Phase 3 trial evaluating the immunogenicity and safety of a three-dose BioThrax® regimen for post-exposure prophylaxis in healthy adults

Hopkins, Robert J.; Howard, Cris; Hunter-Stitt, Ericka; Kaptur, Paulina E.; Pleune, Brett; Muse, Derek; Sheldon, Eric; Davis, Matthew W.; Strout, Cynthia; Vert-Wong, Katya

doi:10.1016/j.vaccine.2014.01.073

Cited by 19 publications

(14 citation statements)

References 7 publications

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“…The BioThrax group (Group 5) failed to meet this success criterion on Day 63, which differs from previous BioThrax vaccine studies [5, 6] and is likely explained by low sample size and/or difference in route of administration (IM vs. SC) [8]. …”

Section: Discussionmentioning

confidence: 72%

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Randomized, double-blind, active-controlled study evaluating the safety and immunogenicity of three vaccination schedules and two dose levels of AV7909 vaccine for anthrax post-exposure prophylaxis in healthy adults

Hopkins

Kalsi

Montalvo-Lugo

et al. 2016

Vaccine

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AV7909 vaccine being developed for post-exposure prophylaxis of anthrax disease may require fewer vaccinations and reduced amount of antigen to achieve an accelerated immune response over BioThrax® (Anthrax Vaccine Adsorbed). A phase 2, randomized, double-blind, BioThrax vacccine-controlled study was conducted to evaluate the safety and immunogenicity of three intramuscular vaccination schedules and two dose levels of AV7909 in 168 healthy adults. Subjects were randomized at a 4:3:2:4:2 ratio to 5 groups: 1) AV7909 on Days 0/14; 2) AV7909 on Days 0/28; 3) AV7909 on Days 0/14/28; 4) half dose AV7909 on Days 0/14/28; and 5) BioThrax vaccine on Days 0/14/28. Vaccinations in all groups were well tolerated. The incidences of adverse events (AEs) were 79% for AV7909 subjects and 65% for BioThrax subjects; 92% of AV7909 subjects and 87% of BioThrax subjects having AEs reported Grade 1-2 AEs. No serious AEs were assessed as potentially vaccine-related, and no AEs of potential autoimmune etiology were reported. There was no discernible pattern indicative of a safety concern across groups in the incidence or severity of reactogenicity events. Groups 2, 3, and 4 achieved success for the primary endpoint, demonstrated by a lower 95% confidence limit of the percentage of subjects with protective toxin neutralizing antibody NF50 values (≥ 0.56) to be ≥ 40% at Day 63. Group 1 marginally missed the criterion (lower bound 95% confidence limit of 39.5%). Immune responses were above this threshold for Groups 1, 3 and 4 at Day 28 and all groups at Day 42. Further study of an AV7909 two-dose schedule given 2 weeks apart is warranted in light of the favorable tolerability profile and immunogenicity response relative to three doses of BioThrax vaccine, as well as preliminary data from nonclinical studies indicating similar immune responses correlate with higher survival for AV7909 than BioThrax vaccine.

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Section: Discussionmentioning

confidence: 72%

“…The BioThrax immunization regimen used in this study has been shown to achieve circulating TNA titers that have conferred at least 70% survival to rabbits and non-human primates after B. anthracis spore challenge [5, 6]. …”

Section: Methodsmentioning

confidence: 99%

Randomized, double-blind, active-controlled study evaluating the safety and immunogenicity of three vaccination schedules and two dose levels of AV7909 vaccine for anthrax post-exposure prophylaxis in healthy adults

Hopkins

Kalsi

Montalvo-Lugo

et al. 2016

Vaccine

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“…This vaccine is produced from a culture filtrate of a non-virulent Bacillus anthracis strain. BioThrax is administered by subcutaneous injection of six doses per treatment [ 25 , 26 ]. Raxibacumab is a monoclonal antibody (human γ IgG1) produced by rDNA technology in a murine cell expression system.…”

Section: Discussionmentioning

confidence: 99%

Expression, Purification, and Biophysical Characterization of a Secreted Anthrax Decoy Fusion Protein in Nicotiana benthamiana

Karuppanan

Duhra-Gill

Kailemia

et al. 2017

IJMS

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Anthrax toxin receptor-mediated drug development for blocking anthrax toxin action has received much attention in recent decades. In this study, we produced a secreted anthrax decoy fusion protein comprised of a portion of the human capillary morphogenesis gene-2 (CMG2) protein fused via a linker to the fragment crystallizable (Fc) domain of human immunoglobulin G1 in Nicotiana benthamiana plants using a transient expression system. Using the Cauliflower Mosaic Virus (CaMV) 35S promoter and co-expression with the p19 gene silencing suppressor, we were able to achieve a high level of recombinant CMG2-Fc-Apo (rCMG2-Fc-Apo) protein accumulation. Production kinetics were observed up to eight days post-infiltration, and maximum production of 826 mg/kg fresh leaf weight was observed on day six. Protein A affinity chromatography purification of the rCMG2-Fc-Apo protein from whole leaf extract and apoplast wash fluid showed the homodimeric form under non-reducing gel electrophoresis and mass spectrometry analysis confirmed the molecular integrity of the secreted protein. The N-glycosylation pattern of purified rCMG2-Fc-Apo protein was analysed; the major portion of N-glycans consists of complex type structures in both protein samples. The most abundant (>50%) N-glycan structure was GlcNAc 2 (Xy l )Man 3 (Fuc)GlcNAc 2 in rCMG2-Fc-Apo recovered from whole leaf extract and apoplast wash fluid. High mannose N-glycan structures were not detected in the apoplast wash fluid preparation, which confirmed the protein secretion. Altogether, these findings demonstrate that high-level production of rCMG2-Fc-Apo can be achieved by transient production in Nicotiana benthamiana plants with apoplast targeting.

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“…Live, nonencapsulated toxigenic strains (similar to the historic Sterne veterinary vaccine) are used as vaccines in Russia and China. Although improvements have been made in new generations of the US vaccine, the major changes are less-frequent dosages or altered routes of administration of a vaccine very similar to its 1960s counterpart (100,201,275). Recently advances in enhancement of the immune response through cofactors targeting TLR signaling have been reported as well (219).…”

Section: Vaccinesmentioning

confidence: 99%

Anthrax Pathogenesis

Moayeri

Leppla

Vrentas

et al. 2015

Annu. Rev. Microbiol.

235

213

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Anthrax is caused by the spore-forming, gram-positive bacterium Bacillus anthracis. The bacterium's major virulence factors are (a) the anthrax toxins and (b) an antiphagocytic polyglutamic capsule. These are encoded by two large plasmids, the former by pXO1 and the latter by pXO2. The expression of both is controlled by the bicarbonate-responsive transcriptional regulator, AtxA. The anthrax toxins are three polypeptides-protective antigen (PA), lethal factor (LF), and edema factor (EF)-that come together in binary combinations to form lethal toxin and edema toxin. PA binds to cellular receptors to translocate LF (a protease) and EF (an adenylate cyclase) into cells. The toxins alter cell signaling pathways in the host to interfere with innate immune responses in early stages of infection and to induce vascular collapse at late stages. This review focuses on the role of anthrax toxins in pathogenesis. Other virulence determinants, as well as vaccines and therapeutics, are briefly discussed.

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Phase 3 trial evaluating the immunogenicity and safety of a three-dose BioThrax® regimen for post-exposure prophylaxis in healthy adults

Cited by 19 publications

References 7 publications

Randomized, double-blind, active-controlled study evaluating the safety and immunogenicity of three vaccination schedules and two dose levels of AV7909 vaccine for anthrax post-exposure prophylaxis in healthy adults

Randomized, double-blind, active-controlled study evaluating the safety and immunogenicity of three vaccination schedules and two dose levels of AV7909 vaccine for anthrax post-exposure prophylaxis in healthy adults

Expression, Purification, and Biophysical Characterization of a Secreted Anthrax Decoy Fusion Protein in Nicotiana benthamiana

Anthrax Pathogenesis

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