scholarly journals 2755. Phase 1/2, First-in-Human Study of the Safety, Tolerability, and Immunogenicity of an RSV Prefusion F-Based Subunit Vaccine Candidate

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S970-S970 ◽  
Author(s):  
Beate Schmoele-Thoma ◽  
Ann R Falsey ◽  
Edward E Walsh ◽  
Kena Swanson ◽  
Agnieszka Zareba ◽  
...  
Keyword(s):  
Pregnant Women ◽  
Subunit Vaccine ◽  
Vaccine Candidate ◽  
Phase 1 ◽  
Geometric Mean ◽  
Human Study ◽  
Safety Data ◽  
Vaccine Antigen ◽  
Tolerability Profile ◽  
Neutralization Titer

Abstract Background The respiratory syncytial virus (RSV) fusion glycoprotein (F) is a molecule that fuses the viral and host cell membranes during virus entry as it rearranges from a meta-stable prefusion to a stable postfusion conformation. Using structure-guided design, Pfizer engineered a prefusion RSV F subunit vaccine antigen with stable and well-characterized conformational homogeneity. Methods We report results of a 1,182 subject, first-in-human, phase 1/2, placebo-controlled, randomized, observer-blind, dose-finding study to describe the safety, tolerability, and immunogenicity of the Pfizer RSV vaccine candidate in healthy men and non-pregnant women from 18 to 85 years of age. The study compares three dosages of the vaccine candidate, with and without aluminum hydroxide, and also compares immunization with the RSV vaccine candidate alone or concomitantly with influenza vaccine. The study is ongoing to collect antibody persistence and additional safety data. Results The data, which are currently available for the 18- to 49-year-old subgroup, demonstrate an excellent safety and tolerability profile. Immunization with the various formulations of the vaccine candidate elicited RSV 50% neutralization titer geometric mean fold rises (GMFRs) of 10.6–17.2 for subgroup A and 10.4–19.8 for subgroup B, measured one month after immunization, with evidence of a dose–response. Conclusion The 10- to 20-fold increases in neutralizing antibody titers elicited by this vaccine with a stable prefusion F antigen represent a step change relative to the historical performance of vaccine candidates, such as Wyeth’s PFP, with F antigens that were not stabilized in the prefusion conformation (Simoes et al., Vaccine 20:954–60, 2002). The data strongly support development of this vaccine candidate to prevent RSV disease in infants, by immunizing pregnant women, and to prevent RSV disease in older adults, by direct immunization. Disclosures All authors: No reported disclosures.

scholarly journals A Phase 1/2 Clinical Trial Evaluating Safety and Immunogenicity of a Varicella Zoster Glycoprotein E Subunit Vaccine Candidate in Young and Older Adults

2012 ◽  
Vol 206 (8) ◽  
pp. 1280-1290 ◽  
Author(s):  
Isabel Leroux-Roels ◽  
Geert Leroux-Roels ◽  
Frédéric Clement ◽  
Pierre Vandepapelière ◽  
Ventzislav Vassilev ◽  
...  
Keyword(s):  
Older Adults ◽  
Clinical Trial ◽  
Subunit Vaccine ◽  
Vaccine Candidate ◽  
Phase 1 ◽  
Glycoprotein E ◽  
Varicella Zoster

scholarly journals A phase 1 study of single and repeat oral doses of GSK3439171A, a highly selective H-PGDS inhibitor, in healthy adult participants

2021 ◽  
Author(s):  
Thomas Haws ◽  
Nilay Thakkar ◽  
Summer Goodson ◽  
Caroline Sychterz ◽  
Nisha George ◽  
...  
Keyword(s):  
Therapeutic Potential ◽  
Drug Hypersensitivity ◽  
Phase 1 ◽  
Geometric Mean ◽  
Human Study ◽  
Study Drug ◽  
Prostaglandin D2 ◽  
Dose Escalation Study ◽  
Double Blind ◽  
Oral Doses

Aim: Prostaglandin D2 (PGD2) is implicated in the pathophysiology of inflammatory diseases. GSK3439171A is a potent, reversible, and highly selective azetidine urea inhibitor of haematopoietic prostaglandin D synthase (H-PGDS, a key promoter of PGD2 production in several inflammatory cell types). Based on favourable preclinical data, we performed a first-time-in-human study to assess the safety, tolerability, pharmacokinetics, and pharmacodynamics of GSK3439171A, and the effect of food on these parameters. Methods: This was a phase 1, randomized, double-blind, placebo-controlled, dose-escalation study. Single and repeat oral doses of GSK3439171A were administered to healthy males aged 18–65 years. Levels of inflammatory markers including tetranor-prostaglandin D metabolite (tPGDM) were measured in urine samples. Results: Sixty-six participants were enrolled, with 57 receiving GSK3439171A. Single doses (5–180 mg) and repeat once-daily doses (5 and 11 mg for 14 days; 40 mg for 7 days) were administered. Seven participants (12%) had adverse events (AEs) related to study drug, mainly drug hypersensitivity (n=4 [7%]; non-serious, transient skin rash). There were no serious AEs (SAEs) or clinically significant changes in vital signs, electrocardiogram, or laboratory parameters. Dose-proportional increases in Cmax and AUC(0–inf) were observed, and the geometric mean half-life of GSK3439171A was up to 12 hours. Results were similar when GSK3439171A was taken with or without food. No consistent suppression of tPGDM levels was observed. Conclusion: GSK3439171A was well tolerated in healthy participants and there were no SAEs. Selective inhibition of H-PGDS offers therapeutic potential for muscle-related disorders (e.g. Duchenne Muscular Dystrophy) and muscular recovery following injury.

scholarly journals Cryo-EM structure of S-Trimer, a subunit vaccine candidate for COVID-19

2021 ◽  
Author(s):  
Jiahao Ma ◽  
Danmei Su ◽  
Yinyan Sun ◽  
Xueqin Huang ◽  
Ying Liang ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Receptor Binding ◽  
Subunit Vaccine ◽  
Vaccine Candidate ◽  
Phase 1 ◽  
Full Length ◽  
Effective Vaccine ◽  
S Protein ◽  
Closed Conformation ◽  
A Subunit

Within a year after its emergence, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has infected over 100 million people worldwide with a death toll over 2 million. Vaccination remains the best hope to ultimately put this pandemic to an end. Here, using Trimer-Tag technology, we produced both wild-type (WT) and furin site mutant (MT) S-Trimers for COVID-19 vaccine studies. Cryo-EM structures of the WT and MT S-Trimers, determined at 3.2 Å and 2.6 Å respectively, revealed that both antigens adopt a tightly closed conformation and their structures are essentially identical to that of the previously solved full-length WT S protein in detergent. The tightly closed conformation is stabilized by fatty acid and polysorbate 80 binding at the receptor binding domains (RBDs) and the N terminal domains (NTDs) respectively. Additionally, we identified an important pH switch in the WT S-Trimer that shows dramatic conformational change and accounts for its increased stability at lower pH. These results validate Trimer-Tag as a platform technology in production of metastable WT S-Trimer as a candidate for COVID-19 subunit vaccine. IMPORTANCE Effective vaccine against SARS-CoV-2 is critical to end the COVID-19 pandemic. Here, using Trimer-Tag technology, we are able to produce stable and large quantities of WT S-Trimer, a subunit vaccine candidate for COVID-19 with high safety and efficacy from animal and Phase 1 clinical trial studies. Cryo-EM structures of the S-Trimer subunit vaccine candidate show that it predominately adopts tightly closed pre-fusion state, and resembles that of the native and full-length spike in detergent, confirming its structural integrity. WT S-Trimer is currently being evaluated in global Phase 2/3 clinical trial. Combining with published structures of the S protein, we also propose a model to dissect the conformation change of the spike protein before receptor binding.

scholarly journals Antibodies to Pneumococcal Proteins PhtD, CbpA, and LytC in Filipino Pregnant Women and Their Infants in Relation to Pneumococcal Carriage

2009 ◽  
Vol 16 (6) ◽  
pp. 916-923 ◽  
Author(s):  
Emma Holmlund ◽  
Beatriz Quiambao ◽  
Jukka Ollgren ◽  
Teija Jaakkola ◽  
Cécile Neyt ◽  
...  
Keyword(s):  
Cord Blood ◽  
Pregnant Women ◽  
Vaccine Candidate ◽  
Geometric Mean ◽  
Protein A ◽  
Nasopharyngeal Swab ◽  
Serum Samples ◽  
Blood Samples ◽  
Clear Cut ◽  
Pneumococcal Carriage

ABSTRACTThis study focuses on the immunogenicity of the following three pneumococcal vaccine candidate proteins in Filipino infants, all inducing protection in animal models: pneumococcal histidine triad protein D (PhtD), choline binding protein A (CbpA), and the lysozyme LytC. The immunoglobulin G antibody concentrations to PhtD, its putative, protective, and exposed C-terminal fragment (PhtD C), CbpA, and LytC were measured by enzyme immunoassay in 52 serum samples from pregnant women, 39 cord blood samples, and consecutive serum samples (n= 263) from 52 newborns between 6 weeks and 10 months of age scheduled to be taken at six time points. A nasopharyngeal swab to detect pneumococcal carriage was taken parallel to the serum samples. The antibody concentrations in the cord blood samples were similar to those in the samples from the mothers. In infant sera, the geometric mean antibody concentrations (GMCs) for all three proteins decreased until the age of 18 weeks and started to increase after that age, suggesting that the infants' own antibody production started close to the age of 4 to 5 months. The increase in GMCs by age, most clear-cut for CbpA, was associated with pneumococcal carriage. Anti-PhtD concentrations were higher than anti-PhtD C concentrations but correlated well (rof 0.89 at 10.5 months), suggesting that antibodies are directed to the supposedly exposed and protective C-terminal part of PhtD. Our results show that young children are able to develop an antibody response to PhtD, CbpA, and LytC and encourage the development of pneumococcal protein vaccines for this age group.

A phase 1 study of TAK-164, an anti-guanylyl cyclase C (GCC) antibody-drug conjugate (ADC), in patients (pts) with advanced gastrointestinal (GI) cancers expressing GCC.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3050-3050
Author(s):  
Richard D. Kim ◽  
James M. Cleary ◽  
Alexis Diane Leal ◽  
Aparna Raj Parikh ◽  
David P. Ryan ◽  
...  
Keyword(s):  
Platelet Count ◽  
Hepatic Failure ◽  
Phase 1 ◽  
Human Study ◽  
Safety Data ◽  
Maximum Plasma ◽  
Hepatic Toxicity ◽  
Antibody Drug Conjugate ◽  
Gi Cancers ◽  
Grade 3

3050 Background: TAK-164 is a second-generation ADC comprising a human IgG1 monoclonal antibody targeting GCC conjugated to a DNA-damaging alkylating agent by a peptide linker. TAK-164 demonstrated cytotoxic and antitumor activity in GCC-expressing cells and xenograft mouse models. This first-in-human study investigated the safety, pharmacokinetics (PK), and preliminary efficacy of TAK-164. Methods: Adult pts with GCC-positive, advanced/metastatic GI cancers received TAK-164 intravenously on day 1 of a 21-day cycle (Q3W). Dose escalation proceeded based on cycle 1 safety data via a Bayesian model of modified toxicity probability interval starting at 0.004 mg/kg. Results: Thirty-one pts were enrolled. Median age was 58 years (range 32–72), 58.1% of pts were female and 64.5% had colon carcinoma. The median number of prior lines of therapy was 4 (range 2–9). TAK-164 was given at 0.004 (n = 1), 0.008 (n = 1), 0.016 (n = 1), 0.032 (n = 5), 0.064 (n = 7), 0.12 (n = 7), 0.16 (n = 2), 0.19 (n = 3), 0.25 (n = 3) and 0.32 mg/kg (n = 1). No pts had dose-limiting toxicities (DLT) in cycle 1 up to 0.32 mg/kg. Three pts had adverse events (AEs) after cycle 1 considered to be DLTs: 1 pt receiving 0.19 mg/kg (grade 3 pyrexia and grade 5 hepatic failure) and 2 pts receiving 0.25 mg/kg (1 pt had grade 3 nausea, and grade 4 platelet count decrease and neutrophil count decrease; 1 pt had grade 4 hepatic failure and grade 4 platelet count decrease). Dosing was capped at 0.19 mg/kg due to hepatic toxicity and the recommended phase 2 dose (RP2D) was determined as 0.064 mg/kg based on safety and tolerability beyond cycle 1. Overall, pts received a median of 2 (range 1–8) treatment cycles. TAK-164-related treatment-emergent AEs (TEAEs) reported in 77.4% of pts included platelet count decrease (58.1%), fatigue (38.7%), and anemia (32.3%). TAK-164-related grade ≥3 TEAEs reported in 32.3% of pts included platelet count decrease (12.9%), alanine aminotransferase increase, aspartate aminotransferase increase, fatigue, and anemia (all 9.7%). Three pts discontinued due to TAK-164-related TEAEs. There was a dose-dependent increase in TAK-164 maximum plasma concentration and exposure over the range 0.016–0.32 mg/kg, with no meaningful accumulation in PK with repeat Q3W dosing. One pt receiving TAK-164 0.19 mg/kg showed γH2AX induction via immunohistochemistry in a post-treatment biopsy, demonstrating target engagement. One pt with low baseline GCC expression who received 5 cycles of TAK-164 0.008 mg/kg had an unconfirmed partial response at cycle 4; 11 of 25 (44.0%) evaluable pts had a best overall response of stable disease. Conclusions: TAK-164 appeared to have a manageable safety profile up to 0.064 mg/kg in pts with advanced GI cancers; hepatic toxicity was identified as a potential risk. The RP2D was determined as 0.064 mg/kg but was considered insufficient to derive significant clinical benefit. Clinical trial information: NCT03449030.

scholarly journals Immunogenicity of E2CD154 Subunit Vaccine Candidate against Classical Swine Fever in Piglets with Different Levels of Maternally Derived Antibodies

Vaccines ◽  
2020 ◽  
Vol 9 (1) ◽  
pp. 7
Author(s):  
Yusmel Sordo-Puga ◽  
Danny Pérez-Pérez ◽  
Carlos Montero-Espinosa ◽  
Aymé Oliva-Cárdenas ◽  
Iliana Sosa-Teste ◽  
...  
Keyword(s):  
Adverse Effects ◽  
Classical Swine Fever Virus ◽  
Envelope Protein ◽  
Subunit Vaccine ◽  
Vaccine Candidate ◽  
Geometric Mean ◽  
Classical Swine Fever ◽  
Neutralizing Antibody ◽  
Modified Live Vaccine ◽  
Different Levels

E2CD154 is a novel subunit vaccine candidate against classical swine fever virus (CSFV). It contains the E2 envelope protein from CSFV fused to the porcine CD154 molecule formulated in the oil adjuvant MontanideTM ISA50 V2. Previous works evidenced the safety and immunogenicity of this candidate. Here, two other important parameters related to vaccine efficacy were assessed. First, the existence of high maternally derived antibody (MDA) titers in piglets born to sows vaccinated with E2CD154 was demonstrated. These MDA titers remained above 1:200 during the first seven weeks of life. To assess whether the titers interfere with active vaccination, 79 piglets from sows immunized with either E2CD154 or a modified live vaccine were vaccinated with E2CD154 following a 0–21-day biphasic schedule. Animals immunized at either 15, 21, or 33 days of age responded to vaccination by eliciting protective neutralizing antibody (NAb) titers higher than 1:600, with a geometric mean of 1:4335, one week after the booster. Those protective levels of NAb were sustained up to six months of age. No vaccination-related adverse effects were described. As a conclusion, E2CD154 is able to induce protective NAb in piglets with different MDA levels and at different days of age.

scholarly journals Phase 1/2 Study to Describe the Safety and Immunogenicity of a COVID-19 RNA Vaccine Candidate (BNT162b1) in Adults 18 to 55 Years of Age: Interim Report

2020 ◽  
Author(s):  
Mark J. Mulligan ◽  
Kirsten E. Lyke ◽  
Nicholas Kitchin ◽  
Judith Absalon ◽  
Alejandra Gurtman ◽  
...  
Keyword(s):  
Vaccine Candidate ◽  
Phase 1 ◽  
Geometric Mean ◽  
Interim Report ◽  
Dose Escalation Study ◽  
Human Sera ◽  
Local Reactions ◽  
To Receive ◽  
Dose Dependent ◽  
Rna Vaccine

AbstractIn March 2020, the WHO declared a pandemic of coronavirus disease 2019 (COVID-19), due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2).1 With >8.8 million cases and >450,000 deaths reported globally, a vaccine is urgently needed. We report the available safety, tolerability, and immunogenicity data from an ongoing placebo-controlled, observer-blinded dose escalation study among healthy adults, 18-55 years of age, randomized to receive 2 doses, separated by 21 days, of 10 μg, 30 μg, or 100 μg of BNT162b1, a lipid nanoparticle-formulated, nucleoside-modified, mRNA vaccine that encodes trimerized SARS-CoV-2 spike glycoprotein RBD. Local reactions and systemic events were dose-dependent, generally mild to moderate, and transient. RBD-binding IgG concentrations and SARS-CoV-2 neutralizing titers in sera increased with dose level and after a second dose. Geometric mean neutralizing titers reached 1.8-to 2.8-fold that of a panel of COVID-19 convalescent human sera. These results support further evaluation of this mRNA vaccine candidate.

A phase 1 open label trial of intravenous administration of MVA-BN-Brachyury vaccine in patients with advanced cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2617-2617
Author(s):  
Peter Joseph DeMaria ◽  
Katherine Lee-Wisdom ◽  
Ravi Amrit Madan ◽  
Fatima Karzai ◽  
Renee Nicole Donahue ◽  
...  
Keyword(s):  
Phase 1 ◽  
Locally Advanced ◽  
Human Study ◽  
Safety Data ◽  
Vaccine Dose ◽  
Cytokine Release ◽  
Cytokine Release Syndrome ◽  
Open Label ◽  
Dose Escalation Study ◽  
Mesenchymal Transition

2617 Background: Brachyury is a member of the T-box family of transcription factors which is overexpressed in several tumor types and has been associated with treatment resistance, epithelial to mesenchymal transition and metastatic potential. MVA-BN-Brachyury vaccine is a vector-based therapeutic cancer vaccine which demonstrated immunogenicity and safety in previous clinical trials. Preclinical studies suggested that IV administration of vaccines can induce superior CD8 + T-cell responses as compared with SC or IM routes. This is the first-in-human study to evaluate safety and tolerability of IV administration of this vaccine. Methods: Patients with metastatic or unresectable locally advanced malignant solid tumors were treated with MVA-BN-Brachyury vaccine in a phase 1, open-label, 3+3 dose-escalation study. Eligible patients received a total of three vaccine doses intravenously Q3W at 1x107 (DL1), 1x108 (DL2), or 1x109 infections units (Inf.U) (DL3). Patients were admitted for 48 hours for observation after each dose and had imaging at baseline and 1 and 3 months after the last vaccine dose. Primary objective was to determine the safety and tolerability and establish the recommended phase 2 dose (RP2D). Immune assays were performed in the first 10 enrolled patients. Results: In 13 patients (10 chordoma, 1 small cell breast, 1 prostate, 1 colorectal cancer), no dose-limiting toxicities were observed. Right upper quadrant abdominal pain was the only grade 3 TRAE. All other TRAEs were grade 1 or 2; most common was cytokine release syndrome (four grade 2 and one grade 1. As of Feb 2021, 9 patients completed treatment and two planned restaging scans: 5 patients had PD (3 in DL1 and 2 in DL2), 3 had SD (2 in DL2 and 1 in DL3) and 1 had PR (DL3) as their best treatment response per RECIST 1.1. One patient with advanced sacral chordoma had significant reduction of ulcerated skin metastases after 2 doses, followed by 33% shrinkage at the end of trial. Two chordoma patients with SD reported significant pain improvement. Multifunctional Brachyury, CEA, and MUC1 specific T cells were increased after vaccination in in 60%, 67%, and 50% of patients, respectively. Conclusions: MVA-BN-Brachyury IV vaccine is safe across all tested dose levels and suggesting activity in chordoma at DL3 for which this vaccine was granted FDA orphan drug designation. Mild cytokine release syndrome (rigors, chills, fever and hypotension) has been observed in 5 patients and managed with IV fluids and steroids in 2 patients. A dose 1 x 109 Inf.U (DL3) was selected for RP2D based upon available safety data. Further research is pending to evaluate clinical benefit and immunogenicity. Clinical trial information: NCT04134312.

scholarly journals Evaluation of a SARS-CoV-2 Vaccine NVX-CoV2373 in Younger and Older Adults

2021 ◽  
Author(s):  
Neil Formica ◽  
Raburn Mallory ◽  
Gary Albert ◽  
Michelle Robinson ◽  
Joyce Plested ◽  
...  
Keyword(s):  
Dose Regimen ◽  
Phase 1 ◽  
Geometric Mean ◽  
Age Groups ◽  
Safety Data ◽  
Neutralizing Antibody ◽  
Spike Protein ◽  
Wild Type Virus ◽  
Type Virus ◽  
Wild Type

Background NVX CoV2373 is a recombinant severe acute respiratory coronavirus 2 (rSARS-CoV-2) nanoparticle vaccine composed of trimeric full-length SARS CoV-2 spike glycoproteins and Matrix-M1 adjuvant. Methods The phase 2 component of our randomized, placebo-controlled, phase 1-2 trial was designed to identify which dosing regimen of NVX-CoV2373 should move forward into late phase studies in younger (18-59 years) and older (60-84 years) participants and was based on immunogenicity and safety data through day 35 (14 days after the second dose). Participants were randomly assigned to receive either one or two intramuscular doses of 5-microgram or 25-microgram NVX-CoV2373 or placebo, 21 days apart. Primary endpoints were immunoglobulin G (IgG) anti-spike protein response, 7 day solicited reactogenicity, and unsolicited adverse events. A key secondary endpoint was wild type virus neutralizing antibody response. Results After randomization, approximately 250 participants each were assigned to one of four vaccine groups or placebo. Of these, approximately 45% were older participants. Reactogenicity was predominantly mild to moderate in severity and of short duration (median <3 days) after first and second vaccination with NVX-CoV2373, with higher frequencies and intensity after second vaccination and with the higher dose, and occurred less frequently and was of lower intensity in older participants. The two-dose regimen of 5-microgram NVX-CoV2373 induced robust geometric mean titer (GMT) IgG anti-spike protein (65,019 and 28,137 EU/mL) and wild-type virus neutralizing antibody (2201 and 981 titers) responses in younger and older participants, respectively, with seroconversion rates of 100% in both age groups. Neutralizing antibody responses exceeded those seen in convalescent sera for both age groups. Conclusions The study confirmed that the two-dose regimen of 5 microgram NVX CoV2373 is highly immunogenic and well tolerated in both younger and older participants. (Funded by the Coalition for Epidemic Preparedness Innovations; ClinicalTrials.gov number: NCT04368988).

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