Making Sense of Medical Science (MSMS)

Yet More Good Vaccine News

November 16, 2020

Just two days ago, I reported that Pfizer’s interim data analysis indicated that its vaccine is 90% effective and safe. Not to be outdone, yesterday, the US biotech company, Moderna, also announced that interim data analysis show that its vaccine candidate is 94.5% effective and safe. The preliminary data analysis from more than 30,000 subjects showed that Moderna’s vaccine prevented almost all symptomatic cases of COVID-19. Only five vaccine recipients became sick and those displayed mild symptoms. In contrast, almost 100 study volunteers who received placebo came down with COVID-19 and a dozen required hospitalization. The results were highly significant (p<0.0001). The study was conducted along with NIH and the Biomedical Advanced Research and Development Authority (BARDA) as part of Trump’s Operation Warp Speed.

Both studies will continue for a couple more months, primarily collecting more safety data needed for final FDA approval. Moderna expects to get Emergency Use Authorization from the FDA by early December and begin immunizations by the end of December, a nice Christmas present to the world.

Both, the Pfizer and Moderna shots are RNA vaccines and if approved, will represent the first vaccines of this type. However, Moderna’s vax comes with a decided advantage. As I explained earlier, the Pfizer vaccine needs to be stored at ultra-cold temperatures, which no other vaccine needs. Since ultra-cold freezers often are not available in poorer countries, or even in doctors’ offices and clinics, this presents a logistical problem in safely distributing it. In contrast, the Moderna vaccine can be safely stored in any home style freezer and kept unfrozen up to 30 days in a refrigerator. Pfizer’s vaccine can only be kept up to five days in a fridge.

Just keep it away from the beer….
Great News On The CoV-2 Vaccine Front

November 14, 2020

The news: Pharma giant, Pfizer, and its German biotech partner, BioNTech, just announced that preliminary indications show that its two-shot anti-CoV-2 vaccine is 90% effective in preventing infection. The study is not yet complete, meaning that this is based on what is called interim data analysis. All large scale clinical trials schedule such interim analysis in order to detect potential problems with the study such as potential side effects, enrollment problems, and to make a preliminary assessment on the trial's outcomes. The review is done by a Data and Safety Monitoring Board (DSMB), an independent panel of scientists and statisticians who are not part of the study. Using an independent DSMB allows study personnel to remain blinded as the trial proceeds.

In this case, the interim review of data by the DSMB compared the number of subjects in the placebo control group who became infected to the number of infected subjects who received both vaccine doses. This showed that vaccinated subjects were 90% less likely to be infected. The interim analysis also showed negligible adverse effects in the group who received the vaccine. While still preliminary, these results are encouraging. The study will continue over the next couple of months and even beyond in order to learn how long the immunity lasts and how effective it is in different populations including the elderly and other high risk groups. There seems to be a good chance that final approval will come around the end of year and vaccinations begin shortly after that.

Pfizer began manufacturing the vaccine a few months ago so that they would have a stockpile ready to distribute as soon as FDA approval comes. While this eliminates the usual post-approval delay to ramp up production capability, this strategy is a major gamble for the company since it is not guaranteed that the vaccine would be approved. If the vaccine does not pan out, the company will have to eat the cost for manufacturing a useless vaccine. On the other hand, if the vax is approved, Pfizer is poised to immediately deliver hundreds of millions of doses while their production efforts continue.

This is the first RNA vaccine tested in humans. The potential advantage of this approach is that it completely avoids using the virus itself. “Old fashioned,” vaccines required growing the virus in mass quantities and then crippling or killing it for injection, which is labor intensive, entails certain risks, and is expensive. Instead, the Pfizer vaccine involves cloning part of the genome that is thought to be a target for the immune system, packaging it in an inert lipid nanoparticle, and injecting it in order to aggravate the immune system. The idea is that this fragment of the viral genome will be taken up by human cells and the cellular machinery will use it to produce the viral protein that can stimulate an immune response in the absence of the virus itself. The cells will soon degrade the cloned RNA fragment leaving only immunological memory with which to fight reinfection.

What is next? While this is encouraging news, this brings us to perhaps a larger problem to solve, which is how the early vaccine will be most effectively and fairly distributed. By the end of the year, Pfizer will have a few hundred million doses and predicts it can produce 1.3 billion doses in 2021. Since this is a two-dose vaccine, that means that that will be enough to vaccinate about 650 million people, or less than 10% of the 7.8 billion who live in the world. Who will have priority for the first doses of the vaccine? Will front line health care workers and high risk people be given the first doses? What about world-wide distribution? Since the vaccine is being tested and made by an American company (Pfizer) using technology developed by a German biotech (BioNTech), should those two countries reap the immediate benefit of the early limited doses of vaccine, while the rest of the world waits months for sufficient doses of the vax to meet their needs?

The WHO recommends that the vax be distributed to each country based on its population. Another recommendation from the National Academies of Sciences, Engineering, and Medicine is to distribute it based on each country's number of health care workers and high risk populations. Others argue that the US should base distribution on racial and socioeconomic disparities. U Penn doctor and medical ethicist, Ezekiel Emanuel (a primary author of Obamacare), proposed a Fair Priority Model that would favor countries with younger populations, weaker economies, and with poor health access–in other words, third world countries.

These suggestions seem moot since advanced purchase agreements already give 80% of that early vax supply to the US, UK, Canada, and Japan.

Another issue regarding distribution is that the vaccine needs to be stored and transported in ultra-cold conditions (-80 degree C. or -112 degrees F.). Such ultra-cold storage facilities are in short supply around the world, meaning that countries with poor health infrastructure will be at a significant disadvantage because they cannot store the vaccine. This ultra-cold storage requirement will also make it challenging for the vax to be administered in a normal doctor’s office or pharmacy, which typically do not have ultra-cold freezers.

Logistics: Once the vaccine is approved, the enormous task of getting billions of doses distributed across the US and around the world begins. This is where Trump’s Operation Warp Speed comes into to play. Even though the Pfizer vaccine was not developed under that program, the logistics of its distribution will be part of Warp Speed, which also includes massive pre-planning for storing, distributing, and delivering two doses of the vaccine ultimately to 300 million Americans. The US Army Materiel Command, headed by four star general Gus Perna, has been tapped for this undertaking. He is the one who sees that American military forces around the globe have sufficient housing, clothing, food, and beer. So, he seems like a good choice to oversee the distribution of billions of doses of a vaccine. You can see more about this on the Nov 8 episode of 60 Minutes. The logistics and planning for this almost makes the development of the new vaccine a trivial issue.

There is joke that goes something like this: Hell is where the English are the cooks, Italians the managers, and Americans the soccer lovers. Heaven is where the English are the soccer lovers, Italians the cooks and Americans the managers. This is a good example of American large-scale management, so we must be in heaven.
Refusing To Treat COVID Patients Based On “Quality Of Life” Determinations

November 8, 2020

FYI: While your humble blogger earned a PhD in viral immunology from the University of Texas, and spent most of his career investigating the causes and cures of leukemia at UCLA and the University of Wisconsin, he also was trained in ethics at Indiana University, the University of Montana, and Calvin College. He taught bioethics and research ethics at the U of W. His closet hooks are full of different hats.

Biomedicine is rife with ethical conundrums, a few of which already have been mentioned in these pages about the coronavirus pandemic, to wit: Should we wave inspection of vaccine manufacturing facilities and risk production mistakes in order to speed release of a CoV-2 vaccine, which will save lives? Or, whose rights do we ignore during a pandemic—the freedom to live as we choose vs the freedom to remain free of infection? Or, do we abandon all social restrictions in attempt to achieve herd immunity via natural infection, realizing that we would be sacrificing many to the disease? All, conundrums, indeed.

Ethical dilemmas entail at least two conflicting choices, neither of which is perfectly good nor perfectly bad. That is why these problems are often referred to as “horns of a dilemma.” Which horn should we embrace, and which should we avoid, knowing that both can stick us?

An ethical dilemma has arisen in healthcare circles, but for which the popular press has largely been silent. This issue is about how “quality of life” factors into health care decisions for COVID-19 patients. The following example of how this ethical conundrum can play out is excerpted and modified from the journal, First Things.

A man, Michael, was refused treatment for COVID-19 because the hospital he was admitted to and State bureaucrats believed that he did not enjoy sufficient quality of life to warrant curative treatment for the disease. In 2017, Michael had a heart attack that caused brain damage leaving him a quadriplegic and suffering frequent seizures. But he was conscious, able to do simple math calculations, answer trivia questions, and interact with his family. Then, in late Spring of 2020, he caught COVID-19 and was hospitalized. The hospital decided to withhold his tube feeding despite the objections of his wife, and the fact that he had a fair chance of surviving if provided with appropriate COVID treatment and sustenance care. He died on June 11.

He was denied care because his doctors determined that he did not have a sufficient “quality of life” to justify treatment. Because of his disabilities, saving his life was deemed “futile.” The medical team and the “State,” through a court appointed guardian, reasoned that treatment for COVID-19 would not improve the quality of his life (meaning, he would remain quadriplegic and cognitively disabled if he survived the disease); therefore, they decided to end all treatment care except hospice comfort care.

His wife, Melissa, had been appointed Michael’s temporary guardian, but she was in a legal struggle with Michael’s sister over his custody, a dispute that predated Michael’s hospitalization. Family Eldercare, a nonprofit agency, was then appointed interim guardian until a final decision could be made about permanent guardianship. Hospital doctors convinced Family Eldercare to approve Michael’s transfer to hospice care where he would only receive palliative care and not curative or sustenance care. Michael died of pneumonia after six days on hospice; the withdrawal of nutrition and hydration having no doubt weakened his body’s ability to fight disease. Even without pneumonia, Michael would have soon died of dehydration.

Melissa recorded her conversation with an unnamed physician and posted it on YouTube so we can all hear for ourselves. Here’s the substance of the conversation from the YouTube transcript, with my commentary.

Doctor: At this point, the decision is, do we want to be extremely aggressive with his care or do we feel like this will be futile? And the big question of futility is one that we always question. The issue is: Will this help him improve the quality of life, will this help him improve anything, will it ultimately change the outcome? And the thought is the answer is no to all of those.

Melissa: What would make you say no to all of those?

Doctor: As of right now the quality of life, he doesn’t have much of one.

Melissa: What do you mean? Because he was paralyzed with a brain injury, he doesn’t have a quality of life?

Doctor: Correct

My Comment: The doctor did not base his decision about Michal’s medical care on the illness for which he was hospitalized, but on his unrelated disability. This is a classic example of applying the invidious “quality of life” ethic, which deems people with disabilities, the elderly, the chronically ill, and the dying to have a lower worth than the healthy, able-bodied, and young. Back to the conversation…

Melissa: Who gets to make that decision whether somebody’s quality of life, if they have a disability that their quality of life is not good?

Doctor: Well, it’s definitely not me. I don’t make that decision. However, will it affect his quality, will it improve his quality of life, and the answer is no.

My Comment: After denying that he had any part in determining Michael’s quality of life, the Doctor then admits that he believes that Michael’s quality of life is negligible. By doing so, he is being duplicitous regarding his role in the decision, and he is not acting as Michael’s doctor, beholden to the Hippocratic Oath he took. Rather, he is acting as an agent for the hospital and State bureaucracies rather than acting in Michael’s interest, a dramatic violation of the Oath he took. Back to the conversation…

Melissa: Why wouldn’t it? Being able to live isn’t improving the quality of life?

Doctor: There’s no improvement with being intubated, with a bunch of lines and tubes in your body and being on a ventilator for more than two weeks. Each of our people here have COVID and they are in respiratory failure. They’ve been here for more than two weeks.

Comment: The Doctor again makes a statement of his opinion of Michael’s quality of life. He admits that many of their OOVID patients are in respiratory failure and on ventilators, but implies that they are more valuable than Michael and deserve such therapy, while Michael does not.

Melissa: So the fact that you are killing someone doesn’t make sense in your mind?

Doctor: We don’t think it’s killing. Because I don’t know when or not if he will die. But at this point I don’t think it would be humane or compassionate to put a breathing tube in this man and do the lines and the tubes and all that stuff because I don’t think it will benefit him.

Melissa: And I totally agree with you on the intubation part of it. I don’t want him intubated. But I also don’t think you should just sit him somewhere to be comfortable until he finally just drifts away. That to me is futile too. That’s saying you’re not trying to save someone’s life. You’re just watching them go. The ship is sailing. I mean that just doesn’t make any sense to me to not try. I don’t get that part. I don’t like that part.

Doctor: But what I’m going to tell you is that this is the decision between the medical community and the State.

Melissa: And the State. Forget about his wife and his family and his five kids.

Doctor: I have nothing to do with that.

The recording ends there.

At first blush, it might seem like a reasonable decision to withhold essential care from someone as damaged as Michael was, but what if we change the selection criteria from “quality of life” to “preciousness of life?” Wasn’t his life as precious as everybody else’s, especially to his family? It was not, according to Michael's doctors and faceless bureaucrats in his State who had never met him, all of whom believed that they could better judge Michael’s worth better than his family could. And, what about Michael’s wishes? The article did not indicate whether, after his hospitalization, he was able to express his desires in the matter, but I will assume he was incapable of doing so. In which case, the medical ethicist must look at Michael’s family as well as his life near the time he was hospitalized. Before catching COVID-19, were his actions consistent with someone who wanted to live, even with his disabilities? Even if a hospitalized patient cannot communicate, it is still possible to divine his wishes from the period before he became, possibly temporarily, non-communicative due to the disease. That divination is more relevant than faceless bureaucrats when making life and death decisions for him.

This is the great ethical problem of quality of life decisions being made by impersonal, anonymous administrators who can overrule the wishes of a patient’s immediate family and even the demonstrated wishes of the patient. The bottom line is to make sure you have your final wishes legally documented and use power of attorney to put your fate in the hands of highly trusted family or friends.

Even then, you still might encounter faceless bureaucrats making life and death decisions for you based on how they judge the quality of your life.

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CoV-2 Causes Denmark To Cull All Mink

November 5, 2020

Coronaviruses, especially SARS-CoV-2, are pretty adept at jumping between different species, which is a concern. As written before in these pages, that means that animals can serve as a virus reservoir even after humans achieve herd immunity. Another concern around inter-species virus transfer that I raised earlier is that as viruses pass between species, they have a penchant for mutating and acquiring new behaviors and capabilities. This leaves to genetic chance the possibility of producing an even more virulent strain. It is a roll of the genetic dice as a virus randomly gains small mutations while it spreads.

On October 23, I wrote about how mink farms around the world have become CoV-2 hot spots. In that post, I mentioned that Denmark was particularly hard hit with animals catching the virus from their human handlers, causing the country to cull one million mink across several farms to prevent further spread of the virus. Well, in just two weeks, the situation has gotten much worse, leading to a new decision to cull the country’s entire population of 17 million mink as reported yesterday by Reuters.

Danish scientists found increased spread of the virus from mink back to humans, and the spread to humans involved a new virus strain that seems more resistant to human antibodies. The ongoing efforts to develop a vaccine are focused on viral strains that were isolated last Spring. If a new strain emerges that can avoid the immunity conferred by the vaccines under development, it could greatly reduce the ability of the forthcoming vax to give us significant herd immunity; in which case, we would need to develop another vaccine to handle the new virus strain, if possible. And while that vaccine is under development, what if yet another virus strain arises that resists that new vax? It would be a game of catch-up and extend the pandemic possibly by years.

This is the concern for viruses that jump between species. We will see.
Vaccine Makers Can Skip U.S. Pre-production Inspections

October 27, 2020

Typically, before a new drug is released, the U.S. Food and Drug Administration regularly inspects the drug manufacturing plants and processes to ensure that quality and safety standards are up to par. This comes after the FDA has examined and approved the safety and efficacy profile of any new drug. Only after both inspections are done will the FDA gives its imprimatur on the production of a new drug. But that won’t be the case for COVID-19 vaccine developers. It seems that the vax makers will apply to the FDA for Emergency Use Authorization (EUA) of their vaccines, which will eliminate the requirement for a manufacturing pre-approval inspection.

Even though by asking for EUA approval in order to avoid the lengthy inspection process, vaccine developers still have to submit complete details of their manufacturing process and show they’ve established a quality control unit, but this is not the same as a full inspection. And the vaccine itself still need to be approved for efficacy and safety.

This represents quite a conundrum; we all want a vaccine as quickly as possible and this EUA would greatly help make that happen and reduce morbidity and mortality caused by the virus. We also want to know that our medicines are produced in as safe a way as possible, which also would reduce possible morbidity and mortality caused by tainted vaccines. It seems that we have to choose one of these desires and sacrifice the other; we cannot have both. Do we bow to our reasonable fear of this nasty virus and growing need to return to normal and go for the earliest vaccine? Or do we act cautiously and risk more people dying and more economic devastation in order to ensure that vaccine production is safe?

There are several examples of vaccine production errors that led to tragic consequences. In 1955, the Salk polio vaccine was rushed into production just hours after it was approved. This was an inactivated virus, which means that live virus was grown, then killed, then injected. Some lots from one of the manufacturers, Cutter Laboratories, were not fully inactivated and some patients received injections of live virus leading to tragic results. The problem involved a production error. Similar production errors have led to people being infected with live measles virus, and respiratory syncytial virus. Then, in 1976, an H1N1 flu that was similar to the 1918 Spanish flu reached pandemic stage. The US rushed out a vaccine that was associated with a spike in the very rare Guillame Barre disease, which is a type of paralysis. It is believed that the rushed vaccine somehow caused the small, but significant spike in the disease in fewer than 500 patients across the country (note: your humble blogger was a college student and working in a hospital physical therapy clinic at the time, and worked with two GBD patients).

Based on this prior experience with problems in vax production, it seems that it is more likely that delaying a vaccine would lead to more COVID-19 disease than would be caused by tainted vaccines, hence the willingness of the FDA to waive pre-production inspections. All policy decisions entail risks and benefits, and when lives are at stake, it is generally accepted that it is better to err on the side of overreaction rather than underreaction.

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CoV-2 In Animals

October 23, 2020

Coronaviruses are promiscuous critters. We know that the several coronaviruses that cause significant human disease passed from bats to other species and then to people. The virus that caused SARS came from a bat that infected a civet that then infected a human who passed it on to other people. MERS was similar—a bat virus infected a camel that spread it to people. There is good evidence that the SARS-CoV2 virus also came from a bat to infect humans, but we are not sure what animal was the intermediate vector.

Usually there is a biological barrier that limits virus spread between species. When viruses do jump between species, it usually is a result of chance mutation that makes a different non-host species a more hospitable home. That doesn’t seem to be the case with many coronaviruses, which seem to jump between species without markedly changing their genome. Notably, early in this pandemic, we realized that humans were spreading the virus to lions and tigers in the Bronx zoo. Since then, there have been increasing reports of pet cats and dogs catching the virus from their owners and even spreading it to other animals. Also there are reports that monkeys, ferrets and hamsters have caught the virus.

Human to animal spread is not confined to zoo and pet mammals. It has devastated mink farming activities around the world as well. Denmark recently announced plans to cull one million mink after finding extensive spread of the virus in several mink farms. Last May, Spain ordered the culling of 93,000 mink at one farm. The Netherlands also undertook a large cull after two, maybe four people, were reported to have caught the virus from infected mink. Several cats that roamed the affected mink farms were also infected, meaning that the virus was spreading between three different species. And on October 9, it was reported that 10,000 mink died at fur farms in Utah and Wisconsin following COVID-19 outbreaks. It was noted that the virus progressed quickly in mink, with most infected animals dying in one day.

It is unclear why mink seem more susceptible to the virus than other animals, but it is concerning. Similarly, we also do not fully understand why some people, but not other others are highly susceptible to the disease. What would it take for the virus to change and become even more deadly to more humans like it is in mink?

All this suggests that animals that are in very close contact with humans might become a growing reservoir for the virus. So, when a vaccine for humans is available, should we also vaccinate our pets to also give them herd immunity, which would protect them and us? That probably would be easier than trying to make your cat wear a face mask! Experts also are advising people to keep their pets safe by avoiding contact with other people and animals. They even advise to isolate pets from household members who catch the virus.

Another concern is that as viruses pass between animal species, they often acquire new behaviors via genetic drift and rearrangement between different viral genomes. It is believed that a simple mutation increased the ability of CoV-2 to infect human cells. We have found about 500 different coronaviruses in bats alone, while other animals often carry coronaviruses typical to their species. There might be thousands of different coronaviruses out there. 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.

It is relevant here that a new coronavirus that causes gastrointestinal distress in pigs has emerged in China. It is especially lethal to baby pigs, killing 90% of them. It is called swine acute diarrhea syndrome virus, or SADS-CoV and is 98.48% genetically identical to a virus collected from horseshoe bats in China. Research recently published in the Proceedings of the National Academy of Science (PNAS) show that the virus can also infect human cells, but, so far as your humble blogger knows, no human disease has been associated with SADS-CoV. Yet.

Seeing as how coronaviruses readily transmit between different species, I predict that we can expect more novel human coronavirus disease in the future. Hopefully, things we continue to learn about the current CoV-2 virus and COVID-19 disease will translate to more rapid and effective responses to new coronavirus pathogens that are likely to pop up in pigs, people and pets.

We will see.
SARS-CoV-2 vs Hepatitis C: SpaceX vs NASA: New vs Old

October 19, 2020
What does hepatitis C have to do with the coronavirus subject of this blog? More to the point, why in the world bring up SpaceX and NASA in a blog on the coronavirus? Let me make a couple of seemingly disparate points and then try to tie them together.

First point: American scientists Harvey J. Alter and Charles M. Rice, and British scientist Michael Houghton were just awarded the Nobel Prize for Medicine or Physiology for the discovery of the hepatitis C virus (HCV). Their work led to new diagnostic and treatment developments for HCV that have saved millions of lives. That research took almost four decades.

Second point: Let’s compare the NASA space shuttle to the SpaceX rocket that just took astronauts to the International Space Station.
- Flight control:
  
  Shuttle–human drivers
  
  SpaceX–totally autonomous. Humans not needed at all.
- Reusability:
  
  Shuttle–only the shuttle was reusable. The launch vehicle was not.
  
  SpaceX–totally reusable.
- Cost to launch each human passenger:
  
  Shuttle–$170 million
  
  SpaceX–$60-70 million
- Cost per kilogram of cargo:
  
  Shuttle–$54,500
  
  SpaceX–$2,720
- Development cost:
  
  Shuttle–$27.4 billion
  
  SpaceX–$1.7 billion
Bringing it all together: The science around the CoV-2 virus and SpaceX represent the new science world that contrasts to the old science world of hepatitis C and NASA, respectively. Make no mistake; the old science was very successful; it led to the Nobel Prize for discovering HCV, and to putting men on the moon and the Hubble space telescope. Those old science accomplishments took decades to achieve and cost billions of dollars. The second point above, comparing SpaceX to NASA, points out how far technology has come in a few years regarding space flight. Just a few weeks ago, many of us saw a SpaceX rocket launch astronauts to the space station. Rather than just letting the rocket that propelled the astronauts’ craft to burn up, it was designed to reenter the atmosphere and land upright in the middle of a bulls-eye, on a small barge just off the coast of Ireland. The great increase in technical capability, along with the great decrease in cost of developing SpaceX is a great testimony to our modern science and technology.

Similarly, new bioscience technology that has led to the rapid identification and treatment of the virus that causes COVID-19 represents our modern “BioX” vs the old standard of molecular biology. The “old biology” (it greatly pains me to describe it that way) was highly successful. It illuminated great things about our microscopic world that have been critical in learning how to deal with our macroscopic world. But the old molecular biology is the “biological NASA” that is being usurped by “BioX.”

Consider the great and significant accomplishments of the three scientists who just won the Nobel Prize for discovering HCV. Decades ago, we knew that two types of viruses caused hepatitis in people exposed to bodily fluids of infected people. The viruses were designated hepatitis viruses A and B. Yet, when blood products destined for patients were screened for both of these viruses, people still contracted hepatitis. It was then well accepted that there was yet another blood-borne pathogen that caused non-A, non-B type hepatitis. And the search for the bug was on.

It took a couple of decades to identify the suspected pathogen as a virus. That happened at the end of 1989. Because of the virus’s peculiarities, we still have not been able to develop a vaccine for it, but a drug cure was approved in 2014. That cure took fifteen years to develop and that was on top of the 20 or so years it took to identify the virus; almost four decades in total.

Compare how long it took to identify the pathogen and develop a treatment for HCV to today’s situation with the novel CoV-2 virus. According to a timeline I posted earlier, in Dec/Jan an unusual flu was discovered in China’s 10^th largest city, Wuhan. In just a couple of weeks the virus was isolated and just a few weeks later, we knew its genome sequence. In February, the Chinese began developing the first vaccines. According to the Milken Institute tracker, today 315 treatments for COVID-19 are in development around the world. 199 vaccines also are being developed, 11 of which are in late stage trials and we should have more than one vaccine available in the next 2-5 months. All of this has happened in about a year after the virus was first suspected to exist! That is bioscience working at the speed-of-light, and that is only possible because of what we learned in the “dark ages” of molecular biology.

The age of BioX has turned your humble blogger into a dinosaur.

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Higher-Than-Normal Death Rate In The US Since March

October 15, 2020

Some people insist on viewing the coronavirus pandemic through a subjective political lens and downplay the seriousness of the disease and assert that the COVID-19 mortality rate is overblown. Then there are those of us who view the pandemic through an objective scientific lens and come to a diametrically different conclusion. Earlier in these pages, I reported on two studies, one done in the UK and the other in the US, that used actuarial and hospital data to show a 35% increase in all deaths compared to a comparable period of time before the pandemic. Both papers concluded that the COVID-19 deaths were, in fact, being undercounted.

Continuing to look through the science lens, we see recent confirmation of those studies in a paper published Oct 12, in the Journal of the American Medical Association (JAMA). While total US deaths usually are remarkably consistent from year to year, this study reported a 20% increase in total deaths between March 1 and August 1 this year compared to historical data. States with the highest rate of excess deaths included NY, RI, NJ, MA, LA, AZ, MS, MD DE and MI. Excess deaths in these states ranged from 22% in RI and MI, to 65% in NY. States that reopened earlier saw greater increases in total extra deaths.

67% of the excess deaths across the country were associated with COVID-19. The 33% of deaths unrelated to COVID-19 were statistically elevated for patients with heart disease and Alzheimer disease. Deaths not linked to COVID-19 were probably due either to unrecognized COVID-19 disease, or to disruption of normal health and personal care due to pandemic-related shutdowns.

The current JAMA study analyzed death data for 2014-2020 from the National Center for Health Statistics to conclude that the excess US death rate is 20%, while the previous studies used actuarial and hospital data to conclude that the excess death rate was 35%. The different conclusions regarding death rates could reflect using different sources of data, or different science filters.

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COVID-19 Immunity: Too Little Can Be As Bad As Too Much

October 11, 2020

Precis: When two brothers fell critically ill with COVID-19 around the same time in March, their doctors were baffled. Both had been young and healthy, but within days they were unable to breathe on their own and one of them died. It suggested a genetic risk factor for severe COVID-19 disease. Two weeks later, a second pair of stricken brothers appeared in the Netherlands, and geneticists were called to investigate. They found a flaw in the brothers’ DNA that affected their resistance to the virus.

From the beginning of the COVID-19 pandemic, medical scientists have been baffled by the ferocity of the disease in some patients but not others. Especially baffling is the severity of the disease that sometimes even appears in healthy young people who have no preexisting high risk conditions. As we gain experience with this new pathogen and its disease, we are learning that there are several distinct factors related to viral pathology as well as to how the host responds to infection that lead to the disparate responses to CoV-2 infection.

Story: A pair of studies by the international COVID Human Genetic Effort research team that was recently published in the journal Science reveals novel aspects about what causes severe COVID-19 disease in certain patients. The studies report that about 15% of severe COVID-19 patients are deficient in a single cytokine called interferon. In other words, their severe disease is linked to an insufficient early immune response, which is the opposite of the over-reactive immune response called a “cytokine storm” that has been linked to severe disease in other patients.

“Cytokines” is the collective term for a wide range of small proteins secreted by a wide variety of immune cells, and even by non-immune body cells in response to infections. They play many roles in modulating the immune response, resisting infection, promoting inflammation, regulating temperature, blood pressure, and more. Some cytokines are important for mediating the earliest immune response we make to an infection, which is called “innate immunity.” This early response provides the first line of defense against a pathogen while a second, slower-developing response, or “adaptive immunity,” gears up to provide a more pathogen-specific, robust, and long-lasting protection.

Interferon (IFN) is one of the many cytokines that mediate the early innate immune response. There are several types of interferons that can interfere with viral replication, hence their name and role in innate immunity to viral infection.

In the first paper, investigators sequenced DNA from several genes known to affect early IFN responses. Genes from 659 critically ill patients who did not show signs of a cytokine storm, and from 534 patients with mild disease were compared. About 3.5% of the critically ill patients carried mutations in IFN regulatory genes and had almost undetectable IFN function. None of the control group showed any mutation in these genes or reduction in IFN levels or function. Notably, some of the IFN genetic defects also have been linked to life-threatening influenza pneumonia.

In the second study, scientists examined blood samples from 987 gravely ill patients and found that >10% of them had anti-IFN antibodies that neutralized their IFN activity leaving their cells unprotected against the early stages of CoV-2 infection and spread. None of the 663 patients with mild COVID-19 had the anti-interferon antibodies.

Intriguingly, 94% of the very ill patients with anti-interferon antibodies were men, which might partly explain why men are more susceptible to serious COVID-19 disease. However, this preponderance of male patients was surprising since women generally have a higher incidence of autoimmune disease. This observation suggests that there is an unknown X chromosome-linked recessive trait that influences the production of anti-IFN antibodies. Since women have two X chromosomes, both of them would have to carry the recessive gene in order to develop the antibodies while men, who only have one X chromosome, would only need the recessive gene on their lone X chromosome, giving them a greater probability of producing the anti-IFN antibodies.

Bottom line: It seems significant that none of these patients with deficient IFN responses had a history of other severe viral illnesses requiring hospitalization. This suggests that we are more reliant on this IFN response to protect ourselves against CoV-2 versus other viral infections.

Also, these studies have practical implications for treating COVID-19 patients. Recombinant interferon made in the laboratory has long been used to treat other viral diseases and could be part of an important therapeutic toolbox to treat COVID-19 patients who fail to produce sufficient IFN response to infection. Of course, this will not work in patients who have anti-IFN auto-antibodies that neutralize the activity of any IFN. But from years of experience dealing with auto-immune diseases, we do have an arsenal of other therapies that can mitigate these damaging auto-antibodies. Finally, recognition of these new high-risk subtypes, which can be identified via genetic and immunological screening, can identify individuals who should take extra precautions to avoid exposure to the virus, and those who should be at the head of the list to receive a vaccine when they are available.

In summary, both an over-exuberant immune response in the form of a cytokine storm, as well as an unenthusiastic immune response in the form of IFN deficiency can lead to severe COVID-19 disease. The optimal middling response is true for much of bioscience. You do not want to have a too high or too low blood pressure; ditto for body temperature; ditto for respiratory rate, blood pH, blood sugar, cholesterol, and so on.

Gotta love that happy middle.
Trump’s Treatment

October 3, 2020

Being, male, elderly (74 years old), and borderline clinically obese, Mr. Trump meets three high-risk criteria for severe COVID-19 disease. Despite reporting negligible symptoms at this point, his doctors at Walter Reed have him on aggressive precautionary therapeutic measures.

He has been given the anti-viral drug, Remdesivir that shows moderate effects against the CoV-2 virus and has become a standard-of-care treatment for hospitalized COVID-19 patients. He also has received an intravenous dose of Regeneron Pharmaceutical’s cocktail of two experimental anti-CoV-2 monoclonal antibodies. These are antibodies produced in the lab that are designed to mimic the naturally occurring antibodies the immune system produces in response to CoV-2 infection. They provide a boost to the natural immune system, especially during the early stages of infection when one’s natural immunity is still ramping up. While the monoclonal antibody therapy is experimental, early evidence suggests that it provides a significant protective effect. It was approved for Mr. Trump under a “compassionate use” clause for experimental therapies.

He reportedly also has been taking daily aspirin, which has anti-coagulant properties, as well as over-the-counter vitamin D and minerals needed for a healthy immune response. A paper published last month in the journal PLOS ONE found a higher rate of coronavirus cases in people who were deficient in vitamin D than in people who had normal levels of vitamin D. But this is just a correlation and more research is needed to confirm that there is a biological cause-and-effect relationship between vitamin D levels and COVID-19.

It is interesting that it appears Mr. Trump has not been taking hydroxychloroquine, which he earlier pushed, and which more recently has been pushed by some physicians and touted by many lay people to be a COVIID-19 cure despite growing scientific evidence showing that it is not effective, even when given to early stage COVID-19 patients.

Update (Sunday 10/4): It was reported today that Trump has displayed transient low oxygen levels that seemed to be taken care with supplemental oxygen. He also has been given dexamethasone, a steroid, in order to prevent inflammation of his lungs. His doctor expects him to be released from Walter Reed tomorrow (Monday).

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