title: Comprehensive analysis and selection of anthrax vaccine adsorbed immune correlates of protection in rhesus macaques.
abstract: Humoral and cell-mediated immune correlates of protection (COP) for inhalation anthrax in a rhesus macaque (Macaca mulatta) model were determined. The immunological and survival data were from 114 vaccinated and 23 control animals exposed to Bacillus anthracis spores at 12, 30, or 52 months after the first vaccination. The vaccinated animals received a 3-dose intramuscular priming series (3-i.m.) of anthrax vaccine adsorbed (AVA) (BioThrax) at 0, 1, and 6 months. The immune responses were modulated by administering a range of vaccine dilutions. Together with the vaccine dilution dose and interval between the first vaccination and challenge, each of 80 immune response variables to anthrax toxin protective antigen (PA) at every available study time point was analyzed as a potential COP by logistic regression penalized by least absolute shrinkage and selection operator (LASSO) or elastic net. The anti-PA IgG level at the last available time point before challenge (last) and lymphocyte stimulation index (SI) at months 2 and 6 were identified consistently as a COP. Anti-PA IgG levels and lethal toxin neutralization activity (TNA) at months 6 and 7 (peak) and the frequency of gamma interferon (IFN-γ)-secreting cells at month 6 also had statistically significant positive correlations with survival. The ratio of interleukin 4 (IL-4) mRNA to IFN-γ mRNA at month 6 also had a statistically significant negative correlation with survival. TNA had lower accuracy as a COP than did anti-PA IgG response. Following the 3-i.m. priming with AVA, the anti-PA IgG responses at the time of exposure or at month 7 were practicable and accurate metrics for correlating vaccine-induced immunity with protection against inhalation anthrax.
authors.affiliation: Centers for Disease Control and Prevention, Atlanta, Georgia, USA Atlanta Research and Education Foundation, Inc., Decatur, Georgia, USA.
authors.forename: Ligong
authors.initials: L
authors.lastname: Chen
authors.affiliation: Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Jarad M
authors.initials: JM
authors.lastname: Schiffer
authors.affiliation: Centers for Disease Control and Prevention, Atlanta, Georgia, USA Atlanta Research and Education Foundation, Inc., Decatur, Georgia, USA.
authors.forename: Shannon
authors.initials: S
authors.lastname: Dalton
authors.affiliation: Battelle, Columbus, Ohio, USA.
authors.forename: Carol L
authors.initials: CL
authors.lastname: Sabourin
authors.affiliation: Battelle, Columbus, Ohio, USA.
authors.forename: Nancy A
authors.initials: NA
authors.lastname: Niemuth
authors.affiliation: Centers for Disease Control and Prevention, Atlanta, Georgia, USA.
authors.forename: Brian D
authors.initials: BD
authors.lastname: Plikaytis
authors.affiliation: Centers for Disease Control and Prevention, Atlanta, Georgia, USA cquinn@cdc.gov.
authors.forename: Conrad P
authors.initials: CP
authors.lastname: Quinn
mesh_terms: D000818:Animals; D000881:Anthrax / Q000276:immunology* / Q000401:mortality / Q000517:prevention & control*; D022122:Anthrax Vaccines / Q000008:administration & dosage / Q000276:immunology*; D000907:Antibodies, Bacterial / Q000097:blood; D000942:Antigens, Bacterial / Q000276:immunology; D001427:Bacterial Toxins / Q000276:immunology; D015415:Biomarkers; D004195:Disease Models, Animal; D020869:Gene Expression Profiling; D007074:Immunoglobulin G / Q000097:blood; D007371:Interferon-gamma / Q000032:analysis; D015847:Interleukin-4 / Q000032:analysis; D008214:Lymphocytes / Q000276:immunology; D008253:Macaca mulatta; D012141:Respiratory Tract Infections / Q000276:immunology* / Q000401:mortality / Q000517:prevention & control*; D016019:Survival Analysis; D014611:Vaccination / Q000379:methods
chemical_list: D022122:Anthrax Vaccines; D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D001427:Bacterial Toxins; D015415:Biomarkers; C493276:Biothrax; D007074:Immunoglobulin G; C030325:anthrax toxin; D015847:Interleukin-4; D007371:Interferon-gamma