Immunogenicity and safety of an investigational hepatitis B vaccine with a Toll-like receptor 9 agonist adjuvant (HBsAg-1018) compared to a licensed hepatitis B vaccine in healthy adults 40-70 years of age.

BACKGROUND: The currently licensed hepatitis B vaccines have limitations including hyporesponsiveness in older adults, poor compliance, and the extended time for most persons to develop seroprotection (e.g. >6months). A vaccine containing HBsAg combined with a Toll-like receptor 9 agonist adjuvant (HBsAg-1018) has been developed to overcome these limitations. METHODS: A Phase 3, multicenter, randomized, subject- and observer-blinded, active-controlled trial was conducted among healthy subjects 40-70years of age comparing the immunogenicity and safety of two doses of HBsAg-1018 at 0 and 4weeks to three doses of licensed hepatitis B vaccine, HBsAg-Eng, at 0, 4, and 24weeks. The primary immunogenicity endpoint was noninferiority of the seroprotection rate (SPR; % with anti-HBs≥10mIU/mL) of HBsAg-1018 compared to the SPR of HBsAg-Eng at 8 weeks following the last dose of vaccine. Conditional upon meeting noninferiority, superiority of HBsAg-1018 over HBsAg-Eng was assessed. Safety was compared between the two vaccines. RESULTS: At the primary endpoint, the SPR for the HBsAg-1018 group (90.0%) was superior to the SPR for the HBsAg-Eng group (70.5%) with an SPR difference of 19.5% (95% CI, 14.7%, 24.7%). At week 28 when the SPR peaked in the HBsAg-Eng group (72.8%), the SPR in the HBsAg-1018 group (94.8%) was significantly higher than in the HBsAg-Eng group. The SPR in the HBsAg-1018 group was significantly higher than in the HBsAg-Eng group at each study visit from week 4 through week 52. The safety profiles for the two vaccines were similar. CONCLUSION: When compared to the HBsAg-Eng three-dose regimen given at 0, 1, and 6months, HBsAg-1018 demonstrated superior seroprotection with only two doses at 0 and 1month. The safety profile of HBsAg-1018 was comparable to that of the licensed vaccine, HBsAg-Eng. HBsAg-1018 would provide a significant public health contribution toward the prevention of hepatitis B infection.

Oral administration of an adenovirus vector encoding both an avian influenza A hemagglutinin and a TLR3 ligand induces antigen specific granzyme B and IFN-γ T cell responses in humans.

PURPOSE: To test the safety and immunogenicity of an orally delivered avian influenza vaccine. The vaccine has a non-replicating adenovirus type 5 vector backbone which expresses hemagglutinin from avian influenza and a TLR3 ligand as an adjuvant. METHODS: Forty-two subjects were randomized into 3 groups dosed with either 1×10(10), 1×10(9), or 1×10(8) IU of the vaccine administered in capsules. Twelve subjects were vaccinated with identical capsules containing placebo. A portion of the 1×10(9) dose group were immunized a second time 4 weeks after the first immunization. The safety of the vaccine was assessed by measuring the frequency and severity of adverse events in placebo versus vaccine treated subjects. IFN-γ and granzyme B ELISpot assays were used to assess immunogenicity. RESULTS: The vaccine had a positive safety profile with no treatment emergent adverse events reported above grade 1, and with an adverse event frequency in the treated groups no greater than placebo. Antigen specific cytotoxic and IFN-γ responses were induced in a dose dependent manner and cytotoxic responses were boosted after a second vaccination. CONCLUSION: This first in man clinical trial demonstrates that an orally delivered adenovirus vectored vaccine can induce immune responses to antigen with a favorable safety profile. CLINICAL TRIAL REGISTRATION NUMBER: NCT01335347.

A single dose of unadjuvanted novel 2009 H1N1 vaccine is immunogenic and well tolerated in young and elderly adults.

BACKGROUND: When the novel H1N1 influenza A strain appeared in April of 2009, development of novel H1N1 vaccines became a public health priority. METHODS: We conducted a phase­2, multicenter, randomized, placebo­controlled, observer­blind clinical trial of a 2009 H1N1 vaccine in 1313 young (age, 18-64 years) and older (age, >or=65 years) adults. Participants were randomized 1:4:4:4 to receive 2 doses of placebo or 7.5, 15, or 30 µg of H1N1 hemagglutinin administered 21 days apart. In post hoc analyses, hemagglutination inhibition (HI) titers measured at baseline and after vaccination were analyzed for young adults (age, 18-64 years), "younger elderly" adults (age, 65-74 years), and "very elderly" adults (age, >or=75 years). RESULTS: At baseline, 28.8% of young adults, 43.9% of younger elderly adults, and 62.9% of very elderly adults had HI titers to A/2009 H1N1 of >or=1:40. A single 7.5­µg dose induced HI titers >or=1:40 in 94.5% (95% confidence interval [CI], 91.8%-96.3%) of all adults. After one 7.5­µg dose, the geometric mean titers achieved were 326.4 (95% CI, 275.9-386.0) in young adults, 155.4 (95% CI, 123.4-195.8) in "younger elderly" adults, and 243.9 (95% CI, 167.1-356.0) in "very elderly" adults. CONCLUSIONS: This large phase-2 trial demonstrated that a single 7.5­µg dose of a monovalent unadjuvanted H1N1 vaccine induced protective HI antibody levels in adults of all ages, including very elderly adults. TRIAL REGISTRATION: Clinicaltrials.gov identifier NCT00958126.

Phase 1 clinical trials of the safety and immunogenicity of adjuvanted plasmid DNA vaccines encoding influenza A virus H5 hemagglutinin.

BACKGROUND: Development of vaccines against highly pathogenic avian influenza virus H5N1 subtypes posing a pandemic threat remains a priority. Limitations in manufacturing capacity and production time of conventional inactivated vaccines highlight the need for additional approaches. METHODS: We conducted two double-blind, placebo-controlled phase 1 studies involving a total of 103 healthy adults who received two intramuscular injections of Vaxfectin-adjuvanted plasmid DNA vaccine or placebo 21 days apart. Vaccine cohorts received either a monovalent vaccine containing an A/Vietnam/1203/04 H5 hemagglutinin-encoding plasmid or a trivalent vaccine with plasmids encoding H5, NP, and M2 proteins in doses from 0.1 to 1mg of DNA/injection. RESULTS: All doses were well tolerated without vaccine-related serious adverse events or discontinuations. In the monovalent cohorts, hemagglutination inhibition (HI) titers of > or =40 and 4-fold rises from baseline were achieved in 47-67% of subjects and H5-specific T-cell responses in 75-100%. Trivalent cohorts had lower HI response rates (< or = 20%), but 72% of subjects achieved T-cell and/or antibody responses to one or more antigens. CONCLUSIONS: Vaxfectin-adjuvanted monovalent H5 DNA vaccines were well tolerated and induced HI response rates and titers in the reported range of inactivated protein-based H5 vaccines, suggesting that adjuvanted DNA vaccines with rapid vaccine production could be useful for pandemic control.

Diagnostic error in medicine: analysis of 583 physician-reported errors.

BACKGROUND: Missed or delayed diagnoses are a common but understudied area in patient safety research. To better understand the types, causes, and prevention of such errors, we surveyed clinicians to solicit perceived cases of missed and delayed diagnoses. METHODS: A 6-item written survey was administered at 20 grand rounds presentations across the United States and by mail at 2 collaborating institutions. Respondents were asked to report 3 cases of diagnostic errors and to describe their perceived causes, seriousness, and frequency. RESULTS: A total of 669 cases were reported by 310 clinicians from 22 institutions. After cases without diagnostic errors or lacking sufficient details were excluded, 583 remained. Of these, 162 errors (28%) were rated as major, 241 (41%) as moderate, and 180 (31%) as minor or insignificant. The most common missed or delayed diagnoses were pulmonary embolism (26 cases [4.5% of total]), drug reactions or overdose (26 cases [4.5%]), lung cancer (23 cases [3.9%]), colorectal cancer (19 cases [3.3%]), acute coronary syndrome (18 cases [3.1%]), breast cancer (18 cases [3.1%]), and stroke (15 cases [2.6%]). Errors occurred most frequently in the testing phase (failure to order, report, and follow-up laboratory results) (44%), followed by clinician assessment errors (failure to consider and overweighing competing diagnosis) (32%), history taking (10%), physical examination (10%), and referral or consultation errors and delays (3%). CONCLUSIONS: Physicians readily recalled multiple cases of diagnostic errors and were willing to share their experiences. Using a new taxonomy tool and aggregating cases by diagnosis and error type revealed patterns of diagnostic failures that suggested areas for improvement. Systematic solicitation and analysis of such errors can identify potential preventive strategies.