Daily Archives: January 24, 2022

Biotechnology. 2016 : 687719.

Department of Microbiology, Southern Illinois University, Carbondale, Illinois, USA

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The term biological warfare typically conjures images of medieval warriors tossing dead cattle over city walls or clandestine government agents secretly releasing mysterious microbes into enemy territory. Of course, biological warfare does encompass such activity, but the vast majority of what constitutes biological warfare is far more mundane. Ever since life evolved on earth about 3.8 billion years ago, organisms have constantly devised new ways to kill each other. Any organism that makes use of toxinsfrom bacteria to snakesis engaging in a form of biological warfare. Humans who engage in biological warfare do so by taking advantage of these toxin-producing organisms.

Keywords: bacteriocins, biosensors, Black Death, botulinum toxin, bubonic plague, checkerboard hybridization, dominant-negative mutations, ergot, high-containment laboratories, incubation time, kappa particles, lysins, phage therapy, poison sequence, quorum sensing, ricin, siderophores, smallpox, toxins, weaponization

The term biological warfare typically conjures images of medieval warriors tossing dead cattle over city walls or clandestine government agents secretly releasing mysterious microbes into enemy territory. Of course, biological warfare does encompass such activity, but the vast majority of what constitutes biological warfare is far more mundane. Ever since life evolved on Earth about 3.8 billion years ago, organisms have constantly devised new ways to kill each other. Any organism that makes use of toxinsfrom bacteria to snakesis engaging in a form of biological warfare. Humans who engage in biological warfare do so by taking advantage of these toxin-producing organisms.

An entire textbook could be filled with examples of organisms that employ toxins to kill other organisms. We therefore touch only briefly on the natural history of biological warfare.

Bacteria are particularly adept at biological warfare. While humanity finds antibiotics incredibly useful in our battle against infectious disease, bacteria did not create them for our benefit. Instead, they make antibiotics to kill off other bacteria that are competing for the same habitat or resources. Similarly, bacteria synthesize toxic proteins known as bacteriocins to kill their relatives because closely related strains of bacteria are likelier to compete with each other. For example, many strains of Escherichia coli deploy a wide variety of bacteriocins (referred to as colicins) intended to kill other strains of E. coli. The genes for colicins are normally carried on plasmids, and many of these plasmids are commonly used in molecular biology and genetic engineering (see Chapter 3). Yersinia pestis, the plague bacterium, also makes bacteriocins (called pesticins in this case) designed to kill competing strains of its own species ().

Bacteriocins Inhibit Other Bacteria

A bacteriocin-producing strain of Lactococcus in a piece of cheese can inhibit the growth of a related microorganism.

From Garde S, etal. (2011). Outgrowth inhibition of Clostridium beijerinkii spores by a bacteriocin-producing lactic culture in ovine milk cheese. Int. J Food Microbiol150, 5965.

A point of clarification: The distinction between bacteriocin and toxin has to do with the target. Bacteria deploy bacteriocins against their fellowoften closely relatedbacteria with the deliberate intention of killing them. In contrast, proteins produced by bacteria that act against higher organisms are referred to as toxins. Perhaps counterintuitively, pathogenic bacteria do not usually intend to kill the organisms they infect. Rather, they want to manipulate them long enough to survive and reproduce. The longer the host stays alive, the longer it provides a home for the infecting bacteria. Just like antibiotics, some bacterial toxins are useful to humans. The bacterium Bacillus thuringiensis produces an insect-killing toxin that is harmless to vertebrates, and this Bt toxin has been used extensively in genetically modified crops. (See Chapter 15.)

Lower eukaryotes also regularly engage in biological warfare. Paramecium, a ciliated protozoan, carries symbiotic bacteria (Caedibacter) known as kappa particles that grow and divide inside the larger eukaryotic cell ().

Killer Paramecium Uses a Bacterial Toxin

(A) The kappa particles are found in the cytoplasm of the Paramecium. (B) Kappa particles are symbiotic Caedibacter that are found in many strains of Paramecium, yet they have their own DNA and divide like typical bacteria.

Strains of Paramecium with kappa particles are known as killers and, due to unknown genetic factors and resistance mechanisms, are naturally tolerant of them. Killer strains release kappa particles into the environment, and if a sensitive Paramecium (i.e., one lacking the ability to harbor kappa particles) eats and digests just a single kappa particle, a protein toxin is released and kills the Paramecium. Interestingly, the toxin is not encoded by a gene on the bacterial chromosome, but on a plasmid derived from a defective bacteriophage. So a toxin encoded by a virus infecting the kappa particle bacterium has been commandeered for the purpose of killing other strains of Paramecium.

This phenomenon is not at all unusual. Many toxins used by pathogenic bacteria that infect humans are actually encoded by foreign DNA of nonchromosomal origin, such as viruses, plasmids, or transposons. These elements are often integrated into the chromosome of pathogenic strains of bacteria. For example, the only strains of Corynebacterium diphtheriaethe causative agent of diphtheriathat are dangerous to humans are the ones that carry a toxin-encoding virus.

Higher eukaryotes can either create their own toxinssuch as the venom produced by snakes and scorpionsor expropriate toxins produced by other species. One species of caterpillar that feeds on tobacco plants can exhale noxious nicotine at spiders, chasing them away. Other insects rely on microbes to wage biological warfare. Certain parasitic wasps inject their eggs into the maggots (i.e., larvae) of plant-eating insects. After the eggs hatch, the newborn wasps eat the living maggots from the inside ().

Wasps Use Viruses against Maggots

Certain types of wasps lay their eggs inside tobacco hornworm larvae. The wasp lands on the back of the larva and injects the eggs plus adenovirus into the maggot through the ovipositor. The adenovirus prevents the larva from eating and therefore developing into a pupa. When the eggs hatch, the young use the insides of the larva as a food source, to grow and develop into adult wasps.

The maggots are eventually killed, and a new generation of wasps is released. The secret to the wasps success is the injection of an adenovirus along with the eggs. The virus targets the maggots fat body (vaguely equivalent to the liver of higher animals) and cripples the maggots developmental control system and immune system. The maggot loses its appetite for plants and is prevented from molting and turning into a pupa, the next stage in its life cycle.

Many different kinds of organisms engage in biological warfare. Bacteria kill other bacteria with antibiotics or bacteriocins. They also make toxins that are targeted at higher organisms. Eukaryotes can either make their own toxins or commandeer those produced by lower organisms.

Although we rarely perceive it this way, infectious disease is just another manifestation of biological warfare that is ubiquitous throughout life. The evolutionary relationship between hosts and pathogens is essentially a never-ending arms race. When a pathogen evolves a new toxin, the host evolves a response to it. Humanity has taken this arms race one step further by utilizing technology such as vaccines and industrial-scale manufacturing of antibiotics. However, the microbes are fighting back.

Perhaps the biggest problem plaguing medical microbiology today is the rise of antibiotic resistance. There are many reasons why bacteria have developed this resistance, but all of the explanations have one thing in common: the proliferation and misuse of antibiotics. For instance, medical doctors often prescribe antibiotics to patients who have an infection, even if it is unknown whether the disease is bacterial. Other times, the wrong antibiotic is prescribed. In many developing countries, antibiotics can be bought over the counter without a prescription. Compounding the dilemma, patients who receive antibiotics often do not comply with the recommended dose, ending treatment as soon as they feel better. This has the effect of selecting for the survival of the bacteria that have already developed a slight resistance to the drug. When the patient propagates the infection, he unintentionally passes on these toughened survivors. The widespread use of antibiotics in animal feedwhich farmers use to fatten up livestockis also a major contributor to the problem.

Today, many experts worry about incurable infections. Methicillin-resistant Staphylococcus aureus (MRSA) gets a lot of media attention, but it is not the only worrisome microbe. There have been reports from around the world of totally drug-resistant tuberculosis, which as the name implies, appears to be resistant to all treatment. In a 2013 report, the Centers for Disease Control and Prevention (CDC) issued an urgent warning about infections from (1) Clostridium difficile, which causes diarrhea and is often acquired by patients in health-care settings who were treated with antibiotics for other infections; (2) Carbapenem-resistant Enterobacteriaceae (CRE), such as Klebsiella and E. coli, which also cause health-care-associated infections and may be resistant to all known antibiotics; and (3) Neisseria gonorrhoeae, the etiologic agent of gonorrhea, which is growing in resistance to several antibiotics.

While these developments are alarming, much research is being done to combat the rise of antibiotic resistance. Although microbes have responded to our antibiotic assault, we are developing some new weapons to regain the upper hand.

Although there has been speculation of an inevitable post-antibiotic era, there are still plenty of opportunities for the development of novel antibiotics.

One strategy is to attack previously unexploited vulnerable spots in a bacteriums metabolism or life cycle, preferably those that bacteria cannot easily defend by acquiring resistance. For instance, bacteria use iron chelators, known as siderophores, to bind iron and extract it from host proteins. Siderophores are excreted, bind iron, and are then taken back into bacteria by specialized transport systems. Absence of high-potency siderophores largely abolishes virulence in both plague and tuberculosis. Because mammals do not make siderophores, their unique biosynthetic pathways provide an attractive target for development of novel antibiotics. Yersiniabactin, the siderophore of several pathogenic Yersinia species, is capped by a salicyl group ().

Salicyl-AMS Inhibits the Production of Yersiniabactin

The structure of yersiniabactin shows the salicyl group in red. The precursor, salicyl-AMP, is made by activating salicylate with ATP. The sulfamoyl analog, salicyl-AMS, inhibits the incorporation of the salicyl group into yersiniabactin.

The intermediate in the pathway, produced when ATP activates salicylate, is salicyl-AMP. A chemically synthesized analog of salicyl-AMP, called salicyl-AMS, replaces the phosphate with a sulfamoyl group. The compound is highly active and specifically inhibits siderophore synthesis. This prevents the growth of Yersinia under iron-limiting conditions, such as encountered in the human body.

Another strategy is to screen novel microbes for antibiotics. As discussed earlier, bacteria produce antibiotics for the explicit purpose of killing other bacteria. Since most microbes that exist in nature have neither been cultured nor identified, it is likely that many natural antibiotics have yet to be discovered. In 2013, a new antibiotic, called anthracimycin, was isolated from an Actinomycete that lives in the ocean. The new antibiotic is active against Bacillus anthracis and MRSA, and modifying it with chlorine groups expanded its spectrum of activity.

Yet another strategy is to identify and clone potential antimicrobial biosynthetic pathways. For example, based on its DNA sequence, one research group cloned a biosynthetic gene cluster from an Actinomycete called Saccharomonospora that was predicted to produce an antimicrobial lipopeptide. Expressing the gene cluster resulted in the discovery of a new antibiotic, taromycin A. The major advantage of this technique is that it can be applied to microbes that are difficult to culture in the laboratory.

A different approach is to disrupt existing antibiotic resistance, rather than developing new antibiotics. For example bacteriophage, such as those that live in the human gut, can shuttle antibiotic resistance genes between bacteria. Consequently, developing drugs that kill or disable bacteriophage is an innovative way to combat the spread of antibiotic resistance. Additionally, disrupting bacterial quorum sensing has been suggested. Bacteria use quorum sensing as a communication system in order to coordinate behavior ().

Quorum Sensing

Bacteria can coordinate behavior by detecting the presence of a signal molecule that indicates the density of the population.

From Boyen F, etal. (2009). Quorum sensing in veterinary pathogens: mechanisms, clinical importance and future perspectives. Vet. Microbiol135, 187195.

By releasing particular chemical compounds into the environment, bacteria can detect when a threshold population density, or quorum, has been reached. Many pathogens construct antibiotic-resistant biofilms after the population has reached a particular density. Disrupting their communication system would cripple their ability to coordinate behavior and keep the bacteria more vulnerable to antibiotics.

The history of phage therapythat is, using bacteriophage (also called phage) to treat bacterial infectionsbegins in France in 1921. That year, microbiologist Felix dHrelle used phage to treat patients suffering from dysentery ().

Felix dHrelle

Microbiologist Felix dHrelle helped pioneer phage therapy.

In 1927, he also used phage therapy to treat cholera victims in south Asia. Unfortunately, many other scientists in the United States and elsewhere were unable to replicate his work, and when the widespread production of antibiotics started in 1945, the scientific community mostly lost interest in phage therapy. The French, however, enthusiastically practiced phage therapy into the 1990s and, during those seven decades, there were reports of successful treatment of typhoid fever, colitis, septicemia, skin infections, and various other bacterial diseases. Other countries that embraced phage therapy include Poland, Russia, and Georgia. Today, patients there can receive phage therapy for chronic and antibiotic-resistant bacterial infections.

Since the 1990s, the Western scientific community has renewed its interest in phage therapy. One benefit of using phage, as opposed to antibiotics, is their specificity. Antibiotics kill many different types of bacteriawhich is harmful if they destroy helpful gut bacteriabut individual phage species infect only a group of very closely related bacteria. Every bacterial infection could, in theory, be targeted by a highly specific phage.

As predicted, however, bacteria also can develop resistance to phage, mainly through thwarting viral attachment. Now, researchers are investigating the use of lysins, a class of toxins that phage use to dismantle bacterial cell walls as part of their lytic cycle (). Because lysins target conserved regions within peptidoglycan, it is believed that bacteria will be less able to develop resistance. Lysins work best against Gram-positive bacteria, but genetic engineering can expand the spectrum of activity to include Gram-negative bacteria also.

Bacteriophage Tsamsa Kills Bacillus anthracis

The lysin isolated from the bacteriophage Tsamsa kills Bacillus anthracis and other closely related species.

From Ganz HH, etal. (2014). Novel giant Siphovirus from Bacillus anthracis features unusual genome characteristics. PLoS One9(1), e85972.

As an alternative to phage, it may be possible to deploy predatory bacteria against human pathogens. Bdellovibrio, which invades other bacteria rather like a virus, and Micavibrio, which attaches to bacterial cell surfaces, have been shown to kill antibiotic-resistant pathogenic bacteria invitro.

Because of a persistent fear that we will run out of novel antibiotics, many clever new technologies have been suggested to fight bacterial infections. Some of the most promising of these antibiotics utilize genetic engineering.

For example, many pathogenic Escherichia coli use the FimH adhesin to bind to mammalian cells via mannose residues on surface glycoproteins. Several alkyl- and aryl-mannose derivatives bind with extremely high affinity to the adhesin and block its attachment to the natural receptor. Such mannose derivatives, therefore, could serve as anti-adhesin drugs. However, manufacturing pharmaceuticals is quite expensive. It would be far cheaper to genetically engineer nonpathogenic strains of E. coli to express the mannose derivatives on their cell surfaces. Pathogenic bacteria would then bind to these decoys instead of to mammalian cells. This would also avoid the need for continuous administration of sugar derivatives because the decoy strains of E. coli would multiply naturally in the intestine. Alternatively, nonpathogenic strains of E. coli could be engineered with genes for adhesins that would allow them to compete with pathogens for mammalian cell receptors. (Such engineered strains would also have the advantage of being able to deliver protein pharmaceuticals or large segments of DNA for gene therapy into mammalian cells.)

A different approach is to generate altered toxins that interfere with their natural analogs. Typical A-B bacterial toxins are made from a single active A subunit, which carries out a toxic enzymatic reaction inside a target cell, and often several binding B subunits, which serve as a delivery system by attaching to the cell surface. Because several properly functioning binding subunits are required to deliver the active subunit, one approach to antitoxin therapy relies on utilizing dominant-negative mutations in the binding subunit of the toxin. The mechanism involves the binding of a defective protein subunit to functional subunits resulting in a complex that is inactive overall. (The term dominant-negative refers to mutations in which an abnormal gene product sabotages the activity of the wild-type gene product. Consequently, most dominant-negative mutations affect proteins with multiple subunits.) Dominant-negative mutations have been deliberately isolated in the B protein (called the protective antigen) of anthrax toxin. Mixing mutant subunits with wild-type ones resulted in the assembly of inactive heptamers that bind the A subunits (called lethal factor and edema factor) of anthrax toxin. As a result, the toxic A subunits cannot be transported into target cells (). This technique has been shown to protect both cultured human cells and whole mice or rats from death by lethal levels of anthrax toxin.

Dominant-Negative Mutations

For anthrax, the B subunit (called PA63 protein or protective antigen) binds the A subunits (called lethal factor, LF, and edema factor, EF) and transports them into the target cell cytoplasm via an endocytic vesicle. The dominant-negative inhibitory (DNI) mutant of the PA63 protein (purple) assembles together with normal PA63 monomers (pink) to give an inactive complex that cannot release the LF and EF toxins from the vesicle into the cytoplasm.

Many of the advances in nanotechnology aimed at fighting pathogens involve the creation of bactericidal surfaces (see Chapter 7 for more on nanotechnology). Several metals are inherently antibacterial. For instance, silver ions kill bacteria through several mechanisms, such as generating reactive oxygen species and disrupting protein disulfide bonds. Surfaces coated with silver, selenium, and copper nanoparticles all show antimicrobial activity.

Metals are not the only option. A substance known as black silicon is made of tiny nanopillars that are able to physically destroy bacteria, including endospores, through mechanical stress (). Antimicrobial activity has also been demonstrated with stacked carbon nanotubes called nanocarpets (see Chapter 7). Additionally, polymers of esters and cyclic hydrocarbons reduce attachment of bacteria. Such discoveries could allow for improved sanitation in health-care settings and the manufacture of antimicrobial medical devices.

Antibiotic resistance is a growing concern, but contrary to popular reports, it is not necessarily an intractable problem. Novel targets for antibiotics, phage therapy, genetic engineering, and nanotechnology provide multiple possibilities for fighting antibiotic-resistant pathogens.

Nanostructures Can Kill Bacteria

Scanning electron micrograph of black silicon surface showing its hierarchical structures. (A) Periodically arranged micropillar arrays; (B) a micropillar with nanostructures; (C) nanostructures formed on the top of the micropillar.

From He Y, etal. (2011). Superhydrophobic silicon surfaces with micro-nano hierarchical structures via deep reactive ion etching and galvanic etching. J Colloid Interface Sci364, 219229.

Throughout history, humans have devised new and innovative ways to kill other humans. When technology was primitive, warriors used whatever nature provided. Burning crops was probably the easiest and earliest form of warfare aimed at undermining an enemy, as was poisoning a communitys drinking water with dead or rotting animals.

Slightly more advanced forms of biological warfare emerged when soldiers began dipping spears in feces and throwing poisonous snakes. During the Black Death epidemic of the mid-1300s, the Tartars catapulted plague-ridden corpses over the walls into cities held by their European enemies. Although this is sometimes credited with spreading the plague, rats and their fleas were far more effective at spreading bubonic plague than contact with corpses ().

Bubonic Plague

This painting by Arnold Bcklin, simply titled Plague, depicts the fear that bubonic plague provoked in antiquity.

From ET Rietschal, etal. (2004). How the mighty have fallen: fatal infectious diseases of divine composers. Infect Dis Clin North Am18, 311339.

Given the state of hygiene in most medieval towns or castles, there was little need to provide an outside source of infection. With plague, typhoid, smallpox, dysentery, and diphtheria already around, all that was usually necessary was to let nature take its course. Similarly, a widespread myth exists that European settlers purposefully infected Native Americans with smallpox. While it is true that the British military attempted this strategy during the French and Indian War in the mid-1700s, the vast majority of Native American deathsperhaps as much as 95% of the populationwere due to inadvertent infection with smallpox and other diseases.

The truth is, until very recently, humans were not particularly hygienic. Consider, for instance, that antiseptic surgeryinvented by Joseph Lister and now considered a mainstay of modern medicinewasnt widely adopted until the late 1870s. Before then, armies and civilian populations were so dirty and disease-ridden that practicing germ warfare was like throwing mud on a pig. It is only in our modern hygienic age that biological warfare has become a more meaningful threat.

Modern biological warfare began during World War I. Although the Germans refused to use biological agents against people, they did use them against animals, infecting Allied horses with glanders (Burkholderia mallei) and anthrax. The French also employed glanders against German horses. During World War II, the infamous Japanese Unit 731 experimentally infected Chinese prisoners of war with horrifying diseases, such as cholera, epidemic hemorrhagic fever, and venereal disease. It was also responsible for dropping plague-infected flea bombs on cities in China, although this likely had little effect partly because plague was already endemic to the region ().

Unit 731

Japanese military Unit 731 killed thousands of Chinese people with experimental infections and biological warfare.

Source: Figure 6 from: Lpez-Muoz F, etal. (2007). Psychiatry and political-institutional abuse from the historical perspective: the ethical lessons of the Nuremberg Trial on their 60th anniversary. Prog Neuropsychopharmacol Biol Psychiatry31, 791780.

After World War II, particularly during the Korean War, the United States ratcheted up its biological weapons program. Perhaps the most controversial aspect of the program was the purposeful release of biological agents, such as the relatively harmless Serratia marcescens, over American cities to study weapons dispersal. The military unintentionally infected 11 civilians, one of whom died. By 1969, the U.S. had weaponized anthrax and tularemia. However, in 1975, the U.S. renounced all biological weapons by signing the Biological Weapons Convention (BWC).

The Soviet Union also signed the BWC but then deceitfully enlarged its efforts. The scope of the Soviet program was astonishing. The Soviets manufactured several hundred tons of anthrax, and an accidental release in 1979 killed 66 people. The former USSR also made thousands of pounds of smallpox and plague, and in 1989, they supposedly managed to weaponize Marburg virus, which causes a deadly hemorrhagic fever similar to Ebola. These allegations remain unconfirmed. Finally, under President Boris Yeltsin in 1992, Russia ended its biological weapons program, but the fate of the weapons stockpiles remains unclear.

Today, biological warfare is feared less from nations and more from terrorist groups or lone wolves. But there is disagreement over just how much of a threat this poses. Many believe that terrorists would be incapable of carrying out an effective, large-scale biological attack. For instance, in 1984, the Rajneesh cult gave food poisoning to about 750 citizens of a small Oregon town for political purposes by adding Salmonella to salad bars. Aum Shinrikyo, a Japanese cult that perpetrated a sarin gas attack in the Tokyo subway in 1995, experimented with biological weapons, but to no avail. The 2001 U.S. anthrax attack (discussed in more detail in the following section) killed only 5 people. Skeptics point to incidents like these as evidence that bioterrorists are incapable of inflicting widespread damage. Other analysts disagree ().

Bioterrorism

Some experts believe that a large-scale bioterrorist attack will occur in the not-too-distant future, but others say bioterrorism is an ineffective tactic. Attack methods include contamination of food and water supplies (A), bombs (B), using the mail (C), contamination of water (F), spraying aerosolized agents (E, G), direct injection (D), or the infiltration of suicide infectees (H).

From Osterbauer PJ, Dobbs MR (2005). Neurobiological weapons. Neurol Clin 23, 599621.

Some biological agents, such as anthrax, require little expertise to grow or weaponize. With microbiological information universally available on the Internet, some experts believe that it is just a matter of time before a large bioterrorist attack occurs. A small crop duster airplane loaded with anthrax and flown over a major city could potentially kill hundreds of thousands if not millions of people. Exacerbating the problem is the fact that a 2010 federal commission found the United States to be completely unprepared in the event of a bioterrorist attack.

During the Vietnam War, the Viet-Cong guerillas dug camouflaged pits as booby traps. Inside, they often positioned sharpened bamboo stakes or splinters smeared with human waste. Although it was possible to contract a nasty infection from these, the main purpose was psychological. The tactic worked. The response of American troops was to alter their movements in a way that was disproportionate to the actual threat. An analogous scenario played out following the 2001 anthrax attack in the United States in which there was a colossal disruption of postal services and massive new expenses. Yet, only 5 people died in the attack. (Compare that to the roughly 62,000 Americans who died from influenza and pneumonia that same year.)

Both of these examples serve to underscore two important points: First, biological warfare will almost certainly have a far greater psychological impact than direct impact; and second, protective measures against biological attacks are costly and inconvenient. For instance, giving soldiers vaccines against all possible biological agents would be impractical and possibly dangerous if they have been developed under emergency conditions without thorough testing. Also, vaccines have side effects. Consider the anthrax vaccine used by the U.S. army that was approved in 1971. Vaccination requires six inoculations plus annual boosters. It produces swelling and irritation at the site of injection in 5% to 8% and severe local reactions in about 1% of those inoculated, although major systemic reactions are rare. Although it works against natural exposure, it is uncertain whether it would protect against a concentrated aerosol of anthrax spores.

Or consider the smallpox vaccine (). For every 1 million people vaccinated, the CDC estimates that 1,000 people will have serious side effects, 14 to 52 people will have life-threatening side effects, and 1 or 2 people will die. Is it worth vaccinating an entire army or nationknowing ahead of time that many will die or become sickto protect them against an unlikely threat? From an epidemiological standpoint, the answer is clearly no, which explains why citizens do not receive smallpox vaccinations. The general rule in public health is to vaccinate only if the risk of the disease is greater than the risk of vaccination.

Smallpox Vaccine

How the normal skin reaction to smallpox vaccination progresses in two patients.

Source: Centers for Disease Control and Prevention.

Even if widespread vaccination is forgone in favor of other measures, such as protective clothing or respirators, there is still the financial cost. A nation that invests heavily in bioterrorism preparedness could have spent that money in more productive ways. Dressing troops in special clothing and equipment could promote heat stress or make them easier targets for conventional weaponry. Additionally, medications taken prophylactically to prevent infectious diseases are expensive, rarely 100% effective, and may have long-term negative health consequences.

Biological warfare has been practised since ancient times. However, it has only rarely been effective. Naturally occurring infectious diseases have killed far more people. Still, bioterrorism may pose a serious threat today. Even if an attack kills relatively few people, the psychological impact could be enormous.

Biological warfare is used to kill, injure, and psychologically intimidate enemies. Many naturally occurring diseases are effective agents, although it might be possible to improve them with genetic engineering, as discussed later.

What makes for an effective biological agent? Five major factors need to be considered.

Preparation. Some pathogenic microorganisms are relatively easy to grow in culture, whereas others are extremely difficult or expensive to manufacture in sizeable quantities. Viruses, for instance, can grow only inside host cells, and culturing animal cells is more complex than growing bacteria. Similarly, pathogenic eukaryotes such as Plasmodium (malaria) or Entamoeba (amoebic dysentery) are difficult to culture on a large scale, although some pathogenic fungi can be grown relatively easily. Bacteria are generally the easiest to manufacture on a large scale, but most bacterial infections can be cured with antibiotics. Viruses, though more difficult to grow, have the advantage of being largely incurable despite a small and growing range of specific antiviral agents.

Another factor is weaponization. The disease agent must be prepared in a manner that facilitates storage and dispersal. Because bacterial cells and spores tend to clump together spontaneously, they must be weaponized to allow effective delivery.

Dispersal. Dispersal is a particular challenge for biological weapons. The most likely option would be some form of airborne delivery. However, if applied outdoors, this tactic would be vulnerable to the whims of the weather. Not only is a pleasant breeze required, but also the wind needs to blow in the right direction! During the 1950s, the British government conducted field tests with harmless bacteria. When the wind blew them over farmland, many of the airborne bacteria survived the trip and reached the ground alive. In contrast, when the wind blew the bacteria over industrial areas, especially oil refineries or similar installations, the airborne bacteria were almost all killed. Ironically, air pollution may help protect an urban population from a bioterrorist attack. To aerosolize a biological agent for an indoor attack, a buildings ventilation system or a medical nebulizer could be used ().

Nebulizer

A medical nebulizer could be used to aerosolize a biological agent for an indoor attack. Two general types of nebulizer are in use: the jet nebulizer that uses pressurized gas and the ultrasonic nebulizer that relies on ultrasonic vibrations.

Persistence. Persistence may be the most difficult factor to consider. On the one hand, the biological agent should be able to persist in storage until it is ready to be deployed, and it must survive long enough in the environment to infect the enemy. On the other hand, it should not persist so long that the victor is unable to invade and conquer enemy territory.

Many infectious agents are sensitive to desiccation and become inactive if exposed to air for significant periods of time. Moreover, natural UV radiation from the sun also inactivates many bacteria and viruses. Thus, most biological warfare agents must be protected from this open air factor before use and then dispersed as rapidly as possible. For instance, many viruses last only a few days, if even that, outside their animal or human hosts. (However, infections due to these agents may persist among the local population.)

Anthrax is often chosen as a biological weapon because of its ability to persist for long periods of time. The bacterium Bacillus anthracis, which causes the disease, spreads by forming spores that are tough and difficult to destroy (). When suitable conditions return, for example, inside the lungs of a human, the spores germinate and resume growth as normal bacterial cells, releasing life-threatening toxins.

Spores of Bacillus anthracis

Anthrax spores, which are seen here forming inside bacterial cells, are difficult to destroy and last a very long time.

From Ringertz SH, etal. (2000). Injectional anthrax in a heroin skin-popper. Lancet356, 15741575.

Incubation time. A problem unique to biological warfare, compared to conventional weapons, is that death or incapacitation from infectious disease is a relatively slow process. Even the most virulent pathogens, such as Ebola virus or pneumonic plague, can take a few days to kill. An infected enemy would therefore still be capable of fighting for a significant period. Yet, a biological agent that kills too quickly may not have time to spread among the enemy population.

High-containment laboratories. High-containment laboratories are needed for research and development of infectious biological agents. Biological containment is rated on a scale with four levels. Biosafety level 1 (BSL-1) microbes are mostly harmless, such as nonpathogenic E. coli. BSL-2 organisms are human pathogens, but not easily transmitted in the laboratory, such as Salmonella. BSL-3 organisms are dangerous and often can be transmitted via aerosol, such as tuberculosis and SARS. BSL-4 laboratories are for extremely dangerous and easily transmissible microbes, such as Ebola.

Read the rest here:

Biological Warfare: Infectious Disease and Bioterrorism

Photo illustration by The Globe and Mail

Norman Doidge, MD, is a psychiatrist, psychoanalyst and author of The Brain That Changes Itself. He is executive director of Health and the Greater Good.

Just before Christmas, without much fanfare, Ontario became the first province to approve fluvoxamine a decades-old drug few had heard of for the early treatment of COVID-19. The December 20 announcement, coming at a time when Canadians were preoccupied with Omicron, and the fear hospitals would soon be overwhelmed, received hardly any news coverage.

Fluvoxamine is a repurposed drug, and comes from what might seem like a most unlikely source psychiatry. It is an antidepressant used most commonly to treat obsessive-compulsive disorder. The drug has had two randomized control trials, or RCTs (the highest level of evidence) and four observational studies showing it keeps people with COVID out of hospital, from requiring intubation, and helps prevent death. The discovery of its anti-COVID properties came after impressive sleuthing in France and the United States. Then a partnership co-led by a team of Canadians conducted the large randomized trial that proved what it could do.

This is a good news story, about our public-health officials doing something right, and showing flexibility, at a time when we are learning the limits of our vaccines and accompanying strategies. Reappraisal is in the air, driven by everyones two-year-experience with the pandemic scientists included.

Philanthropist Bill Gates.Arnd Wiegmann/Reuters

Consider how things appeared in April, 2020, when Bill Gates, whose foundation is the largest private contributor to the World Health Organization, said: The ultimate solution, the only thing that really lets us go back completely to normal and feel good is to create a vaccine. His only meant, that in practice, our chief hope and focus in research, policy, in the media, and even emotionally, for many became the vaccines. Mr. Gates articulated what became our master narrative: Public health would stop the spread with extemporizing measures such as lockdowns, discouraging social functions and travel, and closing schools and businesses until the vaccines arrived, all of which would protect us until we achieved vaccine-induced herd immunity everywhere, which, we were told, would eliminate the virus. We put our faith in the vaccines, while other approaches such as drugs for early treatment, or a role for our natural immunity, or lowering our personal risk factors, for instance got comparatively less attention.

Key individuals predicted half promised, really wed be done with COVID, at least in the West, by the summer of 2021. In February, 2021, Pfizers CEO, Albert Bourla, said the vaccine was still offering strong protection at the six-month mark and indicators right now are telling us that there is a protection against the transmission of the disease. That April, Dr. Ugur Sahin, the CEO of BioNTech (which developed the vaccine for Pfizer), told reporters, Europe will reach herd immunity in July, latest by August. It wasnt a tough sell. Who would not want it to be true? Having no pandemic experience, we took them at their word. Politicians fostered the idea that our proper aim for handling COVID would be to eliminate it everywhere, as Prime Minister Justin Trudeau said. Early treatment doesnt promise that, though it might lower death rates. Eradication had more psychological appeal: lets get it out of our lives forever.

Yet, in dismal December, 2021, two years in, with cases soon to reach record highs, and another lockdown looming and vaccines waning, it wasnt working out that way. Perhaps if we hadnt been so focused on one tool things might have gone differently. And perhaps if certain voices hadnt been silenced, and others handed a megaphone, our pandemic tool kit, and mindset, would have been different too.

People applaud health-care workers from their balconies on the second day of France's first pandemic-related lockdown in Paris, 2020. Paris is home to a psychiatric hospital where COVID-19 questions raised theories about the antiviral properties of antidepressants.THOMAS COEX/AFP via Getty Images

Early in the pandemic, at the Sainte-Anne site of the Parisian mental hospital, Psychiatrie & Neurosciences, something mysterious occurred. The staff started contracting COVID in high numbers, but their patients, gravely mentally ill, did not. Three staff got COVID for every patient, despite the patients having more risk factors, such as being overweight, or having cardiovascular disease.

Someone wondered, could it be that the patients psychiatric medications were protecting them? The staff homed in on chlorpromazine, a common antipsychotic medication, and learned it had antiviral properties against SARS-Cov-1 and MERS-CoV (the predecessors to SARS-CoV-2). In a May, 2020, publication, they proposed repurposing it for treating COVID-19.

French psychiatrists and scientists next did a multicentre study, looking at 7,230 patients who had been hospitalized in Paris for severe COVID-19. Coincidentally, 300 of the patients were taking antidepressants. The data showed that those on Selective Serotonin Uptake Inhibitors (SSRI) a kind of antidepressant were less likely to require intubation or die. Not all SSRIs worked equally, but those that did reduced major inflammatory problems (the COVID cytokine storm that often kills). Lab research showed that the SSRI fluvoxamine had an antiviral effect, and a salutary effect on blood platelets that might protect patients from blood clots.

A sample of SARS-CoV-2, the virus that causes COVID-19.NIAID-RML via AP

Meanwhile, back in the U.S., in parallel process, a child psychiatrist, Dr. Angela Reirson, caught COVID in early 2020. Sick at home, she started doing research. She recalled a study on mice she had read the previous year. The mice had sepsis a dangerous response to infection that can kill. Something akin to sepsis can happen in serious COVID. In the 2019 study, mice with sepsis were given fluvoxamine, which halted the condition. So, in March, 2020, Dr. Reirson contacted another psychiatrist, Eric Lenze, a colleague of hers at Washington University in St. Louis. Dr. Lenze was a specialist in repurposing drugs. Realizing fluvoxamine had a great safety record, he launched its first small randomized control trial of COVID patients. Not one of the 80 volunteers who got fluvoxamine deteriorated or got COVID lung damage, whereas 8 per cent of the 72 who got a placebo did deteriorate. The findings were published in JAMA in November, 2020.

Next came the Together Trial, the worlds largest placebo study of COVID drugs, co-led by McMaster researcher Edward Mills and Brazilian physician Gilmar Reis. To do large trials you need a lot of cases, and Brazil had two million. The study was published Oct. 27, 2021, in the Lancet. It studied about 1,500 unvaccinated patients with COVID-19 who also had another serious illness and were at high risk for hospitalization. Half were given fluvoxamine, half a placebo. In those who took the fluvoxamine as prescribed it reduced the odds of hospitalization or emergency care by 66 per cent and death by 90 per cent.

Ontario Premier Doug Ford and government officials give a news conference in 2020 about the pandemic.Nathan Denette/The Canadian Press

The Ontario Science Table noticed these findings and on Dec. 20 it put fluvoxamine in the guidelines, for doctors to prescribe on an outpatient basis if needed, recognizing the need for outpatient treatment options with a reasonable safety profile during an anticipated spike in COVID-19 cases due to the Omicron variant.

That was significant, because early treatment of COVID measures we can take to avoid symptomatic cases from worsening, requiring hospitalization has been so minimal. In Ontario, treatment includes monoclonal antibodies (now only one works with Omicron) for specific people at risk, and steroids. Otherwise outpatients were told to rest, drink fluids, and hope their immune system would handle the virus.

True, there was much talk of brand-new, non-repurposed drugs for early treatment. Pfizers Paxlovid, just approved by Health Canada on Monday, is very new. But repurposed drugs have a track record, and thus often a safety advantage. And the generic ones are cheap. Fluvoxamine costs about $15 for a course of treatment. Repurposed drugs are used by poorer countries that cant afford vaccines or expensive early treatment drugs such as Paxlovid ($500) or Molnupiravir (US$700 and not yet approved in Canada).

So why hasnt treatment focused more on repurposed drugs?

First, because the master narrative, once it took hold, directed our attention away from this possibility. Second, in North America, the first repurposed drug that came to public attention was hydroxychloroquine. When it was endorsed by then-president Donald Trump it became highly politicized. Peoples opinions about it often had more to do with their political affiliation than whether they had read any of the (now) 303 studies. Third, agencies that regulate drugs, such as the U.S. Food and Drug Administration and Health Canada, mandate that any drug they evaluate have a sponsor, usually a drug company agreeing to assume liabilities for the drug. Its an extremely expensive process. If an old, cheap generic drug shows promise for repurposing, it still needs a sponsor to get approved for that. But drug companies have no financial incentive to do so. So usually there are no sponsors, and the drugs languish.

A person walks past a mural honouring health-care workers in Toronto. Imagery of war and communal struggle became a big part of the COVID-19 narrative: This mural, for instance, uses the pose and bandana of Rosie the Riveter, a Second World War icon.Nathan Denette/The Canadian Press

Of all the reasons that we didnt focus on repurposed drugs, I would argue, the master narrative was the most important, because of the way it organized so many peoples thoughts, attention and emotions.

The narrative would not have been nearly as problematic had it not been so tied into something else: the military metaphor that has defined our COVID experience from the beginning. This master narrative was our battle plan and this was a war to eradicate the enemy virus.

This military metaphor seems second nature in medicine. We are always in a war against cancer, or combatting heart disease, Alzheimers, and AIDS. But this way of thinking only became common in medicine several hundred years ago, after the philosopher Francis Bacon argued the goal of science should change from what it had been the study of nature to the very practical conquest of nature. Soon physicians were speaking of conquering disease, with magic bullets. We increasingly left behind the original Hippocratic mindset of medicine as an extension of nature, which involved working with it, as an ally, wherever possible not to conquer, but to heal, often with the help of the patients own healing capacities.

Scientists were to be soldiers in this new army. And here a problem arose. Despite some similarities, science (and medicine) is really best not construed as warfare and the kind of virtues that may suit soldiers in an army (following an authority without questioning), are vices in science, which is a mode of critical inquiry. Modern science arose because the world was filled with too many dogmas and orthodoxies that were not to be questioned. That is why the motto of the Royal Society, the first national scientific institution, became Nullias in verba, Take Nobodys Word For It. Its the role of scientists, as Nobel Prize-winning physicist Richard Feynman said, to question the experts, and fellow scientists, and debate each experimenters conclusions, which are based on human judgments and interpretations of data, until there is certainty the conclusion can resist all onslaughts.

Reappraisal of any prevailing narrative requires taking in new insights, which, by definition, arise from a minority viewpoint. When a military metaphor sweeps through a society or a bureaucracy beset by fear, all-or-nothing, you-are-with-us-or-against-us thinking follows. We become more prone to see someone who doesnt go along with the majority view including scientists who spot problems with the reigning narrative as putting the rest of us at risk, and a traitor, rather than as someone doing their job. They are attacked, censored or self-censor to survive. In war, you shut up and follow orders, or get court-martialed.

We are especially suspicious of other people during contagion, because our brains are fired up by a primitive circuit that protects us by making us obsessively preoccupied with the purity of those around us. Will this person get me sick? It even fires if we think their actions, or even policy proposals might be risky. The circuit, called the behavioural immune system, causes us to fear, loathe and feel rage toward the impure germ bearer. It results in many false alarms (think of someone driving alone with a mask on). Its one reason debates about vaccines are emotionally radioactive. Some vaccinated people feel all the unvaccinated bear germs, while some unvaccinated people feel vaccine may put germs or toxins in their bodies.

A nurse administers a COVID-19 vaccine in Orange, Calif., this past summer.Jae C. Hong/The Associated Press

This past summer, as news broke that there were breakthrough infections and vaccine protection against infection was waning, the North American media began to advise us to lower our expectations for them: Vaccines Can Only Do So Much, read a headline in The Washington Post. Many readers were caught completely off guard. In part they were surprised, because the censorship of scientists who held dissenting views and had been warning this might happen was much more widespread than many are aware of.

According to an Amnesty International report published in October, censorship and harassment of health professionals, and others, has been a problem across the world, during the pandemic. Most singled out are those who express critical opinions of their governments policies (e.g. restrictions of movement, lockdown, or criticisms of government dispensing with civil liberties).

The censors justified these actions as simply banning misinformation and prevent[ing] panic. In North America people were not imprisoned, but many brilliant scientists and physicians with proper credentials from places such as Harvard, Oxford and Stanford, were under fire. Physicians were vilified for questioning government policies on lockdowns, masks, aspects of vaccines, mitigation or unproven treatments the very things that were, of course, the subject of serious continuing scientific debate. In some jurisdictions in North America physicians are threatened by their regulating boards with suspension or revocation of their medical licenses for spreading misinformation, forcing some doctors to have to choose between what they rightly or wrongly see as their patients best interests, and their own livelihood. But as the Amnesty report states, Winning the battle against the virus includes not just government led actions and top-down diktats, but also bottom-up approaches which can only come about if the rights to freedom of expression and access to information are fully enabled.

Warning signs are seen at a COVID-19 testing lab in Ingelheim, Germany.Kai Pfaffenbach/Reuters

There were snake oil claims on the internet, yes, but generally when scientists and health care workers were party to these quarrels, it was because there was a scientific debate. In such a case, to accuse ones opponent of spreading misinformation is to pre-emptively ascribe to oneself an unjustified certainty and to ones opponent bad faith. At times no one really knew what was more harmful e.g. keeping children out of school, or sending them in. There was incorrect information aplenty in our novel situation, and that included some spread by officials who flip-flopped multiple times on masks, or who, claiming to follow the science, differed with officials in similar jurisdictions, based on changing data.

This, in medicine, is called the problem of medical reversal. An approach thought to be helpful is proven to be harmful, and vice versa. Sometimes two studies can contradict each other even on the same day. Physician-scientist Vinayak Prasad, of UC San Francisco, argues it is the most important problem facing medicine today. The problem of medical reversals didnt disappear the day the virus landed on our shores. We had not only a virus problem, but a medical reversal problem.

The medical boards were in an unusual situation, torn between once-cherished traditions of scientific debate, and the atmosphere of crisis and their wish to do their part in the war. After all, it is vital that public health, and its officials, in a crisis, be able to convey consistent messages as they ask citizens to change their behaviours, and undergo various privations. But if those messages are to be persuasive, and the requests for such privations scientifically arguable and legitimate, the actions must be based on a full, open, unhampered scientific process solid enough to withstand scientific criticism and debate. Why else should the public go along? Censorship, by giving the public the false impression there are no medical controversies, undermines the censors own claim to speak in the name of science and public safety. Ironically, it guarantees the public will be left misinformed.

People light a display of about 1,500 candles in memory of COVID-19 victims in Greifswald, Germany. After the original virus spread around the world, more contagious variants like Delta and Omicron superseded it, and researchers scrambled to understand how effective vaccines would be against them.Stefan Sauer/dpa via AP

The authors of the master narrative tend to say the main reason that things have not gone as they predicted is because variants arose. But if anything could have been predicted, it is that viruses mutate. Columbia virologist Vincent Racaniello described how fellow scientists were worried that the new mRNA technology, by focusing on only a small portion of the virus, the spike protein, would make it easy for the virus to get around or escape the vaccine through mutations. Thats partly why, he said in May, all the variants are arising now, because we have only the spike epitopes in there. That view didnt get much of a hearing.

It wasnt just the variants role in declining vaccine efficacy that surprised people. There was something about the execution of the original clinical trials, conducted by the pharma companies themselves, on their own products that also led to this surprise. Its worth going back for a moment and looking at how the problem unfolded.

In December, 2020, the new mRNA vaccines were rolled out, and were, according to the randomized clinical trials, 95 per cent (Pfizer) and 94.5 per cent (Moderna) efficacious in stopping infection. Physician-scientist Eric Topol, head of Scripps Labs, said these vaccines will go down in history as one of science and medical researchs greatest achievements.

But by the time summer 2021 arrived, real world experience contradicted Mr. Bourlas and Dr. Sahins claims of potency at six months, no transmission by the vaccinated, and imminent herd immunity. Pfizers Mr. Bourla, in his February interview, had called Israel the worlds lab, because it was vaccinated with the Pfizer extensively and several months ahead of other countries, giving the world a glimpse of its future. But when Israeli public health released its six-month data, they showed that vaccine effectiveness had dropped to 39 per cent, and Delta was surging. (The FDA had originally said it would not approve a vaccine less than 50-per-cent effective.) A Mayo clinic study showed that after six months, protection granted by the two Pfizer doses dropped from the original 95 per cent to 42 per cent. Another Israeli study showed it had dropped to 16 per cent. That huge discrepancy couldnt be attributed just to the new variant, Delta, because protection was already fading at five months for the earlier variants too.

Pfizer doses are prepared at a temporary vaccination centre in London.DANIEL LEAL/AFP via Getty Images

So why such a discrepancy? The original studies were clinical trials. The Pfizer study followed about 38,000 people without COVID who were divided in two groups half got the vaccine, and half a placebo. The investigators asked the question: could the vaccines prevent symptomatic cases of COVID-19? But, as Peter Doshi, senior editor at the British Medical Journal, warned, None of the trials currently under way are designed to detect a reduction in any serious outcome such as hospital admissions, use of intensive care, or deaths. He explained that, Because most people with symptomatic COVID-19 experience only mild symptoms, even trials involving 30,000 or more patients would turn up relatively few cases of severe disease. Susanne Hodgson of the University of Oxford agreed: The current [randomized control trials] that are ongoing are not powered to assess efficacy against hospital admission and death.

The Moderna report to the FDA on Dec. 17, 2020, confirmed there were no deaths due to COVID-19 at the time of the interim analysis to enable an assessment of vaccine efficacy against death due to COVID-19. Moderna followed about 30,000 people. When asked by the British Medical Journal, why the trial had not been designed to assess if the vaccine could prevent hospitalization and death, Moderna answered: You would need a trial that is either 5 or 10 times larger or youd need a trial that is 5-10 times longer to collect those events. In the Pfizer study of 38,000 people, not a single person in the placebo or the vaccine group died of COVID. By publication date, only one person had died of COVID in the Moderna study. To state it clearly: One person out of about 70,000 in the combined studies of Pfizer and Moderna actually died of COVID. In the real world, at the time, about 60 per cent of COVID deaths were in people over 75 years of age. But only 4.4 per cent of that age group were in the Pfizer study. The sample chosen was not appropriate to answer the publics most pressing question: Could the vaccines save lives?

And how long had the Moderna and Pfizer vaccines been studied, when released for mass use in the winter of 2021? Two months.

These studies looked at the vaccines at their most potent, in a low risk population, and gave us a flattering snapshot. But COVID-19 is a movie.

In contrast, the Mayo study, and the Israeli data, were looking at data over a more realistic time course to test effectiveness.

The waning created a crisis in Israel. Dr. Sharon Alroy-Preis, director of Israels Public Health Services, told the FDA Vaccine Advisory Committee on boosters, why the country became the first to roll out a third shot: What we saw prior to our booster campaign was that 60 per cent of people in severe and critical condition were immunized, doubly immunized, fully vaccinated and as I said, 45 per cent of the people who died in the fourth wave were doubly vaccinated. Most breakthrough infections are indeed mild, but she was describing life-threatening ones in the vaccinated. As breakthrough infections became commonplace throughout the world, noted Harvard epidemiologist Michael Mina said, the message that this is only an epidemic of the unvaccinated is falling flat.

A newly vaccinated patient takes a selfie with the nurse at the Sheba Medical Center in Ramat Gan, Israel.Tsafrir Abayov/The Associated Press

As for Dr. Sahins claim that we were on the brink of vaccine-induced herd immunity and being rid of COVID altogether, experts such as Larry Brilliant (who had helped eradicate smallpox with vaccines) and five other scientists wrote in Foreign Affairs in July, 2021, Among humans, global herd immunity, once promoted as a singular solution, is unreachable. They explained in precise detail why COVID-19 was unlike smallpox, and it could not be eradicated, such as the fact it is growing in a dozen animal species already. If we are forced to choose a vaccine that gives only one year of protection, said Dr. Brilliant, then we are doomed to have COVID become endemic, an infection that is always with us That vaccines would get us to a vaccine-based herd immunity had been one of the two main scientific justifications for vaccine mandates. Now it was gone.

The other justification for mandates had been that the vaccinated dont transmit the virus.

Most of us had presumed, when we got our first doses, that we couldnt pass the virus on to others. Public statements repeatedly praised people for doing your part to stop the spread. But in August, CDC director Rochelle Walensky told CNN, when asked why the vaccinated must wear masks, Our vaccines are working exceptionally well. They continue to work well for Delta; with regard to severe illness and death, they prevent it. But what they cant do any more is prevent transmission.

In fact, the original randomized clinical trials for Pfizer and Moderna did not test if the vaccines stop transmission. Now our best hope was that the vaccinated might transmit less than the unvaccinated. Several studies could be interpreted as showing this. But others found the vaccinated likely had equal transmission. One study, conducted in a prison, concluded that the vaccinated prisoners had as much transmission potential as the unvaccinated prisoners, adding, clinicians and public health practitioners should consider vaccinated persons who become infected with SARS-CoV-2 to be no less infectious than unvaccinated persons. Dr. Cyrille Cohen, head of the immunotherapy lab at Bar-Ilan University, and adviser to the Israeli government on vaccine trials, said that with respect to transmission with Omicron, we dont see virtually any difference between people vaccinated and nonvaccinated, adding both get infected with the virus, more or less at the same pace. The rancour that we, the vaccinated, are increasingly directing against the unvaccinated, fuels itself by remaining wilfully oblivious of this later painful truth: we too spread, to ourselves, and to the unvaccinated, as they to us and each other.

The master narrative was silent about natural immunity and its relationship to vaccination status. Many scientist-physicians, from prominent universities in the U.S. with specialties in public health, argue that one can be for the use of the COVID vaccine, but also against mandating it for unvaccinated people who are already immune.

These scientists maintain what matters is not whether a person is vaccinated or not, but whether they are immune or not. Thus, the European Union recognizes natural immunity in its Digital COVID Certificate, which is in lieu of a vaccine passport, and is not limited to proof of vaccination. You could get a passport and travel if you have been vaccinated or if you have recovered from COVID-19 or if you have a recent test saying you are negative. For air and train travel, Canada has also acknowledged recovery from COVID as an exemption, if one presents a recent negative test but, inconsistently, natural immunity is not recognized in most other quasi-mandate situations here. Such scientists think it irrational that government calls for mass mandates are escalating just as the core original justifications for them that the vaccinated dont transmit the virus, and the vaccine will bring us to herd immunity have collapsed.

A mobile phone shows a European Union digital vaccine certificate.OLIVIER MORIN/AFP via Getty Images

Those unvaccinated people who were exposed to the virus, make up a huge number. For instance, in the U.S., according to a Columbia University study, by Jan. 31, 2021 (before many vaccines had been given) 10 months into the pandemic, 120 million Americans had natural immunity. Now, 12 months later, with the much more infectious Delta and Omicron variants, it is likely a highly significant majority of the unvaccinated now have natural immunity.

A recent pivotal study from South Africa not yet peer reviewed shows that in poor communities, where there was modest vaccination (39 per cent of adults), more than 70 per cent of people had already been exposed to the virus in previous waves, going into Omicron. The twice vaccinated had more protection than those who were unvaccinated and never had COVID. But the unvaccinated who had COVID and recovered had more protection from severe disease than the vaccinated. One Israeli study showed that the unvaccinated who recovered from COVID have 27 times less risk of reinfection compared with the vaccinated, and nine times less risk of hospitalization.

In a recent Munk Debate, Harvards Dr. Martin Kulldorff, an epidemiologist and vaccine safety specialist, argued that mandating vaccines for the naturally immune actually creates problems because when people see that they are forced to take a vaccine that they dont need because they already are immune, that causes a lot of distrust in public health. And we have seen during this last year and a half that all the hard work weve done over many decades to build trust in vaccines is now disappearing because were making these mandates that make no sense from a scientific or public health perspective.

Public health moves at the speed of trust, as physician Rishi Manchanda wrote. Of the two main approaches to public health the participatory, and the coercive the coercive usually makes enemies, and tears society apart. Its like a hare: it has quick victories. The participatory approach, is a tortoise; when it fails to persuade, instead of blaming those it serves, it asks, as a scientist might, where have I fallen short, and aims to do better.

People are seen through a frame that reads 'third dose reinforcement' at a mass vaccination clinic for people over 60, in Mexico City. Third doses proved very effective against Delta, and are still important at preventing hospitalization and death in Omicron cases.Luis Cortes/Reuters

Israels third booster helped beat back the Delta wave. Then Omicron hit. On Dec. 19, The New York Times headlined an article, Most of the Worlds Vaccines Likely Wont Prevent Infection from Omicron. Thankfully, the vaccines still seemed like they would prevent those infections from becoming severe the key point. A Kaiser study showed that two doses, over time, fell to zero efficacy against Omicron. Then Danish data showed that a booster offered protection against severe disease, but only to those over 70 years. But would boosters wane too? The U.K. Health Security Agency study showed the protection from the Pfizer booster (third shot) had dropped to 45-per-cent coverage at only 10 weeks.

Then on Jan. 1, 2022, a study of vaccine effectiveness against getting infection in Ontario not yet peer-reviewed showed a trend that had already shown up in Denmark. It examined provincial data and was authored by members of Public Health Ontario, ICES, the Dalla Lana School of Public Health, UHN, and other major Ontario university and health programs.

They found two things of note. The first was that VE [vaccine effectiveness against getting infection] against Omicron was only 37% > 7 days following a third dose. That doesnt mean that those in the other 63 per cent who did get the infection might not have got some protection from severe infection, but the authors were unable to measure protection from severity from the data that had.

The second finding was more dramatic:, We also observed negative VE against Omicron among those who had received 2 doses compared to unvaccinated individuals. Translation: Negative VE means that the vaccinated got more infections than the unvaccinated.

That negative finding they noted, had already been observed elsewhere. In the Danish study, there was no significant protection against Omicron infection beyond 31 days after the second dose of the Pfizer. The Danes also found significant negative VE estimates 91-150 days after the second dose. The Danish study showed those vaccinated with the Pfizer had a 76.5 per cent greater chance of getting infected than unvaccinated people. With the Moderna, the vaccinated had a 36.7 per cent greater chance of getting infected than the unvaccinated after 90 days.

The authors discuss how negative vaccine effectiveness finding might arise. It may not mean that the vaccine actually decreases the persons immunity. There could be confounding factors. One possible explanation they raise is that in Ontario, a vaccine certificate system was introduced in the fall of 2021, and only those who had two doses could travel by air, rail, go to bars, gyms, etc., and so they may have had more social contacts than the unvaccinated who were shut in. But even if true it would still mean that the vaccines are not protecting us as much as wed like, which is nothing to celebrate.

Another possible explanation the authors raise is the possibility that antigenic imprinting could impact the immune response to Omicron. It had been observed in the past that the immune system is highly influenced by the first exposure to a microbe (antigen) that it encounters. Its called original antigenic sin. When a second exposure occurs, to a similar but not identical microbe, the immune system reacts as though it is targeting the original microbe. But the new invader isnt the original, and so the immune system is actually less effective in dealing with this. In essence the immune system is weakened for a microbe too similar to its first similar exposure. This phenomenon was originally described as occurring in influenza on occasion. This is only a theoretical possibility here, not proven for COVID, but now a matter of scientific discussion. The negative vaccine efficacy has since shown up in Iceland, and the U.K. as well. The Ontario authors are to be applauded for thoughtfully laying out some possibilities to think through, so as to determine what might be the cause.

A COVID-19 mural in Vancouver urges people not to worry.Jonathan Hayward/The Canadian Press

Weve had so many mood swings. We had been through a year of defining vaccine success as eliminating the virus, then as lowering infection and stopping the spread, to discovering there were breakthrough infections and transmission to other people, but that they still lowered our risk of hospitalization and death thats worth a lot though not always in the most vulnerable. In the West, many have responded to waning vaccine protection with time by doubling down, proposing ever more boosters. What is the scientific evidence for frequent boosters? Thats a matter of scientific debate.

The original Pfizer study submitted to the FDA booster meeting was shockingly tiny a mere 306 patients were given the section, and they had been followed for only a month, and, again, most of the subjects were younger than those at risk (18-55). Pfizer wanted it on that basis rolled out to millions. That was enough to get FDA officials asking hard questions. Crucially, nobody had studied the long-term effects of multiple mRNA boosters there hasnt been time. The FDA refused Pfizers recommendation to approve the booster for the entire U.S. population, with the top two heads of its Vaccine Research and Review Committee, Dr. Marion Gruber, (the head, and former acting chief scientist at the FDA), and Philip Krause (deputy director), and international colleagues, writing in the Lancet:

There could be risks if boosters are widely introduced too soon, or too frequently, especially with vaccines that can have immune-mediated side-effects (such as myocarditis, which is more common after the second dose of some mRNA vaccines, or Guillain-Barre syndrome, which has been associated with adenovirus-vectored COVID-19 vaccines [like the AstraZeneca or Johnson & Johnson]). If unnecessary boosting causes significant adverse reactions, there could be implications for vaccine acceptance that go beyond COVID-19 vaccines.

When the head scientists of the FDA Vaccine Review committee and colleagues raise such questions, it cant be dismissed as fringe fear-mongering. Shortly after, Dr. Gruber and Dr. Krause quit the FDA because the Biden administration was putting pressure on them to approve boosters before the vaccine committee had even met. The standard practice for approval is for the agencies to convene panels of outside experts to review the data openly, weigh risks and benefits, and take votes. But in December, the FDA and CDC leadership three times took the extraordinary step of not convening those experts for key booster meetings, in essence going around them because committee members had warned that the science supporting boosters for younger people was weak to non-existent, and they had safety concerns. Dr. Paul Offit, perhaps the most high profile provaccine physician-scientist in America, who was on the FDA panel told The Atlantic, he wouldnt advise a booster for his healthy son in his 20s, or a healthy male in his teens, because the risks of myocarditis (higher in males) outweigh the benefits. Dr. Offit rejects the CDCs and FDAs all-or-nothing approach to childrens vaccination.

Vinayak Prasad, the UCSF epidemiologist, says if you put the Danish, Ontario, U.S., and Kaiser studies about Omicron together, its time to face the reality about the vaccines.

Two doses of vaccine does nothing or almost nothing to stop symptomatic SARS-CoV-2, he says. Three doses barely does anything, and the effect will likely attenuate over time. He says, Booster mandates make no sense. Boosting should happen in populations where it further reduces severe disease and death a.k.a. older and vulnerable people.

With Omicron surging, Israeli public health met to discuss a fourth booster. The New York Times reported that some scientists on the Israeli government booster advisory panel, warned that the plan could backfire, because too many shots might cause a sort of immune system fatigue, compromising the bodys ability to fight the coronavirus. This immune system fatigue was, perhaps, not inconsistent with negative vaccine efficacy. Its not proven, but the fact that public-health officials were voicing such concerns shows that the doubling down strategy on boosters is being reappraised on safety lines. The EU, in a reversal, has just come out against regular, continuing boosters, saying they are afraid it will weaken the immune system.

People at a private nursing home dance before getting their fourth vaccine doses in Netanya, Israel. Israelis are eligible to get Pfizer as a fourth dose if they're over 60, immunocompromised or work in health care.Ariel Schalit/The Associated Press

From the very beginning, some scientists have wondered whether our goal the conquest and eradication of the virus was the right one. As Michael Cordingley reminds us in his book Viruses, in each millilitre of seawater there are about 10 to 100 million viruses, and this was a respiratory virus, free-floating, all around us, likely to shape shift and mutate. Could we, conquerors of nature, really overwhelm an enemy so omnipresent and agile?

As we have seen, as part of the reappraisal, theres an increasingly new goal being articulated by most public-health experts, that its not eradication of the virus, but it is keeping hospitalizations and deaths down, but also, working with the virus. The chairman of the Israeli Association of Public Health Physicians, professor Hagai Levine, said, Because Omicron is so contagious, our efforts to stop its spread are probably pretty futile. We are not going to stop this wave. Then he dared to say, We have been trying to dodge the bullet for two years, and in Israel we have been successful to some extent. But most of humanity is still alive after contracting COVID.

The Jerusalem Post reported, that in Israel some health experts believe the magic bullet this time around will actually be widespread infection. It cited Dr. Cohen, saying, The fifth wave might end when a large number of people will be infected.

Just as deaths have decoupled from cases with Omicron, our COVID mandates have decoupled from the science originally used to justify them. But the goalposts are moving, and now it is argued that only mandates will keep hospitals free of high-risk unvaccinated patients. What are the numbers? As of Jan. 20, there are 740 unvaccinated, and 2,091 fully vaccinated people in hospital for COVID (but not the ICU). In the ICUs there are 208 unvaccinated and 263 fully vaccinated people. True, there are fewer unvaccinated than vaccinated people in Ontario, but if surgeries are delayed, it is clearly because both groups are occupying beds. Portraying the unvaccinated as the sole cause is inaccurate, and deflects from the painful fact that Canada has fewer ICU and acute care beds per capita than almost any country in the developed world, and that the current vaccines are not working as well as hoped. What is called for is not more scapegoating and coercion, but healing, and more early treatment for both groups, now that we have it. Honouring the bedrock of medical ethics, no treatment without consent, is humane, preferable and possible.

Also reappraising is Bill Gates himself. He admitted this past November, We need a new way of doing the vaccines. He also accepted that our focus had been too narrow. We didnt get much in the way of therapeutics way less than should have been the case.

Consider how different our narrative is now. More and more officials are saying openly what the authors of the Great Barrington Declaration the ridiculed view of 60,000 public health scientists and physician signatories said some time ago: Our goal is not eradication of the virus, or a one-size-fits-all policy, but lessening of deaths in the vulnerable through focused protection, and focused vaccination. The immunity we have will be a mix of vaccine immunity and natural immunity, depending on the person. The new plan to live with the virus and get back to living a normal life is a departure from the pure Baconian conquest of nature, and hearkens back to the ancient, Hippocratic, notion that we must work with nature as an ally, in a kind of collaboration.

Since nature can indeed be both the enemy, but also is our very foundation, and potential ally and friend, no narrative that excludes either side of this friend and foe duality can ever do justice to medicine and healing. If the abandonment of Hippocrates was the first medical reversal, we are seeing in its return, a reversal of a reversal.

Its been a blow to our Baconian narcissism to be upended by nature these past two years. That thin-skinned Baconian within seems almost offended to admit that protection has come not only from scientific advances, but from natural immunity. Others might see this as a reassuring reminder that natural processes are not always and only the enemy. We shall find out, as we observe the unvaccinated, to what extent natural immunity, accumulating in waves of infection over time, does or does not protect, for the current or future variants.

Till then, lets give infallibility the day off. We have some ingenuity and some tools in our tool kit, none perfect, but if we use the whole kit, instead of just the hammer, we might be better for it. That goes for how we treat the virus, and how we treat each other. And for those scientists among us those strange creatures, always reappraising! there is comfort in knowing that after two years of hard work, we have a new narrative, or picture of our situation, which though imperfect, is more nuanced and likely closer to the truth.

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Opinion: Vaccines are a tool, not a silver bullet. If we'd allowed more scientific debate, we would have realized this earlier - The Globe and Mail