Defense Systems International Autumn 1998; pp35-9.

Will anthrax vaccine help prevent biological warfare?

Meryl Nass, MD

The US Department of Defense (DoD) has begun vaccinating the first of 2.4 million active duty and reserve service members for anthrax. This is the first vaccine to be administered that is specifically designed as prophylaxis for biological warfare, but many more such vaccines may follow. The DoD recently created the Joint Vaccine Acquisition Program, whose mission is to develop and eventually administer new vaccines for about ten biological warfare threat agents. At the same time, troops are refusing the vaccine, citing safety issues. What is known about this vaccine, and is vaccination an effective way to counter the BW threat? How well does the anthrax vaccine work?

The anthrax vaccine is manufactured through the Michigan Department of Public Health (MDPH) at their Biologic Products Institute, under contract to DoD. According to Fort Detrick scientists whose field is anthrax vaccines, there are three problems with the MDPH-PA vaccine which the troops are receiving.

‘Two problems associated with the vaccine are the high incidence of local reactions [estimated at from two per cent to 33 per cent by different sources] and the requirement for numerous boosters [yearly after an initial six injections]. A third problem is the appar­ent inability of the vaccine to protect guinea pigs fully from challenge by certain highly virulent strains of B anthracis such as Ames and New Hampshire. Turnbull et al reported three biweekly immunisations with MDPH-PA pro-tested only 17 per cent of guinea pigs intramuscularly challenged with 500 to 1000 spores of such B anthracis strains.’ The Fort Detrick scientists concluded, ‘the results presented in this study clearly emphasise the need for a human anthrax vaccine to be efficacious against all virulent B anthracis strains, including those strains that are refractory to immunisation with MDPH-PA in guinea pigs’.

Will anthrax vaccine protect US troops? Hypothetically, the vaccine might save 50 per cent to 90 per cent of troops exposed to lethal doses of aerosolised anthrax, if the enemy limited itself to

strains that are susceptible to the vaccine. However, Iraq has a library of strains to choose from. According to Dr Raymond Zilinskas, former UNSCOM inspector in Iraq, ‘anthrax strains were imported from culture collections in France and the United States; others were local isolates. At Salman Pak, four strains were characterised...and their pathogenicity was evaluated in animal models’. Presumably, if Iraq had a choice, it would not use a strain for which US troops were protected.

Why doesn’t the vaccine protect against all strains of anthrax? The MDPH-PA vaccine is based on pro­tective antigen (PA), which is the molecule that allows the toxins (lethal factor and edema factor) to enter cells. Although Lt General Ronald Blanck, Army Surgeon General, was quoted as saying, ‘Our vaccine protects, as near as we know, against all of these strains because the vaccine is against a part of the

bacteria that doesn’t change, that doesn’t define one strain from another’, he is only partly right. PA is present in all strains of native anthrax, essential for infection, and important for immunity. But it is often not sufficient to provide a good immune response. If it were, the MDPH-PA vaccine would be 100 per cent effective in all animal species studied, and against all strains of anthrax. That is not the case.

For reasons that are at present poorly understood, the MDPH-PA vaccine does not afford protection against all strains of anthrax. For example, a 1986 study from Fort Detrick tested the MDPH-PA vaccine against 27 randomly selected anthrax isolates in guinea pigs. The animals were protected against 18 of the strains; but most of the guinea pigs did not survive challenge with the other nine strains.

Do primate studies belie the equivocal results with MDPH-PA in guinea pigs? Two studies were conducted at Fort Detrick with MDPH-PA in rhesus monkeys exposed to 255 to 900 times the LD5O, using the Ames strain of aerosolised anthrax, one of the vaccine-resistant strains. These are the only studies in primates that have attempted to duplicate the condi­tions that might be faced during a BW attack, using MDPH-PA prophylaxis. The results were spectacular, with nearly every immunised monkey surviving, and all the controls dying. However, these results should be viewed carefully. First, although the vaccine worked well against the Ames strain, it was not tested against other ‘vaccine-resistant’ strains. Second, these results are far superior to the results in humans, thus the findings may not carry over to humans.

In the only human field trial of the vaccine, one fully immunised person developed cutaneous anthrax, as did two partly immunised people. It is likely that many more would have succumbed had they faced hundreds of times the lethal dose. Third, these findings were presented to the International Workshop on Anthrax in 1995 as brief reports, and published in its proceedings. But they have not been published else­where and have therefore not been subject to careful peer review.

Can new vaccine strains be created that will resist our defensive measures? Yes. New strains of anthrax are easily created, using relatively simple techniques as well as sophisticated genetic engineering methods. We have been able to create antibiotic resistant strains for many years, and concerns regarding anti­biotic resistance led the DoD to suggest treatment with ciprofloxacin at the time of the Gulf War, since resistance to this antibiotic was felt to be harder to engineer. Vaccine-resistant strains can also be created. One example was published in the journal Vaccine last December. A Russian group created an anthrax strain which borrowed the cereolysin gene from Bacillus cereus. This construct resisted the Russians’ own vaccine. It is probable that Iraqi or other bioweapon developers could use the techniques described to produce strains likely to evade our vaccine. It is very difficult to be sanguine about one’s defences, even when excellent vaccines and antibiotics are used.

Is the vaccine well standardised? MDPH-PA was developed around 1960 and licensed in 1970. According to Dr Arthur Friedlander, chief of bacteri­

ology at Fort Detrick, and Dr Philip Brachman, lead author of the sole vaccine field trial, ‘The current vaccine against anthrax is unsatisfactory for several reasons. The vaccine is composed of an undefined crude culture supernatant adsorbed to aluminium hydroxide. There has been no quantification of the protective antigen content of the vaccine or of any of the other constituents, so the degree of purity is unknown...clearly a vaccine that is completely defined, that is less reactogenic, and that requires one or two doses to produce long-lasting immunity would be highly desirable The Fort Detrick researchers noted, ‘we have found that other lots of MDPH-PA vary significantly in their efficacy in guinea pigs’. In March, it was reported that the first lot of 200,000 doses of the vaccine had to be replaced, due to freezing during shipping. The FDA has cited numerous failures of quality control during inspections at the Michigan Biologic Products Institute (MBPI) conducted over several years. Yet MBPI is the only producer of the vaccine. Anthrax vaccine production has now been stopped, pending repairs being underwritten by DoD to MBPI’s production line.

Is the vaccine safe? Since the anthrax vaccine takes so many doses to become effective, and even then does not confer as much protection as desired, the use of new adjuvants (materials administered concur­rently with the vaccine to boost its effect) has been studied. In animals, adjuvants have led to stronger, more rapid and long-lasting immunity. British scientists at the PHLS Centre for Applied Microbiology and Research at Porton Down found that administering a vaccine of killed Bordetella pertussis cells along with anthrax vaccine produced enhanced and more long-lasting protection in guinea pigs than was obtained with the anthrax vaccine alone. At the time of the Gulf War, this practice apparently ‘jumped the species barrier’ to use with humans, not just guinea pigs. British troops were given both vaccines, despite the fact that the pertussis vaccine was licensed in France but not in the UK, and that the combination was experimental. The Ministry of Defence (MoD) asked the National Institute for Biologic Standards and Control (NIBSC) to veri~’ the safety of the pertussis vaccine. The NIBSC found that the combination caused ‘severe loss of condition and weight’ in animal studies, and notified the MoD accordingly. However, the warning was overlooked and the vaccine combina­tion widely administered.

These recent revelations lend weight to the suspicion that the vaccinations may contribute to development of Gulf War illnesses. Antibodies to

squalene have been found in the blood of hundreds of American Gulf War vets. Squalene is a component of several experimental adjuvant combinations. But US military physicians have reported that it was not used in Gulf War troops. Colonel Ed Koenigsberg, Director, Persian Gulf War Veterans’ Illness Investigation Team, testified before the Presidential Advisory Commission in October 1995 that no adjuvant other than alum had been used on American soldiers, and no secret immu­nisations were administered. However, anthrax researchers at Fort Detrick did study squalene­containing adjuvants with a PA vaccine, and found they worked better than the vaccine alone in guinea pigs. Squalene is not approved for use in humans, and the older literature suggests that significant problems, such as weight loss and allergic encephalomyelitis, may be associated with its use in experimental animals. The need for stronger, more rapid anthrax vaccine protection, the discovery that squalene containing adjuvants could provide this, and the fact that many vets now demonstrate antibodies to squalene, together suggest that squalene was given to Gulf War troops to enhance and hasten protection against anthrax. It too should now be studied as a possible contributor to Gulf War illnesses.

Why are troops getting anthrax vaccine now? Iraq is a threat today because the world applied no sanctions when it used chemical weapons against Iran and the Kurds in the I980s. Iraq has been a party to the Geneva Protocol since 1931. So there existed a legal framework in which to support an international effort in response to Iraq’s use of CW The short-term goal of using Iraq as a surrogate to weaken Iran, led the US not only to ignore Iraq’s CW use, but to provide aid which indirectly abetted Iraq in developing its chemical and biological weapons. Obviously, the lesson is that the world cannot afford to let any use of BW or CW be ignored, no matter what the imme­diate political issues. When glaring infractions are ignored, these weapons become more attractive, more nations may choose to pursue CBW programs, and the threat grows.

What is the solution? Unfortunately, there are no reliable medical defences against biological warfare, both today and in the foreseeable future, using even the most advanced technologies. Vaccines are not the solution. Even the best vaccines are only partially effective. They cannot protect against newly engineered micro-organisms. No matter how good the technol­ogy gets, there are intrinsic limitations: vaccines must be developed, tested in animals and then in humans, and observed over years, in order to demonstrate effectiveness and safety; new bacteria and viruses, however, can be created in weeks. Thus the development of potential new virulent organisms will necessarily outpace the creation of vaccines against them. Antibiotics may work in some cases, but antibiotic resistance is easy to introduce into bacteria. For a dis­ease like anthrax, by the time you develop symptoms, it is too late for antibiotics to be effective. And there are no effective antiviral drugs for viruses like Ebola, Lassa and Marburg. Newer treatments, such as mono or polyclonal antibody preparations, are still in development. They need intravenous lines and intensive medical care to administer. This will not be available on the battlefield or for massive numbers of patients.

Our medical system works for expected illnesses but when faced with new diseases and numerous casualties, will fail for lack of personnel, supplies, and medical expertise. Even if biosensors become perfectly accurate and provide instantaneous warning of attack, it will still take time to suit up and mask in protective gear. And that time may be sufficient to inhale many lethal doses. Perhaps there is no way to prevent or defend against a small-scale terrorist attack. But BW developed and used on a large scale can be prevented: the answer is to deny nations the opportunity to have these weapons. Serendipitously, the intrusive inspections and declarations that have been applied to Iraq recently can serve as a model of a verification regime that must be applied whenever there is strong suspicion of bioweapons development.

Other measures can be employed to prevent matters from going that far. The 1972 Biological Weapons Convention needs teeth. Now we can provide them. The US position regarding verification has come a long way in the past two years. It now agrees with limited inspections and some other measures. But industry remains nervous about potentially damaging inspections, and possible loss of proprietary secrets. The US government needs to study these issues more thoroughly and develop the technical means to assuage these concerns. If the United States led the way by extending itself to agreement with full inspections and other measures required to ensure treaty compliance, the measures would almost certainly be adopted by the parties to the convention, and the world would become a much safer place. Joshua Lederberg, Nobel prizewinner, put it simply:

‘There is no technical solution to the problem of biological weapons. It needs an ethical, human and moral solution if it’s going to happen at all. There is no other solution?