scholarly journals Phase 1 Clinical Trial of a Replication-Defective Human Cytomegalovirus (CMV) Vaccine

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S308-S309 ◽  
Author(s):  
Stuart Adler ◽  
Nicole Lewis ◽  
Anthony Conlon ◽  
Mark Christiansen ◽  
Mohamed S Al-Ibrahim ◽  
...  
Keyword(s):  
Immune Responses ◽  
Injection Site ◽  
Neutralizing Antibodies ◽  
Phase 1 ◽  
Aluminum Phosphate ◽  
Post Dose ◽  
Viral Shedding ◽  
Vaccine Type ◽  
Dose Levels ◽  
Research Grant

Abstract Background Congenital CMV remains an unmet medical need worldwide. Naturally acquired CMV immunity in women prior to pregnancy has been shown effective in reducing maternal-fetal transmission. V160 is engineered as a replication-defective CMV, and its replication in culture is controlled by a synthetic chemical. V160 can’t replicate in humans but it maintains all virological properties for presentation of viral antigens, including gH/gL/pUL128-131 pentameric complex, important for potent neutralizing antibodies (NABs). Methods Approximately 190 CMV seronegative and seropositive adults at study entry received 3 doses of V160 or placebo administered via intramuscular (IM) or intradermal (ID) route on Day 1, Month 1, and Month 6. Four antigen levels (10, 30, 100, and 250 units per dose) formulated with or without aluminum phosphate adjuvant were evaluated. In each vaccination group, approximately 10 and 4 subjects received study vaccine and placebo, respectively. Injection site and systemic adverse events (AEs) were collected for 14 days after each vaccination. Serious AEs (SAEs) were assessed up to Month 18. Viral shedding (urine and saliva) were monitored up to Month 12. CMV-specific NABs and cell-mediated immune responses (CMI) were measured prior and 1 month after each vaccination, and at Months 12 and 18. Results During the study, no serious AEs were reported and only one CMV seropositive subject had non-vaccine type viral shedding. In both seronegative and seropositive cohorts, proportion of subjects who reported injection site AEs was higher in V160 recipients than placebo controls. Proportion of subjects who reported systemic AEs was comparable across V160 doses/formulations and placebo. In the CMV seronegative cohort, immune responses increased with incremental dosing. More importantly, recipients of V160 from several dose levels mounted NAB and CMI responses at 1 month post dose 3 (PD3) that were comparable to baseline levels measured in seropositive subjects. Conclusion V160 had acceptable safety profile across all dose levels and formulations studied; Vaccine was immunogenic and elicited NAB and CMI responses at 1 month PD3 that were comparable to natural CMV infection. Disclosures S. Adler, Merck: Investigator, Research grant. N. Lewis, Merck: Employee, Salary. A. Conlon, Merck: Employee, Salary. M. Christiansen, Merck: Investigator, Research grant. M. S. Al-Ibrahim, Merck: Investigator, Research grant R. Rupp, Merck: Investigator, Research grant. T. M. Fu, Merck: Employee, Salary. O. Bautista, Merck: Employee, Salary. H. Tang, Merck: Employee, Salary.T. Culp, Merck: Employee, Salary. R. Das, Merck: Employee, Salary. K. Beck, Merck: Employee, Salary. G. Tamms, Merck: Employee, Salary. L. Musey, Meck: Employee, Salary.

Phase 1 Clinical Trial of a Conditionally Replication-Defective Human Cytomegalovirus (CMV) Vaccine in CMV-Seronegative Subjects

2019 ◽  
Vol 220 (3) ◽  
pp. 411-419 ◽  
Author(s):  
Stuart P Adler ◽  
Nicole Lewis ◽  
Anthony Conlon ◽  
Mark P Christiansen ◽  
Mohamed Al-Ibrahim ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Injection Site ◽  
Human Cytomegalovirus ◽  
Neutralizing Antibodies ◽  
De Novo ◽  
Phase 1 ◽  
Vaccine Dose ◽  
Genetically Engineered ◽  
Clinical Trial Registration ◽  
Viral Shedding

Abstract Background A conditionally replication-defective human cytomegalovirus (CMV) vaccine (V160) derived from AD169 and genetically engineered to express CMV pentameric complex (gH/gL/pUL128/pUL130/pUL131) was developed and evaluated for phase 1 vaccine safety and immunogenicity in CMV-seronegative and CMV-seropositive adults. Methods Subjects received 3 doses of V160 or placebo on day 1, month 1, and month 6. Four vaccine dose levels, formulated with or without aluminum phosphate adjuvant, were evaluated. Injection-site and systemic adverse events (AEs) and vaccine viral shedding were monitored. CMV-specific cellular and humoral responses were measured by interferon-gamma ELISPOT and virus neutralization assay up to 12 months after last dose. Results V160 was generally well-tolerated, with no serious AEs observed. Transient, mild-to-moderate injection-site and systemic AEs were reported more frequently in vaccinated subjects than placebo. Vaccine viral shedding was not detected in any subject, confirming the nonreplicating feature of V160. Robust neutralizing antibody titers were elicited and maintained through 12 months postvaccination. Cellular responses to structural and nonstructural viral proteins were observed, indicating de novo expression of viral genes postvaccination. Conclusions V160 displayed an acceptable safety profile. Levels of neutralizing antibodies and T-cell responses in CMV-seronegative subjects were within ranges observed following natural CMV infection. Clinical Trial Registration . NCT01986010.

scholarly journals 2759. Immunogenicity of Inactivated Influenza Vaccines Given Early vs. Late After Pediatric Allogeneic Hematopoietic Cell Transplantation

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S972-S973
Author(s):  
Jennifer E Schuster ◽  
Jennifer E Schuster ◽  
Andrew Speaker ◽  
Lubna Hamdan ◽  
Einas Batarseh ◽  
...  
Keyword(s):  
Immune Responses ◽  
Hematopoietic Cell ◽  
Cell Transplant ◽  
Inactivated Vaccine ◽  
Post Dose ◽  
Material Support ◽  
Vaccine Type ◽  
Significant Difference ◽  
Flu Vaccine ◽  
Research Grant

Abstract Background Pediatric hematopoietic cell transplant (HCT) recipients often fail to have robust responses to influenza (flu) vaccine. We conducted a blinded phase II trial comparing high-dose (HD) trivalent inactivated vaccine (TIV) vs. standard dose (SD) quadrivalent inactivated vaccine (QIV). Methods Children 3–17 years old and 3–35 months post-allogeneic HCT were enrolled at 9 centers and randomized to either 2 doses of HD-TIV or SD-QIV during the 2016–2017 flu season. We compared immune responses by hemagglutination inhibition (HAI) from children 3–11 (early) vs. 12–35 (late) months (m) post-HCT to 3 common flu vaccine antigens, irrespective of vaccine type. HAI responses were evaluated at baseline (visit 1), 1 m post dose 1 (visit 2) and dose 2 (visit 3), and 7 m post dose 2 (visit 4). Geometric mean titers (GMT) were adjusted for baseline log-titer values. Results Thirty-one children, median age 11 (7–15) years, were enrolled; 17 (55%) were immunized early and 14 (45%) late. Over 50% of patients had a potentially seroprotective (≥1:40) HAI titer at baseline, with no significant difference post-vaccination between early and late subjects. Table 1 compares early vs late subjects with HAI seroconversion (4-fold HAI titer rise). Post dose 1, late subjects, compared with early, had higher rates of seroconversion to all influenza strains. Post dose 2, early subjects, compared with late, had increased seroconversion. Late subjects had higher GMTs for H1N1 post dose 1 and 2, H3N2 after dose 1, and strain B/VIC post dose 1 and 2 (Figure 1). Although immunogenicity waned throughout flu season, higher seroconversion rates and GMT to H3N2 and strain B/VIC were retained in late subjects. Conclusion Compared with subjects in early post-HCT group, late post-HCT subjects had better flu vaccine immune responses as noted by higher GMT and HAI seroconversion. However, 2 doses seemed more beneficial in the early post-HCT group. Future analyses are underway, including comparing immunogenicity of HD vs. SD flu vaccine. Disclosures Jennifer E. Schuster, MD, Satchel Health: Shareholder Flor M. Munoz, M.D, Biocryst: Grant/Research Support; CDC: Research Grant; Moderna: Other Financial or Material Support, Safety Monitoring Board Member/Chair; NIH: Research Grant; Novavax: Research Grant; UP to Date: Author and Editor - Royalties, Other Financial or Material Support.

scholarly journals Safety and Immunogenicity of Heterologous and Homologous 2-Dose Regimens of Adenovirus Serotype 26– and Modified Vaccinia Ankara–Vectored Ebola Vaccines: A Randomized, Controlled Phase 1 Study

2020 ◽  
Author(s):  
Neil Goldstein ◽  
Viki Bockstal ◽  
Stephan Bart ◽  
Kerstin Luhn ◽  
Cynthia Robinson ◽  
...  
Keyword(s):  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Ebola Virus ◽  
Phase 1 ◽  
Booster Vaccination ◽  
Controlled Study ◽  
Adenovirus Serotype ◽  
Cellular Immune Responses ◽  
High Doses ◽  
Cellular Immune

Abstract Background This phase 1 placebo-controlled study assessed the safety and immunogenicity of 2-dose regimens of Ad26.ZEBOV (adenovirus serotype 26 [Ad26]) and MVA-BN-Filo (modified vaccinia Ankara [MVA]) vaccines with booster vaccination at day 360. Methods Healthy US adults (N = 164) randomized into 10 groups received saline placebo or standard or high doses of Ad26 or MVA in 2-dose regimens at 7-, 14-, 28-, or 56-day intervals; 8 groups received booster Ad26 or MVA vaccinations on day 360. Participants reported solicited and unsolicited reactogenicity; we measured immunoglobulin G binding, neutralizing antibodies and cellular immune responses to Ebola virus glycoprotein. Results All regimens were well tolerated with no serious vaccine-related adverse events. Heterologous (Ad26,MVA [dose 1, dose 2] or MVA,Ad26) and homologous (Ad26,Ad26) regimens induced humoral and cellular immune responses 21 days after dose 2; responses were higher after heterologous regimens. Booster vaccination elicited anamnestic responses in all participants. Conclusions Both heterologous and homologous Ad26,MVA Ebola vaccine regimens are well tolerated in healthy adults, regardless of interval or dose level. Heterologous 2-dose Ad26,MVA regimens containing an Ebola virus insert induce strong, durable humoral and cellular immune responses. Immunological memory was rapidly recalled by booster vaccination, suggesting that Ad26 booster doses could be considered for individuals at risk of Ebola infection, who previously received the 2-dose regimen.

scholarly journals 12. Randomized Studies of Two Clostridioides (Clostridium) difficile Vaccine Formulations

2020 ◽  
Vol 7 (Supplement_1) ◽  
pp. S29-S29
Author(s):  
Jody Lawrence ◽  
Nicholas Kitchin ◽  
Annaliesa S Anderson ◽  
Michael W Pride ◽  
Kathrin U Jansen ◽  
...  
Keyword(s):  
Clostridium Difficile ◽  
Injection Site ◽  
Neutralizing Antibodies ◽  
Phase 1 ◽  
Age Groups ◽  
Stopping Rules ◽  
Vaccine Formulation ◽  
Randomized Studies ◽  
Grade 3 ◽  
To Receive

Abstract Background Two formulations of investigational bivalent Clostridioides (Clostridium) difficile vaccine (QS-21 adjuvanted toxoid and toxoid-alone) were assessed for safety and immunogenicity in randomized studies in healthy adults 50–85 years of age. Methods The Phase 1 study of QS-21 adjuvanted toxoid vaccine randomized subjects 3:1 to 100 μg QS-21-containing C difficile vaccine or placebo; 3 doses were given according to 2 different schedules: a shortened month (Months 0, 1, 3) or day (Days 1, 8, 30) regimen. The Phase 2 toxoid-alone vaccine study randomized subjects 3:3:1 to receive 100 or 200 μg unadjuvanted C difficile vaccine formulation or placebo in Stages 1 and 2 (sentinel cohorts of different age groups), and 3:1 to receive the selected dose of unadjuvanted C difficile vaccine formulation or placebo in Stage 3. Three doses were given on a day (Days 1, 8, 30) regimen. Safety was the primary outcome for both studies. Immunogenicity was determined by measuring serum toxin A– and B–specific neutralizing antibodies. Results In the day regimen, 10 reports across both studies of grade 3 injection site redness postdose 2 triggered predefined stopping rules. Local reactions in both studies were more common among vaccine versus placebo recipients. Injection site pain predominated and was generally mild in severity. Systemic events were infrequent and generally mild-to-moderate in severity. Adverse events were reported by 50.0%–75.0% and 16.7%–50.0% of subjects in the QS-21 and toxoid-alone studies, respectively. Immune responses peaked around Day 37 (shortened-month regimen) or between Day 15 and Month 2 (day regimen), and remained above baseline throughout follow-up. Conclusion Both formulations demonstrated robust immunogenicity. However, both studies stopped early due to grade 3 injection site redness postdose 2 of the day (Days 1, 8, 30) regimen; neither formulation progressed to later stage development. Instead, an aluminum hydroxide-containing formulation of the vaccine candidate administered at 0, 1, and 6 months, which was safe and immunogenic in phase 1 and 2 studies, advanced to phase 3 studies. Disclosures Jody Lawrence, MD, Pfizer, Inc (Employee) Nicholas Kitchin, MD, Pfizer, Inc (Employee) Annaliesa S. Anderson, PhD, Pfizer (Employee, Shareholder) Michael W. Pride, PhD, Pfizer (Employee, Shareholder) Kathrin U. Jansen, PhD, Pfizer (Employee, Shareholder) William C. Gruber, MD, Pfizer (Employee, Shareholder) Yahong Peng, PhD, Pfizer (Employee, Shareholder) Charles Knirsch, MD, Pfizer (Employee) Chris Webber, MD, Pfizer Inc (Employee, Shareholder)

scholarly journals EXTH-39. HEXON SWAPPING MITIGATES ANTI-VIRAL IMMUNE RESPONSE DURING BRAIN TUMOR VIROTHERAPY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii95-ii95
Author(s):  
Dong Ho Shin ◽  
Teresa Nguyen ◽  
Hong Jiang ◽  
Sagar Sohoni ◽  
Sumit Gupta ◽  
...  
Keyword(s):  
Immune Response ◽  
Brain Tumor ◽  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Phase 1 ◽  
Malignant Gliomas ◽  
Oncolytic Viruses ◽  
Comparable Efficacy ◽  
Host Immune System ◽  
Serotype 5

Abstract Cancer virotherapy is a paradigm-shifting treatment modality based on the capabilities of virus-mediated oncolysis to elicit an anti-tumor immune response. Phase 1 and 2 clinical trials have demonstrated the safety and efficacy of our oncolytic adenovirus DNX-2401 (Delta-24-RGD) for patients with recurrent malignant gliomas. While a subset of the patients showed significant benefits, our goal is to improve the response rate. Clearance of the therapeutic virus by dominant anti-viral immune responses may contribute to the observed limits of the virotherapy. Adenovirus serotype 5 that provides the backbone of most oncolytic adenoviruses is highly prevalent in the human population and neutralizing antibodies against the capsid protein hexon may inhibit viral infection and replication. In this study, we showed using immunofluorescence that in mice bearing orthotopic syngeneic glioblastoma GSC005 treated with Delta-24-RGD, IgG antibodies crossed the disrupted blood-brain barrier and infiltrated the brain tumor parenchyma to colocalize with the viral hexon, suggesting that the systemic immune response may eradicate the virus within the infected tumor. To overcome this obstacle, we generated a chimeric virus called Delta-24-RGD-H43m with hexon hypervariable regions replaced with those from a lesser prevalent serotype 43 to avoid recognition by antibodies generated against serotype 5. The molecular swapping of the hexon did not significantly interfere with virion assembly nor attenuate its anti-glioma effect. Thus, the two viruses showed comparable efficacy in vitro (P= 0.568) and in vivo for animals without prior virus exposures (P= 0.228). Importantly, Delta-24-RGD-H43m evaded neutralizing antibodies generated against Delta-24-RGD and maintained its oncolytic ability (P< 0.0001). We conclude that hexon swapping strategies may improve virotherapy by alleviating the dominant immune response against the virus. Despite limited understanding of the interaction between oncolytic viruses and the host immune system, further research on strategies to circumvent virus-specific immune responses should aid the development of enhanced, glioma-targeted virotherapies.

scholarly journals A Novel SARS-CoV-2 Multitope Protein/Peptide Vaccine Candidate is Highly Immunogenic and Prevents Lung Infection in an Adeno Associated Virus Human Angiotensin-Converting Enzyme 2 (AAV hACE2) Mouse Model

2020 ◽  
Author(s):  
Farshad Guirakhoo ◽  
Lucy Kuo ◽  
James Peng ◽  
Juin Hua Huang ◽  
Ben Kuo ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Vaccine Candidate ◽  
Phase 1 ◽  
Peptide Vaccine ◽  
Neutralizing Antibody ◽  
Aluminum Phosphate ◽  
Initial Development ◽  
Angiotensin Converting Enzyme 2 ◽  
Adjuvant System ◽  
Favorable Safety

AbstractIn this report, we describe the initial development and proof-of-concept studies for UB-612, the first multitope protein-peptide vaccine against Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2), the pathogen responsible for the Coronavirus Disease of 2019 (COVID-19). UB-612 consists of eight components rationally designed for induction of high neutralizing antibodies and broad T cell responses against SARS-CoV-2: the S1-RBD-sFc fusion protein, six synthetic peptides (one universal peptide and five SARS-CoV-2-derived peptides), a proprietary CpG TLR-9 agonist, and aluminum phosphate adjuvant. Through immunogenicity studies in guinea pigs and rats, we optimized the design of protein/peptide immunogens and selected an adjuvant system, yielding a vaccine that provided excellent S1-RBD binding and high neutralizing antibody responses, robust cellular responses, and a Th1-oriented response at low doses of the vaccine. Our candidate vaccine was then advanced into challenge studies, in which it reduced viral load and prevented development of disease in a mouse challenge model and in nonhuman primates (NHP, immunogenicity part is completed, challenge is ongoing). A GLP-compliant toxicity study has shown a favorable safety profile for the vaccine. With the Phase 1 trial ongoing in Taiwan and additional trials planned worldwide, UB-612 is a highly promising and differentiated vaccine candidate for prevention of SARS-CoV-2 transmission and COVID-19 disease.

scholarly journals 2754. Phase 1 Trial of an mRNA-Based Combination Vaccine Against hMPV and PIV3

2019 ◽  
Vol 6 (Supplement_2) ◽  
pp. S970-S970 ◽  
Author(s):  
Christine Shaw ◽  
Heather Lee ◽  
Conor Knightly ◽  
Shiva Kalidindi ◽  
Tal Zaks ◽  
...  
Keyword(s):  
Single Dose ◽  
Respiratory Tract ◽  
Neutralizing Antibodies ◽  
Phase 1 ◽  
Geometric Mean ◽  
Vaccine Dose ◽  
Neutralizing Antibody ◽  
Combination Vaccine ◽  
Tract Infections ◽  
Dose Levels

Abstract Background Human metapneumovirus (hMPV) and parainfluenza virus type 3 (PIV3) are important causes of upper and lower respiratory tract infections, particularly in young children. Despite their public health impact, no effective therapeutic or preventive options are available. mRNA-1653 is a mRNA-based investigational combination vaccine against hMPV and PIV3, and consists of two distinct mRNA sequences encoding the fusion proteins of hMPV and PIV3, co-formulated in lipid nanoparticles. Methods This phase 1, first-in-human, randomized, placebo-controlled, dose-ranging study assesses the safety and immunogenicity of mRNA-1653 in healthy adults aged 18–49. The 124-subject study evaluates four vaccine dose levels (25, 75, 150, and 300 µg) administered intramuscularly in either single-dose or two-dose (Day 1, Month 1) vaccination schedules, with follow-up through 1 year after the last vaccination. Objectives include safety and immunogenicity measured by hMPV- and PIV3-specific neutralizing antibody titers. Results An interim analysis demonstrated that the mRNA-1653 vaccine was generally well-tolerated at all dose levels. Neutralizing antibodies against hMPV and PIV3 were present at baseline in all subjects, consistent with prior exposure to both viruses. A single dose of mRNA-1653 boosted serum neutralization titers against both hMPV and PIV3, and the magnitude of boosting was similar at all dose levels. The geometric mean ratio of Month 1 to baseline titers was approximately 6 for hMPV and 3 for PIV3. A second dose of mRNA-1653 at Month 1 was not associated with further increase of hMPV or PIV3 neutralization titers. Conclusion mRNA-1653 is well-tolerated and induces a functional immune response, and is therefore a promising vaccine candidate for the prevention of pediatric respiratory tract diseases caused by hMPV and PIV3. Disclosures All authors: No reported disclosures.

scholarly journals Assessments of different batches and dose levels of a two-dose Ad26.ZEBOV and MVA-BN-Filo vaccine regimen

npj Vaccines ◽  
2021 ◽  
Vol 6 (1) ◽  
Author(s):  
Viki Bockstal ◽  
Auguste Gaddah ◽  
Neil Goldstein ◽  
Georgi Shukarev ◽  
Stephan Bart ◽  
...  
Keyword(s):  
Immune Responses ◽  
Phase 3 ◽  
Two Phase ◽  
Post Dose ◽  
Clinical Dose ◽  
Viral Particles ◽  
The Usa ◽  
Dose Levels ◽  
Dose Dependent ◽  
Dose Consistency

AbstractTwo phase 3 clinical studies were conducted in the USA to bridge across different Ad26.ZEBOV manufacturing processes and sites, and to evaluate the immunogenicity of different dose levels of Ad26.ZEBOV and MVA-BN-Filo. Study 1 evaluated the immunological equivalence of three batches of Ad26.ZEBOV administered as dose 1, followed by one batch of MVA-BN-Filo as dose 2. In Study 2, immunogenic non-inferiority of intermediate (Ad26.ZEBOV: 2 × 1010 viral particles [vp], MVA-BN-Filo: 5 × 107 infectious units [Inf.U]) and low (8 × 109 vp, 5 × 107 Inf.U) doses of Ad26.ZEBOV and MVA-BN-Filo were evaluated against the full clinical dose (5 × 1010 vp, 1 × 108 Inf.U). In Study 1, equivalence was demonstrated for two of three batch comparisons post-dose 1 and all three batches after the full regimen. Study 2 demonstrated a dose-dependent response; however, non-inferiority against the full clinical dose was not met. All regimens were well tolerated and immune responses were observed in all participants, regardless of manufacturing process or dose. Consistency of immunogenicity of different Ad26.ZEBOV batches was demonstrated and a dose-dependent response was observed after Ad26.ZEBOV, MVA-BN-Filo vaccination. ClinicalTrials.gov identifiers: NCT02543268; NCT02543567.

scholarly journals Phase 1 Assessment of the Safety and Immunogenicity of an mRNA- Lipid Nanoparticle Vaccine Candidate Against SARS-CoV-2 in Human Volunteers

2020 ◽  
Author(s):  
Peter Kremsner ◽  
Philipp Mann ◽  
Jacobus Bosch ◽  
Rolf Fendel ◽  
Julian J. Gabor ◽  
...  
Keyword(s):  
Adverse Events ◽  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Clinical Investigation ◽  
Phase 1 ◽  
Fold Increase ◽  
Serious Adverse Events ◽  
S Protein ◽  
Human Volunteers ◽  
Dose Dependent

ABSTRACTThere is an urgent need for vaccines to counter the COVID-19 pandemic due to infections with severe acute respiratory syndrome coronavirus (SARS-CoV-2). Evidence from convalescent sera and preclinical studies has identified the viral Spike (S) protein as a key antigenic target for protective immune responses. We have applied an mRNA-based technology platform, RNActive®, to develop CVnCoV which contains sequence optimized mRNA coding for a stabilized form of S protein encapsulated in lipid nanoparticles (LNP). Following demonstration of protective immune responses against SARS-CoV-2 in animal models we performed a dose-escalation phase 1 study in healthy 18-60 year-old volunteers.This interim analysis shows that two doses of CVnCoV ranging from 2 μg to 12 μg per dose, administered 28 days apart were safe. No vaccine-related serious adverse events were reported. There were dose-dependent increases in frequency and severity of solicited systemic adverse events, and to a lesser extent of local reactions, but the majority were mild or moderate and transient in duration. Immune responses when measured as IgG antibodies against S protein or its receptor-binding domain (RBD) by ELISA, and SARS-CoV-2-virus neutralizing antibodies measured by micro-neutralization, displayed dose-dependent increases. Median titers measured in these assays two weeks after the second 12 μg dose were comparable to the median titers observed in convalescent sera from COVID-19 patients. Seroconversion (defined as a 4-fold increase over baseline titer) of virus neutralizing antibodies two weeks after the second vaccination occurred in all participants who received 12 μg doses.Preliminary results in the subset of subjects who were enrolled with known SARS-CoV-2 seropositivity at baseline show that CVnCoV is also safe and well tolerated in this population, and is able to boost the pre-existing immune response even at low dose levels.Based on these results, the 12 μg dose is selected for further clinical investigation, including a phase 2b/3 study that will investigate the efficacy, safety, and immunogenicity of the candidate vaccine CVnCoV.

First-in Man, Phase 1 Study of CSL362 (Anti-IL3Rα / Anti-CD123 Monoclonal Antibody) in Patients with CD123+ Acute Myeloid Leukemia (AML) in CR at High Risk for Early Relapse

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 120-120 ◽  
Author(s):  
B. Douglas Smith ◽  
Gail J. Roboz ◽  
Roland B. Walter ◽  
Jessica K. Altman ◽  
Anna Ferguson ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Phase 1 ◽  
Phase 1 Study ◽  
Post Dose ◽  
Infusion Reactions ◽  
Grade 3 ◽  
Dose Levels ◽  
Acute Myeloid

Abstract Background: Most patients with acute myeloid leukemia (AML) die from relapsed disease, including those who attain complete remission (CR). Post-remission treatment designed to kill chemoresistant leukemia stem cells (LSC) and eradicate minimal residual disease (MRD) could delay or prevent relapse. The Interleukin-3 Receptor alpha chain (IL3Rα/CD123) is overexpressed on LSC and AML blasts compared to normal hematopoietic cells. CSL362 is a fully humanized anti-CD123 monoclonal antibody, engineered for greater antibody-dependent cell-mediated cytotoxicity (ADCC) by high affinity for NK cell CD16. CSL362 has potent activity against AML cells in vitro and in mouse xenograft models. In this Phase 1 study we evaluated the safety, PK and immunogenicity of repeat doses of CSL362 as post-remission treatment for AML patients. Exploratory endpoints include effects on CD123+ normal blood cells (basophils and pDC), NK cells, levels of serum cytokines, CSL362 binding to CD123 on monocytes, and MRD. Methods: Eligibility criteria include CD123+ AML in 1st or 2nd CR /CRp, adverse risk factors (disease history, cytogenetics, molecular mutations or MRD), and no plan for allogeneic stem cell transplantation. Intravenous CSL362 is given over 3 hours every 14 days x 6 doses. Final evaluation for safety is at week 16 and for remission status is at week 24. Sequential cohorts of 3 - 6 pts have been treated at 5 dose levels, from 0.3 to 9.0 mg/kg. Serum is assayed centrally for cytokines, PK and immunogenicity. Standardized whole blood biomarker assays are performed at each site by flow cytometry, and analyzed centrally. Bone marrow is sampled at baseline, weeks 5 and 12. Results: To date, 25 pts (16M, 9F) median age 66 yr (range 32-83 yr) have received 118 infusions of CSL362; 15 pts received all 6 doses, 6 pts relapsed on study, 1 pt was withdrawn for an SAE (infusion reaction); 3 pts are ongoing. Adverse events related to CSL362 in ≥ 10% of pts (CTCAE V4 grades) were infusion reactions (12 pts; 15 grade 1-2, 2 grade 3 events), increased C-reactive protein (3 pts; 4 grade 2 events), hypertension (3 pts; 6 grade 1-2, 2 grade 3 events), and hypotension (3 pts; 2 grade 2, 1 grade 3 events). There have been 3 dose limiting toxicities (1 hypertension, 2 infusion reactions), and 3 related SAEs (2 infusion reactions, 1 transient delirium). Infusion reactions have been manageable with supportive care. A protocol amendment to allow hydrocortisone premedication has been effective to prevent or reduce the severity of reactions. At follow-up ≥ 6 months from first dose, 10 of 20 evaluable pts maintained CR. Median duration of CR from start of CR and ongoing at last follow-up was 34+ weeks [range 26 – 52+ weeks]. Of 6 evaluable pts who were MRD positive at baseline, 3 converted to negative on study. Biomarker assays show rapid, complete in vivo depletion of basophils and pDC (cells that have high expression of CD123) at all dose levels, ≤ 6 hours post-dose. Depletion is sustained for ≥ 15 days at doses ≥ 3.0 mg/kg. NK cells (which do not express CD123) in blood fall transiently then recover from day 3 post-dose to ≥ baseline by day 8. CSL362 saturation of CD123 on monocytes (cells that have low CD123 expression) in vivo occurs rapidly post-dose at all dose levels and is sustained ≥ 15 days at dose levels ≥ 3.0 mg/kg. Serum CSL362 concentration demonstrated a nonlinear PK profile with slower clearance and longer half-lives at higher doses. PK profiles at doses above 3 mg/kg seem to be dose proportional. The half-life for the two higher dose levels is 4-5 days. Cytokine assays showed increased levels of GM-CSF, IFN-γ, IL-1β, IL-6, IL-8, TNF-α, IL-15 and IL-1RA after the 1st dose, returning to baseline by day 8. Levels after dose 6 were lower than after the dose 1. Low level anti-CSL362 antibody titers were detected coincident with trough concentrations of CSL362 in 6 of 18 pts tested thus far, with no effects on PK or association with adverse events. Conclusion: CSL362 is safe and well tolerated in AML pts with CR/CRp and high risk of relapse. Potent, targeted ADCC of normal cells (basophils and pDC) that highly express CD123 is evident at all dose levels tested, with durable depletion at ≥ 3.0 mg/kg. At dose levels ≥ 3.0 mg/kg, saturation of CD123 on marker monocytes is durable for the inter-dose interval. These data indicate it is likely that dose levels ≥ 3.0 mg/kg are required to maximize ADCC against residual AML. A phase 2 study of CSL362 is planned. Figure 1 Figure 1. Disclosures Roboz: Glaxo SmithKline: Consultancy; Celgene: Consultancy; Agios: Consultancy; Novartis: Consultancy; Astra Zeneca: Consultancy; Sunesis: Consultancy; Teva Oncology: Consultancy; Astex: Consultancy. Busfield:CSL Limited: Employment. Barnden:CSL Limited: Employment. Sedgmen:CSL Limited: Employment. Ghosh:CSL Limited: Employment. Hosback:CSL Limited: Employment. Davis:CSL Limited: Employment. Dyson:CSL Limited: Employment. Dasen:CSL Behring: Employment. DeWitte:CSL Behring: Employment, Equity Ownership. Bensen-Kennedy:CSL Behring: Employment.

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