Coronavirus news & views

Vaccine Makers Can Skip U.S. Pre-production Inspections

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

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

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

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

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

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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