flu

Gain-Of-Function Viral Research: What’s The Big Deal?

Senator Rand Paul and many others have raked Dr. Anthony Fauci, long-time director of the National Institute for Allergy and Infectious Diseases (NIAID), over the coals for supporting research at the Wuhan Institute of Virology, and especially for supporting “gain-of-function” (GoF) research at that facility.

This needs some ‘splaining.

First, Senator Paul and the anti-Fauci crowd need to give us their definition of GoF research and then explain why it is bad. If they mean research that gives viruses new capabilities, then most labs seeking to learn how a virus functions is guilty. For example, University of Wisconsin flu researcher, Yoshi Kawaoka, did research that exchanged genes from the 1918 H1N1 Spanish flu virus with less virulent H1N1 viruses in order to learn why the Spanish flu caused so much death back then. That is classical gain-of-function research and it was done under strict quarantine and safety conditions (disclaimer, your blogger was on the safety review committee that vetted and approved Kawaoka’s Spanish flu research). It is legitimate and important research.

The Wuhan Institute of Virology had a small bit of indirect funding from Fauci’s NIAID to support a genetic registry of coronavirus sequences that is freely available to all researchers around the world. As new coronaviruses were discovered and their genomes sequenced, the lab investigators cataloged them. They also inserted the new spike protein genetic sequences into incipient, harmless viruses to see how well the new spike proteins allowed a virus to infect mammalian cells in tissue culture. This was done to help assess how much of a risk a new coronavirus was for spreading among mammals. Strictly defined, this research gave the engineered test viruses new capabilities—they acquired new spike proteins and gained the new functions that came with that. This is legitimate research and not some nefarious plot to weaponize coronaviruses that Rand Paul, et al., dishonestly allude to in their allegations.

Furthermore, there are the thousands of other labs around the world, including mine at UCLA and the University of Wisconsin that use viruses as tools for gene transfer in order to study the activity of newly discovered genes. For example, my lab discovered an aberrant gene that was associated with a particular human leukemia that used to be untreatable. We wanted to learn how the abnormal gene affected blood cells, so we cloned it and inserted it into a virus that could infect mouse cells. We then gave mice leukemia by infecting them with a virus that expressed a human cancer gene. That recombinant virus gained the function of the human cancer gene. Rand Paul, et al., would call that sinister gain-of-function virus research. However, from that and other research, that incurable leukemia now is 95% curable. Sinister?

Sure, using modern molecular technology, a minacious actor could help a pathogen gain super-lethal function and develop a super-pathogen, or a weaponized bug, like antibiotic resistant anthrax or super-spreading Ebola virus. It would be pretty easy to do. But, by far, the GoF research routinely done in labs around the world is done for learning not for killing.

When Paul accuses Fauci of supporting GoF research, that accusation is attached, without evidence, to an implicit accusation that the Wuhan labs are creating more virulent pathogens for nefarious reasons. So, why does Paul not go after Kawaoka or me for using NIH money to create viruses that might be able to kill people (Kawaoka’s flu construct) or that could cause cancer (my virus expressing a human cancer gene)?  

Could it be for political reasons?


Lions And Tigers And…Deer? Oh My!

First it was bats and humans, then domestic cats and dogs, farmed mink, and big zoo cats; now gorillas, hippos, and wild deer that have been infected by the SARS-CoV-2 (CoV-2 for short) virus. Many of these animals have become ill and several have died of COVID-19, most recently three snow leopards in South Dakota and Nebraska zoos. This is quite a wanton virus.

Of course, before CoV-2 and COVID-19 were known to the world, we knew that bats, humans and a few other animals, notably civets and even camels, were ready hosts of several different strains of “‘rona” viruses. We also knew that domesticated animals are also susceptible to their own coronavirus diseases—in fact veterinary coronavirus vaccines have been in use for years. Humans are known hosts for several coronaviruses, including those that cause the common cold, as well as the viruses that cause SARS, MERS, and now COVID-19. And we know that humans often catch these germs from bats and other intermediate hosts as diverse as civets and camels. After we genetically identified CoV-2 and were able to follow its spread, we quickly noticed that domestic pets also could be infected. This was closely followed with news that seven big cats at the Bronx zoo had become infected, and that mink farms across Europe were hotbeds for CoV-2 spread between humans and the animals and back. In fact, mink farms became such a hotbed of CoV-2 zoonotic spread that a couple of European countries completely shut down mink farming and culled all their animals. Several US states have also sharply curtailed mink farming. PETA probably applauds.

More recently two snow leopards at the Lincoln, NE children’s zoo and one in a zoo in South Dakota died from COVID. The Lincoln zoo also had two infected Sumatran tigers who recovered after being treated with steroids and antibiotics to prevent secondary infections and pneumonia. How the animals were infected is uncertain, but the most likely scenario is that they caught the virus from a caretaker. The problem is, none of the caretakers tested positive for the virus. Bats? Something else?

Since April 2020, when a tiger tested positive at the Bronx Zoo, dozens of other animals in zoos around the world have caught COVID. This month, the Denver Zoo reported the first coronavirus cases in hyenas, and the St. Louis Zoo found eight positive cases among its big cats, including two snow leopards. Abroad, the virus has killed a lion in India and two tiger cubs in Pakistan. Big cats seem especially susceptible since three other snow leopards at the Louisville Zoo were infected last December, and another snow leopard tested positive at the San Diego Zoo in July. The virus doesn’t just infect our fuzzy friends either; two hippos, named Imani and Hermien, at a zoo in Antwerp recently tested positive for COVID-19. Zoo keepers were first alerted to a potential problem when they noticed that the colossi had “runny noses.”  One reckons that a runny nose for a hippo is a big deal. One also wonders who gets to dab that nasal maw in order to test for the virus.

In fact, zoo and domestic animal infections have become so prevalent that an animal COVID vaccine developed by Zoetis, a NJ-based veterinary pharma company and former Pfizer subsidiary, has been authorized by the USDA for experimental use. The Cincinnati Zoo, for one, has vaccinated  80 animals, from giraffes to apes, against COVID.

Deer too. Oh my! It is one thing for zoo animals to acquire COVID—their captivity makes it easy to limit their interaction with other animals and humans to prevent spread of contagions, and they seldom complain that their rights are being infringed when they are quarantined. However, COVID in wild animals is a different story, as we have seen with bats and how easily they transmit the virus to humans. Scientists now have evidence that CoV-2 also readily propagates in white-tailed deer. In fact, the virus is already widespread in cervids across the US, which likely has significant implications for the long-term course of this pandemic.

In September of last year, genetic analysis of the gene that encodes the ACE2 protein (i.e., the viral receptors expressed on many cells in the body) in many different animal species suggested that CoV-2 could easily infect deer (and several other animals too). A survey of white-tailed deer in the Northeast and Midwest found that 40% had antibodies against the CoV-2 virus, indicating prior exposure. Between April and December 2020, veterinarians at Penn State found active CoV-2 infections in ~30% of deer tested across Iowa. Then during the winter COVID surge in humans from Nov. 23, 2020, to Jan. 10 of this year, ~80% of the tested deer were infected. The prevalence of the virus in deer was 50 to 100 times greater than in Iowa residents at the time (and the deer reportedly did not wear face masks). The study, published about two months ago, indicates that white-tailed deer have become a permanent reservoir for CoV-2. While it is not fully understood how the virus entered the deer population, genetic sequence analysis of nearly 100 viral samples found that the variants circulating in deer matched the variants circulating in people. This suggests that deer caught the virus from people multiple times in Iowa alone. How that happens is not known since people usually do not have close contact with live deer. More concerning is whether viral variants arising in deer readily pass back to people.

Bottom line. Clearly, a lot of different animal species can catch Cov-2 and spread it. It is clear that people can spread coronaviruses to pets and other animals, but the FDA says that the reverse, animal-to-human virus transmission, is not common. But, it clearly happens as we have seen with this pandemic, and with many other viruses that cause SARS, MERS, AIDS, Ebola, flu, etc., that spread from animals to humans. The prevalence of CoV-2 infection in so many species of mammals, especially in animals that have close contact with humans, suggests that several animal species, not just bats, can serve as permanent reservoirs for the virus and the jump to humans is something that can happen over and over. This is not unprecedented. It is what we see with influenza, which is carried back and forth between the Northern and Southern hemispheres with migratory birds, in which different flu viruses shuffle their genomes to create the new strains of flu for which we have to vaccinate against each year. This animal reservoir for flu makes it next to impossible to eliminate influenza, and similar animal hosts for CoV-2 likely would make it nigh impossible to eliminate COVID too. I raised this specter some months ago in these pages when reporting that pet dogs and cats can carry the virus. Our furry friends represent a viral reservoir that is in even closer contact with people than bats, deer, and fortunately, hippos and leopards.

We also have to be worried about the CoV-2 virus mutating in the different animal species that harbor and spread it. We know that happens in bats, which makes it almost certain that new strains of the virus will arise in deer and dogs too. We have already seen this on mink farms in the Netherlands and Poland. Farmworkers passed the virus to captive animals where it spread, mutated, and then spilled back into humans. In fact, zoonotic transmission from animals to humans probably happens thousands of times a year. Researchers from the EcoHealth Alliance and from Duke-NUS Medical School in Singapore, estimate that each year many people are newly infected with SARS-related coronaviruses. Many may get sick, but there are many reasons why most of these infections never grow into noticeable outbreaks (for example see my earlier blog post about unusual respiratory infection clusters in China and Los Angeles just before COVID). The researchers also created a detailed map of Asian habitats of 23 bat species known to harbor SARS-related coronaviruses then overlaid it with data on where humans live to create a map of potential infection hot spots. They found that close to 500 million people live in areas where bat-to-human transfer is likely, and this risk is highest in southern China, Vietnam, Cambodia, and Indonesia. Other surveys done before COVID-19 showed that many people in Southeast Asia harbor antibodies against other SARS-related coronaviruses. Blending these data with data on how often people encounter bats and how long antibodies remain in the blood, the researchers calculated that ~400,000 undetected human infections with these viruses occur each year across the region.

That is just for bat-to-human transfer in Southern Asia. It now looks like we will have to also concern ourselves with zoonotic coronavirus transfer from Buddy and Bambi too.

For this reason, researchers are working to develop a universal coronavirus vaccine that will be effective against most viral strains and variants. I will write about this soon. Stay tuned.

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Lessons for COVID Vaccinations And Herd Immunity From Influenza And Rubella

Note: The following is modified from the blog post, “Rubella: We vaccinate for far less,” by Katelyn Jetelina, MPS, PhD who is an “epidemiologist, biostatistian, professor, researcher, wife, and mom of two little girls.” She writes a blog entitled, “Your Local Epidemiologist.”

 “Those who cannot learn from history are doomed to repeat it.”

 George Santayana

 

In the US, more than 300,000 kids aged 5-11 have been vaccinated with the Pfizer COVID-19 vaccine, which has proven that the vaccine is safe and can benefit some kids. It prevents infection, COVID-19 disease, death, long COVID-19, and keeps kids in school. Admittedly, only a few kids develop serious COVID disease and fewer have died from it. Most infected kids only have mild, if any, symptoms. Vaccine skeptics use this fact to stridently argue against childhood COVID vaccines. So, why are we pushing to vaccinate children who rarely get seriously ill?

There are two reasons why we vaccinate anyone. The first reason is to protect the vax recipient from the disease; this is an individual-level benefit of the vaccine. The second is to protect a larger population by trying to retard disease spread; this is a population-level benefit of vaccines that is better known as herd immunity.

But, anti-vaxers only focus on the fact that childhood vaccines provide little individual-level benefit to children and wholly ignore the larger population-level benefit of the vaccines. As I have written before, vaccinating children who are at low risk for serious disease is still very important for reducing viral spread in order to  prevent more dangerous viral mutants from emerging. It also is important for reducing infection and disease in more vulnerable people in the population. It is these population-level benefits that are the most important reason to vaccinate low-risk children. Vaccinating children for a population-level benefit, rather than for individual-level benefit, is not at all new and is a very acceptable practice. Here are a couple of examples.

Influenza: A few decades ago, Japan mandated flu vaccines for all school kids. That vaccine slowed the spread of flu in schools leading to many fewer student illnesses and absences. More significantly, vaccinating all school kids also caused a sharp drop in flu deaths in older people like school teachers and staff, parents, and grandparents who have close contact with the kids.

Kids are walking incubators for respiratory viruses and readily spread their germs to others. Infected children essentially are virus vectors much like mosquitoes are vectors for malaria and yellow fever. Therefore, in Japan, the flu vaccine effectively shut down a major vector of influenza infection for at-risk older people. That is an undeniable and important population-level benefit of vaccinating school kids against the flu.

Rubella: Now, let us take a deeper dive into rubella, or German measles, and its vaccine, which is the “R” in the MMR shot. It is especially enlightening to compare the natural history of rubella to what we are learning about COVID-19.

Both COVID and rubella are caused by airborne viruses that spread when infected people cough, sneeze, or even talk. As with COVID, rubella symptoms in children are quite mild. They include its tell-tale measles-like rash, sore throat, low grade fever, mild pink eye, and general discomfort. But, about 25 to 50% of infected children will not experience any symptoms. Likewise, many CoV-2 infected kids also do not develop symptoms. But, asymptomatic kids infected with either rubella or CoV-2 readily spread their viruses to friends and family; hence, they can be significant vectors delivering both viruses to people at-risk for serious disease.

Over the last two years, we have learned that COVID mostly (with significant exceptions) causes serious illness and death in older people or for those with certain other health conditions. Similarly, while rubella only causes mild disease in most children, it is incredibly dangerous for developing fetuses. A woman infected with rubella during the first 3 months of pregnancy has a 90% chance that the fetus either will not survive or will develop Congenital Rubella Syndrome (CRS), characterized by deafness, blindness, heart defects, and/or severe brain damage. In the early 1960s, a rubella outbreak began in Europe and spread to the US. In 1964-65 ~12.5 million total cases were reported in America affecting nearly 50,000 pregnancies. More than 11,000 of the infected mothers miscarried, or delivered still-born babies. Of the >20,000 infants born alive to infected mothers, the majority had severe illnesses: 2,100 died shortly after birth, 12,000 were deaf, 3,580 were blind, and 1,800 had permanent mental disabilities.

The rubella outbreak proved hard to contain because, as with COVID, infected asymptomatic people make it hard to know when someone is spreading the virus. Rubella also is just as contagious as COVID. Both viruses have an R0 = 6-7 meaning that each infected person will infect, on average, 6-7 other people. For comparison, flu’s R0 = 2-3, which means it is about half as contagious as the other two viruses. It, therefore, is not surprising that like rubella, the COVID outbreak is proving hard to contain.

Soon after the 1960s rubella pandemic began, a safe and effective vaccine was quickly developed and approved for use in Europe and North America (this is reminiscent of the quick development of the COVID vaccines). Early on, there was a robust international debate on who should get the rubella vaccine. There were two schools of thought:

  1. Despite the fact that rubella only caused mild problems in kids, some proposed vaccinating all children hoping to provide indirect population-level protection for pregnant women and their at-risk fetuses.
  2. Others argued that because children were only minimally affected they should not be subjected to the vaccine and that only women of childbearing age should be vaccinated. This, proponents argued, would more specifically protect those most at risk.

Ultimately, it was found that countries that chose #2 were not able to sufficiently reduce the virus, because it still spread unfettered among children. This strategy did not reduce the rates of CRS. Eventually, option #1, vaccinating low-risk children (like what we are moving toward with the COVID vaccine) was adopted world-wide. Vaccination rates of school kids reached ~85% in the US, which last experienced a serious rubella outbreak in 1995. In 2004, transmission of rubella was eliminated in the United States and in 2015, it was eliminated in all the countries of North and South America.

Soon, the MMR vaccination was mandated for children in all 50 states. It is important to realize that these mandates were not to protect kids from the mild disease but to protect the at-risk population, or fetuses. In other words, we vaccinate kids against rubella not so much to protect them, but to provide a significant population-level benefit to others.

Today, because of broad rubella vaccination of low-risk children, we see an annual average of just 10-15 cases of CRS in the US that are traced back to international travel to countries with poor rubella vaccination rates. In contrast, in countries with low vaccination rates, about 120,000 children are born each year with severe CRS birth defects and even more die in utero.

Bottom Line: This country, and indeed all of the Americas and most of Europe came together to eliminate endemic rubella through broad population-level vaccination programs targeting low-risk groups responsible for spreading the virus to the high risk population. Japan saw the same effect with influenza. They focused on broadly vaccinating a low-risk population (school kids) and saw great benefits in the high-risk older population. As we approach a broad COVID vaccination strategy that includes giving the shot to low-risk children, it very likely will have a population-level benefit and help protect those most at-risk for serious disease.

It is important to note that the population-benefit conferred by the COVID vaccine also applies to all of us and not just to children. When we are vaccinated, not only does it protect us, it also provides significant protection to at-risk people around us. That, in fact, is called “herd immunity.”

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