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May 2020
Pets: An Unexpected Reservoir for CoV-2?
05/14/2020
Wednesday, researchers at the University of Wisconsin-Madison reported in the New England Journal of Medicine that domestic cats can spread the coronavirus between themselves. But, they did not show any illness, which is troubling. Without testing how do you know that Fluffy did not consort last night with an infected ne’er-do-well in the neighborhood, or even sniffed some infected bat poop in your back yard or on a walk?
Perhaps that news is not too surprising since we have known for a while the virus seems to easily pass between species. After all, we are pretty sure that the SARS coronavirus that infected humans came from a bat by way of a civet, and that MERS went from a bat to a camel to humans. Then there are the recent reports of 7 large cats in the Bronx zoo catching the virus from a human and showed symptoms of illness. Also, at least two pet cats and one pet dog were given the virus from their human owners.
Is this important? Well, it does suggest that animals that are in very close contact with humans might become a growing reservoir for the virus. Not too many of us have camels that sit on our laps while we binge on Netflix or have a tiger that shares our bed and cuddles with us. Many of us do have dogs and cats with which we enjoy close contact like that.
As the stay at home restrictions seem to have slowed the virus spread and we are beginning to open up, we will likely do so without sufficient “herd immunity” to quell a second or third wave of the pandemic. That means we will approach a semblance of normal activities while the virus remains with us. In turn, relaxed restrictions will likely spread more virus, including to pets and hence back to humans. It is one thing to have a coronavirus reservoir in bats that few of us directly encounter; it is another thing to have a reservoir of the virus in our animal companions.
Another concern is that as viruses pass between animal species, they often acquire new behaviors. We have found about 500 different coronaviruses in bats alone. Other animals often carry other coronaviruses typical to their species. When a coronavirus from one species enters a cell from another species that has its own endogenous coronavirus, the viruses can shuffle their genes creating new strains with new capabilities. And when we are talking about viruses infecting an animal, we are talking about billions of virions being produced that are capable of shuffling genomes with endogenous viruses. All it takes is one particularly nasty and overly competitive virion to emerge and find a new host that has not seen it before.
So, there potentially is a “perfect storm” arising consisting of having poor human herd immunity, a ready reservoir of virus, and a lot of friendly furry factories making viral variants that could prove even more virulent. Yes, this scenario is speculative, but we have seen it happen before and all the pieces seem to be in place. Time will tell.
In a separate statement, the authors of the research paper mentioned above recommended keeping pets away from other animals and even isolating them if someone in the home becomes positive for the virus.
This blogger fully expects a second wave of the pandemic.
COVID Vaccine Update
05/12/2020
The Milken Institute launched a tracker with which you can follow progress in the development of drugs and vaccines for COVID-19. As of May 11, the tracker lists 125 vaccines in development around the world. Below, I provide a summary of what is going on. I first highlight the challenges of quickly developing a vax. Then, I give you a sample of some of these efforts and discuss some of the ingenuity that is going into these efforts around the world.
Challenges: An immediate challenge with fully developing a vax is being able to test it before the pandemic fizzles out on its own. That is what derailed the full development of the SARS and MERS vaccines. In a vaccine trial, you have to wait for people to be naturally exposed to the virus in order to learn whether the experimental vax is effective. Since there is no effective treatment for COVID-19, it would be highly unethical to deliberately expose test subjects to the pathogen in order to see if a test vax protected them. If the pandemic fizzles before a vax can be fully tested, we will never know how effective any of the 125 vax candidates are.
Yet, there is the very real threat that we will see a second and maybe third wave of the pandemic that would naturally generate new infections for the vaccine trials. Also, while the pandemic might be on the downswing in Europe, it seems to be catching fire in India and Africa and places in the Southern hemisphere. For this reason, vax researchers are partnering with health scientists in places of the world where the pandemic is expected to soon take off. Therefore, there might be enough “life” left in the pandemic to fully develop and test a human coronavirus vaccine. But, it is something hard to hope for.
Another potential concern is uncertainty regarding what kind of immune response an experimental vaccine would generate in people. We have to make sure that the immune response does NOT exacerbate the problems of the COVID-19 disease. That is a real concern since we know that the immune response to Dengue virus can actually enhance its ability to infect cells. Also, a very recent paper from MIT scientists indicates that a cytokine called interferon produced by immune responses can actually increase the level of expression of the viral receptor in human cells. That means that the immune system might make it easier for the virus to infect cells. Earlier animal studies to develop a SARS vax showed that animal test subjects often fared worse after immunization.
As I discuss below, we will soon know the answers to these questions.
Progress: With these challenges in mind, scientists around the world plod on to develop an effective vaccine as quickly as possible. These are scientists more used to the long-term development of vaccines and therapies that go into humans. Now they are like marathon runners having to learn how to sprint.
- Perhaps the lead vaccine candidate at this point is being developed by investigators at Oxford University in England. Years earlier they developed a vax candidate to MERS that showed good promise in early clinical trials. Their approach to the MERS vax is being repeated for the CoV-2 vax. This entails inserting the CoV-2 spike protein, which is what gives the virus its corona appearance, into a crippled form of an adenovirus that causes common colds in humans. The crippled adenovirus was genetically engineered so that it can infect human cells, but not spread or cause illness. This “fake” virus makes the immune system think that the body is infected with CoV-2 and respond to that molecular sleight of hand.
The crippled virus was tested on six monkeys at the US NIH Rocky Mountain Laboratory in Montana. Vaccinated and unvaccinated monkeys were then challenged with live CoV-2 virus. 28 days later the vaccinated animals were completely protected from the virus and showed no illness while the unvaccinated animals became very sick.
Based on this encouraging, but extremely small preclinical study, the Oxford team has recruited and vaccinated about 1000 volunteers in order to assess safety and to determine the type of immune response generated by the vax. It is a blinded, placebo-controlled trial where one-half of the subjects received the CoV-2 vax and the remainder received a control vax against unrelated meningitis. The investigators anticipate releasing the results of this initial safety trial by the end of next week. If things go well, they plan to recruit another 5000 patients by the end of the month for efficacy trials. At this aggressive pace, they hope to have a fairly good idea if the vax is safe and effective sometime in September. Whew!
The most innovative aspect of this effort is not in the science, but in the more mundane area of product development. Even while this lightning-fast R&D is still underway and the vax still uncertain, the biopharma company, AstraZeneca, has agreed to begin large scale production of the vaccine with no guarantee that it will ever work. They say that there will be 100 million doses of the experimental vax by the summer and 1 billion doses by the end of the year. For context, several pharma companies together produce about 150 million vaccine doses each year to deal with seasonal influenza in the US. Thus, a single company producing 1 billion doses in about 6 months is unprecedented and represents a huge risk if the vaccine fizzles or if another lab develops a better one.
The idea is that if the vax does prove to be effective, it will be immediately available for dissemination around the world without the normal delay of ramping up production and distribution capacity. Other companies have said that they also will begin large scale production of other experimental vaccines while they are still under development. Most of these vax candidates will fail, which means that the pharma companies are assuming huge risk in order to make sure an effective product gets out into the world as quickly as possible. That is unheard of.
- In April, Chinese scientists from a biotech company in Beijing developed an “old-school” inactivated viral vaccine. This is the intact CoV-2 virus itself that has been chemically “killed” or inactivated. Typically, a solution of virus is inactivated by treating it with formalin. The formalin is dialyzed out from the now inactive virus, which is then used to vaccinate people or animals. This was the way that most early viral vaccines were developed and has been quite successful, although not always. A monkey trial published May 6 in the journal Science indicates that this inactivated CoV-2 virus is safe and fully protected them from a challenge infection with live virus. The Chinese lab says that placebo-controlled human trials are underway in Jiangsu province, which is north of Shanghai.
- In the US and Germany, the pharma company, Pfizer, and its biotechnology partners have human trials underway to determine the safety and immune response to four novel vaccine candidates. This effort uses a totally unique vaccination approach that has never been used to prevent any infectious disease. Most vaccines use crippled or killed virus, or “pseudo-viruses” that have been genetically engineered to express select viral proteins that can potentially be recognized by the immune system. These inactivated, crippled or “pseudo-viruses” trick the immune system into thinking that there is an active infection.
In contrast to these standard approaches, Pfizer, as well as biotech companies in Seattle, Pennsylvania and elsewhere are developing totally novel RNA or DNA-based vaccines. RNA and DNA are the genetic material viruses use to express proteins that the immune system recognizes and responds to. The idea is that if genetic material encoding these proteins enters human cells, the cells will use the genetic information to make select viral proteins without producing any virus. Again, this should trick the immune system into making a response that, hopefully, will protect against future infection with the live virus.
Results on the safety of this initial Pfizer trial involving 360 subjects should come early next month. If the results are encouraging, larger trials to test the efficacy of the vaccine will be launched. The other three vaccines in development will also soon begin human trials. Ultimately, the most promising vax will be moved forward. Depending on the results of these studies, Pfizer believes that a vax could be ready for emergency use as early as this fall.
- In Madison, WI, investigators at FluGen and the University of Wisconsin (disclosure: the author is retired from the University of Wisconsin Medical School) are working on an innovative flu/Cov-2 vaccine combination. FluGen has already developed a crippled flu vaccine candidate that consists of a live flu virus that has been genetically engineered to be able to infect cells, but not to spread or cause disease. To this “vehicle,” investigators added the CoV-2 spike protein gene so that cells infected with this engineered, defective virus will stimulate immune responses to both flu and CoV-2 molecules. Also, unlike most of the 125 CoV-2 vaccines in current development, this combination vaccine candidate will not be injected, but will be given as a nasal spray in order to better mimic the major route of exposure to both viruses. Vaccine exposure to mucosal membranes generates a somewhat different type of immune response compared to vaccines that are injected. The idea is that a nasal vaccine might produce a more relevant immune response to stop the viruses in the mucosa before it can ever enter the lungs and other organs. A clinical trial of this vax is expected to happen in India by August.
Bottom line: Stay tuned. My view is that these aggressive predictions for finding a safe and effective virus are overly optimistic and if a vaccine is possible, it will take quite a bit longer to find.
I would be very happy if I was wrong.
Me and My PPE...
05/11/2020
PPE Demand
05/09/2020
A New York City hospital just revealed that pre-COVID, they used about 4000 surgical masks each day. During the COVID peak, they used 100,000! Who would have planned for that? No wonder there is a PPE shortage.
Interesting Factoid About the Coronavirus Diagnostic Test
05/08/2020
Background: The current diagnostic test to detect whether someone is infected with the Wuhan virus is something called RT-PCR. PCR, or polymerase chain reaction, is a way to amplify a DNA sequence that is present in low abundance. It was developed in the mid 80s by Kerry Mullins and it revolutionized DNA cloning and diagnostics. It now is a widespread technology that you can find in about every bio lab in the world. For that, Kerry (who was a collaborator of mine) was awarded a Nobel Prize.
But, coronaviruses have an RNA, not a DNA genome so, since PCR only amplifies DNA, Mullins’ technology would not work to detect coronavirus. This is where the RT part comes in. RT stands for reverse transcriptase. Back in the 50s-70s, the "central dogma" of molecular biology was that DNA makes RNA which then makes proteins. That was believed to be a one-way pathway. Then Howard Temin came along and found chicken tumor viruses that had an RNA genome, but somehow were able to insert a copy of that RNA genome as DNA into the cellular genomes of the tumor cells. Somehow the viral RNA was made into DNA. He was widely disbelieved and even ridiculed, until he, and an MIT scientist, David Baltimore, purified the enzyme reverse transcriptase and directly demonstrated that it could copy an RNA sequence into DNA. That revolutionized molecular biology and for that, they shared a Nobel Prize.
So, they use RT to copy the Wuhan viral RNA into DNA and then do the PCR reaction on the DNA to detect the presence of the virus in a throat swab.
I am descended from the David Baltimore scientific lineage, having done my post-doc work at UCLA with a scientist who was a post-doc in Baltimore’s lab at MIT. And Howard Temin was a colleague and mentor of mine as a faculty member at the University of Wisconsin until he passed away in the mid-90s.
And now the interesting factoid. In the late 80s while at UCLA, we published the first paper to describe RT-PCR. We weren’t trying to detect viruses, but developed the technology to detect very rare leukemia cells in the blood of patients after marrow transplants to see if we could identify very early cases of post-transplant leukemia relapse.
"Plandemic" Video Is Nonsense
05/08/2020
A video interview of former NIH scientist, Dr. Mikovits, has been making the rounds and is being promoted as being critical of Dr. Anthony Fauci, the director of the National Institute for Allergy and Infectious Diseases. The title of the 25 minute video is Plandemic. The link is at the bottom of the page. Don't be surprised if it does not open, though, since someone keeps blocking it.
I watched about half of this video and could not continue. This is nothing but inflammatory BS. Mikovits makes a lot of unsupported, sweeping statements that are flat wrong and often just fearmongering.
I mostly can’t comment on the legal aspects and claims Mikovits makes in the video and fails to corroborate. They are just her opinions and statements with precious little evidence backing them up.
One silly thing she said that I can comment on was how, in the early 80s, she refused to give Fauci a copy of her controversial Science paper that was in press (meaning that it would be published in a couple of weeks) because it was “confidential.” That is nonsense. A paper in press is NOT confidential and authors usually freely "in press papers" with others and the press. I have done that several times, and have seen it done many times! It is BEFORE a journal accepts a paper for publication when they are considered confidential. She goes on to say that “several weeks later” Fauci asked again for the paper. It would have been published by then! I have published in the journal Science and they move quickly. She also said Fauci held up the paper’s publication, but that claim is highly suspect unless Fauci called the science into question. So, I believe that she is inflating this episode for her own ends, or the science was suspect.
She goes on to criticize the Bayh-Dole act, which suggests that she is a fringe activist who thinks that financial incentives are bad for science. In the past, before Bayh-Dole, if a federally funded university scientist came up with an invention, the government had dibs on the patent and took it from the inventor and the University. That was unfair to the researcher and the university where the research was done. The act changed that and allowed the inventors to own the patent to their discovery. It is a good and fair law. There is nothing wrong with profiting from your ideas and Mikovits is among the fringe who think that is wrong. She is wrong.
She also made the amazing statement that there is no vaccine for any RNA virus that works (coronaviruses are RNA viruses). That is flat wrong. Flu is an RNA virus and the vaccines do work. Poliovirus is an RNA virus and there has long been very good vaccines for it. There are also several effective veterinary vaccines for different coronaviruses that cause animal diseases. So, her credibility takes a huge hit on this point.
She said it is very clear that the virus was manipulated and studied in a lab. I am a viral immunologist and have seen zero evidence to support that claim. In fact, I have seen some evidence to say that is not true. From the sequence data of the CoV-2 genome, it is clear that it was not engineered in a lab. If it was, there would be telltale signs of that in the genome. The Wuhan Institute of Virology researcher who studies coronaviruses has found dozens and dozens of different coronaviruses in bats from different places in China. She sequences their genomes and places them in an open library for any researcher in the world to investigate. She does not grow the viruses. The sequence of CoV-2 is not in the library and that strongly suggests, but does not prove, that her lab never saw it.
Mikovits goes on to say that getting coronaviruses from animals to humans is “not how it works.” Bullscat! It is quite clear that is how SARS and MERS and EVERY OTHER coronavirus came about. She claims that such zoonotic transfer represents accelerated viral evolution that would take "800 years," but that does NOT have to be the case. Flu shuttles between the North and South hemispheres each year carried by migrating birds that poop around animals (often pigs) who pick up the virus and transfer it to humans. That happens YEARLY! Current evidence is that the Wuhan coronavirus infected humans from some undetermined animal, and there is compelling evidence that humans gave it back to 7 big cats in the Bronx zoo and to two pet cats and one pet dog (so far). So, it quite easily shuttles between different species.
Basically, I got frustrated watching the video and didn’t follow it to the end. I think that Mikovits has an unhealthy, personal agenda. I would not put much credence into what she says. You can try to access the video here, if you still want to.
Is an Immune Response to SARS-CoV-2 a Good Thing?
05/07/2020
There’s a chance that if you have already been exposed to SARS-CoV-2, it can worsen your response to a subsequent exposure. For example, the first time someone is exposed to the virus, they often have only a mild infection, but if they encounter it a second time, it can become deadly. Researchers believe this is due to the antibodies your immune system generates after the first exposure to the virus, which start to diminish over time. If they drop to a low enough level they’re not able to fight off the virus, but instead, during a second exposure, they can inadvertently assist the virus in infecting cells. This is what often happens with Dengue virus. It’s called antibody-dependent enhancement, and researchers are investigating whether past exposure to this coronavirus could worsen the symptoms of COVID-19 after a subsequent exposure to the virus.
This is a potential concern with a CoV-2 vaccine. An international consortium of European and US healthcare agencies is overseeing the dozens of anti-coronavirus vaccines in development around the world. This concern is one of the first things they want to address in animal models before a vax moves into human trials.
At this point, we even need to be careful about "herd immunity" until we know more about this novel pathogen.
In the meantime, remember to wash your hands and avoid French kissing strangers!
How Bad is COVID-19?
05/07/2020
Here are excerpts from the Wall St Journal story, Mortality Rates Tell True Tale of Coronavirus’s Effect:
“By comparing mortality statistics for this year with those from the same period in past years, a rough measure of the pandemic’s impact emerges. In parts of the U.S. and Europe that have been hit hard, weekly fatalities from all causes are up by more than 25%, and in some places almost 80%.”
“Total-death data, which in many places break out influenza and pneumonia, show that among affected communities, coronavirus is killing far more people than seasonal flu does.”
“…an analysis of British hospital data indicates that accelerated deaths are just a fraction of fatalities, said Stuart McDonald, an actuary at insurer Scottish Widows. He studied reports from U.K. intensive care units that showed only 7% of deaths linked to coronavirus were among people who already suffered from seriously debilitating ailments. The other 93% (of ICU patients) were able to live without any intervention before falling ill.”
“His analysis of the data for patients admitted to intensive care units with other serious ailments is that the mortality rate linked to coronavirus was 10 times greater than would have been expected without the virus.”
Doing Science During a Pandemic
05/06/2020
A friend recently asked me, "Can you explain how the various universities, hospitals, NIH and others share data to build off each others work?" That is a good question. These are not normal times and normal avenues of science communication will not suffice.
Typically, data from the lab and clinic are shared between Universities, NIH, CDC, and hospitals in the US and beyond via word-of-mouth between friends and collaborators, via annual meetings, and via publication. The informal word-of-mouth sharing of observations and data can be quite fast, but also is quite limited to a narrow range of recipients. The other, more formal, ways to share data via publication and meetings are slow (it can take a year or more to write a paper and get it published) but can reach a very wide professional audience.
During this time of urgency, I see that short cuts are being taken to get papers about the disease out very rapidly to a broad audience. For example, in early March a prominent French infectious disease expert quickly published very preliminary data on the encouraging effects of hydroxychloroquine on a small number of COVID-19 patients.
Normally, a paper with such preliminary results would not have been approved for publication at all. Normally, it also would have gone through three months or more of peer review and then put in the back of the queue of other papers approved for publication a couple of months after that. However, in this example, the paper was rushed past a couple of editors then put at the head of the publication queue and quickly published. Other journals are doing the same.
Also, an international consortium of EU and US healthcare and public health groups, including the CDC and NIH, has recently formed in order to provide oversight into the 70-some vaccines that are underway. The consortium provides a central clearing house for collecting and sharing information on the progress and testing of the vaccines.
In sum, many of the normal, stodgy, careful avenues for science communication have been set aside in order to facilitate rapid exchange of information about this virus and disease. It seems that this is needed in this time of urgency, but it also comes with some risks of sharing information that may not be solid or well vetted. Unfortunately, non-experts in the press and politics see these rushed results and leap to unwarranted conclusions ignoring the caution that should be given such preliminary data. We saw that with the early enthusiasm around hydroxychloroquine and people drinking aquarium cleaner. Later, more thorough studies indicated that the early enthusiasm over hydroxychloroquine was not warranted.
There is a trade off. We need information that will help us learn how to fight this virus and treat the disease, and we need it fast. Fast means we also compromise a bit in confidence in the data.
But, what do you do during a pandemic?