Ailments and Age Groups: What Makes Illness Age Dependent?

By Chris Healey

An uncommon and underreported virus has affected children in states across America. State health departments around the country have reported an unusual number of enterovirus D68 infections this season. Many hospitalizations – but no deaths – have been reported.

Enterovirus D68 was first isolated in California in 1962 from four children with pneumonia. Enteroviruses generally inflict a wide range of symptoms, but species D68 almost exclusively affects the respiratory system. D68 also shares genetic similarity with rhinoviruses—the viral species responsible for the common cold.

Past outbreaks of enterovirus D68 have occurred mostly in children. Although health experts aren’t sure why children are vulnerable to the illness relative to other age groups, the answer probably lies with the immune system. Age effects immune function. In prepubescence, the immune system is immature and naïve toward host threats. In old age, deterioration of essential immune system tissues – such as bone marrow – contribute to immune system decline.

Due to dampened immunity in childhood and late adulthood, illness is more common – and more often fatal. However, one historical exception stands out: the Spanish Flu of 1918.

Flu subtypes undergo antigenic drift, a process resulting in subtle genetic changes prompting the need for new flu vaccines each year. However, the Spanish Flu of 1918 was a result of dramatic genetic change called antigenic shift. The result was a new subtype to which the population had no immunity.

Many health experts consider the Spanish Flu of 1918 the worst pandemic in history – with at least 40 million deaths worldwide. By comparison, the Black Death was responsible for 25 million deaths. The Spanish Flu pandemic was caused by a direct transmission of influenza subtype H1N1 from bird to human.

The Spanish Flu of 1918 was unique because of its W-shaped mortality curve. When Spanish Flu mortality among age groups are plotted on an x-y axis – with x as age groups and y as specific death rate – the graph shows there were more deaths among the 18-to-40-age group than any other. That trend is unusual – 18-to-40 age groups typically have the highest immune function of all age groups, providing the greatest defense against pathogens.
For the Spanish Flu, the immune system actually worked against the host. The immune system reacted so violently to the novel Spanish Flu that it damaged the host more than the flu infection itself, leaving those with the strongest immune systems – ages 18-to-40 – most grievously affected.

 

Image Credit: Fox6Now

Reston Ebola: NOVA’s Namesake Emerging Infectious Disease

By Chris Healey

Almost 25 years before the 2014 Ebola epidemic began spreading through West Africa – and the resulting treatment of two American Ebola patients on U.S. soil – public health officials responded to an Ebola outbreak inside the U.S.

Reston Ebola is the name given to an Ebola species discovered among macaque monkeys in a pharmaceutical research company’s primate quarantine unit in Reston, VA.

In 1989, a veterinarian at Hazelton Research Products, a pharmaceutical research company, contacted the United States Army Institute of Infectious Diseases at Fort Detrick, MD, concerning an unusually high mortality rate among macaques in a shipment from the Philippines. The veterinarian wanted USAMRIID to confirm suspected simian hemorrhagic fever, a viral illness lethal to primates but innocuous to humans. Tests on macaque carcasses unexpectedly showed signs of a deadly filovirus infection – Ebola hemorrhagic fever virus.

Initially, Ebola species Zaire – with mortality rates as high as 90%, and the cause of the 2014 African Ebola epidemic – was implicated as the agent at work. Faced with an unprecedented public health threat, state and federal health agencies converged on the primate quarantine facility in Reston. The Centers for Disease Control and Prevention monitored quarantine facility employees for Ebola symptoms. USAMRIID euthanized primates and sterilized the quarantine facility.

Comprehensive tests later identified the Zaire species identification as an error – Reston Ebola was a new species incapable of infecting humans. However, the enormous public health response was not unwarranted.

Unlike other Ebola species, researchers suspected Reston Ebola demonstrated airborne transmission at the quarantine facility. The longer the virus remained in human presence, the longer it was given opportunities to adapt. If Reston Ebola were to adapt to humans with airborne communicability it would pose a catastrophic public health risk.

Although no quarantine facility employees demonstrated Ebola-like symptoms during the 1989 outbreak, six workers produced Reston Ebola antibodies, meaning the virus elicited an immune response. Reston Ebola’s quick eradication was paramount to ensure that the virus—with its suspected airborne communicability—did not adapt to humans.

Restriction of the 2014 African Ebola epidemic to only a few countries has been attributed to the limited means of Ebola virus transmission. All Ebola species which affect humans are communicable only through direct contact with an infected person or their bodily fluids. Airborne transmission would increase viral spread and undermine containment efforts.

 

Image Credit

Plants and Their Growing Role in the Pharmaceutical Industry

By Chris Healey

Pharmaceutical production using plants has been in the spotlight after Mapp Pharmaceutical revealed its experimental Ebola serum ZMapp—credited with saving the lives of two Americans—was created using antibodies harvested from genetically-modified tobacco plants.

ZMapp is part of a growing trend of pharmaceuticals created from proteins produced in plants, a practice considered safer, cheaper, and more practical than common production methods.

There has been outcry about claims ZMapp will not be sent to Africa to combat the ongoing Ebola epidemic. Those claims come after the pharmaceutical industry has been slow to adopt plant production methods, despite cost-effectiveness relative to traditional production methods.

Large pharmaceutical powerhouses, such as Pfizer and Merck, have adhered to traditional production methods despite newer and cheaper techniques. However, smaller companies, such as Mapp Pharmaceutical and IBio, have taken advantage of the low cost of plant production to produce their pharmaceutical ingredients.

Transgenic techniques allow scientists to hijack existing cellular processes in plants to produce desired proteins, such as enzymes and antibodies. DNA instructions for a desired protein (also called a gene) can be created in laboratory settings and inserted into a plant cell nucleus. After insertion, the gene instructs the cells how to make the desired proteins.

Once the proteins are produced, scientists can harvest them for use in pharmaceuticals. Transgenic techniques can be repeated and scaled to fit need. There are two methods commonly used to insert genes into plants.

One widely-used transgenic technique involves Agrobacterium tumefaciens bacteria as a gene transportation medium. Scientists introduce a gene into bacteria prior to plant inoculation. Bacteria then release desired DNA into plant cell nuclei and gene expression proceeds normally.

An alternative method, called biolistic transformation, involves the use of a gene gun to launch desired genes at clusters of plant cells. Some of the clusters will land inside cell nuclei, where the introduced DNA will integrate with the plant’s genome for expression.

Regardless of technique, using plants to create proteins eliminates the threat of human pathogen contamination which is possible with animal-derived mediums. Plants and animals do not share common pathogens, so a potential infection present at the time of harvesting will have no effect on protein recipients.

 

Image Credit: HPR2

Ebola’s “Top-Secret” Serum: What Is It? Why Would It Be Kept Secret?

By Chris Healey

The deadliest and most pervasive Ebola outbreak in history is underway in Africa. As of August 8, the World Health Organization reported 1134 confirmed cases of Ebola in Guinea, Liberia, Nigeria, and Sierra Leone with 622 confirmed deaths.

Two Americans, Kent Brantly and Nancy Writebol, contracted Ebola while helping contain the epidemic in Africa. Both were flown to isolation units in Atlanta’s Emory University Hospital after receiving an experimental treatment called ZMapp. Brantly and Writebol’s condition is reportedly improving because of the drug.

ZMapp is the experimental brainchild of several pharmaceutical companies and their collaboration with the U.S. and Canadian governments. It is a combination of three antibodies determined to be the best components of two experimental Ebola treatments: MB-003 and ZMAb.

MB-003 is composed of a monoclonal antibody and an immune system stimulant. The monoclonal antibody binds to Ebola virus surface proteins to form a structure easily recognized as a threat by the host’s immune system. Mimicry allows the immune system stimulant to produce an inflammation-like response without causing tissue damage, serving to amplify immune response without damaging the host.

ZMAb, a combination of mouse-derived antibodies, inactivates Ebola virus surface proteins necessary for host cell entry. If Ebola virus cannot enter a host cell, it cannot cause illness. For higher efficacy, ZMAb antibodies target different parts of the surface proteins, making viral adaptation to the antibodies difficult.

ZMapp attracted much attention because it was used without being tested. Mapp Biopharmaceutical was preparing to enter Phase 1 clinical trials prior to the Ebola outbreak. Use of ZMapp in lieu of clinical trials is permitted by FDA regulations allowing drugs currently, or not at all, involved in clinical trials to be used in extenuating circumstances where no other pharmaceutical is appropriate.

ZMapp is not the first untested pharmaceutical to be used against Ebola in humans. In 2009, a researcher in Germany accidently exposed herself to Ebola virus when she pricked herself with an ebola-contaminated needle during a laboratory experiment. Within 48 hours, she was given an experimental Ebola vaccine never before used in humans. After 21 days, physicians prepared to discharge her from a Hamburg, Germany hospital because she had not developed any symptoms.

It is unclear if the vaccine prevented illness, or if the needle stick simply didn’t infect her with Ebola. Regardless, she produced Ebola virus antibodies after vaccine administration, indicating the vaccine produced an immune response.

When use of ZMapp was first reported, it was hailed in stories circulated by CNN as a “secret” and “top-secret” serum. However, current versions of the story now portray the serum as an “experimental drug.” It is unclear if the original reports of the serum’s secrecy were in error.

However, development of secret therapeutics is not farfetched. Classified treatments could conceivably serve national security interests.

State-sponsored bioweapon programs, for example, could use knowledge of existing therapeutics, such as those kept in the strategic national stockpile, to engineer biological agents resistant to available therapeutics. Such a tactic would cripple U.S. public health response to any weaponized agent. If ZMapp truly was classified, the U.S. may have been protecting the drug’s therapeutic mechanisms from those who would seek to overcome them.

Although withholding treatments would benefit the U.S., it raises ethical concerns. Some could argue treatment sequestration provides little benefit outside the U.S. A novel, effective treatment withheld in preparation for an attack –that may never occur– could be used in the present to treat the sick.

The merits of transparency must be weighed against interests of national security. For ZMapp, if it was classified, two American candidates for the drug were enough to bring it into the public domain.

 

Image Credit: International Business Times

Biocrime: Lessons Learned Contribute to Future Cases

By Chris Healey

Three individuals associated with Peanut Corp. of America are going to court over charges  related to intentionally shipping tainted peanuts. Those charges come after nine people died and 714 people were infected with Salmonella typhimurium after consuming peanut products shipped from the company.

Most cases of food contamination are not prosecuted, but the Justice Department alleges the individuals involved knew the peanuts were tainted and shipped their product anyway to avoid lost revenue.

Their case is considered a biocrime, a distinct offense unrelated to a more common term – bioterrorism. Biocrime involves the use of a biological agent to kill or sicken one or more individuals for revenge or monetary gain. Bioterrorism, however, is the use of biological agents to create casualties, terror, societal disruption, or economic loss inspired by ideological, religious or political beliefs. Biocrime is personal; bioterrorism is theater.


A notable, unsolved biocrime took place October 1996 at a large medical center in Texas. 12 laboratory workers became ill after eating muffins and doughnuts tainted with Shigella dysenteriae, which has been anonymously left in a break room between the night and morning shift. All 12 had consumed muffins, and stool isolates from nine of the victims were identical to Shigella dysenteriae retrieved from an uneaten muffin in the break room. Bacterial isolates from stool samples and the uneaten muffin were identical to a partially-missing laboratory stockpile of the same pathogen.

Biocrime is an attractive avenue for criminals with biological agent knowhow. Toxins and pathogens are indirect and stealthy. Pathogens must pass an incubation period—the time between introduction of the pathogen into the body and the onset of symptoms. During that time, criminals can escape and distance themselves from victims to avoid discovery.

Determining if an infection is the result of biocrime is extremely difficult. Many agents which can be used criminally, can also occur naturally. Biocrime identification depends on astute epidemiologic investigation and successful communication between scientific and law enforcement officials.

The advent of molecular biology in the late 20th century birthed the field of microbial forensics—assisting criminal investigations involving microbial organisms. However, it wasn’t until the anthrax letter attacks of 2001 that investigative short comings, such as inadequate methods of identifying agent sources based on genetic mutations, were addressed.

The anthrax letter attack investigation was a turning point in microbial forensics. It served as a proverbial rough draft that established a template for future biocrime and bioterrorism investigations. The justice system demonstrated it could wield biological science as an investigative tool and apply that knowledge toward identifying and prosecuting perpetrators.

 

Image Credit: Bhaskaranaidu

Listeria: Deadly Foodborne Threat to Vulnerable Populations

By Chris Healey

A listeria contamination scare has prompted a fruit packing company to issue a voluntary recall of peaches, nectarines, plums, and pluots shipped to Costco, Trader Joe’s, Kroger, Walmart, Sam’s Club, Ralphs, and Food 4 Less. The company—Wawona Packing Co.—issued the recall after an internal bacterial test found listeria on two nectarines. So far, no one has been sickened from affected fruit.


Listeria monocytogenes, the causative agent of listeriosis, is a common foodborne bacterial pathogen. With the ability to thrive in refrigerated foods, it can quickly multiply and spread on foods which have been properly stored and otherwise deemed safe for consumption. It is unique among foodborne illnesses for its tendency to cause miscarriages and encephalitis in sickened individuals.

Although listeria infection is uncommon, fatality rates reach as high as 30%. Several groups are prone to infection – pregnant women, infants, the elderly, organ transplant recipients, leukemia patients, and those with AIDS. The highest infection rates occur in infants younger than one month and adults older than 60 years.

Once ingested, listeria crosses the mucosal barrier of the intestines to the bloodstream. From there, listeria tends to target neuronal and placental tissue. Defenses associated with those tissues, such as the blood brain barrier of the central nervous system, are not effective because infected host cells can slip by unaffected and release bacteria.

CDC surveillance studies in the 1980s brought listeria to the attention of health professionals in the United States. Those studies determined L. monocytogenes was the causative agent of approximately 1850 cases of food poisoning and 425 deaths annually. Since identification, listeriosis incidence and associated death has decreased. Today, the CDC estimates 1600 cases of listeriosis with 260 fatalities yearly.

In 2002, Listeria was responsible for the largest meat recall in U.S. history. An epidemiologic investigation conducted after a listeriosis outbreak determined 54 case patients had consumed sliced deli-style turkey meat tainted with listeria. As a result, over 30 million pounds of food products were recalled.

The largest listeria outbreak occurred in 2011 due to contaminated cantaloupe from Jensen Farms in Colorado. During that outbreak, 147 people from 28 states became ill. Of those cases, 33 died. The CDC website reports a listeriosis outbreak occurrence every year since 2011.


To prevent listeriosis, the CDC recommends consumers rinse raw produce thoroughly before eating. Full recommendations from the CDC can be accessed here.

 

(Image Credit: Ximeg)

Abrin: More Deadly and Less Common than Ricin

By Chris Healey

Abrin was among toxins found during an apartment search of a San Francisco man charged with possessing explosive material. An FBI affidavit states the suspect told investigators he acquired abrin to ease the suffering of cancer patients.

Abrin is a protein-based toxin from the jequirity bean, colloquially known as a rosary bead. The toxin is lethal in minute doses and causes serious symptoms in even smaller amounts. It is almost identical to a better-known toxin—ricin. Abrin is more lethal than ricin. Toxicologists estimate abrin’s lethal dose between .1 and 1 microgram per kilogram. In comparison, ricin is lethal between 5 and 10 micrograms per kilogram.

Both abrin and ricin consist of two proteins, A chain and B chain, linked by a disulfide bond. The proteins work together to enter the cell and disrupt its activity. B chain grants cell entry, while A chain transports to the ribosome and destroys it. Cells die shortly after ribosome destruction.

Abrin’s nonuse despite toxic superiority to ricin is ostensibly due to a matter of availability. As a byproduct of castor oil, an ingredient in soap and mechanical lubricant, ricin is very common. Conversely, rosary beads serve a limited purpose in prayer and are not consumed or destroyed in their role. One set of rosary beads can last for years before replacement is necessary. Their limited and reusable role makes them uncommon.

Availability also contributes to abrin and ricin’s historical precedence. According to a study conducted by the Federation of American Scientists, ricin has been maliciously used 37 times since 1983. Malicious abrin use is almost nonexistent except for several reports in India and Sri Lanka in the early 20th century.

Abrin is released from crushed jequirity beans. Individuals who handle beans whole and unaltered, as in prayer, are not exposed. Even in cases of jequirity bean ingestion, intoxication is dependent on how thoroughly beans are chewed. Symptoms include nausea, vomiting, diarrhea, abdominal pain, and colic. Some less common symptoms include irregular heartbeat, irrationality, hallucinations, and seizures. In fatal cases, cause of death has been traced to gastrointestinal damage.

Abrin is a select agent designated by the Department of Health and Human Services. It is illegal to manufacture or possess any quantity of the toxin. Although jequirity beans contain abrin, they are not illegal. The law is broken when abrin toxin is isolated from a bean.

 

(Image Credit: Satdeep gill)

Bio-error and Insider Threats: A Two-Pronged Hazard of Biodefense Research

By Chris Healey

Researchers may have been exposed to live anthrax bacteria during a laboratory procedure at the CDC in Atlanta sometime between June 6 and 13. A CDC statement said established safety practices were not followed in that incident.

A follow-up statement by the CDC said risk assessment evaluations have determined anthrax exposure was unlikely. Most of the CDC employees involved have been advised to stop antibiotic and vaccine administration.

This scare marks the second anthrax mishap in little over a decade. In 2004, Scientists at Southern Research Institute in Frederick, Maryland inadvertently shipped live anthrax to colleagues in California who were expecting dead specimens.

Laboratory mistakes involving pathogens, dubbed “bio-error,” has recently acquired much media attention. To date, there have been no confirmed instances of bio-error causing illness outside the laboratory. However, another laboratory threat has materialized, one which resulted in infection and several deaths outside the laboratory almost 14 years ago.

Insider threats, or the potential for laboratory workers to exploit the dangerous material they work with to harm others, present a precarious laboratory safety problem.

Laboratory insider threats became salient after the FBI’s investigation of Bruce Ivins, a microbiologist with the United States Army Medical Research Institute for Infectious Diseases at Fort Detrick, Maryland, as the suspect of the 2001 Anthrax letter attacks. Ivins worked with the anthrax strain he allegedly mailed across the United States.

Researchers working with select agents must register with the FBI and maintain a security clearance. The same requirement stood when Ivins began his work on live anthrax.

Following Ivins’ implication, a U.S. National Research Council committee and the National Science Advisory Board for Biosecurity reviewed researcher fidelity protocols and determined revision was unnecessary. No changes to the rigor or frequency of character and fitness standards for those who work with select agents were made.

Researchers working on nuclear and radiological material are subjected to more stringent evaluations. In addition to FBI registration and security clearance maintenance, random drug testing, observations of off-duty behavior, video monitoring of laboratory activity, and annual psychological assessments are required.

Those additional fidelity evaluations have contributed to the lack of incidents among nuclear and radiological researchers. There is no known instance of a nuclear or radiological research insider causing public harm.

 

Image Credit: CDC

Hendra Virus: Vaccines Available but Underused

By Chris Healey

Horse owners in Australia are reluctant to vaccinate their horses against an emerging viral illness capable of sickening humans.

Hendra virus, an emerging infectious disease of horses and humans, has been responsible for the death of 4 people and dozens of horses in Australia since its discovery during a 1994 outbreak of an acute respiratory illness among horses and stable workers in Queensland, Australia. Laboratory tests performed during that outbreak confirmed horses and humans became sick from identical viral agents.

An epidemiologic investigation revealed flying foxes of the Pteropus genus act as Hendra virus reservoirs. Health officials have hypothesized that horses contract the illness through inadvertent consumption of infected bat urine. Hendra virus spreads to humans who come into contact with body fluids, tissues, or excretions of infected horses. Those who work closely with horses, such as equine veterinarians and stable hands, are most at risk of Hendra virus infection.

Early on, researchers discovered Hendra virus glycoproteins could be exploited as an immunization strategy. Following a human Hendra virus death in 2009, and an exposure in 2010, a vaccine for horses was released in 2012 by Zoetis, Inc. As an animal vaccine, developers were spared arduous human pharmaceutical testing protocols and quickly released the product.

The vaccine, called Equivax HeV, is unprecedented in preventative medicine. Not only is it the first vaccine licensed and commercially available to prevent illness from a BSL-4 agent, a pathogen requiring the highest laboratory safety protocols, but it is also the first veterinary vaccine used to transitively prevent illness in humans.

Similar to how smallpox and measles vaccination prevents spread of their respective illnesses, Hendra-vaccinated horses are less likely to transmit Hendra virus to humans by reducing viral shedding. Equivax HeV provides Hendra protection for the horse and the people who interact with it.

Despite vaccine advantages, horse owners say they cannot afford it. A single administration can cost upwards of $200, and booster administration is needed every 6 months for the life of the horse to maintain immunity. Many are unwilling to pay. As a result, only 11% of horses in Australia are estimated to have received the vaccine.

Health authorities are working to approve guidelines recommending yearly booster administrations, cutting immunity maintenance costs in half.  Veterinarians say more horse owners will choose to vaccinate as attitudes toward occupational safety change. Greater awareness of the danger posed to equine veterinarians and stable hands working with unvaccinated horses is expected to place a stigma on non-vaccinating establishments.

 

(Image Credit: Fainmen)

Smallpox Stockpiles Avoid Chopping Block… Again

By Chris Healey

Last month, World Health Organization officials at the 106th World Health Assembly in Geneva decided not to eliminate the last stockpiles of smallpox. That decision marks the sixth time the assembly has chosen to maintain stockpiles in lieu of destruction.

Some health officials consider smallpox the deadliest disease in human history. Until vaccination eradicated the disease in 1980, smallpox infected people around the world and killed 30% of sickened individuals. The disease no longer exists in nature, but samples of the virus are stockpiled at research facilities in the United States and Russia. Elimination of those stockpiles is the only way to categorically prevent theft or accidental release of smallpox from those facilities.

One source of hesitance to eliminate is international intrigue. In 2008, representatives from Vector, the Russian facility responsible for the country’s stockpile in Novosibirsk, announced researchers had discarded 200 smallpox samples without notice. Elimination of those samples remains unverified.

Another reason to keep stockpiles is research potential. Access to samples in the event of a smallpox resurgence, or another poxvirus outbreak, may be beneficial in efforts to quell illness spread. Most poxviruses have strikingly similar genomes.

Smallpox is part of the orthopox genus. A characteristic of orthopox genomes is conservation of genetic material, meaning viruses in the genus share many identical genetic sequences.

Genetic similarity among viruses in the orthopox genus is exploited to prevent smallpox. Vaccinia virus,the pharmacologic active ingredient in smallpox vaccines, shares enough genetic similarity with variola virus, the causative agent of smallpox, to confer immunity to both viruses. In fact, inoculation with any orthopoxvirus confers immunity to all members of the genus.

Some health officials claim the conserved nature of orthopoxviruses undermines needs to preserve smallpox. Due to similarity among orthopoxviruses, smallpox can be studied through less virulent orthopoxviruses. However, not all health officials believe orthopoxviruses are one in the same.

Authors of an article recently published in The Lancet make an argument for the preservation of smallpox stockpiles. The authors mention the need for better countermeasures against smallpox and other orthopoxviruses. Those countermeasures, when developed, should be tested against authentic smallpox viruses. The authors argue smallpox stockpiles should be maintained to facilitate orthopoxvirus research.

A comprehensive review of the smallpox stockpile elimination debate by biological weapons and arms control expert Jonathan Tucker is available here.