A Randomized, Double-Blind, Placebo-Controlled Phase II Trial Investigating the Safety and Immunogenicity of Modified Vaccinia Ankara Smallpox Vaccine (MVA-BN\u3csup\u3e®\u3c/sup\u3e) in 56-80-Year-Old Subjects

Background Modified Vaccinia Ankara MVA-BN® is a live, highly attenuated, viral vaccine under advanced development as a non-replicating smallpox vaccine. In this Phase II trial, the safety and immunogenicity of Modified Vaccinia Ankara MVA-BN® (MVA) was assessed in a 56–80 years old population. Methods MVA with a virus titer of 1 x 108 TCID50/dose was administered via subcutaneous injection to 56–80 year old vaccinia-experienced subjects (N = 120). Subjects received either two injections of MVA (MM group) or one injection of Placebo and one injection of MVA (PM group) four weeks apart. Safety was evaluated by assessment of adverse events (AE), focused physical exams, electrocardiogram recordings and safety laboratories. Solicited AEs consisted of a set of pre-defined expected local reactions (erythema, swelling, pain, pruritus, and induration) and systemic symptoms (body temperature, headache, myalgia, nausea and fatigue) and were recorded on a memory aid for an 8-day period following each injection. The immunogenicity of the vaccine was evaluated in terms of humoral immune responses measured with a vaccinia-specific enzyme-linked immunosorbent assay (ELISA) and a plaque reduction neutralization test (PRNT) before and at different time points after vaccination. Results Vaccinations were well tolerated by all subjects. No serious adverse event related to MVA and no case of myopericarditis was reported. The overall incidence of unsolicited AEs was similar in both groups. For both groups immunogenicity responses two weeks after the final vaccination (i.e. Visit 4) were as follows: Seroconversion (SC) rates (doubling of titers from baseline) in vaccine specific antibody titers measured by ELISA were 83.3% in Group MM and 82.8% in Group PM (difference 0.6% with 95% exact CI [-13.8%, 15.0%]), and 90.0% for Group MM and 77.6% for Group PM measured by PRNT (difference 12.4% with 95% CI of [-1.1%, 27.0%]). Geometric mean titers (GMT) measured by ELISA two weeks after the final vaccination for Group MM were 804.1 and 605.8 for Group PM (with ratio of GMTs of 1.33 with 95% CI of [0.96, 1.84]). Similarly, GMTs measured by PRNT were 210.3 for Group MM and 126.7 for Group PM (with ratio 1.66 and 95% CI [0.95, 2.90]). Conclusions One or two doses of MVA were safe and immunogenic in a 56–80 years old vaccinia-experienced population. No cases of myopericarditis were observed following vaccinations with MVA. The safety, reactogenicity and immunogenicity were similar to that seen in younger (18–55 year old) healthy populations as investigated in other MVA trials. The results suggest that a single dose of MVA in a 56–80 years old population was well tolerated and sufficient to rapidly boost the long-term B cell memory response induced by a prior vaccination with a traditional smallpox vaccine. Trial Registration ClinicalTrials.gov NCT00857493

Clinical protocol. Immunization of patients with malignant melanoma with autologous CD34+ cell-derived dendritic cells transduced ex vivo with a recombinant replication-deficient vaccinia vector encoding the human tyrosinase gene: a phase I trial

Protocol title: Immunization of Patients with Malignant Melanoma with Autologous CD34+ Cell-Derived Dendritic Cells Transduced Ex Vivo with a Recombinant Nonreplicating Vaccinia Vector Encoding the Human Tyrosinase Gene: A Phase I Trial. Study Phase: Phase I. Study Design: Nonrandomized, noncontrolled, single center. Study Objectives: Primary objective: Define the safety and toxicity of DCs/MVA-hTyr vaccine in patients with measurable metastatic melanoma. Secondary objectives: (1) to determine whether immunization with DCs/MVA-hTyr vaccine induces tyrosinase and melanoma-specific immune responses such as (a) development or enhancement of T lymphocyte-mediated responses in peripheral blood; (b) measurable delayed-type hypersensitivity (DTH) response in vivo; (c) development of antityrosinase antibodies in serum of treated patients; and (d) infiltration and expansion of tyrosinase-specific T lymphocytes in the inoculation site; and (2) to document any tumor regression and/or pigmentation modification that may result from immunization against tyrosinase. Number of Subjects: The total number of patients expected to complete this study is six. Study Population: Patients with malignant melanoma stage IV or high-risk stage III with measurable metastatic melanoma. Treatment Groups: Four vaccinations containing 100 X 106 DCs/MVA-hTyr will be given four times at 2-week intervals; the 1° vaccination will be given intravenously; the 2°, 3°, and 4° vaccinations will be given subcutaneously. Duration of Study: 20 weeks. Visit Schedule: Screening visit(s) Admission to the general clinical research center and baseline studies Preparative phase with the administration of filgrastim for six consecutive days followed by leukapheresis Immunization phase Follow-up visits monthly for 3 months and then at 2-month intervals for survival and general condition until death Safety parameters: Physical examination and measurements of melanoma lesions Complete blood tests Antimelanoma T lymphocyte (both CD8+ and CD4+) responses Ophthalmology evaluation including fundoscopy and visual acuity Neurological evaluation Cardiac rhythm, including Holter. Efficacy Parameters: Tumor response and time to progression by physical examination and CT scan Progression-free survival Overall survival Hypopigmentation Immunological evaluation: Melanoma antigen-specific and/or melanoma-specific CTL precursor frequency; antigen-specific HLA class II-restricted T cell responses; anti-tyrosinase antibodies in serum of treated patients; whenever possible biopsy at the site of vaccination to evaluate the infiltrate

Seroconversion.

<p>Seroconversion rates were determined by vaccinia-specific ELISA (A) and PRNT (B). Data set is FAS (full analysis set), N = 632 (for Week 32 N = 235). Error bars represent upper and lower confidence intervals. Vaccinations were given at Week 0 and Week 4. AD = atopic dermatitis.</p

A Multicenter, Open-Label, Controlled Phase II Study to Evaluate Safety and Immunogenicity of MVA Smallpox Vaccine (IMVAMUNE) in 18–40 Year Old Subjects with Diagnosed Atopic Dermatitis

<div><p>Background</p><p>Replicating smallpox vaccines can cause severe complications in individuals with atopic dermatitis (AD). Prior studies evaluating Modified Vaccinia Ankara virus (MVA), a non-replicating vaccine in humans, showed a favorable safety and immunogenicity profile in healthy volunteers.</p><p>Objective</p><p>This Phase II study compared the safety and immunogenicity of MVA enrolling groups of 350 subjects with AD (SCORAD ≤ 30) and 282 healthy subjects.</p><p>Methods</p><p>Subjects were vaccinated twice with MVA, each dose given subcutaneously 4 weeks apart. Adverse events, cardiac parameters, and the development of vaccinia virus humoral immune responses were monitored.</p><p>Results</p><p>The overall safety of the vaccine was similar in both groups. Adverse events affecting skin were experienced significantly more often in subjects with AD, but the majority of these events were mild to moderate in intensity. Seroconversion rates and geometric mean titers for total and neutralizing vaccinia-specific antibodies in the AD group were non-inferior compared to the healthy subjects.</p><p>Limitations</p><p>The size of the study population limited the detection of serious adverse events occurring at a frequency less than 1%.</p><p>Conclusion</p><p>MVA has a favorable safety profile and the ability to elicit vaccinia-specific immune responses in subjects with AD.</p><p>Trial Registration</p><p>ClinicalTrials.gov <a href="https://clinicaltrials.gov/ct2/show/NCT00316602?term=NCT00316602&rank=1" target="_blank">NCT00316602</a></p></div

Vaccinia-specific ELISA GMTs by Week (IAS, N = 119).

<p>Administrations at week 0 (Group MM: first MVA vaccination; Group PM: Placebo) and at week 4 (Group MM: second MVA vaccination; Group PM: first MVA vaccination). No samples were taken between week 8 and 32, therefore the graph was cut. IAS = Immunogenicity Analysis Set, GMT = geometric mean titer, ELISA = enzyme-linked immunosorbent assay, CI = confidence interval.</p

Subjects Experiencing at Least One Unsolicited Adverse Events (Occurring in ≥ 2% of Subjects in any Study Group, FAS, N = 632).

<p>N = number of subjects in the specified group; n = number of subjects in the specified category (with at least one report of a unsolicited AE); % = percentages of n based on N; AD = atopic dermatitis; AE = adverse event; MedDRA = Medical Dictionary for Regulatory Activities; FAS = full analysis set.</p><p>Subjects Experiencing at Least One Unsolicited Adverse Events (Occurring in ≥ 2% of Subjects in any Study Group, FAS, N = 632).</p

GMT for ELISA and PRNT at all post-baseline visits (FAS, N = 632).

<p>N = number of subjects in the specified group.</p><p>GMT for ELISA and PRNT at all post-baseline visits (FAS, N = 632).</p

Disposition of subjects.

<p>AD = atopic dermatitis; n = number of subjects in the specified category; FAS = full analysis set; PPS = per-protocol analysis set. ^a: There was one subject that did not receive the second vaccination but did not terminate the study prematurely, i.e. returned for the final visit. ^b: more than one reason per subject possible. ^c: 10 subjects with currently active AD had a SCORAD >30 at screening; 2 of these subjects had a SCORAD >39 and were excluded from PPS as major protocol violations. For the volunteers that were excluded from the PPS but had samples available, immunogenicity results were similar to those of the PPS subjects.</p