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Smallpox viruses threaten again / Sonia Shah

Smallpox has been eradicated, but viruses belonging to the family, such as the monkeypox and cowpox viruses, are coming back to the fore

Ten thousand years ago, when the smallpox virus first emerged, the only thing humans could do to get help was to pray to the gods. The virus that causes the disease, later known as variola, first attacks the mucous membranes of the nose or throat and spreads throughout the body until a characteristic rash appears. Then blisters full of viruses develop on the skin. In the course of recorded history, the "spotted monster" killed up to a third of the people infected with the virus. In the 20th century alone it killed more than 300 million men, women and children.

Credit: James Lloyd-Smith lab

The deadly plague was wiped off the face of the earth in the late 70s thanks to mass vaccination campaigns that protected millions in exchange for a small scar up the arm. Because humans are the only hosts of the virus, and in the absence of another hiding place in the natural world, the variola virus has been eradicated. Today the only known samples of the virus are locked away in two special government laboratories, one in the United States and the other in Russia. Barring a catastrophic laboratory accident, or unless the virus is deliberately released or genetically engineered, smallpox will never again spread death and misery across the planet.

The World Health Organization, which planned the eradication campaign, sounded the siren call in 1979, two years after the last patient with the disease was recorded, a hospital worker in Somalia. Since then, no country has routinely vaccinated its residents against smallpox. However, the US began vaccinating certain health workers and selected military personnel after the terrorist attacks on September 11, 2001. That is, an entire generation reached adulthood without exposure to the disease or the vaccine, which sometimes causes serious side effects.

And here lies the sting. The smallpox vaccine protected not only against variola. In fact, anyone vaccinated against smallpox has also developed immunity against the virus's cousins, including the monkeypox and cowpox viruses. Since in the old days infection with the smallpox virus was much more common, secondary protection against the other viruses did not seem to be of great importance.

But now, when most people are no longer vaccinated against smallpox, the question arises: Is it possible that these forgotten pathogens, which, like the smallpox virus, belong to the biological species Orthopox virus, are they a danger to humans? There are reasons for concern. Unlike smallpox, the monkeypox and cowpox viruses naturally reside in rodents and other creatures, so we can never completely eradicate them. The number of humans infected with monkeypox and cowpox has increased steadily in recent years, and both viruses have begun to infect creatures other than their usual hosts. This phenomenon raises the possibility that they will spread around the world in new routes.

No one knows how these viruses will change over the years, but virologists fear that if they mutate to help them pass more easily from one person to another, they will spread across large parts of the world. This grim possibility prompted a small group of virologists to learn more about possible smallpox epidemics in the making so they could sound the alarm if signs of more threatening viral forms appeared.

different degrees of severity

A boy with smallpox is immortalized on a stamp from Guinea. Photo: shutterstock.
A boy with smallpox is immortalized on a stamp from Guinea. Photo: shutterstock.

The history and biology of viruses close to the smallpox virus suggest their future. The origin of 60% of all pathogens that affect humans, including smallpox viruses, is in the bodies of other vertebrates. The living virus most similar to variola, tetrapox, was isolated from a wild gerbil in Africa in 1968. Chemical-molecular analysis indicates that the origin of the ancestors of the smallpox virus is in an African rodent that may already be extinct. Similarly, the monkey and cattle pox viruses, despite their names, reside in squirrels, squirrels and other rodents.

When variola's ancestors first moved to humans, they probably weren't highly contagious, says Mark Buller, a microbiologist at St. Louis University. But he and other researchers speculate that somewhere down the track, a variant emerged that infected humans more easily. The critical change allowed the virus to spread itself through the coughs, puffs or sneezes of an infected person. At that time, people began to live more densely, and thus the risk of transmitting the virus from person to person increased. The combination of biological and environmental changes gave the emerging virus the advantage it needed to become a global pandemic.

However, the ability of a virus to infect easily does not necessarily make it deadly. And indeed, scientists do not know why there is such a large variation in the severity of the diseases caused by the smallpox viruses. For most people, infection with cattle, camel or raccoon pox causes a slight rash on the skin accompanied by blisters full of viruses that disappear on their own without damage. But monkeypox can be quite deadly in humans. The worst subtype, found in the Congo basin, kills about 10% of people who become infected, while another variant, from West Africa, causes little or no death. As luck would have it, in 2003 the West African strain caused the first ever recorded human infections in the West of the Earth. The outbreak, which took place in six states in the US, led to the hospitalization of 19 people, including a child who suffered from encephalitis and a woman who went blind and needed a corneal transplant. The source of the infection was rodents that were imported from Ghana and passed the virus to barking marmita (marmita barking) that were raised as pets. The test subjects, for their part, passed the virus on to their husbands. Such transitional animals allow the virus, which naturally lives in animals that do not come into contact with humans, to reach many people.

Subtle genetic changes may explain the variable level of severity of the smallpox viruses. For example, some of them contain genes for proteins that prevent the immune system from responding effectively to infection. When researchers compared such genes from different smallpox viruses, they focused on one gene that was found in several types of viruses from the family. They found that in the deadliest strains of variola, this gene encodes a protein that the evidence suggests prevents certain cells of the immune system from effectively coordinating an attack against the virus. But the corresponding gene in Congo Basin strains of monkeypox (strains less deadly than smallpox) contains instructions for making a much shorter protein. In the milder version of the West African strain of monkeypox, the gene is not present at all and therefore the protein in question is not produced. That is, according to these results, the shorter protein in the Congo Basin strains of monkeypox made them, in some way, less lethal than smallpox.

The researchers hypothesize about how biological species of smallpox viruses acquired this gene and others may explain why the monkeypox virus and its cousins ​​may be more dangerous in the future. The genes, which are not essential for the replication of the viruses, are apparently faithful copies of genes that the viruses acquired somewhere in the course of evolution from the creatures they infected. However, amazingly, in a normal infection cycle the viruses do not approach the genetic material stored in the host's cell nuclei at all.

One possible explanation, favored by smallpox virologists, is that a person or another vertebrate was infected with two viruses at the same time: smallpox and a retrovirus. According to the researchers, such double infections are probably quite common. It is known that retroviruses insert their genes into the host's DNA. (Approximately 8% of the human genome is DNA derived from retroviruses.) It is possible that the extraordinary biochemical activity of retroviruses within the cell allows the smallpox viruses to capture the host's genes.

If this hypothesis is correct, it may bode ill. Smallpox viruses are genetically stable, and usually do not mutate easily. If they can steal genes from their hosts and thus become more violent, then it is impossible to predict what a relatively mild smallpox virus might do under the right circumstances, much less what a deadly smallpox virus might do in the first place. The transition from a mild to dangerous virus may occur more quickly and less predictably than we thought.

"Our younger cousin" of the smallpox virus

The monkeypox virus is in the best position of its viral cousins ​​to become a global threat. Virologists consider it the "younger cousin" of smallpox, partly because it causes the same disease clinically. The first report of the virus was in 1957, after it was discovered in captive monkeys. The virus usually resides in African rodents, possibly the rope squirrel. So far, outbreaks have occurred mainly in Central Africa, and two unusual events have been reported, one in the USA in 2003 and the other in Sudan in 2006.

Ann V. Rimoin of the University of California, Los Angeles was in Kinshasa in the Democratic Republic of the Congo in 2002 when she first heard about local residents who had contracted monkeypox. She did not know how many people were infected, how they were exposed to the virus or whether the virus could spread to other people. But she knew it was a life-threatening disease and wanted to understand more.

With blond hair and a bright pedicure, you can't be mistaken and think that Remoine is a local inhabitant of the remote jungles of the Congo. But as part of her undergraduate studies, she studied the history of Africa and got to know the politics of the Congo. She also speaks fluent French, which is still common in the former Belgian colony, as well as Lingala and other local languages. Rimouin therefore began to find out what was going on. "I just connected with the right people and asked the right questions," she says. "And it became clear to me that there are probably many cases that are not reported."

But how to find them? Not surprisingly, due to the paucity of medical facilities in rural Congo, most patients did not visit doctors. And those who recovered could not be easily identified through blood tests because it is impossible to know whether the existence of antibodies against smallpox viruses indicates a previous smallpox vaccination or infection with another smallpox virus. To estimate the scope of the monkeypox disease it was therefore necessary to find people with the disease, and then test the virus actually found in the smallpox.

Rimoin began the task and established a research site deep in the forest. There were no roads leading to the site and there was no cell phone or radio reception. She chartered planes to get in and out of the place and spent days walking, canoeing and riding a motorcycle to locate monkeypox patients among Lingala-speaking villagers in the interior of the Congo.

The results were startling. Rimoin discovered a 20-fold increase in the number of people infected with monkeypox since the years 1981-1986, when the World Health Organization (WHO) collected similar data. And she still believes that her findings, published in 2010, express a lack of appreciation. "This is the tip of the iceberg," she claims. After all, 30 years ago the WHO invested far more resources than she did in finding monkeypox. Rimoin's people undoubtedly missed more patients than the WHO people.

The rise of monkeypox

Although the increase in the number of people infected with monkeypox was greater than expected, it was not unexpected. After all, most of the country's population is not vaccinated against smallpox viruses. (The Democratic Republic of Congo stopped vaccinating against smallpox in 1980.)

Further studies suggested that something else was also going on. James Lloyd-Smith, an ecologist and Rimoin fellow at Los Angeles University, uses computational models to study how diseases pass from animals to humans. According to Lloyd-Smith's analysis of Rimoin's data, the discontinuation of the vaccine and the loss of immunity it conferred against similar smallpox viruses cannot fully explain the increase in the number of patients. There also had to be at least a fivefold increase in the number of cases where the virus passed from infected rodents to humans.

It is not known why monkeypox virus may be transmitted to humans more frequently. Deforestation for agriculture and wood burning may have brought more people into contact with squirrels, mice and other infected rodents. Also, it is possible that due to the civil war in the Congo, more and more locals were forced to eat animals that might be infected. A 2009 survey, published in October 2011, revealed that a third of the rural population in the Congo eats rodents found dead in the forests, and that 35% of monkeypox infections occur during the hunting and farming season. (Most people contract monkeypox from contact with infected animals, such as handling or eating them.)

Rimouin Other virologists fear that as the opportunities to infect humans expand, the monkeypox virus may become better adapted to the human body. Buller investigates how viruses from the smallpox family cause disease in both humans and animals. The monkeypox virus "can already kill humans," he says, and it can also spread between people, just not yet efficiently. A few minor changes in an existing viral trait may be enough to make it a much more infectious pathogen for humans.

The spread of cowpox

Reports of people and animals infected with the cowpox virus, which originates from rodents, are also on the rise, this time in Europe.

Cowpox causes a mild illness in most people. After the virus penetrates the cells and suppresses the host's initial immune response, the infected person produces a barrage of antibodies against the virus that prevent it from spreading in the body's tissues. But this is not the case in people whose immune system is weakened, for example due to HIV, chemotherapy for cancer treatment or treatments to prevent transplant rejection. "They can get a smallpox-like disease and die," says Malcolm Bennett of the University of Liverpool in England. Public health experts estimate that the number of people in the US whose immune system is weakened and who are exposed to serious illness as a result of infection with the cowpox virus or other smallpox viruses has increased 100-fold since 1972.

Bennett, a veterinary pathologist, studies the ecology and evolution of cowpox in the wild. In Britain, he says, the cowpox virus often resides unharmed in barnacles and wild mice. Domestic cats contract the virus when they hunt rodents, and then expose their owners to cowpox. This chain of events is responsible for the cowpox disease among half of the people infected with it in the UK.

Like monkeypox, cowpox began attacking creatures other than their usual hosts. As the cannibal populations thrive due to mild winters and other climatic conditions, rats may have begun to play an intermediary role in the transmission of cattle pox, similar to the role played by rats in the 2003 American outbreak of monkeypox. "There is an increase in the number of reports of infections in zoos or pets involving rats," says Mary Reynolds, an epidemiologist at the US Centers for Disease Control and Prevention (CDC). This trend "may be worrisome because black and brown rats spread safely across the planet and very efficiently," she says. If the cowpox virus found its home in rats, and not only in ferrets and wild mice, millions of people could easily become infected, by being bitten or by contact with them.

And indeed, the smallpox viruses are known to be experts in infecting new biological species. For example, the vaccinia virus, which was used to make the modern smallpox vaccines, now breeds freely in cattle in Brazil and buffalo in India. And there are "a variety of smallpox viruses in the world that have never been fully isolated or characterized," says Reynolds. Under the right conditions those unfamiliar species may expand their habitat to new areas and new biological species. "Some of them will cause disease in humans," adds Bennett. "They just haven't made the jump to our species yet."

armed and alert

As there are more people who have never been vaccinated against smallpox, smallpox virologists predict that the incidence of monkeypox, cattlepox, and other smallpox strains in humans will continue to rise.

If one of these viruses becomes specialized in infecting humans, we will need new drugs and vaccine compounds and the resources to manufacture them to eradicate the threat. Since after 11/246 there were fears that smallpox viruses would be deliberately released, a host of new ingredients and drugs for smallpox are now being developed. These drugs will likely also protect against naturally occurring smallpox viruses. However, the production of the drugs and their distribution, as well as protection against the side effects that will surely occur, are an expensive and complex operation. New ingredients against smallpox, such as Bavarian Nordic's Imvamune, have been designed so that they can be given safely even to people with a weakened immune system, but they must be given in higher doses and in two injections instead of one, so they are more expensive than the previous ingredients for smallpox. The new drug ST XNUMX, produced by Siga Technologies, prevents smallpox viruses from moving from one cell to another in the host's body. Although it has not yet been approved by the US Food and Drug Administration, the US government has already purchased a large amount of the drug and added it to the US biological defense stockpile.

In places like the rural areas of the Congo River basin, where funding for vaccines and innovative drugs is limited, the best hope right now is increased surveillance combined with community outreach programs. For example, the awareness program about monkeypox, which the CDC manages in cooperation with local health officials and associations in the Democratic Republic of the Congo, increased the percentage of locals able to recognize the disease from 23% to 61%. Rimoin's painstaking follow-up of the monkeypox disease also continues, and new studies focus on testing the gene sequence in the versions that currently infect animals and humans to find out how the virus changes. More successful identification will allow for better treatment and isolation of patients and will reduce the chances that the virus will undergo mutations that will allow it to spread with increased efficiency between people.

The age-old war between smallpox viruses and humans apparently did not end the day a 21-year-old Somali hospital worker recovered from smallpox in 1977. With new tools and improved surveillance, scientists are more alert and armed with more options than before. In order to prevent humanity from another epidemic, we will have to maintain these protections in the future as well.


in brief

About 35 years ago, when smallpox was eradicated, people stopped getting vaccinated against the virus.

In the years that have passed, the general population has lost immunity not only against smallpox but also against other smallpox viruses, which were previously suppressed by the smallpox vaccine.

More people are now sick with monkeypox and cowpox, and there is a possibility that a new world epidemic will take the place of the smallpox disease.

A worrying trend

The number of monkeypox patients increased faster than expected

It is difficult to track the number of people infected with monkeypox: the disease often strikes in remote areas far from medical centers, and it is not easy to confirm infection retrospectively. In any case, it was clear that the number of patients would increase after 1980, with the cessation of vaccinations against smallpox, which confer immunity against monkeypox as well. However, the results of surveys conducted in the last 40 years indicate that the monkeypox disease is more widespread than we thought. Researchers suspect that political instability and deforestation are causing more and more people to eat and treat infected wild animals without any awareness of the diseases. An increase in the number of patients can have far-reaching effects because it gives the virus more opportunities to adapt more easily to humans.

And more on the subject

Extended Interhuman Transmission of Monkeypox in a Community Hospital in the Republic of the Congo, 2003. Lynne A. Learned et al. in American Journal of Tropical Medicine and Hygiene, Vol. 73, no. 2, pages 428-434; August 2005.

Monkeypox Virus and Insights into Its Immunomodulatory Proteins. Jessica R. Weaver and Stuart N. Isaacs in Immunology Reviews, Vol. 225, pages 96-113; October 2008.

Major Increase in Human Monkeypox Incidence 30 Years after Smallpox Vaccination Campaigns Cease in the Democratic Republic of Congo. Anne W. Rimoin et al. in Proceedings of the National Academy of Sciences USA, Vol. 107, no. 37, pages 16,262-16,267; September 14, 2010.

Ann V. Rimoin Research Laboratory Web Site at UCLA. where photo gallery, publications and press clippings:


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