scholarly journals Assessing the Progress of Various Novel SARS-CoV-2 Vaccine Tests and Clinical Trials

2020 ◽  
Author(s):  
Yasmin Khajenoori ◽  
Ayesha Aslam-Mir ◽  
Arezo Ahmadi ◽  
Risa Iwazaki ◽  
Shiv Puliady
Keyword(s):  
Clinical Trial ◽  
Immune Response ◽  
Clinical Trials ◽  
T Cell ◽  
Phase 1 ◽  
T Cell Response ◽  
Antibody Responses ◽  
Spike Protein ◽  
Post Inoculation ◽  
Pharmaceutical Manufacturers

The SARS-CoV-2 outbreak of winter 2019 and 2020 has boomed into a global pandemic of a highly contagious respiratory illness, COVID-19. This affliction causes severe acute respiratory distress and, for many with pre-existing conditions, can threaten to be fatal. Many pharmaceutical manufacturers have been allowed to accelerate their vaccination development, an otherwise lengthy and several stage process. Vaccines being developed are both novel and traditional; some target the spike protein, an agent in SARS-CoV-2 contagion, as recent studies showed that it produced polyclonal antibody responses and neutralized SARS-CoV-2 S-mediated entry, as well as the receptor binding domain. Animal testing used pre-clinical trial in Sinovac’s PiCoVacc show promise to create SARS-CoV-2–specific antibody responses targeting S-specific and RBD-specific IgG in mice, which is why PiCoVacc was shown to mitigate the severity of the virus’s symptoms in all rhesus macaques tested. Additionally, testing of Novavax’s NVX-CoV2373 used live mice and baboon models and has shown promising results of high affinity antibody responses targeting SARS-CoV-215. In this pre-clinical trial, the spleens of animal models who received NVX-CoV2373 followed by a Matrix-M adjuvant, or an immune response boosting agent, showed increased frequencies of TFH cells and GC B cells, encouraging Novavax to continue into clinical trial stages15. Vaccine candidates have already produced post-clinical trial results. INO-4800, a DNA vaccine made by INOVIO, has passed phase 1 clinical trials, while demonstrating general safety in all volunteers and generating immunological response rates and T cell immune responses in 94% of the participants. Moderna and Pfizer show promise with mRNA vaccines, both for the spike protein and receptor domain12; these follow a novel approach and have currently moved into their phase two trials due to increased immune response and reduced adverse effects initially in clinic; Moderna’s spike protein vaccine showed titers of antibody 2.1 times higher than those convalescent with the 100ug dosage, in addition to elevated T-cell response post inoculation for all tested doses.3, 9 Another vaccine, known as ChAdOx1 nCoV-19, a chimpanzee adenovirus-vectored vaccine, has been tested on 1077 healthy adults through single and double doses. The results have shown that the single dose elicited both humoral and cellular responses against SARS-CoV-2, with a booster immunization augmenting antibody titers. Within the ChAdOx1 nCoV-19 groups, local and systemic reactions were more common5. Patients were randomly assigned single intramuscular injections of ChAdOx1 nCoV-19 at doses of 5 × 1010 viral particles or MenACWY5. After the vaccination procedure, participants were observed in the clinic for 30-50 minutes and asked to take note of any abnormal events during the 28-day follow up period5. Evaluating the adenovirus, mRNA, DNA, inactivated, and subunit vaccines currently in accelerated development by pharmaceutical manufacturers will allow for a comprehensive review of which vaccine is most ready for widespread use and can successfully and safely curtail further spread of SARS-CoV-2.

Combining chemotherapy and programmed death 1 (PD-1) blockade to induce a T-cell response in patients with metastatic triple negative breast cancer (mTNBC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 11563-11563 ◽  
Author(s):  
Elias Obeid ◽  
Chun Zhou ◽  
Alexander Macfarlane ◽  
R. Katherine Alpaugh ◽  
Cecilia McAleer ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cell Function ◽  
T Cell Response ◽  
Number Of Patients ◽  
Correlative Studies ◽  
Immune Changes

11563 Background: Correlative studies to determine the effect of combining chemotherapy (CT) simultaneously with checkpoint inhibition on the peripheral immune response are planned as part of a clinical trial in MTNB. The trial design is a Safety run-in, into a randomized phase II trial of combination pembrolizumab (P) with carboplatin (C) and gemcitabine (G) in patients with mTNBC. One key concern is that CT may suppress immune cell function, thereby diminishing the efficacy of PD-1 blockade. Methods: Patients with a diagnosis of mTNBC are recruited to this trial with a Safety Run-in (N = 6-12 subjects), followed by a randomized design of C + G with/without P (2:1 randomization, N = 75). Safety run-in consists of P 200 mg on day 1 of each 21-day cycle, and C (AUC2) + G (800mg/m2) on days 1 and 8. Patients are consented for a peripheral blood (PB) collection pre-cycle 1 and on day 1 of cycle 3, in order to phenotype immune system changes by flow-cytometry. Results: Six patients have been recruited as of this interim analysis. Data from PB analysis of 3 on-treatment patients is available. In 2 subjects, the activation marker CD69 increased on CD4+ and CD8+ T cells from baseline, indicating enhanced T cell function. Also the ratio of CD8+ T cells to regulatory T cells (CD25high CD127low) has increased. Both patients expressed PD-1 on T cells at baseline. The 2 subjects with evidence for enhanced immune response have a continued clinical benefit (12 cycles subject 1, 8 cycles subject 2). In contrast, subject 3 (who discontinued P and received corticosteroids for grade a 2 immune-related hepatitis during cycle 2) lacked expression of PD-1 on T cells and did not exhibit these immune changes, and her disease clinically progressed after 4 cycles of CT. Conclusions: Although comprising a very limited number of patients, early analysis from our correlative studies of combining CT with the PD-1 blockade revealed evidence for effective immune stimulation in two subjects. Furthermore, immune changes accompanied a lasting clinical response. Although early, we conclude that combining CT with checkpoint blockade can achieve its goal of unleashing an anti-tumor immune response in mTNBC patients. Clinical trial information: NCT02755272.

Phase I/II clinical trial of NY-ESO-1-specific TCR-engineered T-cell transfer combined with a novel T-cell stimulator CHP:NE1 for patients with refractory soft tissue sarcoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS11074-TPS11074 ◽  
Author(s):  
Mikiya Ishihara ◽  
Hiroyoshi Hattori ◽  
Eisuke Arai ◽  
Yoshihiro Nishida ◽  
Kohichi Takada ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Combination Therapy ◽  
Phase I ◽  
Phase 1 ◽  
Peptide Antigen

TPS11074 Background: Combination therapy to enhance the efficacy of T cell receptor (TCR)-engineered T cells (TCR-T) has received increasing attention. We found that a combination therapy of TCR-T and a long peptide vaccine with CpG adjuvant without lymphodepletion regimen caused regression of immune checkpoint inhibitor-resistant sarcoma in a preclinical mouse model. Based on this finding, we initiated a clinical trial of TBI-1301 combined with CHP:NE1 without lymphodepletion for the patients with NY-ESO-1-expressing advanced soft tissue sarcoma. TBI-1301 is an NY-ESO-1157–165/HLA-A*02:01- or -A*02:06-specific TCR-T engineered to reduce endogenous TCR mRNA expression. CHP:NE1 is a novel T cell stimulator consisting of NY-ESO-1 long peptide antigen, cholesteryl pullulan (CHP) nanogel, and CpG oligoDNA. CHP nanogel is used for efficient delivery of long peptide antigen into the lymph nodes. CpG oligoDNA is a TLR9 agonist and used as an adjuvant. CHP:NE1 is expected to reinforce TBI-1301 T cells in the lymph nodes. Methods: This is an investigator-initiated multi-institutional first-in-human phase I/II clinical trial. TBI-1301 is infused at 5×109 cells one day after subcutaneous injection of CHP:NE1. CHP:NE1 is injected again 7 days after TBI-1301 infusion. This cycle is repeated once more. Lymphodepletion using cyclophosphamide and/or fludarabine is not performed. Key inclusion criteria include: refractory soft tissue sarcoma with NY-ESO-1 antigen expression, HLA-A*02:01- or HLA-A*02:06- positive, ECOG Performance Status 0 or 1, and adequate organ function. The primary objective is to assess the safety and efficacy in the phase 1 and 2 parts, respectively. The secondary objective is to assess the efficacy and immune response (blood concentration, immunophenotype and activity of TBI-1301) in the phase 1 part and the safety and immune response in the phase 2 part. Enrollment in this study is currently ongoing. Clinical trial information: JMA-IIA00346.

scholarly journals Immunization with a Mixture of HIV Env DNA and VLP Vaccines Augments Induction of CD8 T Cell Responses

2010 ◽  
Vol 2010 ◽  
pp. 1-11 ◽  
Author(s):  
Ling Ye ◽  
Zhiyuan Wen ◽  
Ke Dong ◽  
Lei Pan ◽  
Zhigao Bu ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Dna Vaccine ◽  
Cell Response ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Antibody Responses ◽  
Cell Responses ◽  
Virus Like Particle

The immune response induced by immunization with HIV Env DNA and virus-like particle (VLP) vaccines was investigated. Immunization with the HIV Env DNA vaccine induced a strong CD8 T cell response but relatively weak antibody response against the HIV Env whereas immunization with VLPs induced higher levels of antibody responses but little CD8 T cell response. Interestingly, immunization with a mixture the HIV Env DNA and VLP vaccines induced enhanced CD8 T cell and antibody responses. Further, it was observed that the mixing of DNA and VLP vaccines during immunization is necessary for augmenting induction of CD8 T cell responses and such augmentation of CD8 T cell responses was also observed by mixing the HIV Env DNA vaccine with control VLPs. These results show that immunization with a mixture of DNA and VLP vaccines combines advantages of both vaccine platforms for eliciting high levels of both antibody and CD8 T cell responses.

scholarly journals T cell and antibody responses induced by a single dose of ChAdOx1 nCoV-19 (AZD1222) vaccine in a phase 1/2 clinical trial

2020 ◽  
Author(s):  
Katie J. Ewer ◽  
◽  
Jordan R. Barrett ◽  
Sandra Belij-Rammerstorfer ◽  
Hannah Sharpe ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Single Dose ◽  
T Cell ◽  
Phase 1 ◽  
Antibody Responses

scholarly journals Author Correction: T cell and antibody responses induced by a single dose of ChAdOx1 nCoV-19 (AZD1222) vaccine in a phase 1/2 clinical trial

2021 ◽  
Author(s):  
Katie J. Ewer ◽  
◽  
Jordan R. Barrett ◽  
Sandra Belij-Rammerstorfer ◽  
Hannah Sharpe ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Single Dose ◽  
T Cell ◽  
Phase 1 ◽  
Antibody Responses

scholarly journals Heterologous vaccination regimens with self-amplifying RNA and adenoviral COVID vaccines induce robust immune responses in mice

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Alexandra J. Spencer ◽  
Paul F. McKay ◽  
Sandra Belij-Rammerstorfer ◽  
Marta Ulaszewska ◽  
Cameron D. Bissett ◽  
...  
Keyword(s):  
Immune Response ◽  
Clinical Trials ◽  
T Cells ◽  
Immune Responses ◽  
Viral Vectors ◽  
Cytotoxic T Cells ◽  
Antibody Responses ◽  
Limited Data ◽  
Vectored Vaccine ◽  
Cellular Immune

AbstractSeveral vaccines have demonstrated efficacy against SARS-CoV-2 mediated disease, yet there is limited data on the immune response induced by heterologous vaccination regimens using alternate vaccine modalities. Here, we present a detailed description of the immune response, in mice, following vaccination with a self-amplifying RNA (saRNA) vaccine and an adenoviral vectored vaccine (ChAdOx1 nCoV-19/AZD1222) against SARS-CoV-2. We demonstrate that antibody responses are higher in two-dose heterologous vaccination regimens than single-dose regimens. Neutralising titres after heterologous prime-boost were at least comparable or higher than the titres measured after homologous prime boost vaccination with viral vectors. Importantly, the cellular immune response after a heterologous regimen is dominated by cytotoxic T cells and Th1+ CD4 T cells, which is superior to the response induced in homologous vaccination regimens in mice. These results underpin the need for clinical trials to investigate the immunogenicity of heterologous regimens with alternate vaccine technologies.

scholarly journals Checkpoint blockade accelerates a novel switch from an NKT-driven TNFα response toward a T cell driven IFN-γ response within the tumor microenvironment

2021 ◽  
Vol 9 (6) ◽  
pp. e002269
Author(s):  
Shota Aoyama ◽  
Ryosuke Nakagawa ◽  
Satoshi Nemoto ◽  
Patricio Perez-Villarroel ◽  
James J Mulé ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Tumor Growth ◽  
Ex Vivo ◽  
T Cell Response ◽  
Effector Function ◽  
Checkpoint Blockade ◽  
Necrosis Factor Alpha ◽  
Ifn Γ

BackgroundThe temporal response to checkpoint blockade (CB) is incompletely understood. Here, we profiled the tumor infiltrating lymphocyte (TIL) landscape in response to combination checkpoint blockade at two distinct timepoints of solid tumor growth.MethodsC57BL/6 mice bearing subcutaneous MC38 tumors were treated with anti-PD-1 and/or anti-CTLA-4 antibodies. At 11 or 21 days, TIL phenotype and effector function were analyzed in excised tumor digests using high parameter flow cytometry. The contributions of major TIL populations toward overall response were then assessed using ex vivo cytotoxicity and in vivo tumor growth assays.ResultsThe distribution and effector function among 37 distinct TIL populations shifted dramatically between early and late MC38 growth. At 11 days, the immune response was dominated by Tumor necrosis factor alpha (TNFα)-producing NKT, representing over half of all TIL. These were accompanied by modest frequencies of natural killer (NK), CD4+, or CD8+ T cells, producing low levels of IFN-γ. At 21 days, NKT populations were reduced to a combined 20% of TIL, giving way to increased NK, CD4+, and CD8+ T cells, with increased IFN-γ production. Treatment with CB accelerated this switch. At day 11, CB reduced NKT to less than 20% of all TIL, downregulated TNFα across NKT and CD4+ T cell populations, increased CD4+ and CD8+ TIL frequencies, and significantly upregulated IFN-γ production. Degranulation was largely associated with NK and NKT TIL. Blockade of H-2kb and/or CD1d during ex vivo cytotoxicity assays revealed NKT has limited direct cytotoxicity against parent MC38. However, forced CD1d overexpression in MC38 cells significantly diminished tumor growth, suggesting NKT TIL exerts indirect control over MC38 growth.ConclusionsDespite an indirect benefit of early NKT activity, CB accelerates a switch from TNFα, NKT-driven immune response toward an IFN-γ driven CD4+/CD8+ T cell response in MC38 tumors. These results uncover a novel NKT/T cell switch that may be a key feature of CB response in CD1d+ tumors.

scholarly journals Nano-Microparticle Platforms in Developing Next-Generation Vaccines

Vaccines ◽  
2021 ◽  
Vol 9 (6) ◽  
pp. 606
Author(s):  
Giuseppe Cappellano ◽  
Hugo Abreu ◽  
Chiara Casale ◽  
Umberto Dianzani ◽  
Annalisa Chiocchetti
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Cell Response ◽  
Humoral Response ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Next Generation ◽  
Emerging Viruses ◽  
Whole Cells ◽  
Effector Functions

The first vaccines ever made were based on live-attenuated or inactivated pathogens, either whole cells or fragments. Although these vaccines required the co-administration of antigens with adjuvants to induce a strong humoral response, they could only elicit a poor CD8+ T-cell response. In contrast, next-generation nano/microparticle-based vaccines offer several advantages over traditional ones because they can induce a more potent CD8+ T-cell response and, at the same time, are ideal carriers for proteins, adjuvants, and nucleic acids. The fact that these nanocarriers can be loaded with molecules able to modulate the immune response by inducing different effector functions and regulatory activities makes them ideal tools for inverse vaccination, whose goal is to shut down the immune response in autoimmune diseases. Poly (lactic-co-glycolic acid) (PLGA) and liposomes are biocompatible materials approved by the Food and Drug Administration (FDA) for clinical use and are, therefore, suitable for nanoparticle-based vaccines. Recently, another candidate platform for innovative vaccines based on extracellular vesicles (EVs) has been shown to efficiently co-deliver antigens and adjuvants. This review will discuss the potential use of PLGA-NPs, liposomes, and EVs as carriers of peptides, adjuvants, mRNA, and DNA for the development of next-generation vaccines against endemic and emerging viruses in light of the recent COVID-19 pandemic.

scholarly journals The immune response against myelin basic protein in two strains of rat with different genetic capacity to develop experimental allergic encephalomyelitis.

1975 ◽  
Vol 141 (1) ◽  
pp. 72-81 ◽  
Author(s):  
D E McFarlin ◽  
S C Hsu ◽  
S B Slemenda ◽  
F C Chou ◽  
R F Kibler
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Experimental Allergic Encephalomyelitis ◽  
Cell Response ◽  
Basic Protein ◽  
T Cell Response ◽  
Skin Tests ◽  
Allergic Encephalomyelitis ◽  
Experimental Allergic

After challenge with guiena pig basic protein (GPBP) Lewis (Le) rats, which are homozygous for the immune response experimental allergic encephalomyelitis (Ir-EAE) gene, developed positive delayed skin tests against GPBP and the 43 residue encephalitogenic fragment (EF); in addition, Le rat lymph node cells (LNC) were stimulated and produced migration inhibitory factor (MIF) when incubated in vitro with these antigens. In contrast Brown Norway (BN) rats, which lack the Ir-EAE gene, did not develop delayed skin tests to EF and their LNC were not stimulated and did not produce MIF when incubated in vitro with EF. These observations indicate that the Ir-EAE gene controls a T-cell response against the EF. Le rats produced measurable anti-BP antibody by radioimmunoassay after primary challenge. Although no antibody was detectable in BN rats by radioimmunoassay, radioimmunoelectrophoresis indicated that a small amount of antibody was formed after primary immunization. After boosting intraperitoneally, both strains of rat exhibited a rise in anti-BP antibody; which was greater in Le rats. In both strains of rat the anti-BP antibody reacted with a portion of the molecule other than the EF. Since EF primarily evokes a T cell response, it is suggested that the EF portion of the BP molecule may contain a helper determinant in antibody production.

443 An immunotherapy trio in advanced HNSCC for coordinated B and T cell antigen response

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A469-A469
Author(s):  
Bernard Fox ◽  
Tarsem Moudgil ◽  
Traci Hilton ◽  
Noriko Iwamoto ◽  
Christopher Paustian ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
T Cell Responses ◽  
Data Sets ◽  
Cell Responses ◽  
Anti Cancer ◽  
Bead Arrays ◽  
Hnscc Cell

BackgroundOutcomes for recurrent or metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) are dismal and responses to anti-PD-1 appear best in tumors with PD-1+ T cells in proximity to PD-L1+ cells, arguing that improved outcome is associated with a pre-existing anti-cancer immune response. Based on this, we hypothesize that vaccines which prime and/or expand T cells to a spectrum of antigens overexpressed by HNSCC combined with T cell agonists, like anti-GITR, that provide costimulatory signals will improve the anti-PD-1 response rates. We have developed a cancer vaccine, DPV-001, that contains more than 300 proteins for genes overexpressed by HNSCC, encapsulated in a CLEC9A-targeted microvesicle and containing TLR/NOD agonists and DAMPs. Recently, we reported that combining anti-GITR + vaccine + anti-PD-1 augmented therapeutic efficacy in a preclinical model and now plan a phase 1b trial of this combination in patients with advanced HNSCC.MethodsSera from patients receiving DPV-001 as adjuvant therapy for definitively treated NSCLC, were analyzed for IgG responses to human proteins by MAP bead arrays and results compared to TCGA gene expression data sets for HNSCC. HNSCC cell lines were evaluated by RNASeq and peptides were eluted from HLA, analyzed by mass spectroscopy and correlated against MAP bead arrays and TCGA data sets. Tumor-reactive T cells from a vaccinated patient were enriched and expanded, and used in cytokine release assay (CRA) against autologous NSCLC and partially HLA matched allogeneic HNSCC cell lines.ResultsPatients receiving DPV-001 (N=13) made 147 IgG responses to at least 70 proteins for genes overexpressed by HNSCC. Preliminary evaluation of the HNSCC peptidome against the results of MAP bead array identify antigens that are target of a humoral immune response. Additionally, tumor-reactive T cells from DPV-001 vaccinated patient recognize two partially HLA-matched HNSCC targets, but not a mis-matched target.ConclusionsRecent observations from our lab and others have correlated IgG Ab responses with T cell responses to epitopes of the same protein. Based on the data summarized above, we hypothesize that we have induced T cell responses against a broad spectrum of shared cancer antigens that are common among adenocarcinomas and squamous cell cancers. Our planned clinical trial will vaccinate and boost the induced responses by costimulation with anti-GITR and then sequence in delayed anti-PD-1 to relieve checkpoint inhibition. MAP bead arrays and the peptidome library generated above will be used to assess anti-cancer B and T cell responses.Trial RegistrationNCT04470024Ethics ApprovalThe original clinical trial was approved by the Providence Portland Medical Center IRB, approval # 13-046. The proposed clinical trial has not yet been reviewed by the IRB.

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