Bioterrorism: Category A Agents (Which Are The Most Deadly?)

Category A Agents are the highest-priority risk agents with the greatest potential damage when used as-is or modified by technology such as CRISPR/CAS9.

These agents include:

Anthrax (Bacillus anthracis)
Botulism (Clostridium botulinum toxin)
Plague (Yersinia pestis)
Smallpox (variola major)
Tularemia (Francisella tularensis)
Viral hemorrhagic fevers with two sub-categories:
- Filoviruses (Ebola, Marburg)
- Arenaviruses (Lassa, Machupo)

We’ll break these down to make sense of why they are considered Cat A and what versions are at risk for bioterror modification.

Anthrax

Anthrax is caused by Bacillus anthracis (B. anthracis). It can occur in 4 different forms:

Skin
Lungs
Intestinal
Injection

Typically, when people think of anthrax, they think of the respiratory anthrax (lungs) variant.

Without treatment, the risk of death from skin anthrax is around 24%. With treatment, the risk of morality is very low.

For intestinal infection, the risk of death is 25-75%. Even with treatment, fatality rates only fall to about 25-60%.

Injection anthrax is similar to cutaneous (skin) anthrax, except that it can create abscesses under the skin and spread throughout the body much faster.

Respiratory anthrax, on the other hand, has a morality rate of 50% to 80% even with treatment. Without treatment, the numbers are in the upper 90s.

The respiratory variant is also the most likely to be used for bioterror attacks, as it is more easily distributed and easier to infect. It only takes inhalation of the bacteria, rather than injection, ingestion, or skin contact. And it also causes the highest morality rate, as treatment cannot respond fast enough in most cases.

For this reason, we will focus on respiratory anthrax for the purpose of this article.

Exposure/Spread of Anthrax

Anthrax typically does not spread from human to human. However, if fatal, the infected body becomes a source of infection to others.

Anthrax also has an insane resilience. It can survive in harsh conditions for decades, sometimes centuries. It can even hold out from death, burial sites with anthrax have caused infection up to 80 years after the burial.

Respiratory anthrax, unless treated prior to when symptoms become present, is almost always fatal.

How Anthrax Works

Anthrax is lethal primarily due to two factors:

The poly-D-glutamic acid capsule
The anthrax toxin (tripartite protein toxin)

The first protects the bacteria from being engulfed by the host’s white blood cells (defense mechanism).

The latter holds three additional protein components: PA (protective antigen), EF (edema factor), and LF (lethal factor). PA and LF produce lethal toxin to the host, while PA plus EF produces edema toxin. Both of these protein combinations cause death and edema.

The PA then binds to receptors on the host cell. This results in PA₆₃, which combines with other PA₆₃ fragments to make a prepore. As a prepore, the complex can bind EFs and LFs described above to form the toxin versions.

During this time, LF also inactivates the immune system response. So the immune system does not have the ability to fight the bacteria.

These anthrax complexes then convince the host to create TNF-alpha and IL1B (Interleukin 1, beta) in excess. This overproduction is what leads to the death of the host.

Anthrax also has the ability to target the cells that line cavities, such as lymph vessels and the pericardial cavity. This causes vascular leaking of fluids/cells, and results in hypovolemic shock (decrease of blood plasma necessary to survive) or septic shock.

Treatment for Anthrax

There is currently a vaccine for anthrax, however, its effectiveness is questionable. The vaccine also needs continual annual boosters after a 5-course sequence to be effective.

Antibiotics are used for those who have been exposed. They need to be administered early, as any delay significantly lessens chances for survival.

Typically, this includes huge doses of IV and oral antibiotics. FDA agents approved for treatment include ciprofloxacin, doxycycline, and penicillin.

For respiratory anthrax, prophylaxis treatment is required as soon as possible.

There is also a newer drug available for respiratory anthrax called raxibacumab, which neutralizes the toxins produced by B. anthracis.

Bioterrorism Impact of Anthrax

Anthrax is one of the most well-known biological warfare agents worldwide.

It is used as a respiratory bio-agent, particularly using the spores of anthrax to disseminate. The US and Soviet Union both had massive stockpiles of B. anthracis prior to the Biological Weapons Convention in 1972.

In theory, anthrax spores can be created with easily found equipment and a low level education on microbiology. To get larger variants in aerosol form requires a tad more sophistication.

Likewise, developing this to pandemic level would be nigh-impossible. Simply because of the need to transfer human-to-human, and the fast mortality times.

Anthrax Unique Fact

In 2016, there was an anthrax outbreak in Russia that took the lives of many wild animals and resulted in over 40 people being admitted to the hospital, including some deaths.

Where did the outbreak originate from?

A 75-year-old reindeer carcass that defrosted from a heatwave.

This bacterium is resilient.

Botulism

Botulism is caused by the bacteria Clostridium botulinum toxin. It typically attacks the body’s nerves to cause damage/death.

There are five main kinds of Botulism:

Foodborne
Wound
Infant
Adult Intestinal
Latrogenic

In order:

Is caused by the ingestion of food that has the toxin.
Occurs if the toxin interacts with wounds (open sores, for example) and begins to breed more toxins.
Is when an infant has the toxin in their intestinal system, which results in spores growing inside the child.
Happens to be identical to infant intestinal, but is in adults. This form is very rare.
Occurs when the toxin is injected for cosmetic purposes (like wrinkles, crazy right?). This form is also very rare.

Botulism tends to lead to respiratory failure. It has an incredibly rapid onset, typically in 12-70 hours.

The fatality rate is 5%-10% of infected. So much lower than respiratory anthrax.

Exposure/Spread of Botulism

One microgram of the toxin is lethal to humans when inhaled.

Take note of that: it’s fatal 5-10%, but one microgram (inhaling) would be fatal.

Botulism, when advanced, can lead to respiratory failure by the means of paralyzing the muscles in the chest. Similar to what happens when inhaled.

Currently, the most common form of botulism is infant botulism.

It is not an easy to spread toxin, meaning its exposure is minimal.

It cannot be transmitted human to human, unless the toxin is ingested (Which, as you can imagine, is difficult to accomplish by human to human transfer). This minimizes the risk of botulism as a large scale bioterror agent.

How Botulism Works

The toxin is produced by bacteria when the conditions are favorable for it to grow.

The gene that encodes the toxin protein is actually carried by a phage that infects the bacteria itself.

What botulism does is inhibit acetylcholine, which is a fancy word for a certain neurotransmitter that communicates between neurons and cells. Since acetylcholine can’t work correctly, it leads to paralysis, muscle fatigue, and other medical complications, including respiratory failure.

Treatment for Botulism

Botulism has an antitoxin. Many times, emergency medical intervention is also necessary.

Bioterrorism Impact of Botulism

Botulism is not currently a significant threat with regard to worldwide bioterror threats. As it does not spread easily.

It could however be a localized threat. Any attempt to make botulism into an agent with the ability to be inhaled could conceivably be even more deadly than anthrax, considering the small inhalation required to cause death.

The biggest threat of botulism arises from the ability to create the toxin in an environment that could be transmitted from human to human.

However, even under these conditions, considering the low fatality rate for ingestion (5-10%), it does not pose the largest conceivable threat. An inhalation variant would be even less effective, as the onset is too quick to spread far since sickness begins nearly immediately.

Botulism Unique Fact

Drug addicts, most notably black tar heroin users who inject in the skin instead of vein, are at a large risk of contracting botulism.

The conditions needed for the toxin to thrive are more apparent in drug user conditions, leading to that specific group having one of the highest infection rates worldwide.

Plague

The plague (or “Black Death”) is caused by the bacteria Yersinia Pestis.

There are three types of plague:

Bubonic
Septicemic
Pneumonic

Bubonic plague is the most common variant. It occurs (typically) when bit by an infected rodent or through transmission from another human (some material that is infected). Untreated, it turns into septicemic or pneumonic plague.

Septicemic is a fancy word for “blood plague”. It is when the plague enters the bloodstream and begins to multiply there.

Pneumonic is the deadliest and most dangerous form of the plague. It is the infection of the respiratory system with the plague. When an infected individual coughs, they release the bacteria, increasing exposure to others. It is the only form that can be transmitted directly from person to person, without an intermediary (such as bubonic).

Plague is especially deadly: even those with treatment have a 10% fatality rate. Those without treatment go up to 70%.

Exposure/Spread of Plague

Plague is spread by the following methods:

Droplet contact – coughing or sneezing on another person
Direct physical contact – touching an infected person, including sexual contact
Indirect contact – usually by touching soil contamination or a contaminated surface
Airborne transmission – if the microorganism can remain in the air for long periods
Fecal-oral transmission – usually from contaminated food or water sources
Vector borne transmission – carried by insects or other animals

The most common carriers of the plague are rats, who become infected typically by fleas or feeding on infected carcasses.

As previously mentioned, the pneumonic version of the plague is the most deadly. But it also has the highest infection rate. It is easy for yersinia pestis to infect others when an infected is sick nearby.

During the black plague, tens of millions died through this exact exposure.

In untreated cases, mortality is practically 100% for the pneumonic version of the plague. Death usually onsets within one to six days, making it an extremely prolific vector for bioterror.

How Plague Works

The bacteria first makes its way inside the host and infects a macrophage to camouflage itself to the host’s immune system.

After enough time hidden and ample proliferation, it can easily overcome the host’s immune system.

Y. Pestis then quickly spreads to lymph nodes and interferes with blood coagulation.

When it spreads into the lungs, it results in the onset of all the side effects of the plague, including fatal ones. The bacteria begin to overtake the immune system, eventually resulting in fatal pneumonia.

Treatment for Plague

Various antibiotics are very promising treatments for most versions of the plague. However, pneumonic plague is still problematic, and morality is still very high even with treatment.

This is because it is hard to treat it in time: in the case of a widespread outbreak, faster treatment times may be likely as emergency responders could be more proactive in giving out high dose antibiotics to treat the plague.

Bioterrorism Impact of Plague

Undeniably, yersinia pestis is currently the greatest risk for bioterror worldwide. This is because it has already proven effective three times over with various pandemics in history.

The pneumonic version is especially susceptible, because even antibiotic treatments are not always rapidly effective. And an outbreak would be nearly impossible to control, as the spread is too easy and rapid (simply coughing releases the bacteria).

Plague is also the largest threat regarding modification by CRISPR/CAS9. As a modified form that had a longer incubation time with antibiotic resistance would be nearly unstoppable as a threat once it reached worldwide infection.

Yersinia pestis also holds the crown because of its ease of availability: where anthrax and other Cat A Agents are hard to acquire, Y. pestis is natural in the environment. It can be found and harvested in a common environment, without need for creating the bacteria from scratch.

Plague Unique Fact

The plague is actually still around, and relatively common in some parts of the world.

It infects nearly 1000 people around the world each year. Typically, in rural areas and in certain countries in Africa.

Immediate isolation and CDC-level of control are put into place for each infection, if it became pneumonic and spread. It could cause significant damage in a local community.

Smallpox

Smallpox is caused by one of the two viruses: variola minor or variola major.

It has been eradicated since 1980, due in large part to a vaccination effort by the WHO.

Smallpox had a nearly 30% fatality rate and was incredibly prolific and easy to spread. Death usually occurred between the 10-16th day of the illness.

Russia and the United States still hold vials containing smallpox in research facilities in both countries. It is not completely gone, just out of reach.

Exposure/Spread of Smallpox

Smallpox is transmitted similarly to Y. Pestis. Coughing, sneezing, or coming into direct contact with an individual that was infected was the usual route of exposure.

This also includes contact with materials that held the virus, such as the bedding of an infected person. For this reason, smallpox patients are normally isolated until the scabs fall off and the virus is deemed noncontagious.

How Smallpox Works

The virus cripples immune systems by attacking molecules made by our bodies to block viral replication.

It does this by producing a certain protein in our system, which causes the plethora of signs and symptoms presented by smallpox.

In time, this virus can then replicate freely, overriding our immune system response. While the immune system is down, we become extremely susceptible to other infections and to the viruses’ lethal abilities.

Treatment for Smallpox

There is no known treatment for smallpox, as it was eradicated prior to treatment options. The CDC does have 2 suspected agents that could treat it, but they have not been tested.

Mostly smallpox was eradicated through the vaccine which prevented it.

Even if infected with smallpox, the vaccine could still help as it will instruct your immune system on how to respond.

Bioterrorism Impact of Smallpox

Regardless of what Bill Gates says, smallpox is not an effective bioterror agent. Considering the ease of vaccines (and CDC stockpiles), potential treatment drugs already created, lower mortality rate, wide-scale knowledge on symptoms, and ease of recognition, smallpox is not a viable large-scale threat.

The only way smallpox could be a threat would be through modification with CRISPR/CAS9 or a natural evolution that made it a stronger virus unaffected by the vaccine. However, even a virus of this magnitude could be created into a vaccine relatively quickly. And efficiently, given that we know so much about the virus already.

Likewise, it would be nearly impossible to modify the virus through CRISPR/CAS9, as the only stockpiles are in heavily secured locations in US and Russia. You would need a microbiologist who also happens to be a covert CIA navy seal to infiltrate the secure locations, steal the virus, modify the virus, and expose the virus to all 7 continents at the same time to cause significant damage.

So yeah, not as big of a threat as the other Cat A’s.

Smallpox Unique Fact

Smallpox was coined the “Red Plague” because of the pandemics it caused were similar in catastrophe to the plague prior to vaccination efforts.

Also, during WW2 Japan considered using smallpox as a bioweapon. They changed their mind when they considered the availability of the vaccine would diminish results. And instead, they focused on anthrax/plague research, prior to being defeated by the Allies.

Tularemia

Tularemia is caused by the bacterium Francisella tularensis.

Humans are typically infected through the following methods:

Tick and deer fly bites
Skin contact with infected animals
Ingestion of contaminated water
Inhalation of contaminated aerosols or agricultural dusts
Laboratory exposure

There are numerous variants of Tularemia, including:

Ulceroglandular (most common at around 75% of Tularemia)
Glandular
Oropharyngeal
Pneumonic (the most severe form it is similar in scope to the pneumonic plague)
Oculoglandular
Typhoidal

We will be focusing solely on the pneumonic variant, as the others are less likely to be used as bioterror agents.

Exposure/Spread of Tularemia

The bacteria may be found in contaminated water or soil, infected ticks, wild and domestic animals, and decaying animal carcasses.

Morality is around 60% in the absence of treatment. With treatment, the rate is still around 20%.

Tularemia cannot be spread human-to-human. However, the lethal dose is very small, and it is relatively easy to come into contact with.

How Tularemia Works

Pneumonic tularemia works in the same manner as smallpox: by infecting a macrophage.

After that, it is not currently known exactly how Tularemia causes its symptoms. Likely through a manner similar to harming the immune system’s response.

Treatment for Tularemia

There are no vaccines for Tularemia.

However, antibiotics have proven effective. Since the use of antibiotics, the rate of death decreased from 60% to around 4%. This renders Tularemia significantly less effective in the case of a bioterror attack.

Bioterrorism Impact of Tularemia

This agent is largely a threat because the infecting bacteria can be freeze-dried into a power which can be aerosolized and only a few inhaled bacteria can cause lethal pneumonic disease.

It is one of the most infectious pathogenic bacteria currently known. Inhalation of as few as 10 organisms can cause disease.

Francisella tularensis was also developed into an aerosol biological weapon by several countries in the past.

However, considering it can not spread human-to-human, it is not likely a worldwide bioterror threat. It could be used localized to cause significant harm, but is not likely able to adapt to spread to a pandemic level.

Tularemia Unique Fact

Tularemia is also called “rabbit fever” because it is extremely lethal to rabbits and has spread to humans through handling a rabbit that is infected.

Viral Hemorrhagic Fever

Viral hemorrhagic fevers are caused by a multitude of viruses. They have symptoms that are often accompanied by hemorrhage (bleeding); however, the bleeding is itself rarely life-threatening.

The five types of RNA virus families that cause these are:

Arenaviridae
Filoviridae
Bunyaviridae
Flaviviridae
Rhabdoviridae

Some of these show low-level symptoms, while others are life threatening (such as the most famous one: Ebola).

A listing of the VHF diseases includes:

Alkhurma hemorrhagic fever
Argentine hemorrhagic fever
Bolivian hemorrhagic fever
Chapare hemorrhagic fever
Crimean-Congo hemorrhagic fever
Ebola (Ebola Virus Disease)
Hantavirus Pulmonary Syndrome (HPS)
Hemorrhagic fever with renal syndrome (HFRS)
Hendra virus disease
Kyasanur Forest Disease (KFD)
Lassa fever
Lujo hemorrhagic fever
Lymphocytic choriomeningitis (LCM)
Marburg hemorrhagic fever
Nipah virus encephalitis
Omsk hemorrhagic fever
Rift Valley fever
Sabia-associated hemorrhagic fever
Tick-borne Encephalitis (TBE)
Venezuelan hemorrhagic fever

Because there are so many VHF variants, it is impossible to comment on them all in this one article.

So, I’ll just be doing a general overview here and expanding on them more in later articles.

Exposure/Spread of Viral Hemorrhagic Fevers

VHFs have a large ability to spread drastically. Consider some common ones, for example:

Dengue
Ebola
Lassa
Marburg
Yellow fever

All of these have prominent capabilities to reach exposure to a large audience, especially considering a potential mutation or edit by CRISPR/CAS9.

Likewise, most VHFs can spread human-to-human with relative ease. Medical professionals have to wear extra protective gear when dealing with those infected.

How VHF’s Work

Typically, the overall vascular system is damaged. This makes it so the body’s ability to regulate itself is impaired.

This leads to the bleeding and other life-threatening complications typically brought about by VHFs.

Usually, different infected individuals also show different symptoms. This makes VHFs really hard to regulate and understand. The virus-host interaction between the agent and the host makes it so that each individual tends to experience the effects slightly differently, sometimes with more/fewer complications.

Treatment for Viral Hemorrhagic Fevers

Yellow fever has a vaccine, but no other VHF has one readily available.

There are investigational drugs, but no hardline proven treatments. There is an antiviral drug (Ribavirin) that can sometimes help lessen complications.

Bioterrorism Impact of Viral Hemorrhagic Fevers

Bioterror impact of VHF’s are high. They are easily spread human-to-human, there are currently no known treatment options, and modification of the virus would be easier than the other Cat A’s for someone knowledgeable in microbiology.

Included in this caution is the fact that VHFs are numerous, and naturally occurring.

The virus is also considered having a potential for aerosol dissemination and weaponization.

Considering it could be disseminated in that method, and it has the capabilities to infect further individual’s post-infection, the risk is large.

Viral Hemorrhagic Fever Unique Fact

China attempted to create a biological weapon out of VHFs, but stopped because it was so effective it accidentally caused an outbreak they couldn’t control.

Category A Agents Bioterror and Bioterrorism Summary

Cat A Agents are numerous and significantly different from one another.

In my opinion, the deadliest forms of Cat A Agents likely to cause pandemic-level destruction only include:

Plague
Viral Hemorrhagic Fevers

While the others are definitely agents that could cause bioterrorism, I see them more in-line with localized bio attacks. That, instead of large-scale risks.

My reasoning is:

Anthrax does not have the capabilities to infect a large number over time, as the mortality rate is too quick.
Modifying or releasing smallpox would take an act substantially more difficult than the Y. Pestis or VHFs.
Tularemia does not transmit human-to-human.
Botulism does not spread easily.

So while all Cat A Agents are dangerous threats, they are not all created equal. The biggest threats in the category when considering it from a worldwide view is the plague and VHFs.