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1.
N Engl J Med ; 386(22): 2084-2096, 2022 06 02.
Article in English | MEDLINE | ID: covidwho-1830290

ABSTRACT

BACKGROUND: Coronavirus-like particles (CoVLP) that are produced in plants and display the prefusion spike glycoprotein of the original strain of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are combined with an adjuvant (Adjuvant System 03 [AS03]) to form the candidate vaccine. METHODS: In this phase 3, multinational, randomized, placebo-controlled trial conducted at 85 centers, we assigned adults (≥18 years of age) in a 1:1 ratio to receive two intramuscular injections of the CoVLP+AS03 vaccine or placebo 21 days apart. The primary objective of the trial was to determine the efficacy of the CoVLP+AS03 vaccine in preventing symptomatic coronavirus disease 2019 (Covid-19) beginning at least 7 days after the second injection, with the analysis performed after the detection of at least 160 cases. RESULTS: A total of 24,141 volunteers participated in the trial; the median age of the participants was 29 years. Covid-19 was confirmed by polymerase-chain-reaction assay in 165 participants in the intention-to-treat population; all viral samples that could be sequenced contained variants of the original strain. Vaccine efficacy was 69.5% (95% confidence interval [CI], 56.7 to 78.8) against any symptomatic Covid-19 caused by five variants that were identified by sequencing. In a post hoc analysis, vaccine efficacy was 78.8% (95% CI, 55.8 to 90.8) against moderate-to-severe disease and 74.0% (95% CI, 62.1 to 82.5) among the participants who were seronegative at baseline. No severe cases of Covid-19 occurred in the vaccine group, in which the median viral load for breakthrough cases was lower than that in the placebo group by a factor of more than 100. Solicited adverse events were mostly mild or moderate and transient and were more frequent in the vaccine group than in the placebo group; local adverse events occurred in 92.3% and 45.5% of participants, respectively, and systemic adverse events in 87.3% and 65.0%. The incidence of unsolicited adverse events was similar in the two groups up to 21 days after each dose (22.7% and 20.4%) and from day 43 through day 201 (4.2% and 4.0%). CONCLUSIONS: The CoVLP+AS03 vaccine was effective in preventing Covid-19 caused by a spectrum of variants, with efficacy ranging from 69.5% against symptomatic infection to 78.8% against moderate-to-severe disease. (Funded by Medicago; ClinicalTrials.gov number, NCT04636697.).


Subject(s)
COVID-19 Vaccines , COVID-19 , Adjuvants, Immunologic/administration & dosage , Adjuvants, Immunologic/adverse effects , Adjuvants, Immunologic/therapeutic use , /adverse effects , Adult , Antibodies, Viral , COVID-19/genetics , COVID-19/prevention & control , COVID-19/virology , COVID-19 Vaccines/administration & dosage , COVID-19 Vaccines/adverse effects , COVID-19 Vaccines/therapeutic use , Double-Blind Method , Humans , Injections, Intramuscular , SARS-CoV-2/genetics , Vaccination
2.
Int J Mol Sci ; 23(3)2022 Feb 06.
Article in English | MEDLINE | ID: covidwho-1674673

ABSTRACT

The SARS-CoV-2 pandemic caused a massive health and societal crisis, although the fast development of effective vaccines reduced some of the impact. To prepare for future respiratory virus pandemics, a pan-viral prophylaxis could be used to control the initial virus outbreak in the period prior to vaccine approval. The liposomal vaccine adjuvant CAF®09b contains the TLR3 agonist polyinosinic:polycytidylic acid, which induces a type I interferon (IFN-I) response and an antiviral state in the affected tissues. When testing CAF09b liposomes as a potential pan-viral prophylaxis, we observed that intranasal administration of CAF09b liposomes to mice resulted in an influx of innate immune cells into the nose and lungs and upregulation of IFN-I-related gene expression. When CAF09b liposomes were administered prior to challenge with mouse-adapted influenza A/Puerto Rico/8/1934 virus, it protected from severe disease, although the virus was still detectable in the lungs. However, when CAF09b liposomes were administered after influenza challenge, the mice had a similar disease course to controls. In conclusion, CAF09b may be a suitable candidate as a pan-viral prophylactic treatment for epidemic viruses, but must be administered prior to virus exposure to be effective.


Subject(s)
/therapeutic use , Influenza Vaccines/therapeutic use , Influenza, Human/prevention & control , Orthomyxoviridae Infections/prevention & control , /methods , Adjuvants, Immunologic/administration & dosage , Adjuvants, Immunologic/therapeutic use , /chemistry , Administration, Intranasal , Animals , COVID-19/prevention & control , COVID-19 Vaccines/chemical synthesis , COVID-19 Vaccines/therapeutic use , Cells, Cultured , Chick Embryo , Gene Expression Regulation/drug effects , Humans , Influenza Vaccines/administration & dosage , Influenza Vaccines/chemistry , Influenza Vaccines/pharmacology , Interferon Type I/genetics , Liposomes/chemistry , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Primary Prevention/methods , SARS-CoV-2/immunology
3.
J Med Chem ; 65(3): 2558-2570, 2022 02 10.
Article in English | MEDLINE | ID: covidwho-1655430

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
4.
Lancet ; 399(10323): 461-472, 2022 01 29.
Article in English | MEDLINE | ID: covidwho-1641748

ABSTRACT

BACKGROUND: A range of safe and effective vaccines against SARS CoV 2 are needed to address the COVID 19 pandemic. We aimed to assess the safety and efficacy of the COVID-19 vaccine SCB-2019. METHODS: This ongoing phase 2 and 3 double-blind, placebo-controlled trial was done in adults aged 18 years and older who were in good health or with a stable chronic health condition, at 31 sites in five countries (Belgium, Brazil, Colombia, Philippines, and South Africa). The participants were randomly assigned 1:1 using a centralised internet randomisation system to receive two 0·5 mL intramuscular doses of SCB-2019 (30 µg, adjuvanted with 1·50 mg CpG-1018 and 0·75 mg alum) or placebo (0·9% sodium chloride for injection supplied in 10 mL ampoules) 21 days apart. All study staff and participants were masked, but vaccine administrators were not. Primary endpoints were vaccine efficacy, measured by RT-PCR-confirmed COVID-19 of any severity with onset from 14 days after the second dose in baseline SARS-CoV-2 seronegative participants (the per-protocol population), and the safety and solicited local and systemic adverse events in the phase 2 subset. This study is registered on EudraCT (2020-004272-17) and ClinicalTrials.gov (NCT04672395). FINDINGS: 30 174 participants were enrolled from March 24, 2021, until the cutoff date of Aug 10, 2021, of whom 30 128 received their first assigned vaccine (n=15 064) or a placebo injection (n=15 064). The per-protocol population consisted of 12 355 baseline SARS-CoV-2-naive participants (6251 vaccinees and 6104 placebo recipients). Most exclusions (13 389 [44·4%]) were because of seropositivity at baseline. There were 207 confirmed per-protocol cases of COVID-19 at 14 days after the second dose, 52 vaccinees versus 155 placebo recipients, and an overall vaccine efficacy against any severity COVID-19 of 67·2% (95·72% CI 54·3-76·8), 83·7% (97·86% CI 55·9-95·4) against moderate-to-severe COVID-19, and 100% (97·86% CI 25·3-100·0) against severe COVID-19. All COVID-19 cases were due to virus variants; vaccine efficacy against any severity COVID-19 due to the three predominant variants was 78·7% (95% CI 57·3-90·4) for delta, 91·8% (44·9-99·8) for gamma, and 58·6% (13·3-81·5) for mu. No safety issues emerged in the follow-up period for the efficacy analysis (median of 82 days [IQR 63-103]). The vaccine elicited higher rates of mainly mild-to-moderate injection site pain than the placebo after the first (35·7% [287 of 803] vs 10·3% [81 of 786]) and second (26·9% [189 of 702] vs 7·4% [52 of 699]) doses, but the rates of other solicited local and systemic adverse events were similar between the groups. INTERPRETATION: Two doses of SCB-2019 vaccine plus CpG and alum provides notable protection against the entire severity spectrum of COVID-19 caused by circulating SAR-CoV-2 viruses, including the predominating delta variant. FUNDING: Clover Biopharmaceuticals and the Coalition for Epidemic Preparedness Innovations.


Subject(s)
Adjuvants, Immunologic/therapeutic use , COVID-19 Vaccines/therapeutic use , COVID-19/prevention & control , Spike Glycoprotein, Coronavirus/therapeutic use , Adolescent , Adult , Aged , Alum Compounds/therapeutic use , Belgium , Brazil , Colombia , Double-Blind Method , Female , Humans , Male , Middle Aged , Oligodeoxyribonucleotides/therapeutic use , Philippines , Protein Multimerization , Recombinant Proteins/therapeutic use , Risk , SARS-CoV-2 , South Africa , Young Adult
5.
Carbohydr Polym ; 285: 118971, 2022 Jun 01.
Article in English | MEDLINE | ID: covidwho-1549670

ABSTRACT

Ligusticum chuanxiong, the dried rhizome of Ligusticum chuanxiong Hort, has been widely applied in traditional Chinese medicine for treating plague, and it has appeared frequently in the prescriptions against COVID-19 lately. Ligusticum chuanxiong polysaccharide (LCPs) is one of the effective substances, which has various activities, such as, anti-oxidation, promoting immunity, anti-tumor, and anti-bacteria. The purified fractions of LCPs are considered to be pectic polysaccharides, which are mainly composed of GalA, Gal, Ara and Rha, and are generally linked by α-1,4-d-GalpA, α-1,2-l-Rhap, α-1,5-l-Araf, ß-1,3-d-Galp and ß-1,4-d-Galp, etc. The pectic polysaccharide shows an anti-infective inflammatory activity, which is related to antiviral infection of Ligusticum chuanxiong. In this article, the isolation, purification, structural features, and biological activities of LCPs in recent years are reviewed, and the potential of LCPs against viral infection as well as questions that need future research are discussed.


Subject(s)
COVID-19/drug therapy , Ligusticum/chemistry , Polysaccharides/chemistry , Polysaccharides/pharmacology , Adjuvants, Immunologic/pharmacology , Adjuvants, Immunologic/therapeutic use , Animals , Antineoplastic Agents/pharmacology , Antineoplastic Agents/therapeutic use , Antioxidants/pharmacology , Antioxidants/therapeutic use , Antiviral Agents/pharmacology , Antiviral Agents/therapeutic use , COVID-19/virology , Carbohydrate Conformation , Carbohydrate Sequence , Drugs, Chinese Herbal , Humans , Polysaccharides/isolation & purification , SARS-CoV-2/drug effects , SARS-CoV-2/isolation & purification
6.
Bioconjug Chem ; 32(12): 2497-2506, 2021 12 15.
Article in English | MEDLINE | ID: covidwho-1517581

ABSTRACT

Understanding immune responses toward viral infection will be useful for potential therapeutic intervention and offer insights into the design of prophylactic vaccines. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of the COVID-19 pandemic. To understand the complex immune responses toward SARS-CoV-2 infection, here we developed a method to express and purify the recombinant and engineered viral receptor-binding domain (RBD) to more than 95% purity. We could encapsulate RNA molecules into the interior of a virion-sized liposome. We conjugated the purified RBD proteins onto the surface of the liposome in an orientation-specific manner with defined spatial densities. Both the encapsulation of RNAs and the chemical conjugation of the RBD protein on liposome surfaces were stable under physiologically relevant conditions. In contrast to soluble RBD proteins, a single injection of RBD-conjugated liposomes alone, in the absence of any other adjuvants, elicited RBD-specific B cell responses in BALB/c mice, and the resulting animal sera could potently neutralize HIV-1 pseudovirions that displayed the SARS-CoV-2 spike proteins. These results validate these supramolecular structures as a novel and effective tool to mimic the structure of enveloped viruses, the use of which will allow systematic dissection of the complex B cell responses to SARS-CoV-2 infection.


Subject(s)
Antibodies, Neutralizing/immunology , COVID-19 Vaccines/therapeutic use , COVID-19/prevention & control , Liposomes/therapeutic use , SARS-CoV-2/immunology , Spike Glycoprotein, Coronavirus/therapeutic use , Adjuvants, Immunologic/chemistry , Adjuvants, Immunologic/therapeutic use , Animals , COVID-19/immunology , COVID-19 Vaccines/chemistry , Female , Humans , Immunization , Liposomes/chemistry , Mice, Inbred BALB C , Models, Molecular , Protein Domains , Spike Glycoprotein, Coronavirus/chemistry , Vaccines, Synthetic/chemistry , Vaccines, Synthetic/therapeutic use , /therapeutic use
7.
Front Immunol ; 12: 732992, 2021.
Article in English | MEDLINE | ID: covidwho-1497075

ABSTRACT

Chronic inflammatory disorders (CID), such as autoimmune diseases, are characterized by overactivation of the immune system and loss of immune tolerance. T helper 17 (Th17) cells are strongly associated with the pathogenesis of multiple CID, including psoriasis, rheumatoid arthritis, and inflammatory bowel disease. In line with the increasingly recognized contribution of innate immune cells to the modulation of dendritic cell (DC) function and DC-driven adaptive immune responses, we recently showed that neutrophils are required for DC-driven Th17 cell differentiation from human naive T cells. Consequently, recruitment of neutrophils to inflamed tissues and lymph nodes likely creates a highly inflammatory loop through the induction of Th17 cells that should be intercepted to attenuate disease progression. Tolerogenic therapy via DCs, the central orchestrators of the adaptive immune response, is a promising strategy for the treatment of CID. Tolerogenic DCs could restore immune tolerance by driving the development of regulatory T cells (Tregs) in the periphery. In this review, we discuss the effects of the tolerogenic adjuvants vitamin D3 (VD3), corticosteroids (CS), and retinoic acid (RA) on both DCs and neutrophils and their potential interplay. We briefly summarize how neutrophils shape DC-driven T-cell development in general. We propose that, for optimization of tolerogenic DC therapy for the treatment of CID, both DCs for tolerance induction and the neutrophil inflammatory loop should be targeted while preserving the potential Treg-enhancing effects of neutrophils.


Subject(s)
Adjuvants, Immunologic/therapeutic use , Autoimmune Diseases/drug therapy , Autoimmunity/drug effects , Dendritic Cells/drug effects , Immune Tolerance/drug effects , Inflammation/drug therapy , Neutrophils/drug effects , Th17 Cells/drug effects , Animals , Autoimmune Diseases/immunology , Autoimmune Diseases/metabolism , Dendritic Cells/immunology , Dendritic Cells/metabolism , Humans , Inflammation/immunology , Inflammation/metabolism , Neutrophils/immunology , Neutrophils/metabolism , Th17 Cells/immunology , Th17 Cells/metabolism
9.
Adv Mater ; 33(40): e2102528, 2021 Oct.
Article in English | MEDLINE | ID: covidwho-1358054

ABSTRACT

Dendritic cell (DC) vaccines are used for cancer and infectious diseases, albeit with limited efficacy. Modulating the formation of DC-T-cell synapses may greatly increase their efficacy. The effects of graphene oxide (GO) nanosheets on DCs and DC-T-cell synapse formation are evaluated. In particular, size-dependent interactions are observed between GO nanosheets and DCs. GOs with diameters of >1 µm (L-GOs) demonstrate strong adherence to the DC surface, inducing cytoskeletal reorganization via the RhoA-ROCK-MLC pathway, while relatively small GOs (≈500 nm) are predominantly internalized by DCs. Furthermore, L-GO treatment enhances DC-T-cell synapse formation via cytoskeleton-dependent membrane positioning of integrin ICAM-1. L-GO acts as a "nanozipper," facilitating the aggregation of DC-T-cell clusters to produce a stable microenvironment for T cell activation. Importantly, L-GO-adjuvanted DCs promote robust cytotoxic T cell immune responses against SARS-CoV-2 spike 1, leading to >99.7% viral RNA clearance in mice infected with a clinically isolated SARS-CoV-2 strain. These findings highlight the potential value of nanomaterials as DC vaccine adjuvants for modulating DC-T-cell synapse formation and provide a basis for the development of effective COVID-19 vaccines.


Subject(s)
Adjuvants, Immunologic/therapeutic use , COVID-19 Vaccines/therapeutic use , COVID-19/prevention & control , Dendritic Cells/immunology , Graphite/therapeutic use , Nanostructures/therapeutic use , Adjuvants, Immunologic/chemistry , Animals , COVID-19/immunology , COVID-19 Vaccines/immunology , Dendritic Cells/drug effects , Graphite/chemistry , Humans , Mice , Nanostructures/chemistry , SARS-CoV-2/immunology , T-Lymphocytes/drug effects , T-Lymphocytes/immunology
10.
CNS Drugs ; 35(7): 743-767, 2021 07.
Article in English | MEDLINE | ID: covidwho-1296980

ABSTRACT

Recombinant interferon (IFN) ß-1b was approved by the US Food and Drug Administration as the first disease-modifying therapy (DMT) for multiple sclerosis (MS) in 1993. Since that time, clinical trials and real-world observational studies have demonstrated the effectiveness of IFN therapies. The pivotal intramuscular IFN ß-1a phase III trial published in 1996 was the first to demonstrate that a DMT could reduce accumulation of sustained disability in MS. Patient adherence to treatment is higher with intramuscular IFN ß-1a, given once weekly, than with subcutaneous formulations requiring multiple injections per week. Moreover, subcutaneous IFN ß-1a is associated with an increased incidence of injection-site reactions and neutralizing antibodies compared with intramuscular administration. In recent years, revisions to MS diagnostic criteria have improved clinicians' ability to identify patients with MS and have promoted the use of magnetic resonance imaging (MRI) for diagnosis and disease monitoring. MRI studies show that treatment with IFN ß-1a, relative to placebo, reduces T2 and gadolinium-enhancing lesions and gray matter atrophy. Since the approval of intramuscular IFN ß-1a, a number of high-efficacy therapies have been approved for MS, though the benefit of these high-efficacy therapies should be balanced against the increased risk of serious adverse events associated with their long-term use. For some subpopulations of patients, including pregnant women, the safety profile of IFN ß formulations may provide a particular benefit. In addition, the antiviral properties of IFNs may indicate potential therapeutic opportunities for IFN ß in reducing the risk of viral infections such as COVID-19.


Subject(s)
Adjuvants, Immunologic/therapeutic use , Interferon beta-1a/therapeutic use , Multiple Sclerosis/drug therapy , Antiviral Agents/therapeutic use , COVID-19/drug therapy , Humans , Injections, Intramuscular , Multiple Sclerosis/diagnostic imaging , Multiple Sclerosis/physiopathology , SARS-CoV-2 , Treatment Outcome
11.
J Immunol Res ; 2021: 9934134, 2021.
Article in English | MEDLINE | ID: covidwho-1295258

ABSTRACT

BACKGROUND: Regulation of the immune system is critical for fighting against viral infections. Both suppression and hyperactivity of the immune system result in failure of treatment. The present study was designed to show the effects of immune system-related medications on mortality and length of stay (LOS) in a cohort of Iranian patients with coronavirus disease 2019 (COVID-19). METHODS: A data mining study was performed on 6417 cases of COVID-19 covered by 17 educational hospitals of Iran University of Medical Sciences, Tehran. Association of a researcher-designed drug list with death and LOS was studied. For death outcome, logistic regression was used reporting odds ratio (OR) with 95% confidence interval (CI). For LOS, right censored Poisson regression was used reporting incidence rate ratio (IRR) with 95% CI. RESULTS: Among the corticosteroids, prednisolone was a risk factor on death (OR = 1.41, 95%CI = 1.03 - 1.94). This association was increased after adjustment of age interactions (OR = 3.45, 95%CI = 1.01 - 11.81) and was removed after adjustment of ICU admission interactions (OR = 2.64, 95%CI = 0.70 - 9.92). Hydroxychloroquine showed a protecting effect on death (OR = 0.735, 95%CI = 0.627 - 0.862); however, this association was removed after adjustment of age interactions (OR = 0.76, 95%CI = 0.41 - 1.40). Among the antivirals, oseltamivir showed a protecting effect on death (OR = 0.628, 95%CI = 0.451 - 0.873); however, this association was removed after adjustment of age interactions (OR = 0.45, 95%CI = 0.11 - 1.82). For reduction of LOS, the only significant association was for hydroxychloroquine (IRR = 0.85, 95%CI = 0.79 - 0.92). CONCLUSION: The results of such data mining studies can be used in clinics until completing the evidence. Hydroxychloroquine may reduce mortality in some specific groups; however, its association may be confounded by some latent variables and unknown interactions. Administration of corticosteroids should be based on the conditions of each case.


Subject(s)
COVID-19/drug therapy , COVID-19/immunology , Pandemics , SARS-CoV-2 , Adjuvants, Immunologic/therapeutic use , Adolescent , Adult , Aged , Aged, 80 and over , Anti-Bacterial Agents/therapeutic use , Antiviral Agents/therapeutic use , COVID-19/mortality , Child , Child, Preschool , Cohort Studies , Data Mining , Female , Humans , Immune System/drug effects , Immunologic Factors/therapeutic use , Immunosuppressive Agents/therapeutic use , Infant , Infant, Newborn , Iran/epidemiology , Length of Stay , Logistic Models , Male , Middle Aged , Risk Factors , Young Adult
13.
Int J Biol Macromol ; 182: 1931-1940, 2021 Jul 01.
Article in English | MEDLINE | ID: covidwho-1245965

ABSTRACT

Pathogen transmission is a widespread threat to global human health. Vaccines are very important during the outbreak of a pandemic. Destructive fractures caused by a sudden outbreak of COVID-19 have spurred vaccine production at an unprecedented rate. The strategy of an effective vaccine delivery system is opening up novel probabilities to make more immunization. Indeed, vaccination is the most successful way to prevent deaths from infectious diseases. In order to optimal immune response production or improvement in the effectiveness of vaccines, delivery systems or adjuvants are required. Natural polymers such as chitosan, alginate, hyaluronic acid, gums, and ß-glucan with antiviral activity have good potential as adjuvant or delivery systems for vaccine formulation development and design vaccine delivery devices. According to the antiviral performance and immunomodulation of these biopolymers, they will play significant characters in the anti-COVID-19 field. In this mini-review, the recent progress in vaccine development by using biopolymers is presented which, provides a reference for their research on anti-COVID-19 drugs and vaccines.


Subject(s)
Adjuvants, Immunologic/therapeutic use , Alginates/therapeutic use , COVID-19 Vaccines/therapeutic use , COVID-19 , Chitosan/therapeutic use , Drug Delivery Systems , Hyaluronic Acid/therapeutic use , Plant Gums/therapeutic use , SARS-CoV-2/immunology , beta-Glucans/therapeutic use , Animals , COVID-19/immunology , COVID-19/prevention & control , Humans
14.
Int Immunopharmacol ; 90: 107143, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1084141

ABSTRACT

BACKGROUND: Thymosin α1 therapy was commonly used in patients with coronavirus disease 2019 (COVID-19), while its impact on outcomes and which patients could benefit from thymosin α1 therapy were uncertain. STUDY DESIGN AND METHODS: Patients with COVID-19 from 19 designated hospitals between January 1 to February 29, 2020 were included, and the main exposure of interest was administration of thymosin α1. The primary outcome was 28-day mortality. Propensity score matching (PSM) was used to account for baseline confounders, cluster analysis and Cox proportional hazard model was used to account for subgroup analysis. RESULTS: A total of 771 patients were included, and 327/771 (42.4%) patients received thymosin α1 therapy. The 28-day mortality in thymosin group was significantly lower than that in control group (41.3% vs. 60.6%, p < 0.001). After PSM 522 patients were included in analysis and the 28-day mortality in thymosin α1 group and control group were 51.0% and 52.9% respectively, with no significant difference. In subgroup analyses, the association between thymosin α1 therapy and 28-day mortality appeared to be stronger among male patients (HR 0.673, 95% CI 0.454-0.998; p = 0.049). There were no benefits of thymosin α1 in 28-day mortality in other subgroups. There were two phenotypes after cluster analysis, but no benefits of thymosin α1 were shown in phenotype 1 (HR 0.823 95% CI 0.581-1.166; p = 0.273) and phenotype 2 (HR 1.148 95% CI 0.710-1.895; p = 0.442). CONCLUSION: There was no association between use of thymosin α1 and decreased mortality in critically ill COVID-19 patients. Subgroups analysis and phenotype analysis also showed no differences on mortality after thymosin α1 therapy.


Subject(s)
Adjuvants, Immunologic/therapeutic use , COVID-19/drug therapy , COVID-19/mortality , SARS-CoV-2 , Thymalfasin/therapeutic use , Aged , Critical Illness , Female , Humans , Male , Middle Aged , Retrospective Studies , Survival Analysis
15.
Future Oncol ; 17(9): 1097-1104, 2021 Mar.
Article in English | MEDLINE | ID: covidwho-1067596

ABSTRACT

We presented the rationale for the use of thymosin α1 as prophylaxis of severe COVID-19 in cancer patients undergoing active treatment, constituting the background for the PROTHYMOS study, a prospective, multicenter, open-label, Phase II randomized study, currently in its start-up phase (Eudract no. 2020-006020-13). We aim to offer new hope for this incurable disease, especially to frail patient population, such as patients with cancer. The hypothesis of an effective prophylactic approach to COVID-19 would have immediate clinical relevance, especially given the lack of curative approaches. Moreover, in the 'COVID-19 vaccine race era' both clinical and biological results coming from the PROTHYMOS trials could even support the rationale for future combinatorial approaches, trying to rise vaccine efficacy in frail individuals.


Subject(s)
COVID-19/complications , COVID-19/drug therapy , Neoplasms/complications , Thymalfasin/therapeutic use , Adjuvants, Immunologic/therapeutic use , Clinical Trials, Phase II as Topic , Humans , Randomized Controlled Trials as Topic , Research Design , SARS-CoV-2
16.
Int Immunopharmacol ; 90: 107022, 2021 Jan.
Article in English | MEDLINE | ID: covidwho-1065208

ABSTRACT

Gender influences clinical presentations, duration and severity of symptoms, and therapy outcome in coronavirus disease 2019 (COVID-19) infection. Whether the immune response to Tα1 treatment for SARS-CoV-2 differs between the sexes, and whether this difference explains the male susceptibility to COVID-19, is unclear. This study aimed to investigate the efficiency and safety of Tα1 treatment and provide a basis for practically identifying gender differences characteristics and features of COVID-19. One hundred twenty-seven patients had COVID-19 symptoms and tested COVID19-positive (female 42.52%) in Wuhan union hospital were enrolled for medication. They were randomly divided into groups Control and Tα1 intervention. Seventy-eight patients received a subcutaneous injection of 1.6 mg Tα1, based on supportive treatment for 15 days. The control group included untreated 49 COVID19 patients closely matched for gender and age and received regular supportive treatment. In this retrospective analysis, we found that COVID-19-infected males reported more symptoms than COVID-19-infected females. A high degree of gender differences-related variability was observed in CRP and PCT levels and the cell counts of many lymphocyte subpopulations in the COVID-19 patients after Tα1 intervention. Levels of CRP and IL-6 were higher in Tα1-treated male group than Tα1-treated female group, while the level of PCT was significantly lower in Tα1-treated male group. Gender differences may be a factor in sustaining COVID-19 immunity responded to Tα1, male and female show statistically significant differences in relevance to cytokine production associated with the development of a more significant number of symptoms. This leaves the question of identifying gender-specific risk factors to explain these differences.


Subject(s)
Adjuvants, Immunologic/therapeutic use , Age Factors , COVID-19/epidemiology , Lymphocyte Subsets/pathology , SARS-CoV-2/physiology , Sex Factors , Thymalfasin/therapeutic use , Aged , C-Reactive Protein/metabolism , COVID-19/drug therapy , China/epidemiology , Female , Humans , Interleukin-6/metabolism , Male , Middle Aged , Retrospective Studies
17.
Angew Chem Int Ed Engl ; 60(17): 9467-9473, 2021 04 19.
Article in English | MEDLINE | ID: covidwho-1037522

ABSTRACT

The search for vaccines that protect from severe morbidity and mortality because of infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the virus that causes coronavirus disease 2019 (COVID-19) is a race against the clock and the virus. Here we describe an amphiphilic imidazoquinoline (IMDQ-PEG-CHOL) TLR7/8 adjuvant, consisting of an imidazoquinoline conjugated to the chain end of a cholesterol-poly(ethylene glycol) macromolecular amphiphile. It is water-soluble and exhibits massive translocation to lymph nodes upon local administration through binding to albumin, affording localized innate immune activation and reduction in systemic inflammation. The adjuvanticity of IMDQ-PEG-CHOL was validated in a licensed vaccine setting (quadrivalent influenza vaccine) and an experimental trimeric recombinant SARS-CoV-2 spike protein vaccine, showing robust IgG2a and IgG1 antibody titers in mice that could neutralize viral infection in vitro and in vivo in a mouse model.


Subject(s)
Adjuvants, Immunologic/therapeutic use , COVID-19 Vaccines/therapeutic use , COVID-19/prevention & control , Imidazoles/therapeutic use , Immunity, Innate/drug effects , Quinolines/therapeutic use , Animals , COVID-19 Vaccines/immunology , Cholesterol/analogs & derivatives , Cholesterol/immunology , Cholesterol/therapeutic use , Female , Humans , Imidazoles/immunology , Influenza A Virus, H1N1 Subtype/drug effects , Influenza Vaccines/immunology , Influenza Vaccines/therapeutic use , Influenza, Human/prevention & control , Membrane Glycoproteins/agonists , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Transgenic , Polyethylene Glycols/therapeutic use , Quinolines/immunology , Recombinant Proteins/immunology , SARS-CoV-2/drug effects , Spike Glycoprotein, Coronavirus/immunology , Surface-Active Agents/therapeutic use , Toll-Like Receptor 7/agonists , Toll-Like Receptor 8/agonists
18.
Cytokine Growth Factor Rev ; 59: 101-110, 2021 06.
Article in English | MEDLINE | ID: covidwho-1014439

ABSTRACT

GM-CSF acts as a pro-inflammatory cytokine and a key growth factor produced by several immune cells such as macrophages and activated T cells. In this review, we discuss recent studies that point to the crucial role of GM-CSF in the immune response against infections. Upon induction, GM-CSF activates four main signalling networks including the JAK/STAT, PI3K, MAPK, and NFκB pathways. Many of these transduction pathways such as JAK/STAT signal via proteins commonly activated with other antiviral signalling cascades, such as those induced by IFNs. GM-CSF also helps defend against respiratory infections by regulating alveolar macrophage differentiation and enhancing innate immunity in the lungs. Here, we also summarize the numerous clinical trials that have taken advantage of GM-CSF's mechanistic attributes in immunotherapy. Moreover, we discuss how GM-CSF is used as an adjuvant in vaccines and how its activity is interfered with to reduce inflammation such as in the case of COVID-19. This review brings forth the current knowledge on the antiviral actions of GM-CSF, the associated signalling cascades, and its application in immunotherapy.


Subject(s)
Adjuvants, Immunologic/therapeutic use , Antiviral Agents , COVID-19 Vaccines/immunology , COVID-19/immunology , Granulocyte-Macrophage Colony-Stimulating Factor , MAP Kinase Signaling System , SARS-CoV-2/immunology , Animals , Antiviral Agents/immunology , Antiviral Agents/therapeutic use , COVID-19/prevention & control , COVID-19 Vaccines/therapeutic use , Granulocyte-Macrophage Colony-Stimulating Factor/immunology , Granulocyte-Macrophage Colony-Stimulating Factor/therapeutic use , Humans , MAP Kinase Signaling System/drug effects , MAP Kinase Signaling System/immunology , Macrophages, Alveolar/immunology , Recombinant Proteins/immunology , Recombinant Proteins/therapeutic use
19.
Int Immunopharmacol ; 88: 106873, 2020 Nov.
Article in English | MEDLINE | ID: covidwho-1002650

ABSTRACT

BACKGROUND: COVID-19 characterized by refractory hypoxemia increases patient mortality because of immunosuppression effects. This study aimed to evaluate the efficacy of immunomodulatory with thymosin α1 for critical COVID-19 patients. METHODS: This multicenter retrospective cohort study was performed in 8 government-designated treatment centers for COVID-19 patients in China from Dec. 2019 to Mar. 2020. Thymosin α1 was administrated with 1.6 mg qd or q12 h for >5 days. The primary outcomes were the 28-day and 60-day mortality, the secondary outcomes were hospital length of stay and the total duration of the disease. Subgroup analysis was carried out according to clinical classification. RESULTS: Of the 334 enrolled COVID-19 patients, 42 (12.6%) died within 28 days, and 55 (16.5%) died within 60 days of hospitalization. There was a significant difference in the 28-day mortality between the thymosin α1 and non-thymosin α1-treated groups in adjusted model (P = 0.016), without obvious differences in the 60-day mortality and survival time in the overall cohort (P > 0.05). In the subgroup analysis, it was found that thymosin α1 therapy significantly reduced 28-day mortality (Hazards Ratios HR, 0.11, 95% confidence interval CI 0.02-0.63, P=0.013) via improvement of Pa02/FiO2 (P = 0.036) and prolonged the hospital length of stay (P = 0.024) as well as the total duration of the disease (P=0.001) in the critical type patients, especially those aged over 64 years, with white blood cell >6.8×109/L, neutrophil >5.3×109/L, lymphocyte < 0.73 × 109/L, PaO2/FiO2 < 196, SOFA > 3, and acute physiology and chronic health evaluation (APACHE) II > 7. CONCLUSION: These results suggest that treatment with thymosin α1 can markedly decrease 28-day mortality and attenuate acute lung injury in critical type COVID-19 patients.


Subject(s)
Adjuvants, Immunologic/therapeutic use , Coronavirus Infections/drug therapy , Critical Care/methods , Pneumonia, Viral/drug therapy , Thymalfasin/therapeutic use , APACHE , Adjuvants, Immunologic/administration & dosage , Adjuvants, Immunologic/adverse effects , Aged , Betacoronavirus , COVID-19 , China/epidemiology , Cohort Studies , Coronavirus Infections/immunology , Coronavirus Infections/mortality , Critical Illness , Female , Humans , Male , Middle Aged , Mortality/trends , Pandemics , Pneumonia, Viral/immunology , Pneumonia, Viral/mortality , Proportional Hazards Models , Retrospective Studies , SARS-CoV-2 , Thymalfasin/administration & dosage , Thymalfasin/adverse effects
20.
Adv Drug Deliv Rev ; 169: 168-189, 2021 02.
Article in English | MEDLINE | ID: covidwho-970682

ABSTRACT

The COVID-19 pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to an unprecedented effort toward the development of an effective and safe vaccine. Aided by extensive research efforts into characterizing and developing countermeasures towards prior coronavirus epidemics, as well as recent developments of diverse vaccine platform technologies, hundreds of vaccine candidates using dozens of delivery vehicles and routes have been proposed and evaluated preclinically. A high demand coupled with massive effort from researchers has led to the advancement of at least 31 candidate vaccines in clinical trials, many using platforms that have never before been approved for use in humans. This review will address the approach and requirements for a successful vaccine against SARS-CoV-2, the background of the myriad of vaccine platforms currently in clinical trials for COVID-19 prevention, and a summary of the present results of those trials. It concludes with a perspective on formulation problems which remain to be addressed in COVID-19 vaccine development and antigens or adjuvants which may be worth further investigation.


Subject(s)
Adjuvants, Immunologic/chemical synthesis , COVID-19 Vaccines/chemical synthesis , COVID-19/prevention & control , Drug Development/methods , SARS-CoV-2/drug effects , Adjuvants, Immunologic/therapeutic use , Animals , COVID-19/immunology , COVID-19 Vaccines/therapeutic use , Drug Compounding/methods , Drug Compounding/trends , Drug Development/trends , Humans , Recombinant Proteins/chemical synthesis , Recombinant Proteins/therapeutic use , SARS-CoV-2/immunology
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