). A weak correlation was observed between SARS-CoV-2 NT Ab titer and spike-specific IFN-γ-producing cells at both 6 months and 3 weeks after vaccination (r = 0.467; P = 0.0002 and r = 0.428; P = 0.0006, respectively). CONCLUSIONS: Our work highlights a reduction in the immune response in cancer patients, particularly in SARS-CoV-2-naive subjects. Our data support administering a third dose of COVID-19 vaccine to cancer patients treated with programmed cell death protein 1/programmed death-ligand 1 inhibitors.


Subject(s)
B7-H1 Antigen , COVID-19 , Immune Checkpoint Inhibitors , Neoplasms , Programmed Cell Death 1 Receptor , B7-H1 Antigen/antagonists & inhibitors , B7-H1 Antigen/immunology , /immunology , COVID-19/immunology , COVID-19/prevention & control , Follow-Up Studies , Humans , Immune Checkpoint Inhibitors/administration & dosage , Immune Checkpoint Inhibitors/immunology , Immunity, Cellular/drug effects , Immunity, Humoral/drug effects , Leukocytes, Mononuclear/drug effects , Leukocytes, Mononuclear/immunology , Neoplasms/drug therapy , Neoplasms/immunology , Programmed Cell Death 1 Receptor/antagonists & inhibitors , Programmed Cell Death 1 Receptor/immunology , SARS-CoV-2/immunology
10.
Front Immunol ; 12: 765528, 2021.
Article in English | MEDLINE | ID: covidwho-1555219

ABSTRACT

Influenza vaccination is an effective public health measure to reduce the risk of influenza illness, particularly when the vaccine is well matched to circulating strains. Notwithstanding, the efficacy of influenza vaccination varies greatly among vaccinees due to largely unknown immunological determinants, thereby dampening population-wide protection. Here, we report that dietary fibre may play a significant role in humoral vaccine responses. We found dietary fibre intake and the abundance of fibre-fermenting intestinal bacteria to be positively correlated with humoral influenza vaccine-specific immune responses in human vaccinees, albeit without reaching statistical significance. Importantly, this correlation was largely driven by first-time vaccinees; prior influenza vaccination negatively correlated with vaccine immunogenicity. In support of these observations, dietary fibre consumption significantly enhanced humoral influenza vaccine responses in mice, where the effect was mechanistically linked to short-chain fatty acids, the bacterial fermentation product of dietary fibre. Overall, these findings may bear significant importance for emerging infectious agents, such as COVID-19, and associated de novo vaccinations.


Subject(s)
Dietary Fiber/pharmacology , Immunity, Humoral/drug effects , Influenza Vaccines/immunology , Influenza, Human/immunology , Adolescent , Adult , Animals , Dietary Fiber/metabolism , Fatty Acids, Volatile/metabolism , Fatty Acids, Volatile/pharmacology , Female , Fermentation , Gastrointestinal Microbiome/drug effects , Gastrointestinal Microbiome/immunology , Humans , Immunogenicity, Vaccine , Influenza, Human/microbiology , Influenza, Human/prevention & control , Male , Mice , Middle Aged , Orthomyxoviridae/immunology , Seasons , Vaccination , Young Adult
11.
Ann Rheum Dis ; 81(3): 416-421, 2022 03.
Article in English | MEDLINE | ID: covidwho-1541856

ABSTRACT

OBJECTIVES: To assess the kinetics of humoral response after the first and second dose of messenger RNA (mRNA) vaccines in patients with inflammatory joint diseases compared with healthy controls (HC). To analyse factors influencing the quantity of the immune response. METHODS: We enrolled patients with rheumatoid arthritis (RA) and seronegative spondyloarthritis (SpA), excluding those receiving B-cell depleting therapies and assessed the humoral response to mRNA vaccines after the first and the second dose of the vaccine in terms of seroconversion rate and titre. We compared the results to a HC group and analysed the influence of therapies as well as other characteristics on the humoral response. RESULTS: Samples from 53 patients with RA, 46 patients with SpA and 169 healthy participants were analysed. Seroconversion rates after the first immunisation were only 54% in patients with inflammatory arthritis compared with 98% in the HC group. However, seroconversion rates were 100% in all groups after second immunisation. Patients developed reduced antibody titres after the first vaccination compared with HC, but there was no difference after the second dose. While disease modifying anti-rheumatic drug (DMARD) monotherapy did not affect antibody levels, seroconversion rates as well as titre levels were reduced in patients receiving a combination of DMARDs compared with HC. CONCLUSIONS: Patients with inflammatory joint diseases under DMARD therapy show impaired humoral responses to the first vaccine dose but excellent final responses to vaccination with mRNA vaccines. Therefore, the full course of two immunisations is necessary for efficient vaccination responses in patients with inflammatory arthritis under DMARD therapy.


Subject(s)
Arthritis, Rheumatoid/immunology , COVID-19 Vaccines/immunology , COVID-19/prevention & control , SARS-CoV-2/immunology , Spondylarthritis/immunology , Antirheumatic Agents/immunology , Arthritis, Rheumatoid/drug therapy , COVID-19/immunology , Case-Control Studies , Female , Humans , Immunity, Humoral/drug effects , Immunogenicity, Vaccine/drug effects , Male , Middle Aged , Seroconversion/drug effects , Spondylarthritis/drug therapy
12.
ESMO Open ; 7(1): 100350, 2022 Feb.
Article in English | MEDLINE | ID: covidwho-1536535

ABSTRACT

BACKGROUND: Preliminary analysis from the Vax-On study did not find a correlation between cancer treatment type and antibody response to COVID-19 vaccination. We carried out a secondary subgroup analysis to verify the effects of comprehensive cancer treatment classification on vaccine immunogenicity. METHODS: The Vax-On study prospectively enrolled patients who started a two-dose messenger RNA-BNT162b2 vaccine schedule from 9 March 2021 to 12 April 2021 (timepoint-1). Those on active treatment within the previous 28 days accounted for the exposed cases. Patients who had discontinued such treatment by at least 28 days or received intravesical therapy represented the control cases. Quantification of immunoglobulin G (IgG) antibodies against the receptor binding domain of the S1 subunit of the SARS-CoV-2 spike protein was carried out before the second dose (timepoint-2) and 8 weeks thereafter (timepoint-3). Seroconversion response was defined at ≥50 arbitrary units/ml IgG titer. Classification of antineoplastic agents was based on their pharmacodynamic properties. RESULTS: Three hundred and sixty-six patients were enrolled (86 and 260 as control and exposed cases, respectively). Univariate analysis revealed a significantly lower IgG titer after both doses of vaccine in subgroups treated with tyrosine kinase inhibitors (TKIs), multiple cytotoxic agents, alkylating agents, and topoisomerase inhibitors. At timepoint-3, seroconversion response was significantly impaired in the topoisomerase inhibitors and mechanistic target of rapamycin (mTOR) inhibitors subgroups. After multivariate testing, treatment with alkylating agents and TKIs was significantly associated with a reduced change in IgG titer at timepoint-2. Treatment with mTOR inhibitors resulted in a similar interaction at each timepoint. Cyclin-dependent kinase 4/6 inhibitor treatment was independently correlated with an incremental variation in IgG titer at timepoint-3. Specific subgroups (TKIs, antimetabolites, alkylating agents, and multiple-agent chemotherapy) predicted lack of seroconversion at timepoint-2, but their effect was not retained at timepoint-3. Eastern Cooperative Oncology Group performance status 2, immunosuppressive corticosteroid dosing, and granulocyte colony-stimulating factor use were independently linked to lower IgG titer after either dose of vaccine. CONCLUSIONS: Drugs interfering with DNA synthesis, multiple-agent cytotoxic chemotherapy, TKIs, mTOR and cyclin-dependent kinase 4/6 inhibitors differentially modulate humoral response to messenger RNA-BNT162b2 vaccine.


Subject(s)
Antineoplastic Agents , COVID-19 , Immunity, Humoral , Immunogenicity, Vaccine , Neoplasms , Spike Glycoprotein, Coronavirus , Antibodies, Viral/blood , Antineoplastic Agents/pharmacology , COVID-19/prevention & control , Humans , Immunity, Humoral/drug effects , Immunoglobulin G/blood , Neoplasms/drug therapy , Neoplasms/immunology , Prospective Studies , RNA, Messenger/genetics , RNA, Messenger/immunology , SARS-CoV-2 , Spike Glycoprotein, Coronavirus/immunology
13.
Nat Med ; 27(11): 1990-2001, 2021 11.
Article in English | MEDLINE | ID: covidwho-1526094

ABSTRACT

SARS-CoV-2 messenger RNA vaccination in healthy individuals generates immune protection against COVID-19. However, little is known about SARS-CoV-2 mRNA vaccine-induced responses in immunosuppressed patients. We investigated induction of antigen-specific antibody, B cell and T cell responses longitudinally in patients with multiple sclerosis (MS) on anti-CD20 antibody monotherapy (n = 20) compared with healthy controls (n = 10) after BNT162b2 or mRNA-1273 mRNA vaccination. Treatment with anti-CD20 monoclonal antibody (aCD20) significantly reduced spike-specific and receptor-binding domain (RBD)-specific antibody and memory B cell responses in most patients, an effect ameliorated with longer duration from last aCD20 treatment and extent of B cell reconstitution. By contrast, all patients with MS treated with aCD20 generated antigen-specific CD4 and CD8 T cell responses after vaccination. Treatment with aCD20 skewed responses, compromising circulating follicular helper T (TFH) cell responses and augmenting CD8 T cell induction, while preserving type 1 helper T (TH1) cell priming. Patients with MS treated with aCD20 lacking anti-RBD IgG had the most severe defect in circulating TFH responses and more robust CD8 T cell responses. These data define the nature of the SARS-CoV-2 vaccine-induced immune landscape in aCD20-treated patients and provide insights into coordinated mRNA vaccine-induced immune responses in humans. Our findings have implications for clinical decision-making and public health policy for immunosuppressed patients including those treated with aCD20.


Subject(s)
COVID-19 Vaccines/therapeutic use , Multiple Sclerosis/immunology , Multiple Sclerosis/therapy , SARS-CoV-2/immunology , Animals , Antibodies, Monoclonal/therapeutic use , Antibodies, Viral/analysis , Antibodies, Viral/blood , Antigens, CD20/immunology , COVID-19/prevention & control , Case-Control Studies , Chlorocebus aethiops , HEK293 Cells , Humans , Immunity, Cellular , Immunity, Humoral/drug effects , Immunity, Humoral/physiology , Immunotherapy/methods , Longitudinal Studies , Multiple Sclerosis/blood , RNA, Messenger/immunology , RNA, Viral/immunology , Rituximab/pharmacology , Rituximab/therapeutic use , SARS-CoV-2/genetics , Vaccination , Vero Cells
15.
Adv Drug Deliv Rev ; 179: 114020, 2021 12.
Article in English | MEDLINE | ID: covidwho-1486938

ABSTRACT

Adjuvant is an essential component in subunit vaccines. Many agonists of pathogen recognition receptors have been developed as potent adjuvants to optimize the immunogenicity and efficacy of vaccines. Recently discovered cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway has attracted much attention as it is a key mediator for modulating immune responses. Vaccines adjuvanted with STING agonists are found to mediate a robust immune defense against infections and cancer. In this review, we first discuss the mechanisms of STING agonists in the context of vaccination. Next, we present recent progress in novel STING agonist discovery and the delivery strategies. We next highlight recent work in optimizing the efficacy while minimizing toxicity of STING agonist-assisted subunit vaccines for protection against infectious diseases or treatment of cancer. Finally, we share our perspectives of current issues and future directions in further developing STING agonists for adjuvanting subunit vaccines.


Subject(s)
Adjuvants, Immunologic/administration & dosage , Membrane Proteins/agonists , Membrane Proteins/immunology , Vaccines, Subunit/immunology , CD4-Positive T-Lymphocytes/drug effects , CD8-Positive T-Lymphocytes/drug effects , Dendritic Cells/drug effects , Humans , Immunity, Humoral/drug effects , Nucleotidyltransferases/metabolism
17.
Transplantation ; 105(11): e234-e243, 2021 11 01.
Article in English | MEDLINE | ID: covidwho-1494154

ABSTRACT

BACKGROUND: Data about SARS-CoV-2 vaccines efficacy in renal transplant recipients (RTR) are lacking. METHODS: To reveal predictors for humoral response to BNT162b2 vaccine among RTR, patients were divided into positive (N = 42) and negative (N = 78) response groups based on receptor-binding domain (RBD) immunoglobulin G (IgG) ≥1.1 and neutralizing antibodies (NA) ≥16 dilution versus RBD IgG <1.1 or NA <16, respectively. NA were detected using a SARS-CoV-2 pseudo-virus. RESULTS: NA were detected in only 42 of 120 (35%) of RTR versus 197 of 202 (97.5%) immunocompetent controls (P < 0.001). NA geometric mean titers in RTR were significantly lower versus the control group {83.7 (95% confidence interval [CI], 50.5-138.8) versus 482 (95% CI, 411-566), P < 0.001}. In a multivariable analysis, mycophenolic acid (MPA) dose and hemoglobin level were found to be independent predictors for antibody response in RTR. A positive response rate of 27% versus 63% was observed in patients on and off MPA, respectively. An increase in MPA dose by 1 mg/kg weight reduced the odds for a positive response by 17% (odds ratio = 0.83; 95% CI, 0.75-0.92; P < 0.001). Geometric mean titers for RBD IgG were significantly reduced as MPA daily dose increased. Hemoglobin blood level <13 g/dL reduced the antibody response by 63% (P = 0.04). Pain at the injection site after the second vaccine dose was significantly higher in the responders versus nonresponders (20.5% versus 5.5%, P = 0.01). CONCLUSIONS: Only 35% of RTR develop NA to the BNT162b2 mRNA vaccine. MPA is a major suppressor of antibody response in RTR.


Subject(s)
COVID-19 Vaccines/immunology , COVID-19/prevention & control , Immunity, Humoral/drug effects , Immunogenicity, Vaccine/drug effects , Kidney Transplantation/adverse effects , Adult , Aged , Aged, 80 and over , Antibodies, Neutralizing/blood , Antibodies, Neutralizing/immunology , COVID-19/immunology , COVID-19/virology , COVID-19 Vaccines/administration & dosage , Cohort Studies , Dose-Response Relationship, Drug , Female , Graft Rejection/immunology , Graft Rejection/prevention & control , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Immunosuppressive Agents/administration & dosage , Immunosuppressive Agents/adverse effects , Male , Middle Aged , Mycophenolic Acid/administration & dosage , Mycophenolic Acid/adverse effects , SARS-CoV-2/immunology
19.
Mol Syst Biol ; 17(10): e10387, 2021 10.
Article in English | MEDLINE | ID: covidwho-1478718

ABSTRACT

We need to effectively combine the knowledge from surging literature with complex datasets to propose mechanistic models of SARS-CoV-2 infection, improving data interpretation and predicting key targets of intervention. Here, we describe a large-scale community effort to build an open access, interoperable and computable repository of COVID-19 molecular mechanisms. The COVID-19 Disease Map (C19DMap) is a graphical, interactive representation of disease-relevant molecular mechanisms linking many knowledge sources. Notably, it is a computational resource for graph-based analyses and disease modelling. To this end, we established a framework of tools, platforms and guidelines necessary for a multifaceted community of biocurators, domain experts, bioinformaticians and computational biologists. The diagrams of the C19DMap, curated from the literature, are integrated with relevant interaction and text mining databases. We demonstrate the application of network analysis and modelling approaches by concrete examples to highlight new testable hypotheses. This framework helps to find signatures of SARS-CoV-2 predisposition, treatment response or prioritisation of drug candidates. Such an approach may help deal with new waves of COVID-19 or similar pandemics in the long-term perspective.


Subject(s)
COVID-19/immunology , Computational Biology/methods , Databases, Factual , SARS-CoV-2/immunology , Software , Antiviral Agents/therapeutic use , COVID-19/drug therapy , COVID-19/genetics , COVID-19/virology , Computer Graphics , Cytokines/genetics , Cytokines/immunology , Data Mining/statistics & numerical data , Gene Expression Regulation , Host Microbial Interactions/genetics , Host Microbial Interactions/immunology , Humans , Immunity, Cellular/drug effects , Immunity, Humoral/drug effects , Immunity, Innate/drug effects , Lymphocytes/drug effects , Lymphocytes/immunology , Lymphocytes/virology , Metabolic Networks and Pathways/genetics , Metabolic Networks and Pathways/immunology , Myeloid Cells/drug effects , Myeloid Cells/immunology , Myeloid Cells/virology , Protein Interaction Mapping , SARS-CoV-2/drug effects , SARS-CoV-2/genetics , SARS-CoV-2/pathogenicity , Signal Transduction , Transcription Factors/genetics , Transcription Factors/immunology , Viral Proteins/genetics , Viral Proteins/immunology
20.
JCI Insight ; 6(22)2021 11 22.
Article in English | MEDLINE | ID: covidwho-1476916

ABSTRACT

Understanding the presence and durability of antibodies against SARS-CoV-2 in the airways is required to provide insights into the ability of individuals to neutralize the virus locally and prevent viral spread. Here, we longitudinally assessed both systemic and airway immune responses upon SARS-CoV-2 infection in a clinically well-characterized cohort of 147 infected individuals representing the full spectrum of COVID-19 severity, from asymptomatic infection to fatal disease. In addition, we evaluated how SARS-CoV-2 vaccination influenced the antibody responses in a subset of these individuals during convalescence as compared with naive individuals. Not only systemic but also airway antibody responses correlated with the degree of COVID-19 disease severity. However, although systemic IgG levels were durable for up to 8 months, airway IgG and IgA declined significantly within 3 months. After vaccination, there was an increase in both systemic and airway antibodies, in particular IgG, often exceeding the levels found during acute disease. In contrast, naive individuals showed low airway antibodies after vaccination. In the former COVID-19 patients, airway antibody levels were significantly elevated after the boost vaccination, highlighting the importance of prime and boost vaccinations for previously infected individuals to obtain optimal mucosal protection.


Subject(s)
Antibodies, Neutralizing/immunology , Antibodies, Viral/immunology , COVID-19 Vaccines/administration & dosage , COVID-19 , Immunization, Secondary , Immunoglobulin A/immunology , Immunoglobulin G/immunology , Lung/immunology , SARS-CoV-2/immunology , Adult , Aged , COVID-19/immunology , COVID-19/prevention & control , COVID-19 Vaccines/immunology , Female , Follow-Up Studies , Humans , Immunity, Humoral/drug effects , Longitudinal Studies , Male , Middle Aged
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