Perspectives

27 November 2009 Dr. Kristen Kerksiek

An indefinable risk: when microbes become weapons

Biohazard: Are we ready for the worst-case scenario? © Austrian Armed Forces

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You feel miserable. Fever, headache, backache, nausea, exhaustion…maybe it’s that virus that’s been going around the office. Could it be H1N1 or the common flu? Then your fever goes down, but a red rash appears on your face and then your arms and legs. Somehow the doctor’s response, “that happens sometimes with a viral infection” and “you’ll have to wait it out,” is not terribly comforting. When the rash gets worse instead of better you go back. You’re not prepared for what happens next: hospital, quarantine, tests… others with the same symptoms! And then you hear a word that you’d almost forgotten: bioterrorism.

It’s a nightmare. One that haunts many a government health official but has fortunately not become reality. Not yet. Bioterrorism was a particularly hot topic after September 11 and the anthrax letters that followed. It seemed all too probable that terrorists would use deadly microbiological agents – viruses, bacteria or their toxins – to kill, create fear and panic, and disrupt society. As time has gone by, these worries have faded somewhat from human consciousness, having been replaced by other, more pressing concerns: the H1N1 (swine) flu, the flailing economy, what’s for dinner tonight. But the threat remains.

2001 anthrax attacks in the United States

- Five letters postmarked September 18 were sent to media centers.
- Two letters (with more potent anthrax) postmarked October 9 were sent to politicians.
- The letters declared, "Death to America... Death to Israel... Allah is Great".
- Eleven cases of cutaneous anthrax and eleven cases of inhalational anthrax were diagnosed; five individuals died from inhalational anthrax.
- In mid-2008, scientist Bruce Edwards Ivins, a suspect in the anthrax attacks, committed suicide. Ivins worked with anthrax for vaccine development at the US biodefense labs at Fort Detrick (Maryland). Federal prosecutors later declared Ivins to be the sole perpetrator of the crime, but some controversy remains.

Bioterrorism poses a real – possible - danger that we have to respond to. However, the risk of a bioterrorist attack (the product of its probability and severity) is impossible to measure. And that complicates our response. We need to develop vaccines and therapeutic agents. We need to create response teams and train healthcare professionals. Preparation for an eventual bioterrorist attack requires time, effort and money, taking vital resources away from other areas. How much should we invest to prepare for an event that may never happen?

Worst-case scenario

The smallpox rash is characterized by homogeneous lesions that are most concentrated on the face, hands and feet. © CDC/James Hicks

There are cases all over the country. All people with direct contact to infected individuals are being vaccinated, and vaccine supplies are running low. But vaccination isn’t an option for you anymore. You already have smallpox, one of the most dreaded diseases known to mankind. Fatality rates were historically around 30% in unvaccinated people, and those that survive have terrible scarring. The doctors are taking care of you, giving you intravenous fluids and medicine to control fever and pain, checking for secondary bacterial infections, but there’s no treatment for the smallpox virus. The infection has to run its course, and you’ll just have to “wait it out”.

Smallpox (caused by Variola, an orthopoxvirus) might be an ideal biological weapon: it is highly contagious (by aerosol) with a very low infectious dose and is highly stable for long periods outside the human host (airborne spread to persons other than close contacts is controversial). It has a long, asymptomatic incubation period and results in high mortality and lasting consequences for survivors. Immunity is waning in vaccinated individuals, and a large fraction of the population has absolutely no protection; routine vaccination was stopped in the early 1970s as smallpox neared eradication (the last natural case occurred in Somalia in 1977, and a final, fatal laboratory-acquired case occurred in the United Kingdom in 1978.). Most physicians today have never seen the disease, which could delay the detection of early cases and the implementation of public health interventions. A smallpox epidemic could be devastating, and that’s why the virus is so feared.

Variola is a double-stranded DNA virus that enters the body via the respiratory mucosa and, after systemic spread, localizes in small blood vessels of the dermis. © CDC/ Dr. Fred Murphy

But could it ever happen? Could terrorists get their hands on smallpox virus? The virus still exists at two locations, the Centers for Disease Control and Prevention (CDC) in Atlanta and the Center for Research on Virology and Biotechnology (VECTOR) in Koltsovo (Novosibirsk), Russia. Officially. There are fears, rumors, even sketchy reports that stray viral stocks from the times of Soviet bioweapon research or modern stocks kept under insufficient security conditions may have wandered into the wrong hands. Specimens of virus from the smallpox eradication campaign may also be unaccounted for. And theoretically, a recombinant smallpox virus could also be engineered using the available Variola sequence and a homologous orthopoxvirus (e.g. monkeypox virus) as a starting point. Only time will tell, time we need to use to prepare for the eventuality of an attack.
 

‘Category A’ Bioterrorism Agents/Diseases: defined by easy dissemination or person-to-person transmission and high mortality rates/major public health impact

- Anthrax (Bacillus anthracis)
- Botulism (Clostridium botulinum toxin)
- Plague (Yersinia pestis)
- Smallpox (Variola major)
- Tularemia (Francisella tularensis)
- Viral hemorrhagic fevers (filoviruses [Ebola, Marburg], arenaviruses [Lassa, Machupo])

More information about category A, B and C agents can be found on the CDC website: www.bt.cdc.gov/agent/agentlist-category.asp     

Preparing for the possible

The epidemic still hasn’t ended, but the number of new cases is decreasing; ring vaccination (vaccinating and monitoring a ring of people around each infected individual) seems to be working. The new generation of smallpox vaccines and novel antiviral medications could be used to effectively treat smallpox-exposed individuals who had a high risk of complications from the standard vaccine. You’ve recovered from the infection physically, but you’ll never be the same.

At a meeting organized by the CDC in 1999, experts unanimously deemed smallpox to be the greatest bioterrorism threat to the United States. However, smallpox is certainly not the only biological agent with the potential to wreak havoc on society, and many of the challenges that exist in making a rapid response to smallpox apply just as well to other potential bioterrorism agents.

Take, for example, the challenge of rapid diagnosis, a difficult task for physicians who have only textbook knowledge of these rare – or eradicated – diseases. Containment of an epidemic requires that we know what we’re fighting. And when treatment is available, it’s almost certain that one rule applies: the faster the better. One approach to addressing this problem is a ‘dual-use model’ in which specially educated task forces are trained to investigate any unusual disease outbreak, be it natural or ‘man-made’…killing two birds with one stone.

In the past, ~1000/1 million first-time vaccinees had serious reactions to the smallpox vaccine, and between 14 and 52 people experienced potentially life-threatening complications such as progressive vaccinia. © Moses Grossman, MD/California Emergency Preparedness Office

Vaccination may be the best way to protect the public from bioterrorism, but at the moment vaccines exist only for anthrax and smallpox (among the Category A agents). And they leave room for improvement: the anthrax vaccine requires 6 injections over 18 months followed by yearly boosters, and the live smallpox vaccine causes more serious adverse reactions than any other licensed vaccine. Development of vaccines for other potential biological weapons as well as better anthrax and smallpox vaccines is needed.

Easier said than done. Vaccine development is an expensive, complicated and lengthy process. However, it’s a process that many research groups are dedicated to. In the November 5 issue of Vaccine, a supplementary section is devoted entirely to the topic ‘Biodefense and Vaccines’. Using a variety of modern technological methods, scientists are in the process of designing vaccines against a significant number of microorganisms on the list of bioterrorism agents. While the development of some vaccines is facing fundamental difficulties during development (e.g. the lack of a good animal model for Francisella tularensis), other new vaccines (e.g. a less reactogenic plague vaccine) are already in clinical trials.
 

Contraindications for smallpox (Vaccinia) vaccination*

- Eczema, atopic dermatitis and other acute, chronic or exfoliative skin conditions (vaccination can lead to severe and potentially fatal eczema vaccinatum)
- Diseases or conditions that cause immunodeficiency or immunosuppression (unchecked replication of the Vaccinia virus -progressive vaccinia - can be deadly)
- Treatments that cause immunodeficiency or immunosuppression
- Pregnancy

* apply to potential vaccinees and their household contacts, as the live Vaccinia virus used in the vaccine can be spread to others from the vaccine site

Because of the frequency and severity of complications following smallpox vaccination, renewed mass immunization in the absence of a concrete risk (outbreak/epidemic) is highly unlikely.

The challenges ahead

Quarantine is a vital part of the response plan for smallpox: patients are infectious from the appearance of the rash until the last scab falls off. © WHO/NLM

The good news is that new and better vaccines for a variety of potential biological weapons are on the way; despite the uncertainty as to whether biodefense vaccines will be necessary, money for their development has been granted over the last years. It’s vital that funding remains available and research continues. Several countries (including the United States and Germany) have also stockpiled enough of the current smallpox vaccine to immunize their entire population (worldwide stocks are enough for only ~10% of the world’s population). The bad news is that difficult questions still remain. When vaccine supplies are limited, who should be vaccinated? Should at-risk (smallpox-exposed) persons be forced to receive vaccination for the good of the public? Response plans (see below) were developed by a number of countries in the wake of September 11 and the anthrax attacks, but it’s been a while since we’ve taken a closer look at them. It’s hard to stay diligent when the risk is indefinable, but an optimal response requires optimal preparation…before the crisis.

References and additional reading:

Smallpox attack response plans

- Centers for Disease Control and Prevention (CDC)/USA: www.bt.cdc.gov/agent/smallpox/response-plan/
- Department of Health (Great Britain):
www.dh.gov.uk/en/Publicationsandstatistics/Publications/PublicationsPolicyAndGuidance/DH_4070830
- Robert Koch Institute (Germany):
www.rki.de/cln_160/nn_199522/DE/Content/Infekt/Biosicherheit/Vorsorge/Pockenrahmenkonzept/Ausbildungsmaterialien/Listung__Materialien.html

Information about smallpox and other biological agents

- CDC website on bioterrorism: www.bt.cdc.gov/bioterrorism/
- World Health Organization information about smallpox: www.who.int/mediacentre/factsheets/smallpox/en/
- Robert Koch Institute (information about smallpox and various other biological agents)
www.rki.de/cln_160/nn_494682/DE/Content/Infekt/Biosicherheit/Erreger/dl__pocken.html
www.rki.de/cln_160/nn_199522/DE/Content/Infekt/Biosicherheit/Management/management__node.html

- A history of smallpox: www.ucpress.edu/books/pages/9968/9968.ch01.php
- An overview of smallpox as a weapon: www.globalsecurity.org/wmd/library/report/1997/cwbw/Ch27.pdf

Primary literature and scientific review articles

On November 5, 2009, Vaccine dedicated a supplementary section to Vaccines for Biodefense. In addition to general (introductory) articles on the topic, there are reports on the development of vaccines against specific bacterial and viral pathogens, for example:

Gregory A. Poland, Robert M. Jacobson, Jon Tilburt and Kristin Nichol. The social, political, ethical, and economic aspects of biodefense vaccines. pages D23-D27 (doi: 10.1016/j.vaccine.2009.08.054) dx.doi.org/10.1016/j.vaccine.2009.08.054

Richard B. Kennedy, Inna Ovsyannikova and Gregory A. Poland. Smallpox vaccines for biodefense. pages D73-D79 (doi: 10.1016/j.vaccine.2009.07.103) dx.doi.org/10.1016/j.vaccine.2009.07.103


On April 25, 2002, The New England Journal of Medicine published several articles dealing with smallpox and bioterrorism (including diluting vaccines, vaccine policy):

Perspective: Smallpox and Bioterrorism by J. M. Drazen
Editorial: Smallpox Vaccination Policy — The Need for Dialogue by A. S. Fauci
Review: Current Concepts: Diagnosis and Management of Smallpox by J. G. Breman and D.A. Henderson
Legal Issues: Bioterrorism, Public Health, and Civil Liberties by G. J. Annas
Original Articles:
Frey, S.E. et al. Clinical Responses to Undiluted and Diluted Smallpox Vaccine
Frey, S.E. et al. Dose-Related Effects of Smallpox Vaccine
Access free articles under content.nejm.org/content/vol346/issue17/index.dtl

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