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

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.

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

Open Forum Infectious Diseases ◽

10.1093/ofid/ofx163.718 ◽

2017 ◽

Vol 4 (suppl_1) ◽

pp. S308-S309 ◽

Cited By ~ 4

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.

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Sustained responses to lasmiditan: Results from post-hoc analyses of two Phase 3 randomized clinical trials for acute treatment of migraine

Cephalalgia ◽

10.1177/0333102419859313 ◽

2019 ◽

Vol 39 (12) ◽

pp. 1569-1576 ◽

Cited By ~ 6

Author(s):

Erin Gautier Doty ◽

John H Krege ◽

Leah Jin ◽

Joel Raskin ◽

Rashmi B Halker Singh ◽

...

Keyword(s):

Randomized Clinical Trials ◽

Study Drug ◽

Published Data ◽

Phase 3 ◽

Two Phase ◽

Post Dose ◽

Double Blind ◽

Bothersome Symptom ◽

Post Hoc ◽

Sustained Responses

Background Sustained pain freedom is an important attribute of acute migraine therapies for patients and physicians. Here we report efficacy of the centrally penetrant, highly selective, 5-HT1F agonist lasmiditan on sustained pain freedom and other outcomes at 24 and 48 hours post-dose. Study design and methods Data from the similarly designed, Phase 3, double-blind studies SAMURAI (NCT02439320) and SPARTAN (NCT02605174) were pooled to more precisely estimate efficacy effects in these post-hoc analyses. In both studies, inclusion criteria were 3–8 migraine attacks per month and Migraine Disability Assessment Score of ≥ 11 (at least moderate disability). Patients were randomized equally to lasmiditan 200 mg, 100 mg, 50 mg (50 mg only in SPARTAN), or to placebo. The study drug was to be taken within 4 hours of onset of pain for non-improving headache of at least moderate severity. Sustained pain freedom was defined as being pain free at 2 hours and at the given time point (24 or 48 hours) post-dose without use of additional study drug or migraine medications. Sustained responses were assessed similarly for most bothersome symptom-free, total migraine-free, and disability-free outcomes. For comparisons with previously published data on other acute medications, an additional endpoint of modified sustained pain freedom at 24 hours was defined as being pain free at 2 hours and no moderate-to-severe headache at 24 hours post-dose without use of additional study drug or migraine medications. Results Significantly higher proportions of patients treated with lasmiditan versus placebo achieved headache pain freedom at 2 hours post-dose: 200 mg: 35.6%; 100 mg: 29.9%; 50 mg: 28.6%; placebo: 18.3% (all p < 0.001). Sustained pain freedom was significantly higher in patients treated with lasmiditan versus placebo at 24 hours: 200 mg: 21.2%; 100 mg: 16.9%; 50 mg: 17.4%; placebo: 10.3% (all p < 0.01); and at 48 hours: 200 mg: 18.4%; 100 mg: 15.2%; 50 mg: 14.9%; placebo: 9.6% (all p < 0.05). Similar sustained benefits of lasmiditan versus placebo at 24 and 48 hours were noted for most bothersome symptom-free, total migraine-free and disability-free responses. Modified sustained pain freedom at 24 hours was also observed in significantly higher proportions of lasmiditan-treated patients versus placebo: 200 mg: 27.0%; 100 mg: 21.7%; 50 mg: 21.7%; placebo: 12.9% (all p < 0.01). Conclusion Sustained responses at 24 and 48 hours were noted in significantly more patients treated with lasmiditan versus placebo for several efficacy outcomes including pain freedom, most bothersome symptom-free, total migraine-free and disability-free responses. Clinicaltrials.gov identifier numbers SAMURAI: NCT02439320; SPARTAN: NCT02605174.

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1385. Concomitant Administration of Liquid Porcine Circovirus-free Human Rotavirus Vaccine with Routine Pediatric Vaccines Does Not Impact Immune Responses in Infants: Results from a Phase 3, Randomized Trial in the United States

Open Forum Infectious Diseases ◽

10.1093/ofid/ofaa439.1567 ◽

2020 ◽

Vol 7 (Supplement_1) ◽

pp. S702-S703

Author(s):

Remon Abu-Elyazeed ◽

Nicola P Klein ◽

Leentje Moerman ◽

Michael Povey ◽

Anthony Pruitt ◽

...

Keyword(s):

Immune Responses ◽

Geometric Mean ◽

The United States ◽

Porcine Circovirus ◽

Research Support ◽

Phase 3 ◽

Post Dose ◽

Human Rotavirus ◽

Vaccine Antigens ◽

Pertussis Antigens

Abstract Background Porcine circovirus type 1 (PCV-1) material was detected in the human rotavirus vaccine (HRV) in 2010. Although no safety risk was identified for infants vaccinated with HRV, a PCV-free HRV (no detection of PCV-1 and PCV-2 according to the limit of the tests used) was developed, which showed comparable immunogenicity and safety profile to the initial HRV. We assessed the non-inferiority of immune responses elicited by routine vaccines (co-)administered with either liquid (Liq) PCV-free HRV or lyophilized (Lyo) HRV, and the immunogenicity and safety of HRVs in infants. Methods In this phase 3, randomized, single-blind study (NCT03207750) in the United States, healthy infants aged 6–12 weeks received 2 doses of Liq PCV-free HRV or Lyo HRV at study month (M)0, M2 and routine vaccines at M0, M2, M4 (Figure 1). Co-primary objectives were to hierarchically demonstrate non-inferiority of immune responses to routine vaccine antigens when (co-)administered with Liq PCV-free HRV compared to Lyo HRV, 1 month post-dose 3 of the routine vaccines and to rule out a 10% decrease in seroresponse to pertussis antigens. Immunogenicity and safety of HRVs were also evaluated (Figure 1). Figure 1. Study design Results 1272 infants were vaccinated and 990 (Liq PCV-free HRV: 489; Lyo HRV: 501) were included in the per-protocol set. All statistical criteria were met for the 2 co-primary objectives (Table 1). Seroprotection/seropositivity rates were ≥ 99.3% for all DTaP-HBV-IPV antigens, ≥ 97.4% for Hib and ≥ 90.8% for most PCV13 serotypes. Geometric mean concentrations/titers for the routine vaccine antigens were comparable between groups (Table 2). 76.3% of infants in Liq PCV-free HRV and 78.9% in Lyo HRV had anti-RV antibody concentration ≥ 20 U/mL. The incidence of solicited (Figure 2) and unsolicited adverse events (AEs) were similar in both groups. Of 75 serious AEs (SAEs), 2 (Lyo HRV: abdominal distension; intussusception) were considered vaccine-related by investigator; 1 fatal SAE (Liq PCV-free HRV: sudden infant death syndrome) was considered non-vaccine related by investigator. Table 1. Non-inferiority of the immune responses to routine vaccine antigens when (co-)administered with HRV (Liq PCV-free HRV vs Lyo HRV) and exclusion of 10% decrease in seroresponse to pertussis antigens, 1 month post-dose 3 (per-protocol set) Table 2. Seroprotection/seropositivity rates and geometric mean concentrations/titers for the routine vaccines antigens 1 month post-dose 3 (per-protocol set) Figure 2. The incidence of solicited adverse events occurring within 7 days post-vaccination (overall/infant, exposed set) Conclusion Routine vaccines (co-)administered with Liq PCV-free HRV showed non-inferior immune responses and similar safety profiles compared to (co-)administration with Lyo HRV. Funding GlaxoSmithKline Biologicals SA Disclosures Remon Abu-Elyazeed, MD, PhD, GSK group of companies (Employee) Nicola P. Klein, MD, PhD, GSK group of companies (Research Grant or Support)Merck (Grant/Research Support)Pfizer (Grant/Research Support)Protein Science (now SP) (Grant/Research Support)Sanofi Pasteur (Grant/Research Support) Leentje Moerman, PhD, GSK group of companies (Employee) Michael Povey, MSc, GSK group of companies (Employee) Shelly Senders, MD, Pfizer (Grant/Research Support) Dan Bi, MD, MPH, GSK group of companies (Employee)

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