The term “the duration” immediately recalls the Second World War. Nobody had any idea when it would be over, and so discussions of a lot of World War II-related events and conditions prominently featured the phrase “for the duration” – as in great numbers of combat fatalities would continue to be reported for the duration, and gas rationing would continue for the duration. That basically meant that these conditions would continue as long as they continued, but nobody really knew for how long.
The same thing is the case with COVID 19. It is the dominant reality for the duration, which means it will go on as long as it goes on. How long that will be, no one really knows. But perhaps there are signs and indications that we can look at today as a way of bringing our speculations a bit more into focus.
What makes for hot news is when there are upsurges in new COVID 19 cases, whether these take place in one neighborhood in Brooklyn, in an entire state in the midwestern US, or the whole subcontinent of India. Information about how an upsurge is controlled is, for some reason, not so hot. But if we’re keeping an eye out for relevant developments in this pandemic, the not-so-hot news can be just as important, and perhaps more important.
For a start, let’s look at how two very different places managed, or attempted to manage, the coronavirus.
Sweden and Arizona versus COVID 19
Sweden pinned its hopes on herd immunity. The idea was that as more people become infected and (hopefully) recovered from the disease, and therefore acquired a degree of immunity, there would be a decreasing number of people in the community who would spread the infection. The epidemic in Sweden would therefore diminish along with the proportion of potential disease spreaders. But for this to happen in reality, there either has to be an effective vaccine or a very high fraction of the population has to develop immunity due to having had the disease itself. In terms of defeating COVID 19, this was an optimistic assumption – an assumption that took for granted that many, many people would acquire the infection, and that perhaps a few of these unfortunates would die, but that the COVID 19 plague would go away. That assumption did not work out.
At this point, Sweden has over 100,000 cases and nearly 6,000 COVID 19 deaths. Its immediate next-door neighbor, Norway has about 16,000 cases and fewer than 300 deaths. Sweden’s population is about double Norway’s, but Sweden’s infection rate is triple Norway’s and its death rate is ten times higher.
The inhabitants of the two nations are similar, and both nations have excellent health-care systems. The chief difference is that while Norway put into practice strict preventive measures such as social distancing and masks, Sweden did not. Some individuals in Sweden took precautions as a matter of individual choice, but the government made no move to enforce or even encourage these precautions. The results are evident from the comparable infection and death rates.
Now let’s take a look at Arizona. When the coronavirus started to emerge as a serious threat, Arizona imposed business closures and stay-at-home orders similar to those in many other states. But as there began to be hints that the threat from the virus might be abating, Arizona’s Governor Doug Ducey, yielding to pressure to re-open the state, did not continue these closure orders beyond May 15th. Whereupon daily diagnoses of COVID 19 took off like a rocket, climbing by a factor of ten over the following six weeks. That surge reached its crest around the end of June, at which point Governor Ducey reimposed those previous protective measures. And from that point, the number of new infections plummeted, so that by early August, new infections were down to the levels seen in early May.
The graphic below, from the Morbidity and Mortality Weekly Report (part of the CDC) tells the story.
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Certainly, based on those data, the protective measures that were reimposed in the middle of June are what did the trick.
The moral of this story, if it needs to be pointed out, is that simply letting herd immunity develop on its own causes severe harm to many, many people. It is a deadly strategy.
How to get to herd immunity
The results of Sweden’s reliance on herd immunity should not discredit herd immunity as an effective way of curbing the spread of a communicable disease. The question is, how is herd immunity achieved? Sweden apparently thought that it would come about naturally as more and more people got infected and recovered, having acquired some immunity. This may have led to the conclusion that the best way of achieving this goal was to do little or nothing to prevent the spread of infection. Historically, some epidemics may have been slowed in exactly that same way. At the time of the 1918 flu pandemic, there was no flu vaccine, and it was largely herd immunity that finally slowed it down. However, other devastating infectious diseases have effectively been stopped by means of vaccines, smallpox and polio being prime examples. And, of course, widespread vaccination is the prime means of getting to herd immunity.
A group of three eminent medical scholars have proposed an alternative method of attaining herd immunity in a document entitled “The Great Barrington Declaration,” which reportedly has been signed by over 90 clinicians and 300 medical workers. They propose a strategy which they suggest will offer maximum protection for persons most at risk of serious infections and death, while permitting people who are at lower degrees of risk to continue relatively normal lives. Here’s an excerpt from that document:
“Current lockdown policies are producing devastating effects on short and long-term public health. The results (to name a few) include lower childhood vaccination rates, worsening cardiovascular disease outcomes, fewer cancer screenings and deteriorating mental health – leading to greater excess mortality in years to come, with the working class and younger members of society carrying the heaviest burden. Keeping students out of school is a grave injustice.
“Keeping these measures in place until a vaccine is available will cause irreparable damage, with the underprivileged disproportionately harmed.
“The most compassionate approach that balances the risks and benefits of reaching herd immunity, is to allow those who are at minimal risk of death to live their lives normally to build up immunity to the virus through natural infection, while better protecting those who are at highest risk. We call this Focused Protection.
“Those who are not vulnerable should immediately be allowed to resume life as normal. Simple hygiene measures, such as hand washing and staying home when sick should be practiced by everyone to reduce the herd immunity threshold. Schools and universities should be open for in-person teaching. Extracurricular activities, such as sports, should be resumed. Young low-risk adults should work normally, rather than from home. Restaurants and other businesses should open. Arts, music, sport and other cultural activities should resume. People who are more at risk may participate if they wish, while society as a whole enjoys the protection conferred upon the vulnerable by those who have built up herd immunity.”
… but I strongly disagree with that position
Having quoted extensively from the Great Barrington Declaration, I needed to emphasize my disagreement, in bold italics.
There’s no question that the lockdown caused serious problems to the economy and an enormous disruption of people’s lives. But the authors of this declaration seem to ignore the really horrendous effects on the health and lives of those persons whom they describe as “not vulnerable.” In my view, calling them “not vulnerable” is a flat-out falsehood. Younger people can and will get sick, and some of them will die. And, on top of that, younger people and quite young children can pass the coronavirus infection on to those same susceptible older people. Kids can infect and essentially kill their grandparents. What the Great Barrington Declaration proposes is to trade the lives and health of some for the benefit of others.
On October 15th, a letter was published in The Lancet, signed by 80 medical and scientific professionals, that opposed that proposal in the most emphatic terms:
“This is a dangerous fallacy unsupported by scientific evidence.
“Any pandemic management strategy relying upon immunity from natural infections for COVID-19 is flawed. Uncontrolled transmission in younger people risks significant morbidity and mortality across the whole population. In addition to the human cost, this would impact the workforce as a whole and overwhelm the ability of health-care systems to provide acute and routine care. Furthermore, there is no evidence for lasting protective immunity to SARS-CoV-2 following natural infection, and the endemic transmission that would be the consequence of waning immunity would present a risk to vulnerable populations for the indefinite future. Such a strategy would not end the COVID-19 pandemic but result in recurrent epidemics, as was the case with numerous infectious diseases before the advent of vaccination. It would also place an unacceptable burden on the economy and health-care workers, many of whom have died from COVID-19 or experienced trauma as a result of having to practise disaster medicine.”
The Great Barrington Declaration also provoked stern rebuttal from the Infectious Disease Society of America (IDSA), which issued a statement to the effect that they “strongly denounced” that strategy, saying that “it comes without data or evidence.”
And here’s a quote from Dr Anthony Fauci:
“Anybody who knows anything about epidemiology will tell you that this is nonsense and very dangerous, because what will happen is that if you do that, by the time you get to herd immunity, you will have killed a lot of people – that would have been avoidable.”
Just to be really, really clear, what these people are denouncing is the concept of deliberately trying to get to herd immunity by letting increasing parts of the population get infected with the coronavirus. Arriving at herd immunity by means of a vaccine, on the other hand, is generally agreed to be an objective of the greatest importance.
So, how are we doing in the quest for vaccines?
In spite of repeated proclamations from On High that there would be a vaccine widely available by November 3rd, or at least before Christmas this year, it doesn’t look as though that’s going to happen. Just a few days ago (as I write this), Dr Moncef Slaoui, who is the co-chair of Operation Warp Speed, made a statement that the government agency (which had been organized to accelerate the vaccine process) was urging manufacturers not to apply for emergency use authorization (EUA) until they had enough doses of their vaccine on hand to vaccinate a meaningful portion of the population.
Operation Warp Speed, as perhaps you know, is a $10 billion initiative, whose central goal is to develop, produce, and distribute 300 million doses of an effective vaccine by mid-January of 2021. The organization is quasi-military – more than 60 military officials are on the organization chart. It’s acknowledged that the military have no knowledge of the science of vaccine development. But they have already helped prop up more than two dozen vaccine manufacturing facilities by flying in equipment and raw materials from all over the world. They have also set up significant cybersecurity and physical security operations to ensure that any eventual vaccine is guarded very closely from possible intervention by forces that may not want the US to be the first nation to have an effective vaccine.
Dr Slaoui has suggested that FDA approval of a vaccine that was not actually available at that time would be “a major disappointment.” Polls have shown that many Americans are mistrustful of vaccine development being rushed and inadequately tested; as many as 50% have said that they would refuse a vaccine produced under those circumstances.
The FDA has been trying to clarify the regulations under which a vaccine would receive an EUA. The agency just recently posted their updated safety standards in advance of a meeting of the advisory committee which advises the FDA on safety standards, scheduled for October 22nd. The FDA wants vaccine manufacturers to collect safety data on at least half of the trial subjects for two months after they have received their second dose of a two-dose vaccine.
Of the current frontrunners in the vaccine race, the only one that uses a single-dose vaccine is the Johnson & Johnson candidate. But J & J just recently interrupted its Phase 3 clinical trial due to a “safety incident.” Currently, 60,000 persons are enrolled in the trial, which remains on hold. J & J declined to provide further details, but pointed out that it is not apparent in cases like this whether the adverse event took place in the treatment arm or the placebo arm. Even though the trial has been interrupted, it continues to be blinded, therefore no one knows the status of an individual subject.
At this point Pfizer in collaboration with BioNTech are the leaders of the pack. Their vaccine is a messenger RNA formulation. These are much quicker to be developed, particularly in the early stages. They recently got FDA approval to include subjects as young as 12 years old in their safety trials. Most other vaccine trials are not enrolling any subjects under the age of 18. As of mid-September, Pfizer/BioNTech announced that only 12,000 of the projected 30,000 subjects had received a second dose of the vaccine, meaning that they would have the necessary safety data to apply for an emergency use authorization by mid-November at the earliest, since it usually takes about two months for vaccine-related adverse events to emerge. Data on the efficacy and immunogenicity of the vaccine will follow. Some estimates have put the time frame for such data as mid-January to mid-February of 2021.
It is not clear at this point what standard the FDA will use to judge the effectiveness of vaccine candidates. A potential standard that has been aired and discussed, mostly critically, is that to receive any kind of approval, a candidate would need to demonstrate that in at least half of the vaccinated trial enrollees, the COVID 19 symptoms would be reduced by about half. This “half of a half” standard may have some merits, particularly when it comes to speed of arriving at a decision and getting a vaccine out in quantity, even if it is perhaps only somewhat effective.
As you can see from the table below (which appeared in the October 13th issue of Lancet), there are currently nine Phase 3 clinical trials in COVID 19 vaccines underway. The other presumed front-runner, Moderna, based in Cambridge, MA, has not received FDA approval for its candidate vaccine. Nonetheless, they have announced plans to make between 500 million and 1 billion doses of their vaccine per year, when it gets approval, whenever that might be. It has been pointed out several times, including in past Doc Gumshoe pronouncements, that Moderna has not yet brought a vaccine for any disease through the approval process.
|Phase 3 trials
|AstraZeneca; University of Oxford (30 000 participants)||Chimpanzee adenovirus (ChAdOx1/AXD1222)||UK; India; Brazil, South Africa; USA|
|Moderna; National Institutes of Health (30 000 participants)||RNA (mRNA-1273)||USA|
|Pfizer; BioNTech (44 000 participants)||RNA (BNT162b1 and
|The Janssen Pharmaceutical Companies of Johnson & Johnson (60 000 participants)||Adenovirus serotype 26 vector (Ad26.COV2.S)||USA; Argentina; Brazil; Chile; Columbia; Mexico; Peru; Philippines; South Africa; Ukraine|
|The Gamaleya National Research Centre for Epidemiology and Microbiology; Academy of Military Medical Sciences (40 000 participants)
|Adenovirus serotype 5 vector and adenovirus serotype 26 vector (Sputnik V)||Russia|
|CanSino Biologics; Academy of Military Medical Sciences (40 000 participants)||Adenovirus serotype 5 vector (Ad5CoV)||China; Pakistan|
|Sinovac Biotech (9000 participants)||Inactivated virus (CoronaVac)||Brazil; Indonesia|
|Sinopharm; Wuhan Institute of Biological Products (21 000 participants)||Inactivated virus||The United Arab Emirates; Bahrain; Peru; Morocco; Argentina; Jordan|
|Sinopharm; Beijing Institute of Biological Products (5000 participants)||Inactivated virus (BBIBP-CorV)||The United Arab Emirates|
The AstraZeneca trial is on hold in the US because of an adverse event which took place in the UK. As mentioned earlier, the Janssen/J & J trial is similarly on hold due to an adverse event in one participant.
In addition to the nine Phase 3 trials shown above, 21 Phase 1 and Phase 2 trials are now underway. Inovio, which was one of the first pharmaceutical companies to announce that they were developing a vaccine against the coronavirus, is only now in Phase 1 trials for its candidate vaccine.
Also in Phase 1 are two major contenders – Sanofi and Merck, both of whom entered the race relatively late. Sanofi is developing a messenger RNA vaccine in collaboration with Translate Bio of Lexington, MA, relatively small biotech that has been working with mRNA for the past ten years. Phase 1 trials with this vaccine are expected to start in November. John Shiver, head of vaccine R& D for Sanofi, projected that the earliest their vaccine might be approved, if it has been shown to be safe and effective, would be the second half of 2021. The partners believe that they can make between 90 and 360 million doses of a mRNA vaccine against the coronavirus before the end of 2021.
Sanofi has a second vaccine in development. This one is a recombinant protein vaccine, which is used with another compound to boost the response of the immune system. The second compound is made by Glaxo SmithKline. Currently, a Phase 1/2 clinical trial involving 440 subjects is underway. Safety and preliminary immunogenicity data may become available by the end of December, according to John Shiver. Sanofi/GSK are currently manufacturing doses of the actual vaccine, and expect to have 100 million doses by that time, in case the FDA issues an emergency use authorization that soon.
Sanofi’s recombinant protein vaccine uses the same platform as Sanofi’s Flublok vaccine, which may be an advantage, since regulators are already familiar with the platform’s mechanism, and thus may go through the approval process somewhat more quickly.
One of Merck’s two vaccine candidates also employs a platform that the regulators understand. The vaccine is made by combining genetic material from the coronavirus, SARS-CoV-2, which causes COVID 19, with a virus that can infect humans without making them ill. This virus, the vesicular stomatitis virus (VSV), has been abundantly shown to trigger a robust immune response in humans. The VSV virus was fused with the virus that causes Ebola, producing a vaccine that has been reported to have outstanding efficacy. An unusual feature of the VSV Ebola vaccine is that it works equally well in the elderly as in younger people. If the COVID 19 vaccine had features similar to the Ebola vaccine, that would be a marked advantage.
A second vaccine is being developed by Merck in collaboration with their newly-acquired subsidiary, Themis BioScience. This candidate uses an attenuated measles virus as the vector for the coronavirus genetic material to the human immune system. As yet, no licensed vaccine uses this platform, but other similar vaccines under development are showing promise.
In all, 30 COVID-19 vaccine candidates are at some stage of development. It’s highly likely that some of these will receive emergency use approval, and some may even receive full FDA approval. Some of these will offer only partial protection, and offer protection to some persons but not others. But some vaccines may be highly effective, and some vaccines may protect the great majority of individuals. With a disease that has attained pandemic proportions – at this moment, nearly 40 million cases globally, and well over a million global deaths – even a half-way benefit to half the population is better than nothing, especially if more robust and broadly effective vaccines come along.
Speaking now for myself, if the first vaccine that came along was one of those half and half deals, and I was deemed eligible to receive it – and if it had received EUA from the FDA – I would go ahead and get myself vaccinated. And then, when a better one came along, if there were no contraindication, I would get myself vaccinated again. My guess, based on what we know up to this point about the mutability of the coronavirus, is that there will be no single vaccine that is good for a lifetime of immunity. Whether it will need to be repeated annually, like the flu vaccine, no one yet knows. For the duration, we will need to base our decisions on whatever we know at this point.
Other COVID-19-related topics
Scientists and the medical community in general have now been working with and investigating the coronavirus for almost a year. They have learned a good deal, and although quite a lot about the coronavirus and the disease (or diseases) that the coronavirus causes is still poorly understood, what they have learned will likely provide avenues that lead to effective ways of treating and managing this disease.
Here are a few of the COVID-19-related topics that Doc Gumshoe will take up in the next epistle:
- The relation between virus load and the severity of symptoms;
- The increasing range of treatment options for COVID-19 that, while not offering a cure, do address patient symptoms;
- The relationship between obesity and COVID-19 severity;
- The neurologic symptoms that COVID-19 produces, particularly in young people;
- How the coronavirus affects persons with different blood types;
- The clinical effect of coronavirus antibodies;
- Cardiovascular effects of COVID-19
- The disruption of the renin-angiotensin system (RAS) as the mechanism through which the coronavirus wreaks its devastation.
* * * * * * *
And, in the intervals when I turn my attention away from COVID-19 (believe me, this takes an effort of the will), other topics attract me. For example, one that was suggested by one of the Gumshoe faithful was the possibility that memory loss was mostly due to bacteria. Can this be true? Doc Gumshoe will try to find out. In the meantime, keep those stimulating comments coming at me. Best to all, Michael Jorrin (aka Doc Gumshoe)
[ed. note: Michael Jorrin is a longtime medical writer (not a doctor), who I dubbed “Doc Gumshoe” many years ago — he writes health and medicine-focused columns for our readers a couple times a month, and though he does not generally cover investment ideas he has agreed to our trading restrictions. You can find his past columns here.]