Believe me, I’ve been looking forward to putting Doc Gumshoe to work on topics other than COVID-19, which is far from being the only disease that affects our health and requires careful attention. But as the global case numbers have topped 85 million, and global deaths are approaching 2 million, COVID-19 demands to be first in line. And there certainly are new developments that emerge, just about daily.
Here’s the status in the US as of this morning:
New cases (as of 28 January): 148,733
New deaths: 3,962
Total cases: 25,604,635
Total deaths: 429,322
How is the vaccination drive going?
For a start, we have now definitely entered the era of vaccines. Several are now available, and more will be coming into use. But there are lots and lots of questions about vaccines, for example, how should they be given, who should (or should not) be vaccinated, what are the contraindications. And, are some of the old vaccines helpful?
And there is that new variant, which seems first to have emerged in the UK, but has turned up in a number of other locations. Is it more transmissible? Will the vaccines protect us from this new form of the coronavirus? And, the big question – will it result in a more severe form of the disease?
Beyond those issues, there will continue to be the question of how best to treat patients who have been infected and developed some of the many symptoms associated with COVID-19.
What’s the status of the vaccination drive?
In the United States, the plan was to have about 20 million persons vaccinated – or, at least, having received their first dose of a vaccine – by January 1st, 2021. We came nowhere near attaining that goal. Instead, we just got over the 4 million mark by that date. This was more a matter of logistics than of a major flaw in the planning. There were several agencies involved in the rollout, and they were all to some degree responsible for the delays.
Dr Martin Makary (author of Unaccountable, which I have discussed in some detail) recently pointed out that, for a start, the National Academy of Medicine’s guidance was somewhat abstract, and did not commit to a clear prioritization order, but described the groups that were to receive vaccines earlier only in the most general terms – e.g., “essential workers,” but without defining what an essential worker is. The Centers for Disease Control had plenty of time to develop principles on which prioritizations were to be developed. The CDC’s Advisory Committee on Immunization Practices (ACIP) had nine months to formulate guidance, but it was less than a week before Christmas that they voted on their recommendations on vaccine prioritization. That was two weeks after the FDA authorized the Pfizer vaccine. By that time, significant quantities of vaccine had been shipped to a number of states, but these states were unsure of what to do with it. By Tuesday, January 5, about 17 million doses of the vaccine had been shipped to the states, but only 4.8 million had been used. Clearly, the gears of bureaucracy badly need lubrication (progress has continued since, six weeks into the vaccination campaign the CDC now says 24 million doses have been administered, at a pace now of roughly a million doses a day).
Even with somewhat more specific guidelines, the prioritization guidelines have some pretty obvious flaws. Yes, health-care workers in direct contact with patients should be prioritized, but these priorities should not be completely equivalent. The 35-year-old surgeon who works in a scrupulously sanitary operating room is at much, much less risk than the 65-year-old nurse who sees patients presenting in the emergency department. And, obviously, not only health-care workers, but the population in general should be prioritized according to their over-all risk characteristics. A considerable number of low-risk individuals have been vaccinated because of their connections, such as family members of physicians and hospital board members. Meanwhile, many persons at high risk wait their turn.
At the same time, the dosing issue is somewhat muddled. The clinical trial data suggested that the Pfizer/BioNTech vaccine should be given in two doses, four weeks apart, while the Moderna vaccine’s two doses should be given three weeks apart. However, Moncef Slaoui, who was until recently the chief advisor to Operation Warp Speed, and formerly head of AstraZeneca’s vaccine development department, suggested giving adults between the ages of 18 and 55 two half doses of the Moderna vaccine so as to speed the rollout of vaccines and boost herd immunity.
And the Brits are proposing a dosing schedule that has some scientists a bit worried. They are planning to stretch out the interval between the first and second doses of the COVID-19 vaccines that have been approved in the UK to as long as three months, instead of the three to four week intervals that have been tested in clinical trials. Also, they have stated that the first and second doses could be from different manufacturers, if a second dose of the matching vaccine is unavailable.
The plans to alter the dosing schedules that were used in the clinical trials and shown to be efficacious are based on general knowledge of how vaccines work, not on data about these specific vaccines. That is, an initial dose confers a degree of immunity, mostly based on the generation of antibodies As the antibodies diminish, lasting immunity ramps up, carried by T-cells and memory B-cells. How long this takes varies with individual vaccines.
Paul Bieniasz, PhD, a virologist at Rockefeller University, has suggested that the UK’s delaying the second vaccine dose could be fostering vaccine-resistant forms of the virus. “My concern, as a virologist, is that if you wanted to make a vaccine-resistant strain, what you would do is to build a cohort of partially immunized individuals in the teeth of a highly prevalent viral infection. You are essentially maximizing the opportunity for the virus to learn about the human immune system. Learn about antibodies. Learn how to evade them.”
A contrary view, favoring a more flexible dosing strategy, was put forward by Joshua Salomon, PhD, of Stanford University, and his colleagues. They argued that, whereas a fixed strategy holds 50% of the vaccine supply in reserve for the second dose, a more flexible strategy would hold 10% of the shipment in reserve for the first three weeks, 90% of the remaining portion of that shipment for the next three weeks, and then hold in reserve 50% of the shipment thereafter. The group estimated that a flexible strategy would permit a significantly greater proportion of the population to receive two doses of vaccine. This strategy could prevent between 23% and 29% of additional COVID-19 cases. In the fixed strategy, half of every vaccine shipment would be held in reserve for the second dose. Their calculation is that the flexible strategy would result in an additional 2.4 million people receiving the full two doses of vaccine within six weeks, based on an initial shipment of six million doses. The flexible strategy was described in a letter to the Annals of Internal Medicine on 5 January 2021. (https://doi.org/10.7326/M20-8137)
Nonetheless, Dr Anthony Fauci has stated that in the US, the two vaccines in use will be deployed using the schedules that were tested in the Phase 3 trials on whose evidence the FDA authorized the vaccines for emergency use.
Before his inauguration, President-elect Joe Biden announced that he would order the release of nearly all the available vaccine on January 20. T. J. Ducklo, a spokesman for Biden’s transition was quoted as follows: “The President-elect believes we must accelerate distribution of the vaccine while continuing to ensure the Americans who need it most get it as soon as possible. He supports releasing available doses immediately, and believes the government should stop holding back vaccine supply so we can get more shots in Americans’ arms now. He will share additional details next week on how his Administration will begin releasing available doses when he assumes office on January 20th.”
Then, on Tuesday, 12 January Alex Azar, HHS Secretary, asked states to expand vaccine access to many millions more people who were otherwise further down on the priority list. If states follow his guidance, anyone over the age of 65 and anyone older than 16 with a medical condition that puts them at higher risk of severe COVID-19 infection is eligible to be vaccinated now. The announcement threw a wrench into states’ existing vaccine priorities, which were based on months of work by CDC advisers. The new plan would add 128 million people to the 24 million health workers and residents and staff of long-term care facilities who were already being prioritized for a vaccine.
A transition official said the Biden team believes that vaccine manufacturers will be able to produce enough second doses in a timely fashion while administering first doses to more Americans. Biden’s team plans to use the Defense Production Act to produce vaccine materials and other supplies in order to ensure there’s enough vaccine for both doses, and in the first week since taking office the updates have continued — with the latest numbers indicating that 44 million doses have been shipped, and that the Federal Government will take a more active role in trying to streamline the process… which is expected to now, per the latest press briefings, to increase distribution to 10 million doses a week.
A bit of news about Moderna: they were just anointed with a Shkreli Award, named for the notorious fraud-merchant Martin Shkreli, who is currently doing jail time for his greedy ways. Moderna, having received $1 billion in US taxpayer funds, is charging the government between $32 and $37 per dose, which is the highest per-dose price for a COVID-19 vaccine.
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Are old vaccines at least to some degree effective against SARS-CoV-2?
The answer appear to be “yes,” with emphasis on “at least to some degree.” Three vaccines have been investigated for their effectiveness against the coronavirus – bacillus Calmette-Guérin (BCG), against tuberculosis, the measles-mumps-rubella (MMR) vaccine, and the oral polio vaccine (OPV).
The bacillus Calmette-Guérin vaccine has been discussed in these Doc Gumshoe pieces since the early days of the pandemic. Currently, fifteen clinical trials are evaluating this vaccine versus the coronavirus; a limiting factor is the 1% rate of adverse events.
The oral polio vaccine has been known to reduce the severity of several infections almost since it began to be widely used. It significantly cuts the morbidity of flu by about 75%. However, this vaccine has not been used in the US or in several other nations since 2000, due to the fortunate fact that the prevalence of polio has been reduced to nearly zero.
The measles-mumps-rubella made headlines this past spring when 955 sailors aboard the USS Roosevelt tested positive for COVID-19; but only one was hospitalized. This was attributed to the fact that all recruits routinely receive the MMR vaccine.
While the older vaccines cannot alert the immune system to specifically recognize the coronavirus, what they do accomplish, to some degree, is to reinforce innate immunity. They increase the availability of immunoglobulin G (IgG) antibodies, which will indiscriminately go after any foreign invaders. A clinical trial compared IgG antibody titers in 30 people who’d had mumps (no vaccine) to 50 people who’d been vaccinated. Among the vaccinated, asymptomatic cases of COVID-19 had titers of 134 (in arbitrary units/ml) or higher. Mild cases were below 134, moderate cases below 75, and those who were hospitalized, below 32. The people who’d suffered through the painful swelling of mumps showed no such trend. Presumably, a vaccine confers broader immunity than infection with mumps alone.
It’s possible that none of this is relevant, seeing that within the next few months (we hope!) a large portion of the population will have received the SARS-CoV-2 vaccine. But it speaks to the general benefit of vaccines with regard to boosting our immune systems. So, yes! – get the COVID-19 vaccine, but don’t skip your flu shot.
What do we know so far about the new coronavirus variant?
As living beings reproduce, from the most complex to most simple, they change – the offspring are not identical with the parents. In animal cells, most of those changes are entirely meaningless, but a few may lead to cancer, and a few may produce benefits that enhance survival and get incorporated into the genome. In infective viruses such as that novel coronavirus, many of the changes are similarly meaningless, but a few can lead to increased transmissibility, or perhaps to more severe infections.
Coronaviruses in general evolve more slowly than viruses like flu, but they do pick up mutations as they spread. SARS-CoV-2 has been adding one or two changes a month to its RNA genome since it emerged late last year in China, and different versions of the virus have been continuously circulating throughout the course of the pandemic.
But this variant, referred to as B.1.1.7, showed up with at least 23 mutations, according to genetic analysis. Some of these mutations are in that part of the genome that carries the instructions for the spike protein, which is the part that binds to human cells and enables the virus to infect them. The leading vaccines were designed to teach the immune system to make antibodies that can recognize and block the spike proteins, so it’s possible that changes to the spike could alter how well the vaccines work.
However, as we have pointed out, the immune system has other components that contribute to protection, including T cells that can also recognize and attack invaders. Vaccines also elicit antibodies that can recognize different parts of the spike protein and that take different approaches to fighting off the virus, so even if some lost their ability to target the spike, the vaccines have other ways to block the virus. It would be unlikely that these changes in the variant could overcome all those layers. There is no evidence that either the B.1.1.7 variant, or the variant that has emerged in South Africa, the B.1.351 variant, have any effect on the efficacy of the current vaccines.
The B.1.1.7 variant, initially detected in the United Kingdom and now present in more than three dozen countries, is estimated to be 50% percent more transmissible than the standard form of SARS-CoV-2. This increase in infectiousness will cause the number of new cases to grow much faster. For example, by December it was responsible for around 60% to 70% of new cases in the southeast of England. Reports of this variant have emerged in the US, first in Colorado, and then in California and Florida.
The B.351 variant was first identified in Nelson Mandela Bay, South Africa, in October 2020. Cases have since been detected outside of South Africa. By December 2020, it was the predominant variant in Zambia, and has since spread to other areas in Africa.
Both variants are more transmissible than the original form of the coronavirus, as estimated by the reproduction number, (“R0” or “R naught”), which indicates the number of persons that to whom an infected individual is likely to transmit the infection. It has been estimated that the B.1.1.7 variant’s R0 is 40% to 80% higher than for the unmutated virus. For example, prior research in the US has estimated that the reproduction number for seasonal influenza is 1.28. The number for the 1918 flu pandemic was 1.80, meaning that one infected individual would on average transmit the infection almost to two other persons.
As of 31 December, the Imperial College in London estimated that 50% of all COVID-19 cases in the UK were due to the variant strain. They also noted a small but significant shift in the rate of infection such that more individuals under the age of 20 were affected by the variant strain.
Even though it is not predicted that either of these variant strains will hamper the effectiveness of vaccines, they could significantly delay the attainment of herd immunity and thus the slowing of the pandemic. It has been estimated that with the standard strain of SARS-CoV-2, the threshold for reaching herd immunity would be 66% of the population. If the UK variant, B.1.1.7, is 50% more transmissible, as the evidence suggests, 78% of the population would have to be immune. But since vaccines are never 100% effective, that implies that as many as 90% of the population would have to be vaccinated. This is the upper end of the range that has been cited by Anthony Fauci.
Several infectious disease authorities have called for intensifying containment measures (masks, social distancing, etc) and accelerating the vaccination effort.
The prioritized population should include not only those at greatest risk from the infection, but those who are most likely to transmit the infection. That would call for lowering the age at which an individual would be prioritized to receive the vaccine at least to 65 years of age. The logistical problems caused by that would of course be considerable.
Treatment options for persons infected with the coronavirus
The vaccination program will continue, whether with maximum efficiency, or muddling through, as it now seems to be doing in many parts of the globe. That should not distract the medical community from looking for the most effective ways to treat the great numbers of people who are becoming infected every day. In the US alone (do I really need to remind you?) the number of new cases has recently exceeded 200,000 per day.
The first option we’re going to look at is not, strictly speaking, a treatment. It would likely be considered a prophylactic, although there’s no evidence of a clear prophylactic effect. But there’s a definite relationship between Vitamin D deficiency and the severity/fatality of COVID-19 infections.
As has been pointed out (including by Doc Gumshoe), a correlation is not proof of causality. However, I need to qualify that general statement by pointing to the analysis behind the 1964 report in the UK that examined the link between smoking and lung cancer. That report, which employed criteria developed by Sir Austin Bradford Hill, was the crucial step that led to efforts to limit tobacco smoking and resulted in saving millions of lives. The Bradford Hill criteria are a group of nine principles that can be useful in establishing evidence of a causal relationship between a presumed cause and an observed effect.
Hill surmised that correlational data can be used to infer causality by satisfying various criteria such as consistency, specificity, temporality, and dose-responsiveness. Since that time, the Bradford Hill criteria have been widely used in public health research.
Vitamin D deficiency has many sets of data that satisfy all of Hill’s criteria as a risk factor for severe COVID-19. One was a study in 154 patients with COVID-19 who presented to a medical center during a six-week period. When deaths were evaluated on the basis of vitamin D deficiency, the fatality rate in vitamin D deficient subjects was 21%, compared to only 3% for those with higher levels of vitamin D. Even more striking was that 97% of severely ill patients who required ICU admission were found to have deficient vitamin D levels, while a deficiency was found in only 33% of asymptomatic cases. This suggests that vitamin D deficiency is a necessary precursor to severe COVID-19 infection.
If vitamin D deficiency is a causative factor in severe COVID-19 infection, will vitamin D supplementation have any effect on the course of the infection? A small clinical trial in 40 individuals with mild COVID-19 and vitamin D deficiency demonstrated positive results. These patients were treated with either placebo or 1,500 μg of vitamin D3 per day over seven days. The results demonstrated that supplementation helped clear the virus more quickly. After 14 days, 63% of the patients who received the vitamin D supplements tested negative for SARS-CoV-2 compared with 21% of those the patients in the placebo group. The treated group also showed a decrease in levels of fibrinogen, which is one of the factors that contribute to clot formation in COVID-19.
I need to point out that the 1,500 μg daily dose of vitamin D given to those patients is equivalent to about 60,000 IUs. That’s about 30 times the usual daily maintenance dose that many people take just to maintain normal year-round vitamin D levels. The objective in the clinical trial was quickly to raise the vitamin D levels in the treatment group, not to establish a permanent dose level.
Some other clinical trials pointed in a similar direction. A team in Córdoba, Spain, randomized 76 hospitalized COVID-19 patients in a 2:1 ratio to receive either a fast-acting vitamin D supplement (three times more potent than vitamin D3) or placebo. Of the treated patients, only 2% (1 out of 50) needed ICU admission compared to 50% (13 of 26) of the untreated group. In addition, 8% of the untreated patients died, compared to none in the intervention group. Though vitamin D deficiency was not identified on admission, the researchers cite a report that these levels in Córdoba in wintertime are deficient.
A retrospective study in nursing home patients in France confirmed an association between vitamin D supplementation and protection from the more severe effects of COVID-19 infection. Of the cohort of frail, elderly patients who regularly received vitamin D supplementation, only 10% of those who were infected with the coronavirus progressed to severe COVID-19, compared with 31% of the non-supplemented cohort. Also, 14-day mortality rates were 7% in the supplemented group, compared with 31% (again!) of the patients who had not received supplements.
The following is a quotation from Lancet
On Dec 17, 2020, the National Institute for Health and Care Excellence (NICE), in collaboration with Public Health England and the Scientific Advisory Committee on Nutrition, published an updated rapid review of recent studies on vitamin D and COVID-19. Their recommendations support the current government advice, revised in April, 2020, during the first lockdown in the UK, for everyone to take vitamin D supplements to maintain bone and muscle health during the autumn and winter months. The recommendations are also in line with new guidance from the UK government, released on Dec 22, 2020, allowing extremely clinically vulnerable people to opt in to receive a free 4-month supply of daily vitamin D supplements—similar to an initiative launched earlier in Scotland. However, the rapid review concluded that sufficient evidence to support vitamin D supplementation with the aim of preventing or treating COVID-19 was still lacking and that the topic should be further investigated. Experts studying vitamin D welcomed the call for more research, but the lack of specific recommendations in the context of COVID-19 was also met with disappointment by many in the scientific community who have argued that vitamin D supplementation is generally safe and that any potential low toxicity would likely be strongly outweighed by any potential benefits in relation to protection from COVID-19.
If you didn’t have the patience to read that to the end, I’ll briefly summarize. The authorities are duly reminding the rest of the world that conclusive evidence is lacking for the protective nature of vitamin D supplementation with regard to COVID-19, but they’re going ahead and recommending it anyway.
By the way, vitamin D has been understood for more than 30 years to have a crucial relationship with our immune function, and is involved with the activity of T-cells, which, as we have learned, have a vital role in attacking and destroying pathogens.
But that relationship between vitamin D levels and susceptibility to the coronavirus offers the perfect opportunity to push supplements of dubious merit.
The Feds come down on supplement marketers in Georgia
On 8 January, the Department of Justice (DOJ) announced that two “health and wellness” companies were prohibited from selling unapproved vitamin D products, about which they had made claims that their product, sold in bottles for $19 each, had life-saving capabilities. Sales pitches said that the supplement was potentially “the most important formula in the WORLD right now due to the new pandemic,” and claimed that “the NEXT FIVE MINUTES could save your life.
The companies, Fusion Health & Vitality LLC and Fusion Ionz LLC, both doing business as Pharm Origins, were prohibited from selling their vitamin D supplements, “Immune Shot,” “Immune Boost,” and “Core” as cures for COVID-19.
They pleaded guilty to a civil suit brought by the DOJ and “voluntarily” recalled these products, some of which were also found to contain an unapproved food additive, hordenine HCl, which is potentially unsafe for oral consumption and may cause side effects such as rapid heart rate and high blood pressure.
Does ivermectin have a role in the treatment of COVID-19?
Maybe so and maybe not. A group called Front Line COVID-19 Critical Care Alliance (FLCCC) posted on their own website their position on ivermectin and a summary of the global ivermectin literature on their website. The group is led by three physicians, one of whom testified at a Senate hearing on early treatment options for COVID-19.
The FLCCC group has developed a protocol for treating sepsis, using methylprednisolone, ascorbic acid, thiamine, and heparin, plus a statin, zinc, vitamin D, famotidine, melatonin, and magnesium. They adapted this protocol, labeled MATH+, as a treatment for COVID-19. They point to the results of the RECOVERY study, announced after their introduction of MATH+, which demonstrated the benefits of dexamethasone in COVID-19 patients. As we have discussed in these pages, dexamethasone is the only drug that has so far been demonstrated to reduce the mortality rate in severely ill COVID-19 patients. They assert that methylprednisolone, also a corticosteroid, is more potent than dexamethasone.
One of the group’s leaders, Paul Marik, MD, chief of pulmonary and critical care medicine at Eastern Virginia Medical School in Norfolk, said “People are dying. We treat patients at the bedside. We don’t have the ivory tower syndrome … we see that this works.”
Then, in April 2020, an Australian study was published focusing the attention of FLCCC on ivermectin. The paper, entitled “The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro” (Antiviral Res 178(2020) 104787) observed that ivermectin , an antiparasitic agent, has been shown to have fairly broad anti-viral activity as well, including against simian virus, dengue, West Nile, Venezuelan equine encephalitis, and other viruses. Its activity against the coronavirus that causes COVID-19 was detected in vitro only.
Several other studies thereafter reported some evidence that ivermectin reduced severity of the coronavirus infections, but these were not of the type that produce the highest standard of evidence – not randomized placebo-controlled double-blind trials. These trials were conducted in Egypt, Argentina, Bangladesh, Iraq, Brazil, and Spain, The single study done in the US was a retrospective study in which most patients also received hydroxychloroquine, azithromycin, or both.
And neither the Australian study nor the subsequent trials has done anything to sway the view of the FDA, viz:
To the question, “Should I take ivermectin to prevent or treat COVID-19?” the FDA’s answer was “No. While there are approved uses for ivermectin in people and animals, it is not approved for the prevention or treatment of COVID-19. You should not take any medicine to treat or prevent COVID-19 unless it has been prescribed to you by your health care provider and acquired from a legitimate source.”
“A recently released research article described the effect of ivermectin on SARS-CoV-2 in a laboratory setting. These types of laboratory studies are commonly used at an early stage of drug development. Additional testing is needed to determine whether ivermectin might be appropriate to prevent or treat coronavirus or COVID-19.”
Then, on 14 January, the COVID-19 Treatment Guidelines Panel chimes in with much the same conclusion, that “there are insufficient data to recommend either for or against the use of ivermectin for the treatment of COVID-19. Results from adequately powered, well-designed, and well-conducted clinical trials are needed to provide more specific, evidence-based guidance on the role of ivermectin for the treatment of COVID-19.”
An important point made by the panel is that “ivermectin doses up to 100-fold higher than those approved for use in humans would be required to achieve the plasma concentrations necessary to duplicate the drug’s antiviral efficacy in vitro.”
The FLCCC group members, who are mostly critical care physicians, don’t see a need for more data and argue it would be unethical to give placebo to patients, given the established safety of ivermectin.
The controversy will continue. The group says they’re frustrated that their work is now being championed by the political right, and that it’s become politicized at all. They have had to distinguish themselves from America’s Frontline Doctors, which gained notoriety for its pro-hydroxychloroquine, anti-lockdown rhetoric last summer.
“This is not a political issue and it should never be,” Paul Marik said. “We are driven by the science and the data, not by politics or anything else.”
Will ivermectin turn out to be a bust like hydroxychloroquine, or a vital agent in treating COVID-19 patients like dexamethasone?
We’ll find out before long.
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At some point, Doc Gumshoe won’t need to be paying so much attention to the pandemic, and he’s looking forward to that, as I’m quite sure we all are. In the meantime, issues pop up daily, and I’ll try to address them. But I’m looking forward to other topics of interest to Planet Gumshoe. I have a list of questions that have been put to me in previous comments, and I’ll try to provide satisfactory answers. Stay well, everybody! Bes