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A candidate vaccine against smallpox, modified vaccinia Ankara, was studied in 440 participants. MVA elicited immune responses similar to those associated with the established vaccinia-based vaccine and attenuated vaccinia replication in a human challenge model.

Background. Human immunodeficiency virus (HIV)—infected persons are at higher risk for serious complications associated with traditional smallpox vaccines. Alternative smallpox vaccines with an improved safety profile would address this unmet medical need. Methods. The safety and immunogenicity of modified vaccinia Ankara (MVA) was assessed in 91 HIV-infected adult subjects (CD4 + T-cell counts, ≥350 cells/mm 3 ) and 60 uninfected volunteers. The primary objectives were to evaluate the safety of MVA and immunogenicity in HIV-infected and uninfected subjects. As a measure of the potential efficacy of MVA, the ability to boost the memory response in people previously vaccinated against smallpox was evaluated by the inclusion of vaccinia-experienced HIV-infected and HIV-uninfected subjects. Results. MVA was well tolerated and immunogenic in all subjects. Antibody responses were comparable between uninfected and HIV-infected populations, with only 1 significantly lower total antibody titer at 2 weeks after the second vaccination, while no significant differences were observed for neutralizing antibodies. MVA rapidly boosted the antibody responses in vaccinia-experienced subjects, supporting the efficacy of MVA against variola. Conclusions. MVA is a promising candidate as a safer smallpox vaccine, even for immunocompromised individuals, a group for whom current smallpox vaccines have an unacceptable safety profile. Clinical Trials Registration. NCT00189904.

IMVAMUNE ® is a Modified Vaccinia Ankara (MVA)-based virus that is being developed as a safer 3rd generation smallpox vaccine. In order to determine the optimal dose for further development, a double-blind, randomized Phase II trial was performed testing three different doses of IMVAMUNE ® in 164 healthy volunteers. All three IMVAMUNE ® doses displayed a favourable safety profile, with local reactions as the most frequent observation. The 1 × 10 8 TCID 50 IMVAMUNE ® dose induced a total antibody response in 94% of the subjects following the first vaccination and the highest peak seroconversion rates by ELISA (100%) and PRNT (71%). This IMVAMUNE ® dose was considered to be optimal for the further clinical development of this highly attenuated poxvirus as a safer smallpox vaccine.

•Reintroduction of Variola major as an agent of bioterrorism remains a concern.•A compressed schedule of MVA was evaluated for use in a post event scenario.•MVA is well tolerated when given as two standard doses at Days 0 and 28 or 0 and 7.•A 2nd dose of MVA at Day 28 compared to Day 7 provided greater antibody responses.•INF-γ expression was greatest within 2 weeks after last vaccination. Reintroduction of Variola major as an agent of bioterrorism remains a concern. A shortened dosing schedule of Bavarian Nordic's (BN) IMVAMUNE® (modified vaccinia Ankara vaccine against smallpox) was compared to the currently recommended 0- and 28-day schedule for non-inferiority by evaluating the magnitude and kinetics of the immune responses. Subjects were assigned to receive IMVAMUNE or placebo administered subcutaneously on Days 0 and 7, Days 0 and 28, or Day 0. Blood was collected for antibody and cell-mediated immune assays. Subjects were followed for safety for 12 months after last vaccination. The primary endpoint of this study was the geometric mean antibody titers (GMT) at 14 days post last vaccination. Of 208 subjects enrolled, 191 received vaccine (Group: 0+7, Group: 0+28 and Group: 0) and 17 received placebo. Moderate/severe systemic reactogenicity after any vaccination were reported by 31.1%, 25.4%, and 28.6% of the subjects for Group: 0+7, Group: 0+28, and Group: 0, respectively (Chi-square test, P=0.77). Based on BN's Plaque Reduction Assay GMTs, Group: 0+7 was non-inferior to Group: 0+28 at Day 4, 180, and 365 after the second vaccination. On Day 14, Group: 0+7 and Group: 0+28 GMT were 10.8 (CI: 9.0, 12.9) and 30.2 (CI: 22.1, 41.1), respectively. Based on BN's Enzyme-linked immunosorbent assay, the proportion of subjects with positive titers for Group: 0+28 was significantly greater than that for Group: 0+7 after second vaccination at Days 4 and 180. By Day 14 after the second dose, the IFN-γ enzyme-linked immunosorbent spot (ELISPOT) responses were similar for Group: 0+28 and Group: 0+7. Overall, a standard dose of IMVAMUNE (0.5mL of 1x108TCID/mL) administered subcutaneously was safe and well tolerated. A second dose of IMVAMUNE at Day 28 compared to Day 7 provided greater antibody responses and the maximal number of responders. By Day 14 after the second dose, IFN-γ ELISPOT responses were similar for Group: 0+28 and Group: 0+7.

Introduction. LC16m8 is an attenuated cell culture-adapted Lister vaccinia smallpox vaccine missing the B5R protein and licensed for use in Japan. Methods. We conducted a phase I/II clinical trial that compared the safety and immunogenicity of LC16m8 with Dryvax in vaccinia-naive participants. Adverse events were assessed, as were electrocardiography and laboratory testing for cardiotoxicity and viral culturing of the vaccination sites. Neutralization titers to vaccinia, monkeypox, and variola major were assessed and cell-mediated immune responses were measured by interferon (IFN)-γ enzyme-linked immunosorbent spot and lymphoproliferation assays. Results. Local and systemic reactions after vaccination with LC16m8 were similar to those reported after Dryvax. No clinically significant abnormalities consistent with cardiac toxicity were seen for either vaccine. Both vaccines achieved antivaccinia, antivariola, and antimonkeypox neutralizing antibody titers > 1: 40, although the mean plaque reduction neutralization titer of LC16m8 at day 30 after vaccination was significantly lower than Dryvax for anti-NYCBH vaccinia (P < .01), antimonkeypox (P < .001), and antivariola (P < .001). LC16m8 produced robust cellular immune responses that trended higher than Dryvax for lymphoproliferation (P = .06), but lower for IFN-γ ELISPOT (P = .02). Conclusions. LC16m8 generates neutralizing antibody titers to multiple poxviruses, including vaccinia, monkeypox, and variola major, and broad T-cell responses, indicating that LC16m8 may have efficacy in protecting individuals from smallpox.

A Phase I trial was performed to investigate the safety and immunogenicity of the third generation smallpox vaccine MVA-BN ® (IMVAMUNE™), a highly attenuated clone derived from the Modified Vaccinia Virus Ankara strain 571, in naive and pre-immunized subjects. A total of 86 healthy subjects received the vaccine in five groups using different doses and routes of administration. All 38 subjects seroconverted in the groups receiving the highest dose (10 8 TCID 50). All vaccinations were well tolerated with mainly mild or moderate pain at the injection site being the most frequent symptom. The results indicate that MVA-BN ® has the potential to be developed as an efficient and safe alternative to the conventional smallpox vaccines such as Lister-Elstree or Dryvax ®. Unique attributes render it a promising candidate for prophylactic mass immunization, even in subjects for whom conventional smallpox vaccines are contraindicated.

•Subjects contraindicated to receive traditional smallpox vaccines were examined.•Subjects with atopic dermatitis or allergic rhinitis were vaccinated with MVA.•The non-replicating smallpox vaccine MVA was safe and well tolerated.•MVA induced vaccinia-specific antibody and cellular immune responses.•The results justify clinical trials with individuals suffering from more severe AD. Following vaccination with traditional smallpox vaccines or after exposure to vaccinated individuals, subjects with atopic dermatitis (AD) can develop eczema vaccinatum, a severe disease with disseminated eruption of pustular contagious lesions. Alternative smallpox vaccines with an improved safety profile would address this unmet medical need. An open-label controlled Phase I clinical trial was conducted to investigate the safety and immunogenicity of modified vaccinia Ankara (MVA) in 15 healthy subjects compared to 45 subjects with either mild allergic rhinitis, a history of AD or presenting with mild active AD. MVA was given (Week 0 and 4) by a subcutaneous injection during a 28-week observation period. No serious adverse event was reported and vaccinations with MVA did not lead to any clinically relevant skin reactions in AD subjects. Unsolicited administration site reactions did not show any trends compared to the healthy subject group. The majority of adverse reactions were mild to moderate, and all reactions were transient and resolved without intervention. The majority of vaccinees had seroconverted by ELISA (80–93%) and PRNT (69–79%) already two weeks after the first vaccination, increasing to 100% after the second immunization, with peak GMT above 1000 and 145 for ELISA and PRNT, respectively. MVA was equally well tolerated and immunogenic in all enrolled subjects with mild to moderate pain and redness at the injection site being the most frequent adverse reactions. There were no differences in the safety or immunogenicity profile of MVA in healthy subjects or those with AD or allergic rhinitis. The study has confirmed MVA as a promising smallpox vaccine candidate and demonstrated in a small study population that the vaccine has a similar safety and immunogenicity profile in healthy subjects and people with active AD. Clinical trials registration: NCT00189917.

•The duration and levels of VACV shedding from the vaccination site were lower among naïve smallpox vaccinees using PIO vs. control vaccinees.•At days 28 and 42, 10% and 3.4% of control vaccinees, respectively, continued to shed VACV compared with none of those using PIO.•Among subjects who returned scabs, VACV shedding was noted after scab separation in 23% (control subjects) and 8.3% (PIO subjects).•PIO applied starting on day 7 reduces VACV shedding at the vaccination site without compromising humoral and cellular immune responses.•To avoid inadvertent transmission of VACV, vaccinees should apply PIO starting on post-vaccination day 7, along with a nonocclusive dressing, and continue for 2 weeks after scab separation. The U.S. Department of Defense vaccinates personnel deployed to high-risk areas with the vaccinia virus (VACV)-based smallpox vaccine. Autoinoculations and secondary and tertiary transmissions due to VACV shedding from the vaccination site continue to occur despite education of vaccinees on the risks of such infections. The objectives of this study were to investigate, in naïve smallpox vaccinees, (a) whether the vaccination site can remain contagious after the scab separates and (b) whether the application of povidone iodine ointment (PIO) to the vaccination site inactivates VACV without affecting the immune response. These objectives were tested in 60 individuals scheduled to receive smallpox vaccine. Thirty individuals (control) did not receive PIO; 30 subjects (treatment) received PIO starting on post-vaccination day 7. Counter to current dogma, this study showed that VACV continues to shed from the vaccination site after the scab separates. Overall viral shedding levels in the PIO group were significantly lower than those in the control group (p=0.0045), and PIO significantly reduced the duration of viral shedding (median duration 14.5 days and 21 days in the PIO and control groups, respectively; p=0.0444). At least 10% of control subjects continued to shed VACV at day 28, and 3.4% continued to shed the virus at day 42. PIO reduced the proportion of subjects shedding virus from the vaccination site from day 8 until days 21–23 compared with control subjects. Groups did not differ significantly in the proportion of subjects mounting an immune response, as measured by neutralizing antibodies, IgM, IgG, and interferon-gamma enzyme-linked immunospot assay. When applied to the vaccination site starting on day 7, PIO reduced viral shedding without altering the immune response. The use of PIO in addition to a semipermeable dressing may reduce the rates of autoinoculation and contact transmission originating from the vaccination site in smallpox-vaccinated individuals.

In a randomized, single-blind study, 680 healthy, previously unvaccinated adults were inoculated intradermally with undiluted vaccinia virus vaccine, a 1:5 dilution, or a 1:10 dilution. The success rates were similarly high in all three groups: 97.2 percent, 99.1 percent, and 97.1 percent, respectively. Local and systemic symptoms were common, and 14 percent of subjects had rash at another site, including erythema multiforme in two subjects. The smallpox vaccine can be diluted 1:10 and still induce an immune response. Developing public health strategies to counter bioterrorism threats from smallpox is a high national priority. 1 In the event of an emergency, there is an insufficient supply of smallpox vaccine (vaccinia virus) available to vaccinate all U.S. residents with the recommended quantity of virus. Thus, it is important to determine whether current stocks could be diluted, administered with a traditional bifurcated needle, and still result in a high incidence of viral replication in the skin with vesicle formation. On the basis of the results of a pilot dose-ranging study reported elsewhere in this issue of the Journal, 2 we sought to determine . . .