Summary
Background
Availability of a safe smallpox vaccine may be necessary under certain circumstances. Use of the old life virus vaccine was associated with serious adverse events, particularly in the setting of atopic eczema and immunodeficiency. MVA(modified virus Ankara)-BN, a highly attenuated strain of vaccinia virus, was developed for vaccination with improved safety profile.
Methods
A phase 1 study was conducted in 60 subjects without history of smallpox vaccination to gain experience with smallpox vaccination using this strain in healthy and atopic subjects. Healthy subjects, subjects with a history of atopic eczema (AE), subjects with mild active AE and subjects with mild allergic rhinitis without AE were equally allocated in 4 groups. MVA-BN was injected s.c. in a dose of 108 TCID50 twice in a four weeks interval.
Results
No serious or unexpected adverse reactions were reported. All subjects experienced mild to moderate pain and redness at the injection site. Dermatologic examinations did not reveal any unfavourable reactions to the study medication, particularly no sign or exacerbation of eczema for as long as 196 days. All subjects seroconverted after 2 vaccinations and no significant difference in antibody titers between the four different groups was observed.
Conclusions
A good safety profile of the MVA-BN vaccine was shown. The absence of adverse events in subjects with atopic disorders appears promising for the development of a safe smallpox vaccine for patients with AE or other atopic diseases.
Introduction
Smallpox was one of the major epidemic health threats in the history of mankind. The lethality rates ranged from 1% (variola minor) to about 30% (variola major) [1]. The worldwide eradication of smallpox was declared by the World Health Organization in 1980 [1,2]. Routine vaccination of the general population thus is no longer recommended. Variola showed a typical course: after a 10–12 day incubation period, patients experienced a phase of fever and severe general symptoms, followed by a characteristic papulopustular exanthema after 2–3 days. Over the next 1–2 weeks scab formation and healing followed. Edward Jenner introduced variola vaccination in 1796 using material from cowpox lesions. Later vaccinia virus strains were used and recommended by the WHO, applied into the epidermis by scarification preferredly with a bifurcated needle since 1968 [2,3]. Different attenuated strains caused less local and systemic side effects, but complications and serious adverse reactions were reported with variant rates dependent on the pathogenicity of the vaccinia virus strain. The vaccinia viruses of these first generation vaccines were grown on the skin of calves and thus would not meet the current standards of quality and safety. Adverse reactions of the vaccination like vaccinia with necrosis, generalized vaccinia and eczema vaccinatum were more frequent in individuals with atopic eczema or a compromised immune system, and it was estimated that up to 25% of the population should not be vaccinated with conventional smallpox vaccines [4]. An improved smallpox vaccine with a high standard of quality, safety and efficacy is required for emergency use and prophylactic immunization of first responders - including an increasing number of atopic subjects.
A vaccine derived from modified vaccinia Ankara (MVA) strain 571 (MVA-BN) was originally used as a priming vaccine before administration of conventional smallpox vaccine. It is a replication-defective vaccine with excellent safety profile and has already been used in large groups at risk for side effects of vaccination [5]. In the 1970s, 120,000 German primary vaccinees received MVA with good safety results [6]. Due to the eradication of smallpox in Europe, MVA could only be evaluated in animal models (monkeypox, mice) and few human studies: MVA was found to be safe and immunogenic as measured by antibody titers [7,8]. MVA-BN was developed via additional passages in serum-free chicken embryo fibroblast cultures and is replication-incompetent in mammalian cell lines. Administration is possible both subcutaneously and intramuscularly.
We report on the pilot study using a third-generation smallpox vaccine in patients with atopic diseases (atopic eczema and allergic rhinoconjunctivitis). An open-label controlled phase 1 study was performed to evaluate safety and immunogenicity of MVA-BN smallpox vaccine in 4 groups of 18 to 40-year-old vaccinia naive subjects with and without atopic disorders. Primary objectives of this study were safety assessment in all four study groups, assessment of impact of the vaccination on the course of atopic eczema for 196 days and investigation of reactogenicity of MVA-BN in all study subjects.
Methods
Vaccine
MVA-BN (IMVAMUNE®) was provided by Bavarian Nordic and was produced by IDT (Impfstoffwerke Dessau-Tornau GmbH) under Good Manufacturing Practice (GMP) conditions. The vaccine was reconstituted using sterile water for injection (WFI). It is a freeze-dried product and stored at the investigational site at +2 to +8 °C. Each subject received one vaccination of 0.5 ml (1 x 108 TCID50) MVA-BN on Days 0 and 28.
Study design and subjects
This prospective, open-label, Phase I pilot study in subjects with atopic disorders previously not vaccinated against smallpox was performed in close collaboration between the Department of Infectious Diseases and Tropical Medicine, Ludwig-Maximilian University Munich and the Department of Dermatology and Allergy, Technical University of Munich. The study protocol was approved by the relevant independent Ethics Committees. All study related procedures followed national legal requirements.
The study was divided into three parts: A screening phase of 4 weeks, an active study phase of not more than 10 weeks and a follow-up phase of at least 24 weeks after the last vaccination. Screening was performed at the Dermatology department and included in addition to a careful history with evaluating the eligibility criteria, a physical examination with special attention to the skin, examination including atopy stigmata and including determination of the individual SCORAD (Scoring Atopic Dermatitis) value, a measure of atopic eczema severity [9] and a skin prick test using the eight most common allergens (mugwort, birch, grass pollen, cow’s milk, hen’s egg, cladosporium, cat and house dust mite).
The SCORAD index takes into consideration extent, intensity and subjective suffering like pruritus and loss of sleep; it is given as an absolute number score from 0 – 103 points.
At screening, atopy stigmata like hair line, Dennie-Morgan fold, Hertoghe sign, ichthyosis hands, sebostasis and white dermographism were also recorded.
Based on the screening results, a total of 60 subjects were assigned to one of four parallel groups: Healthy subjects (Group 1), patients with either history of atopic eczema (Group 2) or mild active atopic eczema (Group 3) and mild allergic rhinitis (Group 4). Only subjects allocated to Groups 2 and 3 were allowed to have a history of atopic eczema. Subjects assessed as suffering from active atopic eczema fulfilling the diagnostic criteria of Hanifin and Rajka [10] as well as Ring [11,12] (Group 3) had to have a SCORAD value of 1 – 15.
Subcutaneous vaccinations with 0.5 ml IMVAMUNE® (1 x 108 TCID50) in the non-dominant upper arm were administered at Visit 1 (Day 0) and Visit 3 (Day 28 [+ 7 days]). Study subjects had to return to the investigational site for five scheduled visits (Days 14, 28, 42, 56 and 196) for study-specific assessments.
Safety assessments
Safety and tolerability of MVA-BN were determined by the incidence and grade of local and systemic reactions according to standardized scales and by clinical, dermatological and laboratory examinations (blood count, liver enzymes, CK, CK-MB, troponine, CRP, HIV-testing, hepatitis check, cholesterol, bilirubine, creatinine). Occurrence, relationship and intensity of any adverse events at any time were recorded and documented at each visit during the 24 week study period.
All subjects received diaries for documentation of related local injection site symptoms (erythema, swelling, induration and pain) and body temperature on the day of vaccination and during the 7-day period post-vaccination. Intensity grades were assessed in the following way: For erythema, swelling and induration the diameter was measured in mm. The maximum intensity of local injection site reactions was scored using the following grades: 0 = 0; 1 = < 20 mm; 2 = 20–50 mm and 3 = > 50 mm. For pain the scale was as follows: 0 = No pain; 1 = Painful on touch; 2 = Painful when limb is moved; 3 = Spontaneously painful, prevents normal activity. For general symptoms the following intensity grades were used: Pyrexia: 0 = < 38 °C, 1 = 38.0–39.0 °C, 2 = 39.1–40.0 °C, 3 = > 40.0 °C < 24 h, 4 = > 40.0 °C > 24 h; Headache and Myalgia: 0 = None, 1 = Mild pain, 2 = Moderate pain, 3 = Severe pain, 4 = Disabling; Chills: 0 = None, 1 = Mild, 2 = Severe and/or prolonged, 3 = Not responsive to narcotic medication; Nausea: 0 = None, 1 = Able to eat, 2 = Oral intake significantly decreased, 3 = No significant intake, requiring i.v. fluids; Fatigue: 0 = None, 1 = Increased over baseline, 2 = Moderate, 3 = Severe, 4 = Bedridden/Disabling.
Immune responses
Analysis of the immunogenicity of MVA–BN was based on the humoral immunogenicity as measured by quantification of IgG antibodies using an ELISA and neutralizing antibodies by performing a PRNT (plaque reduction neutralization test), both specific for vaccinia. All subjects were screened for pre-existing immunity against vaccinia and those with pre-existing immunity were excluded.
Statistical analysis
The target enrolment size was 60 subjects (15 per group). The sample size was based on feasibility with the intention to collect a first set of data on safety and immunogenicity of the MVA-BN vaccine in a population with atopic eczema. Data were analyzed descriptively in an explorative way. The full analysis set (FAS) consisted of all subjects who had received at least one dose of study vaccine. The safety analysis was based on the full analysis set. The per protocol (PP) analysis set comprised all subjects evaluable per protocol; this included the condition that they were seronegative before the first vaccination. The immunogenicity analysis was based on the PP analysis set. The terms seroconversion and seropositive are therefore equivalent in this study. All statistical analyses were performed using SAS software. If not mentioned otherwise, arithmetic means ± standard deviations are given.
Results
Subject demographics
Eighty-two subjects were screened and 60 enrolled in the study. Fifteen each were allocated to the groups comprising healthy individuals and subjects with active atopic eczema. Sixteen were allocated to the group with a history of atopic eczema and fourteen to the group of individuals with allergic rhinoconjunctivitis. No statistically significant differences in the demographic characteristics were found between the study groups.
At screening and at follow – up (June to December 2004), total IgE showed the highest levels in patients with mild active atopic eczema and was increased in patients with history of atopic eczema and allergic rhinitis compared to the healthy patients (Table 1).
Table 1.
Demographic data (full analysis set, N = 60).
| Population | Healthy (N* = 15) | History of atopic eczema (N* = 16) | Mild active atopic eczema (N* = 15) | Allergic Rhinitis (N* = 14) | |
|---|---|---|---|---|---|
| Age [years] | Mean ± SD | 25.3 ± 2.2 | 25.2 ± 2.6 | 22.9 ± 2.2 | 26.1 ± 2.7 |
| Median | 25.0 | 25.0 | 23.0 | 26.0 | |
| Range | 22 – 30 | 22 – 32 | 19 – 27 | 23 – 34 | |
| Gender N (%) | Female | 6 (40.0) | 9 (56.3) | 8 (53.3) | 6 (42.9) |
| Male | 9 (60.0) | 7 (43.8) | 7 (46.7) | 8 (57.1) | |
| Screening IgE [KU/l] | Mean ± SD | 70.0 ± 86.6 | 241.4 ± 339.9 | 632.1 ± 888.4 | 113.7 ± 117.7 |
| Median | 42.3 | 93.4 | 174.0 | 95.5 | |
| Range | 3.3 – 290.0 | 2.0 – 1178.0 | 30.9 – 2825.0 | 20.8 – 385.0 | |
| Follow-up IgE [KU/l] | Mean ± SD | 67.2 ± 82.6 | 187.9 ± 212.3 | 547.1 ± 680.5 | 129.9 ± 110.5 |
| Median | 35.5 | 87.5 | 136.0 | 114.0 | |
| Range | 2.5 – 281.0 | 2.0 – 672.0 | 18.4 – 1656.0 | 19.7 – 408.0 | |
According to clinical inclusion criteria, volunteers were allocated to four groups. Total IgE showed the highest levels in patients with mild active atopic eczema and was increased in patients with history of atopic eczema and allergic rhinitis compared to the healthy patients.
N = number of subjects, N* = Number of subjects in the specified group, SD = Standard deviation, % = Percentage based on N*, FAS = full analysis set
According to the inclusion criteria, all subjects in the groups with a history of atopic eczema or with active atopic eczema reported previous eczematous skin lesions. All subjects allocated to Group 3 (active eczema) had a baseline SCORAD value of 3 or higher with a mean value ± SD of 9.3 ± 4.15. The majority (n=11/15) of healthy subjects showed a negative skin prick test. In contrast, most subjects from the other study groups were sensitized to one or more of the substances tested (data not shown). Only subjects with active atopic eczema showed visible signs of eczema at the screening visit. At the screening visit, stigmata of atopy were almost exclusively seen in subjects with a history of or with active atopic eczema (data not shown).
One subject from the group with a history of atopic eczema terminated the study prematurely after Day 42 because he moved abroad. The remaining 59 subjects completed the study (Day 196). All subjects enrolled received at least one dose of study vaccine and were therefore included in the full analysis set (FAS) population. One subject in the allergic rhinitis group did not receive the second vaccination but nevertheless completed the study and was not excluded from the FAS.
The per protocol (PP) analysis set included all subjects of the FAS with no major protocol violation. Four subjects were excluded from the PP analysis set due to major protocol violations (moving to Hong Kong, visit outside window for blood specimen, only one vaccination, unrelated adverse event before the first vaccination).
Safety and reactogenicity
Safety analysis was based on the FAS which consisted of all subjects who had received at least one dose of study vaccine. Adverse events were classified as related local, related general and unrelated. Related local and related general adverse events were recorded during the 8-day period beginning with the day of each vaccination.
Fifty-nine subjects received two vaccinations without any serious reactions reported related to the study vaccine. One subject in Group 4 experienced an adverse event classified as possibly related (“hepatic enzyme increased”) that led to premature withdrawal from vaccination, i.e. the second vaccination was not administered.
Nearly all subjects reported mild to moderate pain and redness at the administration site. However, all adverse reactions were transient and no medical intervention was necessary. The overall incidence of related local adverse events and the incidence of severe (Grade 3) local adverse events in the first 8 days after vaccination are shown in Table 2. In the subjects with active atopic eczema the incidence of adverse events seems to be somewhat higher compared to the three other groups. The majority of side effects in each of the study groups were of Grade 1 intensity.
Table 2.
Incidence of related local adverse events during the 8-day follow-up period after each vaccination (FAS, N = 60).
| Symptom | Healthy (N* = 15) | History of atopic eczema (N* = 16) | Active atopic eczema (N* = 15) | Allergic rhinitis (N* = 14) | |||||
|---|---|---|---|---|---|---|---|---|---|
| n | (%) | n | (%) | n | (%) | n | (%) | ||
| Pain | Total | 14 | (93.3) | 14 | (87.5) | 15 | (100.0) | 14 | (100.0) |
| Grade ≥ 3 | 0 | (0.0) | 1 | (6.3) | 1 | (6.7) | 2 | (14.3) | |
| Erythema | Total | 12 | (80.0) | 15 | (93.8) | 15 | (100.0) | 14 | (100.0) |
| Grade ≥ 3 | 0 | (0.0) | 1 | (6.3) | 2 | (13.3) | 0 | (0.0) | |
| Swelling | Total | 12 | (80.0) | 13 | (81.3) | 11 | (73.3) | 11 | (78.6) |
| Grade ≥ 3 | 0 | (0.0) | 1 | (6.3) | 0 | (0.0) | 1 | (7.1) | |
| Induration | Total | 13 | (86.7) | 11 | (68.8) | 15 | (100.0) | 12 | (85.7) |
| Grade ≥ 3 | 0 | (0.0) | 1 | (6.3) | 1 | (6.7) | 0 | (0.0) | |
Nearly all subjects reported mild to moderate pain and redness at the administration site. The overall incidence of related local adverse events and the incidence of severe (Grade 3) local adverse events in the first 8 days after vaccination are shown. In the subjects with active atopic eczema the incidence of local adverse events seems to be somewhat higher compared to the three other groups.
N* = number of subjects for whom a symptom sheet was completed for at least one local adverse event (%) = number (percentage) of subjects with at least one report of the specific local adverse event, Total = the number of subjects for whom at least one symptom sheet was returned, FAS = full analysis set.
Dermatologic examinations did not reveal relevant unfavorable reactions to the study vaccine. In subjects with active atopic eczema, somewhat increased rates of new skin lesions were documented at the visits performed two weeks after each vaccination (Table 4, see below “SCORAD”). However, the rates were reduced again at the 4 week visit. In particular, there were no cases of eczema vaccinatum, a serious and often severe side effect occasionally observed after vaccination of atopic eczema subjects with conventional smallpox vaccines.
Table 4.
SCORAD values for subjects with atopic eczema (FAS N = 15).
| Day | N | Mean | SD | Minimum | Maximum |
|---|---|---|---|---|---|
| Day 0 | 15 | 8.73 | 4.30 | 0 | 14 |
| Day 14 | 15 | 9.00 | 3.95 | 3 | 14 |
| Day 28 | 15 | 8.33 | 4.25 | 0 | 14 |
| Day 42 | 15 | 9.33 | 5.59 | 0 | 21 |
| Day 56 | 15 | 8.73 | 3.43 | 3 | 13 |
| Day 196 | 14 | 6.14 | 4.50 | 0 | 12 |
In patients with active eczema, no negative influence on the course of the disease up to 196 days observation period.
N = number of subjects, n = number of subjects with SCORAD values; FAS = full analysis set; SD = standard deviation.
Most of the reported related general adverse events were assessed as possibly related to vaccination, with ‘fatigue’ and ‘headache’ most frequently reported in each study group. Table 3 provides an overview of the adverse reactions (related and unrelated) occurring with a frequency of > 5% with a reasonable possibility of a causal (possible, probable or definite) relationship to the vaccine within the first 14 days after each vaccination.
Table 3.
Adverse reactions with an occurrence of ≥ 5% during the 14 - day follow-up period after each vaccination (FAS, N = 60).
| Healthy (N* = 15) | History of atopic eczema (N* = 16) | Active atopic eczema (N* = 15) | Allergic rhinitis (N* = 14) | |||||||||
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| n | (%) | n* | n | (%) | n* | n | (%) | n* | n | (%) | n* | |
| Local symptoms at vaccination site | ||||||||||||
| Pain | 14 | (93.3) | 27 | 14 | (87.5) | 25 | 15 | (100.0) | 28 | 14 | (100.0) | 27 |
| Erythema | 12 | (80.0) | 23 | 15 | (93.8) | 26 | 14 | (93.3) | 23 | 14 | (100.0) | 26 |
| Induration | 13 | (86.7) | 23 | 11 | (68.8) | 17 | 14 | (93.3) | 22 | 12 | (85.6) | 18 |
| Swelling | 12 | (80.0) | 22 | 13 | (81.3) | 20 | 10 | (66.7) | 17 | 11 | (78.6) | 17 |
| Pruritus | 3 | (20.0) | 5 | 4 | (25.0) | 5 | 4 | (26.7) | 6 | 1 | (7.1) | 1 |
| Body Temperature | 1 | (6.7) | 1 | 0 | (0.0) | 0 | 3 | (20.0) | 3 | 0 | (0.0) | 0 |
| Discolouration | 2 | (13.3) | 3 | 0 | (0.0) | 0 | 1 | (6.7) | 1 | 1 | (7.1) | 1 |
| Warmth | 0 | (0.0) | 0 | 2 | (12.5) | 2 | 1 | (6.7) | 1 | 0 | (0.0) | 0 |
|
| ||||||||||||
| General symptoms | ||||||||||||
| Fatigue | 5 | (33.3) | 6 | 10 | (62.5) | 13 | 7 | (46.7) | 9 | 9 | (64.3) | 13 |
| Headache | 6 | (40.0) | 7 | 7 | (43.8) | 12 | 5 | (33.3) | 6 | 6 | (42.9) | 6 |
| Myalgia | 0 | (0.0) | 0 | 6 | (37.5) | 9 | 2 | (13.3) | 4 | 4 | (28.6) | 4 |
| Nausea | 1 | (6.7) | 1 | 1 | (6,3) | 1 | 2 | (13.3) | 3 | 2 | (14.3) | 2 |
No cases of eczema vaccinatum.
% = Percentages based on N*, N = number of subjects, N* = number of subjects with documented vaccination periods, n = number of subjects with findings in specific category, n* = number of events, FAS = full analysis set.
Generally, no clinically significant and relevant changes in hematology or biochemistry values were observed in any study group. No ECG changes related to vaccination or any signs of myo- or pericarditis were reported.
SCORAD during study
For all study patients with mild active atopic dermatitis SCORAD values were performed at every visit.
Table 4 shows that during the study the mean SCORAD values did not show a statistically significant increase. Fig. 1 shows typical eczematous lesions in a patient of group 3 with active atopic eczema before and four days after the first vaccination.
Figure 1.
Scanned typical slide photographs of eczematous skin lesions on the right arm of a 23-years old female volunteer of the active atopic eczema group. A: Before vaccination. B: four days later, after first vaccination with MVA-BN. No eczema flare occurred.
Regarding the individual SCORAD – values of the patients with atopic eczema, only two patients of this group showed a mild increase in SCORAD - both at Day 42. This was attributed to the start of the pollen season which usually impairs eczema in these two individuals (Table 5).
Table 5.
Listing SCORAD values for subjects with atopic eczema (FAS N = 15).
| Subject Number | Day 0 (1. vaccination) | Day 14 | Day 28 (2. vaccination) | Day 42 | Day 56 | Day 196 |
|---|---|---|---|---|---|---|
| 019 | 13 | 13 | 12 | 18* | 8 | 4 |
| 021 | 11 | 11 | 0 | 8 | 11 | 2 |
| 022 | 10 | 11 | 7 | 7 | 11 | 11 |
| 023 | 14 | 14 | 14 | 21* | 7 | 6 |
| 027 | 9 | 9 | 7 | 7 | 11 | 0 |
| 032 | 7 | 7 | 7 | 7 | 7 | 7 |
| 034 | 11 | 11 | 11 | 13 | 13 | NA |
| 045 | 3 | 3 | 11 | 0 | 4 | 4 |
| 064 | 12 | 12 | 12 | 12 | 12 | 12 |
| 067 | 0 | 3 | 3 | 3 | 3 | 3 |
| 068 | 4 | 4 | 4 | 7 | 7 | 0 |
| 070 | 3 | 3 | 3 | 3 | 3 | 3 |
| 072 | 12 | 12 | 12 | 12 | 12 | 12 |
| 074 | 12 | 12 | 12 | 12 | 12 | 12 |
| 080 | 10 | 10 | 10 | 10 | 10 | 10 |
Regarding the individual SCORAD – values of the patients with atopic eczema, only two patients of this group showed a mild increase in SCORAD.
Both subjects 019 and 023 had an exacerbation of atopic eczema (both at the day 42 visit). This was attributed to the start of the pollen season which usually impairs eczema in these two individuals.
NA = not available
Humoral immune responses
Analysis of the humoral immune response to MVA-BN using a validated ELISA measuring vaccinia-specific total IgG showed that all subjects seroconverted with geometric mean titer (GMT) levels between 182 and 251 after only one vaccination but presented with a more than 5-fold increase of GMTs after the second vaccination. All subjects had seroconverted 28 days after the first vaccination, and 14 days after the first vaccination 80% – 93% were already seroconverted. There was no statistically significant difference in the total IgG titers between the four groups.
Total serum IgE concentrations in groups 1–3 showed a tendential decrease comparing pre- to post-vaccination visits, whereas in the rhinitis group a tendential increase (not significant) was noted.
Discussion
In the current pre-event vaccination programs smallpox vaccination is contraindicated for individuals with a history or presence of eczema or atopic eczema (dermatitis). This also includes subjects with household contacts having a history or presence of eczema. Atopic eczema, irrespective of disease severity or activity, is a risk factor for developing eczema vaccinatum, a life-threatening complication after traditional smallpox vaccination among vaccinees and their close contacts [4,13,14]. Because the majority of primary-care providers do not distinguish between different kinds of dermatitis/eczema, the US Advisory Committee on Immunization Practices (ACIP) recommends that the currently available smallpox vaccines should not be administered to individuals with a history of eczema, irrespective of disease severity or activity (pre-event vaccination programs of the last decade). Considering the considerable prevalence of atopic eczema in the general population, an urgent need exists for a smallpox vaccine that can be safely administered to atopic subjects.
We report here results of the pilot clinical study with the 3rd generation, non-replicating smallpox vaccine MVA-BN in subjects with a history of or mild active atopic eczema and allergic rhinoconjunctivtis. We evaluated the safety and immunogenicity of this vaccine with focus on long-term dermatologic aspects, further data on immunogenicity from this study have been published by von Sonnenburg et al [15]. In this study MVA-BN seemed to be safe and was highly immunogenic in all groups. There were no cases of serious vaccine-related adverse events. No unusual trends in the occurrence of unwanted effects were noticed and the side effect profile appeared to be comparable to other modern vaccines. The relatively low number of adverse events in subjects with atopic eczema is certainly promising and justifies further development of MVA-BN for this high risk population. Furthermore, no vaccine-related cardiac side-effects or clinically significant ECG changes were reported, adding additional confidence to be able to develop a safe vaccine for this special population and the general population. A possible limitation of this pilot study is the inclusion of only SCORAD 1–15 patients in group 3, i.e. only mild atopic eczema patients were included in this study, thus it cannot be excluded that the results may not be relevant for severe patients. In addition, data from Table 5 suggests that patients with a higher SCORAD at study start may be running a higher risk for short-term eczema exacerbation. This may become relevant if atopic eczema patients with moderate or severe disease are to be vaccinated at a later time point. This aspect should be addressed in larger trials in the future.
As shown with a vaccinia-specific ELISA, all subjects seroconverted with high GMT levels.
In conclusion, MVA-BN showed an excellent safety profile in this trial studying subjects with history of or mild active atopic eczema. In addition, the immunogenicity results after vaccination with MVA-BN are comparable to healthy subjects. The results of this study were used to design a trial to further investigate the so far excellent safety and immunogenicity profile of MVA-BN in a larger population of patients with atopic eczema.
Figure 2.
SCORAD values for subjects with atopic eczema (FAS N = 15)
Acknowledgments
This clinical trial was supported by NIAID contract N01-AI-30016.
We are grateful for support by A. von Krempelhuber, P. Chaplin, N. Baedeker, V. Sobek, J. Vollmar, S. Rösch of Bavarian Nordic, Martinsried, Germany, providing the vaccine, logistics and financial support for this study.
Footnotes
Disclosure of potential conflict of interest: The conduct of this study was supported by Bavarian Nordic, Martinsried, Germany. Apart from this, authors have declared that they have no conflict of interest.
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