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November 2020

A Third Vaccine Also Shows Success!

Two RNA vaccines developed and produced by Pfizer/BioNTech and Moderna/NIH have already reported highly significant protection against SARS-CoV-2 with negligible side effects. The Pfizer vaccine has been submitted to the FDA for approval, which should be quickly forthcoming. Moderna will soon submit its vaccine for FDA approval.

Now, a third and different type of two-shot vaccine developed by the UK’s AstraZeneca and the University of Oxford also reports 90% efficacy. It also showed minimal adverse effects that are expected from the immune reaction to any vaccine. Unlike the RNA vaccines, this one is a crippled adenovirus engineered to express the CoV-2 spike protein and offers some advantages over the RNA vaccines. First, it can be produced and marketed at a fraction of the cost of the RNA vaccines. Second, it only needs refrigeration storage, not a freezer like the Moderna vaccine, and not an ultracold freezer like the Pfizer vaccine requires. These advantages mean that this vaccine will be more readily available for third-world countries that do not have freezer storage capability. Also, AstraZeneca plans to produce its vaccine in multiple countries, from India to Brazil to Japan and to Australia, and beyond which will facilitate its international distribution.  

Getting a vaccine out to the several billion people around the world is a daunting challenge. Having multiple vaccines produced in various sites around the world should facilitate the distribution to all countries. A global program called Covax has an ambitious effort to deploy vaccines around the world, getting dozens of countries to join and securing deals for 700 million doses so far. AstraZeneca has agreed to supply the initiative, while a collaboration including the Serum Institute of India agreed to accelerate the production of the AstraZeneca or, soon to come, Novavax shots for low- and middle-income nations, priced at only $3 per dose. Another Covax pact with pharma companies Sanofi and GlaxoSmithKline Plc, which are developing their own vaccines, followed last month. The program, led by the World Health Organization, the Coalition for Epidemic Preparedness Innovations, and Gavi, the Vaccine Alliance, expects more deals in the coming weeks. Pfizer/BioNTech, along with Moderna/NIH, are also in talks with Covax.

AstraZeneca/Oxford has easily been the most active company in reaching supply accords around the world. It has assembled an unprecedented global network of manufacturing and distribution partners, and has promised to provide 3.2 billion doses of its vax. More than 50 lower- and middle-income countries in regions including Latin America, Africa, the Middle East, Asia and Eastern Europe would receive AstraZeneca/Oxford’s shot, which will be provided at cost during the current pandemic. The company is poised to be the dominant vaccine supplier to the developing world and it is forgoing any profit to do so.

Trial results for other vaccines produced by Novavax Inc. and Johnson and Johnson are expected soon. The Milken Institute tracks a total of 199 vaccines in development around the world. That means we can soon expect results from 194 more vaccines.

A final note: Some folks with a conspiratorial mindset have pointed out that these positive vaccine results presented just after the November 3rd US election is evidence that the election was rigged. They assume that the vaccine results were delayed in order to prevent giving Trump a bump. But, these folks have to explain why and how German and British pharma and biotech companies, and universities, which had no input from the US, were involved in that conspiracy.

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Pfizer Applies For FDA Approval

Pfizer announced that today it will seek approval for its anti-CoV-2 vaccine. If approved, the vaccine can be distributed as early as December. Given the urgency, the FDA is expected to move quickly.

The final numbers, released last Wednesday, showed that of the 170 subjects in the trial who caught COVID-19, 162 had received the placebo, meaning that the vaccine was 95% effective. It also was 94% effective in people 65 and older. Nine of the 10 subjects who came down with severe COVID-19 had received the placebo, meaning that the vaccine protects against severe disease.

This is a momentous vaccine. It will be the first RNA vaccine and, by far, the fastest to be developed and distributed, which will revolutionize vaccinology. This moved rapidly for several reasons. 1) The RNA vaccine platform had already been developed and it was just a matter of inserting the genome sequence for the viral spike protein into it. 2) RNA vaccine technology greatly speeds vax development since it completely avoids the need to grow massive amounts of virus iteslf. 3) Genome sequencing is now done very rapidly. The Chinese published the CoV-2 genome sequence in just a few weeks after the new virus was identified. 4) Pfizer began mass production of the vaccine while it was still in the experimental stage and not yet approved, thereby eliminating the typical delay required to ramp up production capability. 5) Trump’s Operation Warp Speed pre-planned for the massive storage and distribution effort that will be needed so that as soon as approval is granted, the already manufactured vaccine can immediately be distributed.

After approval, vaccine for about 25 million people will be immediately available for distribution and the US is scheduled to receive half of that. 1.3 billion doses are expected to be produced next year, which will enough to vaccinate 650 million people. In the US, it is likely that the first doses will go to health-care workers, followed by those at high risk, people in nursing homes, and prisoners. The general public probably will not get access until the spring or summer. The US has agreed to pay Pfizer and BioNTech nearly $2 billion for 100 million doses, enough to vaccinate 50 million people at no charge to them.

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Nasal Spray To Prevent CoV-2 Infection?

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A November 5 preprint showed that a nasal spray was 100% effective in preventing infection in an animal CoV-2 infection model. The spray contained a small piece of the SARS-CoV-2 spike protein designed to block the ability of the virus to enter human cells in the respiratory tract.

Ferrets were given the nasal spray and then placed in cages with an infected partner to see if the virus would transfer to the treated animal. After 24 hours, 100% of the animals that received a sham spray were infected while none of the animals that received the experimental nasal spray were infected. This not only shows that the spray seems to work, it also confirms that sinus exposure to the virus is the primary route of infection--at least in ferrets. It shows that saliva exchange, sharing food and water, etc., are not as important routes of infection.

While very encouraging, this also is very preliminary. We need to learn how long such protection lasts, whether it works early after infection, whether it works in humans, and assess its safety profile in humans.

Such a pre-exposure, or even early post-exposure prophylactic, would be very helpful to high risk people, front-line health care workers, teachers, nursing home residents, and many others. If it works, it could provide a relatively inexpensive and readily available prophylaxis and complement the vaccines that will likely be soon approved. Since it seems that only about 50% of the US are willing to get an anti-CoV-2 vaccine, which is not sufficient to confer herd immunity, a preventive measure like this nasal spray could go a long way in reducing the R0 value for CoV-2 to <1.

Yet More Good Vaccine News

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

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

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

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.