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Background: Clinical trials of allergen immunotherapy (AIT) may require up to 5 years to complete. These lengthy trials may be complicated by high and potentially differential dropouts, especially among participants who perceive that they are receiving placebo. We propose a three‐stage design in which the placebo group in Stage 1 crosses over to receive active treatment in Stage 2. In Stage 3, AIT is discontinued to determine whether benefit is maintained post‐treatment. We apply inferential statistics to support the three‐stage design for clinical trials to determine clinical efficacy, treatment response over time, and sustained response to AIT. Methods: The proposed framework constitutes a series of hypothesis tests for comparing treatment responses at the end of each stage. A simulation study was performed to illustrate the statistical properties under varying statistical missing mechanisms and effect sizes. Results: The statistical properties in terms of bias and statistical power were consistent with what are expected from conventional analyses. Specifically, the extent of bias depended on the missing mechanism and magnitude. The statistical powers were largely driven by effect and sample sizes as well as prespecified success margins. As an illustration, assuming relative treatment differences of 25% and stagewise dropout rate of 15%, a sample size of 200 per group may achieve 93% power to demonstrate a treatment effect and 60% power to demonstrate a maintained response post‐treatment. Conclusions: Inferential statistics support our proposed study design for evaluating benefits of AIT over time and inform clinical understanding and decisions. [ABSTRACT FROM AUTHOR]

People who were vaccinated with smallpox in the past can still be successfully vaccinated again, according to a study of 80 people. This group was actually less likely to have a major adverse reaction to the vaccine than people who have never been vaccinated against smallpox. Even when they had a reaction, it was usually less severe.

Objective. To provide additional information on the safety of trivalent, cold-adapted influenza vaccine (CAIV-T) in children. Methods. Children 15 to 71 months of age were enrolled in a multicenter, prospective, randomized, doubleblind, and placebo-controlled trial to receive by nasal spray CAIV-T or placebo. In year 1 (1996-1997), 1314 were enrolled in the 2-dose cohort and 288 were enrolled in the 1-dose cohort. In year 2 (1997-1998), 1358 of the original participants received 1 dose of vaccine or placebo according to their original treatment group assignment. In year 3 (1998-1999) and year 4, the trial continued as an open-label safety trial of CAIV-T. A total of 642 and 549 children enrolled in years 3 and 4, respectively, received their third and fourth sequential annual doses of CAIV-T. Measured were 1) the occurrence of specific respiratory, gastrointestinal and systemic symptoms, unexpected symptoms (not specified in the diary card), and use of medications within the first 10 days after vaccination; 2) the occurrence of an acute illness and use of medication within 11 to 42 days after vaccination; and 3) the occurrence of serious adverse events within 42 days after vaccination. Results. The adjusted odd ratios of specific respiratory and gastrointestinal symptoms during the 10 days after vaccination were determined in years 1 and 2. Runny nose or nasal congestion, vomiting, muscle aches, and fever were significantly associated with the first dose of CAIV-T. With the second dose, runny nose was the only symptom that was associated with CAIV-T. In year 2, CAIV-T did not cause excess in any of the specific respiratory and gastrointestinal symptoms. In years 3 and 4, specific respiratory and gastrointestinal symptoms were comparable to that observed in year 2. A CAIV-T-associated symptom was most likely to occur on day 2 with the first dose of vaccine. The occurrence of unexpected symptoms was primarily of the gastrointestinal system. Approximately 6% of CAIV-T and 3.6% of placebo recipients had a gastrointestinal symptom. CAIV-T seemed to be associated with a mild excess in abdominal pain and vomiting only with the first vaccine dose. A statistically significant increase in the use of analgesics/ antipyretics was detected only with the first dose in CAIV-T vaccinees compared with placebo recipients (23.5% vs 16.6%). Between days 11 and 42, CAIV-T use was not associated with an excess of illness, otitis media, or use of medication. None of the 6 serious adverse events in CAIV-T recipients in years 1 to 4 was attributed to the vaccine. Conclusions. CAIV-T was safe in children. Mild respiratory, gastrointestinal, and systemic symptoms of short duration were observed in a minority of children and primarily with the first vaccine dose. Sequential annual doses of CAIV-T were well tolerated. Pediatrics 2002;110:662-672; trivalent, cold-adapted influenza vaccine; safety; preschool-aged children., ABBREVIATIONS. IIV-T, trivalent inactivated influenza vaccine; CAIV-T, trivalent, cold-adapted influenza vaccine; PD-OM, physician-diagnosed otitis media; PD-FOM, physician-diagnosed febrile otitis media; PD-LRTI, physician-diagnosed lower respiratory tract illness; SAE, serious adverse event; [...]

Abstract: Modified vaccinia Ankara (MVA) was evaluated as an alternative to Dryvax® in vaccinia-naïve and vaccinia-immune adult volunteers. Subjects received intramuscular MVA or placebo followed by Dryvax® challenge at 3 months. Two or more doses of MVA prior to Dryvax® reduced severity of lesion formation, decreased magnitude and duration of viral shedding, and augmented post-Dryvax® vaccinia-specific CD8+ T cell responses and extracellular enveloped virus protein-specific antibody responses. MVA vaccination is safe and immunogenic and improves the safety and immunogenicity of subsequent Dryvax® vaccination supporting the potential for using MVA as a vaccine in the general population to improve immunity to orthopoxviruses. [Copyright &y& Elsevier]