Giuseppe
Emeritus
[Source: The Lancet Infectious Diseases, full text: (LINK). Abstract, edited.]
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Lancet Infectious Diseases, Volume 13, Issue 3, Pages 238 - 250, March 2013
doi:10.1016/S1473-3099(12)70345-6
Published Online: 29 January 2013
Safety and immunogenicity of an oral, replicating adenovirus serotype 4 vector vaccine for H5N1 influenza: a randomised, double-blind, placebo-controlled, phase 1 study
Original Text
Dr Marc Gurwith MD a, Michael Lock PhD a, Eve M Taylor PhD a, Glenn Ishioka PhD a, Jeff Alexander PhD a, Tim Mayall PhD a, John E Ervin MD b, Prof Richard N Greenberg MD c, Cynthia Strout MD d, Prof John J Treanor MD e, Richard Webby PhD f, Prof Peter F Wright MD g
Summary
Background
Replication-competent virus vector vaccines might have advantages compared with non-replicating vector vaccines. We tested the safety and immunogenicity of an oral adenovirus serotype 4 vector vaccine candidate (Ad4-H5-Vtn) expressing the haemagglutinin from an avian influenza A H5N1 virus.
Methods
We did this phase 1 study at four sites in the USA. We used a computer-generated randomisation list (block size eight, stratified by site) to assign healthy volunteers aged 18?40 years to receive one of five doses of Ad4-H5-Vtn (107 viral particles [VP], 108 VP, 109 VP, 1010 VP, 1011 VP) or placebo (3:1). Vaccine or placebo was given on three occasions, about 56 days apart. Participants, investigators, and study-site personnel were masked to assignment throughout the study. Subsequently, volunteers received a boost dose with 90 μg of an inactivated parenteral H5N1 vaccine. Primary immunogenicity endpoints were seroconversion by haemagglutination-inhibition (HAI), defined as a four-times rise compared with baseline titre, and HAI geometric mean titre (GMT). We solicited symptoms of reactogenicity daily for 7 days after each vaccination and recorded symptoms that persisted beyond 7 days as adverse events. Primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01006798.
Findings
We enrolled 166 participants (125 vaccine; 41 placebo) between Oct 19, 2009, and Sept 9, 2010. HAI responses were low: 13 of 123 vaccinees (11%, 95% CI 6?17) and three of 41 placebo recipients (7%, 2?20) seroconverted. HAI GMT was 6 (95% CI 5?7) for vaccinees, and 5 (5?6) for placebo recipients. However, when inactivated H5N1 vaccine became available, one H5N1 boost was offered to all participants. In this substudy, HAI seroconversion occurred in 19 of 19 participants in the 1011 VP cohort (100%; 95% CI 82?100) and eight of 22 placebo recipients (36%; 17?59); 17 of 19 participants in the 1011 VP cohort (89%; 67?99) achieved seroprotection compared with four of 22 placebo recipients (18%; 5?40); GMT was 135 (89?205) with 1011 VP, compared with 13 (7?21) with placebo. The cumulative frequency of abdominal pain, diarrhoea, and nasal congestion after all three vaccinations was significantly higher in vaccinees than placebo recipients (21 [16?8%] of 125 vs one [2?4%] of 41, p=0?017; 24 [19?2%] of 125 vs two [4?9%] of 41, p=0?027; 41 [32?8%] of 125 vs six [14?6%] of 41, p=0?028; respectively). No serious treatment-related adverse events occurred.
Interpretation
Oral Ad4 vector priming might enhance the efficacy of poorly immunogenic vaccines such as H5N1.
Funding
Wellcome Trust Foundation, PaxVax.
a PaxVax, San Diego, CA, USA; b The Center for Pharmaceutical Research, Kansas City, MO, USA; c University of Kentucky School of Medicine, Department of Medicine, Lexington, KY, USA; d Coastal Carolina Research Center, Mt Pleasant, SC, USA; e University of Rochester, Department of Medicine, Rochester, NY, USA; f St Jude Children's Hospital, Memphis, TN, USA; g Geisel Medical School at Dartmouth, Hanover, NH, USA
Correspondence to: Dr Marc Gurwith, PaxVax, 3985-A Sorrento Valley Boulevard, San Diego, CA, USA
-doi:10.1016/S1473-3099(12)70345-6
Published Online: 29 January 2013
Safety and immunogenicity of an oral, replicating adenovirus serotype 4 vector vaccine for H5N1 influenza: a randomised, double-blind, placebo-controlled, phase 1 study
Original Text
Dr Marc Gurwith MD a, Michael Lock PhD a, Eve M Taylor PhD a, Glenn Ishioka PhD a, Jeff Alexander PhD a, Tim Mayall PhD a, John E Ervin MD b, Prof Richard N Greenberg MD c, Cynthia Strout MD d, Prof John J Treanor MD e, Richard Webby PhD f, Prof Peter F Wright MD g
Summary
Background
Replication-competent virus vector vaccines might have advantages compared with non-replicating vector vaccines. We tested the safety and immunogenicity of an oral adenovirus serotype 4 vector vaccine candidate (Ad4-H5-Vtn) expressing the haemagglutinin from an avian influenza A H5N1 virus.
Methods
We did this phase 1 study at four sites in the USA. We used a computer-generated randomisation list (block size eight, stratified by site) to assign healthy volunteers aged 18?40 years to receive one of five doses of Ad4-H5-Vtn (107 viral particles [VP], 108 VP, 109 VP, 1010 VP, 1011 VP) or placebo (3:1). Vaccine or placebo was given on three occasions, about 56 days apart. Participants, investigators, and study-site personnel were masked to assignment throughout the study. Subsequently, volunteers received a boost dose with 90 μg of an inactivated parenteral H5N1 vaccine. Primary immunogenicity endpoints were seroconversion by haemagglutination-inhibition (HAI), defined as a four-times rise compared with baseline titre, and HAI geometric mean titre (GMT). We solicited symptoms of reactogenicity daily for 7 days after each vaccination and recorded symptoms that persisted beyond 7 days as adverse events. Primary analysis was per protocol. This trial is registered with ClinicalTrials.gov, number NCT01006798.
Findings
We enrolled 166 participants (125 vaccine; 41 placebo) between Oct 19, 2009, and Sept 9, 2010. HAI responses were low: 13 of 123 vaccinees (11%, 95% CI 6?17) and three of 41 placebo recipients (7%, 2?20) seroconverted. HAI GMT was 6 (95% CI 5?7) for vaccinees, and 5 (5?6) for placebo recipients. However, when inactivated H5N1 vaccine became available, one H5N1 boost was offered to all participants. In this substudy, HAI seroconversion occurred in 19 of 19 participants in the 1011 VP cohort (100%; 95% CI 82?100) and eight of 22 placebo recipients (36%; 17?59); 17 of 19 participants in the 1011 VP cohort (89%; 67?99) achieved seroprotection compared with four of 22 placebo recipients (18%; 5?40); GMT was 135 (89?205) with 1011 VP, compared with 13 (7?21) with placebo. The cumulative frequency of abdominal pain, diarrhoea, and nasal congestion after all three vaccinations was significantly higher in vaccinees than placebo recipients (21 [16?8%] of 125 vs one [2?4%] of 41, p=0?017; 24 [19?2%] of 125 vs two [4?9%] of 41, p=0?027; 41 [32?8%] of 125 vs six [14?6%] of 41, p=0?028; respectively). No serious treatment-related adverse events occurred.
Interpretation
Oral Ad4 vector priming might enhance the efficacy of poorly immunogenic vaccines such as H5N1.
Funding
Wellcome Trust Foundation, PaxVax.
a PaxVax, San Diego, CA, USA; b The Center for Pharmaceutical Research, Kansas City, MO, USA; c University of Kentucky School of Medicine, Department of Medicine, Lexington, KY, USA; d Coastal Carolina Research Center, Mt Pleasant, SC, USA; e University of Rochester, Department of Medicine, Rochester, NY, USA; f St Jude Children's Hospital, Memphis, TN, USA; g Geisel Medical School at Dartmouth, Hanover, NH, USA
Correspondence to: Dr Marc Gurwith, PaxVax, 3985-A Sorrento Valley Boulevard, San Diego, CA, USA
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