Biodefense and Emerging Infectious Diseases
Could a Blood Test Predict Protective Ability of Anthrax Vaccines in Humans?A sensitive, blood-based assay for measuring vaccine-induced antibodies to anthrax in animals detected a reliably measured protective response in several species, according to a collaborative study by scientists at NIAID and the Centers for Disease Control and Prevention (CDC). The findings, published in the Sept. 12, 2012 issue of Science Translational Medicine, suggest that the assay could potentially be used to predict how vaccines for anthrax might work in humans when studies in people are not ethical or safe to conduct, according to the authors.
Gram-stained cerebrospinal fluid showing anthrax bacilli (purple rods). (Credit: CDC, 2001). Original image, listed as in the public domain.
BackgroundIn 2002, the Food and Drug Administration (FDA) adopted the “Animal Rule,” a regulation enabling medical countermeasures to receive FDA approval based on effectiveness data in animals combined with safety and immune response data in humans. The Animal Rule allows vaccines to be studied and approved in cases where they cannot be ethically or feasibly tested in humans, such as when the disease in question is rare or potentially dangerous. Anthrax falls into this category.
Since natural human infection with anthrax is very rare and can be lethal, humans cannot ethically be exposed to anthrax to evaluate the efficacy of a vaccine. However, these types of studies could be humanely and responsibly performed in animals.
With this in mind, researchers at NIAID, CDC and other institutions examined data from 21 previous U.S. government anthrax vaccine studies in which a particular animal species was vaccinated at various dosages, measured for antibody response and challenged by inhaled Bacillus anthracis spores. The researchers examined the data to find relationships among them that could then be used to design tools to predict vaccine efficacy in humans. Six aspects of the 21 experiments changed from study to study: animal species, vaccine, use of saline or an adjuvant to dilute the vaccine, when immune response was measured, when the animals were challenged with anthrax, and vaccination schedule.
Taking these factors into account, the researchers evaluated animal blood specimens from the studies using a sensitive screening test called the lethal toxin neutralization activity assay (TNA), which measures antibodies resulting from vaccination. The assay involves placing toxin produced by anthrax with the antibodies induced by vaccination in plastic dishes that have a single layer of cells growing on the bottom.
Using the assay, antibodies are shown to be protective when the anthrax toxin is neutralized and the cells live. In contrast, if the antibodies are not protective, the cells are killed by the anthrax toxin. Because the way anthrax attacks cells is the same in animals and humans, the researchers say, the assay could be used in animals to predict vaccine-induced protection in humans.
Results and SignificanceMathematical models were used to determine the contribution of vaccine dilution, dose, and TNA on prediction of survival. For most settings, models using only TNA explained more than 75 percent of the survival effect.
Moreover, the assay performed well when comparing actual survival to predicted survival. For example, using data from cynomolgus macaques, the assay predicted 78.6 percent survival in rhesus macaques (83 percent actual survival) and 72.6 percent survival in rabbits (actual survival, 64.6 percent). Based on these findings, the authors assert that it may be feasible to use TNA as an immunological bridge between species and to extrapolate from animal data to predict anthrax vaccine effectiveness in humans.