Anthrax occupies a special role as a feared and potentially lethal disease, but the culmination of a ten-year research project has identified a section of its toxin that could produce an effective new vaccine. Published in PLOS Pathogens, colleagues and I have found a new inroad to developing an anthrax vaccine.
Since the Cold War, anthrax has had special status through the notion that it might be weaponised as an agent of biowarfare. Its use as a biological weapon in 2001, with spores sent through the US postal system, killed five people, infected 17 others.
Anthrax is caused by the bacterium Bacillus anthracis. It produces spores that release toxins, which can be inhaled, ingested or absorbed into the skin. Those infected by it may suffer disease ranging from treatable skin lesions to sepsis over the whole body. If the spores hit our lungs or intestines they can cause death within a few days. An accident in 1979 at a military facility in Russia accidentally released anthrax spores and more than 100 people died.
Although anthrax has existed for millennia, it has not actually had a major impact on humans, except for occupational exposure in those working with livestock, animal skins or wool, because it exists as long-lived spores in the soil and in the hides of livestock. What has led to work on vaccines more recently, however, is the fear of its use by armies or terrorists and a high value has been placed on ensuring that military personnel are effectively vaccinated.
Initial anthrax vaccines used weakened forms of the anthrax spore, which is a common way of developing vaccines. But its use led to concerns over high levels of “adverse reactions” – both soreness where the injection is delivered and heavy fevers. Until recently, vaccines used to protect against anthrax had been the AVA (Biothrax) vaccine in the US and AVP vaccine in the UK.
Both of these use weakened samples of the bacteria to enable the body to produce antibodies that target one of the key anthrax toxins, the “protective antigen” or “PA”. The idea here is that high levels of antibody to this antigen would mop up and neutralise any incoming anthrax spores before they can do damage. Next generation vaccines work on the same principle, but still require frequent topping up to maintain immunity.
Lethal factor
The toxic effects of anthrax are caused by a combination of three proteins: protective antigen (PA), edema factor (EF) and lethal factor (LF). Our new study reappraised our immune response when exposed to anthrax. So far, existing vaccines have focused on the PA protein, but we decided to look at the lethal factor after learning of farmers and shepherds in the Kayseri region of Turkey who recover from anthrax and never seem to be afflicted by it again.
These farmers and shepherds often had strong, presumably protective immunity to anthrax antigens that seemed to target LF more than PA.
With this in mind, we mapped antigen recognition in exposed and recovered farmers and compared it with biodefense workers who were given the old vaccine containing, as well as in mice. Because white blood cells carry a memory of the pathogens they have previously encountered, allowing a faster and more potent immune response on next encounter, it was possible to track how immunity developed after exposure to both LF and PA.
Surprising findings
There were a number of interesting and sometimes surprising findings. In mapping the antigens, we found some regions that were recognised exceptionally strongly by the immune response. We identified one stretch of 20 to 30 amino acids within LF that caught our attention due to its ability to bind strongly to very diverse human tissue types and, perhaps as a consequence of this, stimulate very powerful, protective immune responses from the relevant white blood cells, “T cells”.
Regions such as this could easily be incorporated into vaccines and we were able to use an LF-based vaccine of this type to successfully protect mice from the toxic effects of anthrax spores.
While this remains some way off development of vaccines for clinical trials in humans, the work points the way to developing a vaccine that may be a little more empirical and fleet of foot than traditional ones, building in data on the strongest antigens targeted by the body’s protective cells.