Immunogenicity of a novel Clade B HIV-1 vaccine combination: Results of phase 1 randomized placebo controlled trial of an HIV-1 GM-CSF-expressing DNA prime with a modified vaccinia Ankara vaccine boost in healthy HIV-1 uninfected adults.

BACKGROUND: A phase 1 trial of a clade B HIV vaccine in HIV-uninfected adults evaluated the safety and immunogenicity of a DNA prime co-expressing GM-CSF (Dg) followed by different numbers and intervals of modified vaccinia Ankara Boosts (M). Both vaccines produce virus-like particles presenting membrane-bound Env. METHODS: Four US sites randomized 48 participants to receiving 1/10th the DNA dose as DgDgMMM given at 0, 2, 4, 6 and 8 months, or full dose DgDgM_M or DgDgMM_M regimens, given at 0, 2, 4, and 8 months, and 0, 2, 4, 6, and 10 months, respectively. Peak immunogenicity was measured 2 weeks post-last vaccination. RESULTS: All regimens were well tolerated and safe. Full dose DgDgM_M and DgDgMM_M regimens generated Env-specific IgG to HIV-1 Env in >90%, IgG3 in >80%, and IgA in <20% of participants. Responses to gp140 and gp41 targets were more common and of higher magnitude than to gp120 and V1V2. The gp41 antibody included reactivity to the conserved immunodominant region with specificities known to mediate virus capture and phagocytosis and did not cross-react with a panel of intestinal flora antigens. The 3rd dose of MVA increased the avidity of elicited antibody (7.5% to 39%), the ADCC response to Bal gp120 (14% to 64%), and the one-year durability of the IgG3 responses to gp41 by 4-fold (13% vs. 3.5% retention of peak response). The co-expressed GM-CSF did not enhance responses over those in trials testing this vaccine without GM-CSF. CONCLUSION: This DNA/MVA prime-boost regimen induced durable, functional humoral responses that included ADCC, high antibody avidity, and Env IgG1 and IgG3 binding responses to the immunodominant region of gp41. The third, spaced MVA boost improved the overall quality of the antibody response. These products without co-expressed GM-CSF but combined with protein boosts will be considered for efficacy evaluation. TRIAL REGISTRATION: ClinicalTrials.gov NCT01571960.

A Geospatial Analysis of Severe Firearm Injuries Compared to Other Injury Mechanisms: Event Characteristics, Location, Timing, and Outcomes.

OBJECTIVES: Relatively little is known about the context and location of firearm injury events. Using a prospective cohort of trauma patients, we describe and compare severe firearm injury events to other violent and nonviolent injury mechanisms regarding incident location, proximity to home, time of day, spatial clustering, and outcomes. METHODS: This was a secondary analysis of a prospective cohort of injured children and adults with hypotension or Glasgow Coma Scale score ≤ 8, injured by one of four primary injury mechanisms (firearm, stabbing, assault, and motor vehicle collision [MVC]) who were transported by emergency medical services to a Level I or II trauma center in 10 regions of the United States and Canada from January 1, 2010, through June 30, 2011. We used descriptive statistics and geospatial analyses to compare the injury groups, distance from home, outcomes, and spatial clustering. RESULTS: There were 2,079 persons available for analysis, including 506 (24.3%) firearm injuries, 297 (14.3%) stabbings, 339 (16.3%) assaults, and 950 (45.7%) MVCs. Firearm injuries resulted in the highest proportion of serious injuries (66.3%), early critical resources (75.3%), and in-hospital mortality (53.5%). Injury events occurring within 1 mile of a patient's home included 53.9% of stabbings, 49.2% of firearm events, 41.3% of assaults, and 20.0% of MVCs; the non-MVC events frequently occurred at home. While there was geospatial clustering, 94.4% of firearm events occurred outside of geographic clusters. CONCLUSIONS: Severe firearm events tend to occur within a patient's own neighborhood, often at home, and generally outside of geospatial clusters. Public health efforts should focus on the home in all types of neighborhoods to reduce firearm violence.