Cardiac Safety of Modified Vaccinia Ankara for Vaccination against Smallpox in a Young, Healthy Study Population

Background Conventional smallpox vaccines based on replicating vaccinia virus (VV) strains (e.g. Lister Elstree, NYCBOH) are associated with a high incidence of myo-/pericarditis, a severe inflammatory cardiac complication. A new smallpox vaccine candidate based on a nonreplicating Modified Vaccinia Ankara (MVA) poxvirus has been assessed for cardiac safety in a large placebo-controlled clinical trial. Methods Cardiac safety of one and two doses of MVA compared to placebo was assessed in 745 healthy subjects. Vaccinia-naive subjects received either one dose of MVA and one dose of placebo, two doses of MVA, or two doses of placebo by subcutaneous injection four weeks apart;vaccinia-experienced subjects received a single dose of MVA. Solicited and unsolicited adverse events (AE) and cardiac safety parameters (recorded as Adverse Events of Special Interest, AESI) were monitored after each injection. Results A total of 5 possibly related AESI (3 cases of palpitations, 2 of tachycardia) were reported during the study. No case of myo- or pericarditis occurred. One possibly related serious AE (SAE) was reported during the 6-month follow-up period (sarcoidosis). The most frequently observed AEs were injection site reactions. Conclusions Vaccination with MVA was safe and well tolerated and did not increase the risk for development of myo-/pericarditis

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

Assessment of the potential public health impact of Herpes Zoster vaccination in Germany

The aim of this study was to compare the public health impact of introducing 2 Herpes Zoster (HZ) vaccines, Zoster Vaccine Live (ZVL) versus a non-live adjuvanted subunit candidate vaccine (HZ/su), in the German population aged 50+ years split into 3 age cohorts, i.e. 50–59, 60–69 and 70+ years, respectively. A multi-cohort static Markov model was developed following age cohorts over their lifetime. Demographic data were obtained from the German federal statistical office. HZ incidence and the proportion of HZ individuals developing post-herpetic neuralgia (PHN) were derived from German specific sources. Age-specific vaccine efficacy and waning rates were based on published clinical trial data. Vaccine coverage for both vaccines was assumed to be 40%, with compliance of the second dose of the HZ/su vaccine of 70%. Sensitivity analyses were performed to assess the robustness of the results. It was estimated that, over the remaining lifetime since vaccination, the HZ/su vaccine would reduce the number of HZ cases by 725,233, 533,162 and 486,794 in the 3 age cohorts, respectively, compared with 198,477, 196,000 and 104,640, using ZVL. The number needed to vaccinate (NNV) to prevent one HZ case ranged from 8 to 11 using the HZ/su vaccine compared with 20 to 50 using ZVL. Corresponding NNV to prevent one PHN case ranged from 39 to 53 using the HZ/su vaccine compared with 94 to 198 using ZVL. Due to the higher, sustained vaccine efficacy, the candidate HZ/su vaccine demonstrated superior public health impact compared with ZVL

Cost-effectiveness of the recombinant zoster vaccine in the German population aged ≥60 years old

Each year, around 300,000 Herpes Zoster (HZ) cases are observed in the German population, resulting in costs over €182 million to society. The objective of this study was to estimate the potential public health and economic impact of the new Adjuvanted Recombinant Zoster Vaccine (RZV, Shingrix) in the German population ≥ 60 years of age (YOA) and to identify the optimal age of vaccination. We used a static, multi-cohort Markov model that followed a hypothetical cohort of 1 million people ≥ 60 YOA life-long after vaccination using German-specific inputs. Both costs and outcomes were discounted at 3%, the incremental cost-effectiveness ratio (ICER) was calculated based on the societal perspective. The coverage of RZV was set at 40% with a second-dose compliance of 70%. Vaccinating the population aged ≥ 60 YOA would result in 45,000 HZ cases avoided, 1,713 quality-adjusted life years (QALYs) gained at a total cost of approximately €63 million compared to 38,000 cases avoided, 1,545 QALYs gained at a total cost of approximately €68 million in the population ≥ 70 YOA. This would result in an ICER of approximately €37,000 and €44,000/QALY, for the age cohort ≥ 60 and ≥ 70 YOA, respectively. Scenario analyses demonstrated that vaccinating at age 60 or 65 YOA would show greater public health impact and would result in the lowest observed ICER compared to vaccinating at 70 YOA. In conclusion, starting vaccination with RZV in the German population ≥ 60 YOA would demonstrate the best value from a public health and economic standpoint.10.1080/21645515.2018.1509645-UF000

Related Adverse Events with a frequency of ≥2% in at least one study group; MedDRA Coding by System Organ Class and Preferred Term (Safety dataset).

<p>Fishers Exact test of comparison to Group 3; NS = Not Significant (p≥0.05);</p><p>* p< 0.05;</p><p>** p<0.01;</p><p>*** p < 0.001).</p><p>Related Adverse Events with a frequency of ≥2% in at least one study group; MedDRA Coding by System Organ Class and Preferred Term (Safety dataset).</p

Consolidated Standards of Reporting Trials (CONSORT) subject flow diagram demonstrating the number of patients recruited into the study, number of subjects randomized and vaccinated, and number of subjects analyzed.

<p>MVA: Modified Vaccinia Ankara; FAS: full analysis set: PP: per protocol</p

Cost-utility analysis of increasing uptake of universal seasonal quadrivalent influenza vaccine (QIV) in children aged 6 months and older in Germany

Seasonal influenza causes many cases and related deaths in Europe annually, despite ongoing vaccination programs for older adults and people at high-risk of complications. Children have the highest risk of infection and play a key role in disease transmission. Our cost-utility analysis, based on a dynamic transmission model, estimated the impact of increasing the current vaccination coverage with inactivated quadrivalent influenza vaccine in Germany to all (healthy and high-risk) children under 5 years of age (40% uptake), or under 18 years (40% uptake), or only high-risk children under 18 years (90% uptake). Eight influenza complications were modeled, hospitalization and death rates were based on age and risk status. All three vaccination strategies provided more health benefits than the existing vaccination situation, reducing influenza cases, complications, hospitalizations and deaths across the entire population. The strategy targeting all children under 5 years was highly cost-effective (€6/quality-adjusted life-year gained, payer perspective). The other strategies were cost saving from the payer and societal perspectives. The vaccination strategy targeting all children under 18 years was estimated to provide the most health benefits (preventing on average 1.66 million cases, 179,000 complications, 14,000 hospitalizations and 3,600 deaths due to influenza annually) and the most cost savings (annually €20.5 million and €731.3 million from payer and societal perspectives, respectively). Our analysis provides policy decision-makers with evidence supporting strategies to expand childhood influenza vaccination, to directly protect children, and indirectly all other unvaccinated age groups, in order to reduce the humanistic and economic burden on healthcare systems and society

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