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Immunogenicity and safety of four different dosing regimens of anthrax vaccine adsorbed for post-exposure prophylaxis for anthrax in adults.

ABSTRACT: BACKGROUND:Strategies to implement post exposure prophylaxis (PEP) in case of an anthrax bioterror event are needed. To increase the number of doses of vaccine available we evaluated reducing the amount of vaccine administered at each of the vaccinations, and reducing the number of doses administered. METHODS:Healthy male and non-pregnant female subjects between the ages of 18 and 65 were enrolled and randomized 1:1:1:1 to one of four study arms to receive 0.5 mL (standard dose) of vaccine subcutaneously (SQ) at: (A) days 0, 14; (B) days 0 and 28; (C) days 0, 14, and 28; or (D) 0.25 mL at days 0, 14, and 28. A booster was provided on day 180. Safety was assessed after each dose. Blood was obtained on days 0, 7, 14, 21, 28, 35, 42, 49, 56, 63, 70, 84, 100, 180, and 201 and both Toxin Neutralizing antibody and anti-PA IgG antibody measured. RESULTS:Almost all subjects developed some local reactions with 46-64% reported to be of moderate severity and 3.3% severe during the primary series. Vaccine groups that included a day 14 dose induced a ? 4 fold antibody rise in more subjects on days 21, 28, and 35 than the arm without a day 14 dose. However, schedules with a full day 28 dose induced higher peak levels of antibody that persisted longer. The half dose regimen did not induce antibody as well as the full dose study arms. CONCLUSION:Depending on the extent of the outbreak, effectiveness of antibiotics and availability of vaccine, the full dose 0, 28 or 0, 14, 28 schedules may have advantages.

SUBMITTER: Bernstein DI

PROVIDER: S-EPMC4250293 | biostudies-literature | 2014 Oct

REPOSITORIES: biostudies-literature

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Immunogenicity and safety of four different dosing regimens of anthrax vaccine adsorbed for post-exposure prophylaxis for anthrax in adults.

Bernstein David I DI Jackson Lisa L Patel Shital M SM El Sahly Hana M HM Spearman Paul P Rouphael Nadine N Rudge Thomas L TL Hill Heather H Goll Johannes B JB

Vaccine 20140917 47

<h4>Background</h4>Strategies to implement post exposure prophylaxis (PEP) in case of an anthrax bioterror event are needed. To increase the number of doses of vaccine available we evaluated reducing the amount of vaccine administered at each of the vaccinations, and reducing the number of doses administered.<h4>Methods</h4>Healthy male and non-pregnant female subjects between the ages of 18 and 65 were enrolled and randomized 1:1:1:1 to one of four study arms to receive 0.5 mL (standard dose) o ...[more]

PMID: 25239484

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Project description:The manufacture of the UK Anthrax vaccine (AVP) focuses on the production of Protective Antigen (PA) from the Bacillus anthracis Sterne strain. Although used for decades, several of AVP's fundamental properties are poorly understood, including its exact composition, the extent to which proteins other than PA may contribute to protection, and whether the degree of protection varies between individuals.This study involved three innovative investigations. Firstly, the composition of AVP was analyzed using liquid chromatography tandem mass-spectrometry (LC-MS/MS), requiring the development of a novel desorption method for releasing B. anthracis proteins from the vaccine's aluminum-containing adjuvant. Secondly, computational MHC-binding predictions using NetMHCIIpan were made for the eight most abundant proteins of AVP, for the commonest HLA alleles in multiple ethnic groups, and for multiple B. anthracis strains. Thirdly, antibody levels and toxin neutralizing antibody (TNA) levels were measured in sera from AVP human vaccinees for both PA and Lethal Factor (LF).It was demonstrated that AVP is composed of at least 138 B. anthracis proteins, including PA (65%), LF (8%) and Edema Factor (EF) (3%), using LC-MS/MS. NetMHCIIpan predicted that peptides from all eight abundant proteins are likely to be presented to T cells, a pre-requisite for protection; however, the number of such peptides varied considerably between different HLA alleles.These analyses highlight two important properties of the AVP vaccine that have not been established previously. Firstly, the effectiveness of AVP within humans may not depend on PA alone; there is compelling evidence to suggest that LF has a protective role, with computational predictions suggesting that additional proteins may be important for individuals with specific HLA allele combinations. Secondly, in spite of differences in the sequences of key antigenic proteins from different B. anthracis strains, these are unlikely to affect the cross-strain protection afforded by AVP.

Project description:BackgroundAnthrax and its etiologic agent remain a biological threat. Anthrax vaccine is highly effective, but vaccine-induced IgG antibody responses vary widely following required doses of vaccinations. Such variation can be related to genetic factors, especially genomic copy number variants (CNVs) that are known to be enriched among genes with immunologic function. We have tested this hypothesis in two study populations from a clinical trial of anthrax vaccination.MethodsWe performed CNV-based genome-wide association analyses separately on 794 European Americans and 200 African-Americans. Antibodies to protective antigen were measured at week 8 (early response) and week 30 (peak response) using an enzyme-linked immunosorbent assay. We used DNA microarray data (Affymetrix 6.0) and two CNV detection algorithms, hidden markov model (PennCNV) and circular binary segmentation (GeneSpring) to determine CNVs in all individuals. Multivariable regression analyses were used to identify CNV-specific associations after adjusting for relevant non-genetic covariates.ResultsWithin the 22 autosomal chromosomes, 2,943 non-overlapping CNV regions were detected by both algorithms. Genomic insertions containing HLA-DRB5, DRB1 and DQA1/DRA genes in the major histocompatibility complex (MHC) region (chromosome 6p21.3) were moderately associated with elevated early antibody response (β = 0.14, p = 1.78×10(-3)) among European Americans, and the strongest association was observed between peak antibody response and a segmental insertion on chromosome 1, containing NBPF4, NBPF5, STXMP3, CLCC1, and GPSM2 genes (β = 1.66, p = 6.06×10(-5)). For African-Americans, segmental deletions spanning PRR20, PCDH17 and PCH68 genes on chromosome 13 were associated with elevated early antibody production (β = 0.18, p = 4.47×10(-5)). Population-specific findings aside, one genomic insertion on chromosome 17 (containing NSF, ARL17 and LRRC37A genes) was associated with elevated peak antibody response in both populations.ConclusionMultiple CNV regions, including the one consisting of MHC genes that is consistent with earlier research, can be important to humoral immune responses to anthrax vaccine adsorbed.

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Immunogenicity and safety of four different dosing regimens of anthrax vaccine adsorbed for post-exposure prophylaxis for anthrax in adults.

Publications

Immunogenicity and safety of four different dosing regimens of anthrax vaccine adsorbed for post-exposure prophylaxis for anthrax in adults.

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