This will surely not be the last time Doc Gumshoe turns his attention to the pandemic that is now imposing misery on many parts of the world.   I need to acknowledge that when what was then generally called the Wuhan virus first came to my attention, I expressed the view that, despite the dire warnings that several infectious disease scientists had stated, it would not become a pandemic.   I’m thankful that I was somewhat tentative in expressing that view, but at that point I thought it would be no worse than SARS or MERS, which were also caused by related corona viruses.   

But that was back in January.   At that point there were only a handful of confirmed cases in the US, and no deaths.   I don’t need to remind you of the current case and fatality counts here in the US.   But projections for other parts of the globe are staggering.   For example, the Institute for Health Metrics and Evaluation (IHME) at the University of Washington is forecasting that about 440,000 people will die from COVID 19 in Latin American and Caribbean nations by October 1^st.   IHME bases the projection on a careful examination of each nation’s current data about COVID deaths and infections.   There is certainly reason to question the accuracy of the figure, based on errors in previous IHME projections.   For example, on May 1^st, IHME projected that the fatality rate in the US would reach 72,500 by August 1^st.   However, by July 1, the US fatality rate from COVID 19 had already reached 128,574.   At this point in time, the CDC predicts that there will be between 140,000 and 160,000 COVID 19 deaths by July 25^th.  So if the CDC is right, IHME’s projection is about 100% too low.   What does that say about COVID 19 projections overall?   Could the deaths in Latin America reach 800,000 or more by October 1^st?   

I cite those projections/predictions to show just how unpredictable, and how genuinely dire, the course of this pandemic is turning out to be.   However, not all the news is bad, and here are a few encouraging items:      

Dexamethasone improves survival in COVID patients with the most severe disease

This is based on a trial in the UK dubbed RECOVERY, which has not yet been published, or peer-reviewed.   The trial randomly assigned hospitalized patients with COVID 19 to one of several open-label treatments with existing drugs, including not only dexamethasone, but also tocilizumab (Actemra), plasma from convalescent COVID patients, azithromycin, and ritonavir/lopinavir (Kaletra).   The hydroxychloroquine arm was stopped on June 5 when it became clear that it conferred no benefit.

Patients receiving dexamethasone were the first to benefit from improved survival compared with those patients receiving usual treatment.    In the trial, 2,104 patients received 6 mg of dexamethasone via intravenous injection for ten days, compared to 4,321 patients receiving usual treatment.   

Benefit from dexamethasone treatment was seen only in patients receiving a form of respiratory support.   In patients who were on mechanical ventilation, deaths in the dexamethasone arm were reduced by 35% compared with patients in the usual-care arm.   In patients who were receiving supplementary oxygen, the mortality rate was reduced by 20%.  In both cases, these results were judged to be highly significant – P = 0.0003 for patients on mechanical ventilation, and P = 0.0021 for those on supplementary oxygen.   The investigators concluded that treating 8 ventilated patients or 25 requiring supplemental oxygen would prevent one death. 

Recruitment for this arm of the trial was stopped early because the investigators concluded that they had sufficient evidence of the benefit of dexamethasone treatment.   The chief investigator in the trial, Peter Horby, MD/PhD of the University of Oxford stated, “The survival benefit is clear and large in those patients who are sick enough to require oxygen treatment, so dexamethasone should now become the standard of care in these patients.”   In other words, there would be no further justification in assigning patients to a “usual-care arm” which did not include dexamethasone.

As to why dexamethasone does not confer any benefit to patients before they have reached the stage where they require some form of supplementary oxygen, the explanation put forward by researchers is that, indeed, the COVID disease has three fairly distinct phases.   The figure below characterizes the three phases and provides some tentative information as to what the appropriate treatment options might be for each phase.

 

The first phase is termed the viremic stage, during which the treatment objective is simply to attack the virus in any way possible.   During this phase, the patient’s essential immune response responds, mobilizing cellular agents to attack the invader.   The host’s immune response has not ramped up to its maximum activity as yet, therefore in that phase an anti-inflammatory drug would have no effect.   Treatment options during this phase include antivirals (such as remdesivir) and drugs targeting the patient’s specific symptoms.

During the second phase the pulmonary symptoms of COVID take hold.   In addition to addressing the initial symptoms of the virus, patients entering this phase of the disease begin to experience difficulties in breathing, requiring supplementary oxygen.   This phase is characterized by the increase in the patient’s immune response, although not yet to the level where the immune response causes harm to the patient.

The third phase, labeled the severe phase, is characterized by an inflammatory response as the patient’s immune system goes into high gear.   Some researchers have called this the “cytokine storm.”   Cytokines are a large class of proteins released by many different cells in the body.   They play an important part in the normal immune response, but the release of a large amount of cytokines at one time can be extremely harmful and even fatal.

The diagram above shows the overlap of the viremic stage and the severe phase.   The overlap is what characterizes the pulmonary phase, as the severity of the disease is growing.   

Dexamethasone, a common steroid, is an active and effective anti-inflammatory and is used in a number of diseases characterized by inflammation, including arthritis, asthma, and cancer.   It is also used in patients with psoriasis, despite recommendations to the contrary.  Dexamethasone, as an agent to counteract the severe inflammatory response, has the added advantage of being widely available and very inexpensive. 

The benefit of dexamethasone treatment in patients in the severe phase of the infection is likely to lead to further research, using other anti-inflammatory agents in COVID 19 patients.  

Of course, a drug that lowers mortality in patients with potentially fatal disease by about a third at most, while a major step forward in reducing the death toll from COVID 19, is far from a definitive solution to the gigantic problem of dealing with this disease.   One of the worst consequences of this pandemic is that it has the capacity of utterly overwhelming and defeating efforts by the health-care system to limit the disease.   The health-care system, and the world in general, continues to pin its hopes on the spread of herd immunity, as a result of an effective vaccine and also as a result of enough COVID survivors with at least a degree of immunity, who therefore resist infection and do not transmit the disease.

So let’s take a look at what’s happening in this race to get a COVID vaccine.

The leading vaccine candidates

Here the question is not only which vaccine will be the most effective, but which vaccine (or vaccines) will be available most quickly.   Globally, more than 140 potential vaccines are at various stages of development.   Most appear to be aiming to have vaccines ready for widespread use early in 2021, although there is strong sentiment in certain quarters to be able to announce that a successful vaccine is ready to go by early November this year.   

Moderna’s mRNA-1273 and other messenger RNA vaccines

Who appears to be in the lead is Moderna (MRNA), a biotech startup with no products whatever on the market.   Moderna’s vaccine candidate, (mRNA-1273) was the first to be injected into human volunteers, in mid-March of this year.   It is based on injecting messenger RNA directly into cells, such that they produce the proteins that attack the virus in the body of the human subject.   This is fundamentally different from conventional vaccines, which challenge the human’s immune system by presenting the immune system either with the inactivated real virus or with antigens derived from the virus.   Essentially, the messenger RNA approach saves steps in the process of creating an acquired immune response.   

Moderna started a Phase 2 trial of their candidate vaccine in 600 human volunteers about two months ago, on May 29.   And on June 11, Moderna announced a Phase 3 trial with 30,000 participants, which was planned to start on July 9.   However, on Thursday July 2, Moderna announced the delay of that Phase 3 trial.   The delay was due, according to sources within the company, to changes in the protocol.   Such changes are not at all unusual in clinical trials, and the company started dosing for the trial last week.   Moderna has lined up manufacturing capability intended to generate 100 million doses starting in the third quarter of this year, and hundreds of millions of doses in early 2021.

Other entities pursuing the mRNA approach include a group based in the Imperial College in London, which began its first human trials on June 24; also a German-based company called BioNTech, which announced that human volunteers in Phase 1/2 have begun taking their first doses of its candidate vaccine.   Another German-based company, Cure-Vac, announced positive pre-clinical results for its lead COVID 19 vaccine candidate.   

Oxford University’s “chimpanzee adenovirus Oxford 1” (ChAdOx1)

Adenoviruses are common viruses which can cause mild infections such as colds.   They can be genetically engineered to express the viral antigens found in the coronavirus that causes COVID 19 (SARS-CoV-2), and when used in a vaccine given to a human subject, they trigger the same immune response as the coronavirus itself.

The Oxford group (working with AstraZeneca) published information on May 13 reporting that their vaccine prevented rhesus macaques monkeys from developing pneumonia when infected with SARS-CoV-2.   The vaccinated monkeys nonetheless remained infected, and apparently had the same level of virus as non-vaccinated monkeys.   What that means is that vaccinated humans could still pass the infection to others, even if they did not develop symptoms.   A Phase 1 trial in over one thousand volunteers in the UK has recently reported positive interim results.

CanSino’s adenovirus vaccine Ad5-nCoV 

CanSino Biologics is the medical science arm of the People’s Liberation Army in China, and their adenovirus vaccine has completed a Phase 1 trial in which 108 healthy adults demonstrated an immune response to the adenovirus vector vaccine.   CanSino published a peer-reviewed paper in Lancet on May 22 reporting the results.   A problem reported in the paper is that since the adenovirus is already common in the human population, persons who are already naturally infected with the adenovirus other than from the vaccine may fail to develop a sufficient immune response to make the vaccine effective against SARS-CoV-2.   

Other contenders employing viral vectors include Johnson & Johnson/Janssen, which is using a proven platform called AdVac.   This was used to produce thousands of doses of their Ebola vaccine, deployed in the Congo last Fall.   And Merck is working on a vaccine that uses an attenuated live measles vaccine.

Sinovac’s vaccine, called PiCoVacc, and now renamed CoronaVac

This is another Chinese company, working in partnership with several medical research institutes in China.   Their method is the time-tested inactivated pathogen approach, in which the patient is injected with virus that has been weakened sufficiently that it will not cause a serious infection.   Polio and flu vaccines are generated by this method, which, unfortunately, is quite time-consuming, since the vaccine is grown inside chicken eggs, an enormous number of which are required to manufacture the needed number of vaccine doses.

At the beginning of May, SinoVac published a paper describing pre-clinical studies in which their vaccine induced SARS-CoV-2-specific antibodies in mice, rats, and non-human primates.   Then, in early June they posted initial results of a Phase 1/2 trial in several hundred human subjects, 90% of whom developed protective antibodies after being inoculated with the vaccine.   They are now starting on a Phase 3 trial, which will be conducted in Brazil.   At the same time, they are preparing a manufacturing facility which can produce 100 million doses of the vaccine annually.

Bacillus Calmette-Guérin (BCG) and SARS-CoV-2

The BCG vaccine has been used worldwide to protect humans from infection from many strains of tuberculosis, which, according to WHO, infected about 10 million people in 2018 and killed 1.5 million.   Can it also be effective, at least to some degree, against the coronavirus?   This vaccine, almost 100 years old, is highly effective in preventing some of the most severe forms of tuberculosis, such as TB meningitis in children.   In several countries with high rates of TB, a dose of BCG is given to babies shortly after birth.   

The BCG vaccine does not specifically target SARS-CoV-2, but it has been shown to boost levels of immunity in general.   It is currently being tested in Phase 3 trials, in 10,000 frontline health workers in Australia, and in 1,500 health workers in the Netherlands.

Inovio’s DNA vaccine, INO-4800

A DNA vaccine would work by injecting a fragment of DNA (a plasmid), which codes the cell for SARS-CoV-2, into human cells.   These cells then would prompt the host’s immune system to produce antibodies which would then lead the battle against the invading virus.   DNA vaccines would be a new technology.   But at present no DNA vaccines have ever been brought into play.   And in four decades of existence, Inovio (INO) has yet to bring a single product to market.

Doc Gumshoe described the status of Inovio’s vaccine candidate in some detail back in March.   At that point, I was somewhat skeptical, and I am still somewhat skeptical, even though a couple of months after that, in May, Inovio published trial results claiming that its candidate demonstrated robust binding and neutralizing antibodies in mice and guinea pigs.   On June 30, Inovio announced interim results of a Phase 1 trial in 40 healthy volunteers, showing that six weeks after two doses of their vaccine, 94% of the subjects demonstrated overall immune responses.   The magnitude of the immune responses was left unstated.   

Sanofi Pasteur’s engineered viral protein approach

This tactic consists of splicing DNA that codes for proteins in the vaccine into different non-infective viruses, so that the resulting virus particle would stimulate the immune system to generate antibodies against the infective virus.   This approach has been used successfully in the HPV vaccine, and Sanofi Pasteur has used it to produce a flu vaccine, which has been licensed in the US for about three years under the name FluBlok.   Sanofi developed an experimental vaccine for SARS, and their candidate vaccine for SARS-CoV-2 is a modification of that vaccine.

Sanofi has announced that Phase 1/2 trials will get going in September of this year, and also that Phase 3 trials could begin by December.   They expect to have 100 million doses of the vaccine ready by the end of the year.   And they hope, if trial results are positive, to have one billion doses manufactured in 2021.  

Might the polio vaccine prevent the most severe SARS-CoV-2 infections?

The polio vaccine is surely one of the miracles of modern medicine.   Prior to the discovery of this vaccine by Dr Jonas Salk, poliomyelitis was a serious threat, particularly to young people.   For example, in 1952, there were 58,000 new cases of polio and 3,000 fatalities.   Then, on March 20, 1953, Dr Salk announced that he had developed an effective vaccine against polio.   From that point on, the rate of polio infections and deaths in the US and the developed world plummeted to the point where the disease can be said to be wiped out.   According to WHO, polio cases have decreased globally from 350,000 in 1988 to 33 in 2018.   The very few cases that occur mostly originate in less developed parts of the world, where polio does continue to be a problem.

Dr Salk’s vaccine was an injected form.   It was the vaccine that largely eliminated polio as a concern in the more developed parts of the planet.   However, in 1962 Dr Albert Sabin introduced an oral polio vaccine, which is the form currently used in those parts of the world where polio is still a threat.   It is this form of the vaccine that may be useful in at least mitigating the effects of the coronavirus infection.            

The thinking is that the oral polio vaccine will trigger a heightened general immune response to any invading organism, including the dangerous coronavirus.   Following the initial response, which is part of the innate immune system, the immune system will then trigger the development of antibodies specific to SARS-CoV-2.   That initial response is temporary, but it could offer protection against invaders which the polio vaccine was not initially designed to attack.   In a sense, what using the oral polio vaccine would do is buy time, during which the innate immune system would at least slow down the virus while the acquired immune system was ramping up.

Experts acknowledge that there is some small risk of using the oral vaccine.   In a very small number of immunocompromised individuals, it has been found to generate circulating vaccine-derived polioviruses.   On balance, if it shown to be effective in mitigating the coronavirus infection, the benefit from using the oral vaccine would outweigh the harm.

Mistrust of “warp-speed” vaccine development may prolong the pandemic

Developing an effective vaccine is a step towards arriving at herd immunity.   But to get to the finish line, where herd immunity stops the pandemic, a significant majority of the population has to be vaccinated.   Recent polls have reported that a growing number of people are responding that they would not be vaccinated against COVID-19 when a vaccine became available.   Anti-vaccine sentiment has apparently grown greatly since the news about possible COVID-19 vaccines emphasized the “warp-speed” plan.   Many people apparently mistrust the reliability of a vaccine that would be developed, tested, and put into service in such a short span of time.   Persons who acknowledge having been vaccinated for such diseases as influenza, shingles, and pneumonia nonetheless have stated that they are not willing to be vaccinated against COVID-19 when such a vaccine becomes available.   But, of course, widespread vaccine refusal would leave big holes in the herd immunity wall, through which the pandemic would continue to spread.    

Another treatment that shows promise – maybe

This one is a drug based on interferon β, which is a cytokine naturally produced by the body to coordinate the response to viruses.   Scientists have found that one of the insidious characteristics of the coronavirus is that it blocks the natural interferon response, disarming cells that would otherwise be signaling neighboring cells to activate their own cells against the invading virus.   However, giving patients interferon as a means of combating an infection has been problematic, since the symptoms of seasonal flu (for example) are caused by mobilizing the body’s interferon response.   This is similar to the “third phase” of the coronavirus infection, when the patient’s own immune response is the source of the virus’s ill effects.

A British drug company, Synairgen, has tried to circumvent that problem by developing an inhaled form of interferon β which would bypass the adverse effects of an interferon β injection.   In a small double-blind trial in patients already hospitalized with COVID-19, the inhaled interferon β was able to reduce the likelihood of these hospitalized patients becoming severely ill by 79%.   The significance of this trial was limited by the small number of patients – only 101 – thus making it impossible to rule out the possibility that the effect was the product of chance.   It was also noted that the outcomes reported were only over a period of two weeks.   Nonetheless, the reported results are definitely hopeful.  

Aerosols as a medium for the transmission of the coronavirus

The World Health Organization has steadfastly maintained that the principal mode of transmission of SARS-CoV-2 is large droplets emitted by infected persons, mostly when sneezing or coughing.   These droplets, more than five microns in diameter (about the diameter of a red blood cell), are heavier than air and typically fall to the ground in about six feet.   That’s the rationale for keeping at least six feet distance from other people.   Aerosols, on the other hand, are also droplets, but they are less than five microns in diameter, and they can remain suspended in the air for as long as three hours.    

Just a few days ago, a group of 239 scientists in 32 nations sent an open letter to WHO stating their position: that, indeed, the coronavirus can be transmitted via aerosols, which are carried in the breath emitted by infected individuals, even when they are only talking, singing, or even breathing.   This would pose a threat primarily in smaller, enclosed spaces with stagnant air.   However, transmission by aerosols could take place wherever an infected individual was in the same space as other persons, or in a crowded space of any kind, and one infected individual could spread the coronavirus to several other persons.   This is what would be termed a “superspreader” event, and events of this sort present a major risk as schools, colleges, and places of business and entertainment reopen.

Measures that could prevent, or at least slow, transmission via aerosols would include measures to improve air circulation – more windows open, more outdoor air in air-conditioned spaces.   Ultraviolet light kills the virus, so it may be helpful for some spaces to install UV light sources.   And, of course, we’re safer outdoors in the sun and breeze than we would be in a small, cramped room with little air circulation.

The settings that would most tend to favor transmission by aerosols would likely be smaller, with less air circulation, and no sunlight.   This describes such settings as examining rooms in health-care settings, prison cells, the living arrangements of low income people in cities, and the rooms of some nursing home residents.   Those, not surprisingly, are the settings in which the highest infection rates have been recorded.

It is not known at this time the quantity of virus that is necessary to cause an infection.   It’s intuitively reasonable that a large infectious dose is likely to cause a more severe infection, and that, at the same time, there is also minimum viral dose, below which no infection will occur.   Since the large droplets spewed forth by a cough or a sneeze presumably carry more virus that the much smaller aerosol particles, it might also be intuitively reasonable that the droplets will lead to more severe infections than aerosols.   However, at the moment, the experts who wrote to WHO with the warning that the virus could be conveyed via aerosols are not making that assumption.   They are warning that the danger of infection by aerosols is real and that all possible precautions against such spread should be taken.      

It should be pointed out that many infectious disease and virology experts are in disagreement with WHO on other matters concerning coronavirus transmission.   WHO continues to emphasize transmission from surfaces, while many experts put this form of transmission at the bottom of the list of likely sources of infection.   In early April, a group of 36 experts on air quality and aerosols met with WHO to discuss the likelihood of aerosol transmission, but the discussion was dominated by other experts who were staunch proponents of hand-washing and decontamination of surfaces, and felt that those should be emphasized over aerial transmission.

It is not unusual, of course, for experts to disagree.   Rather than take sides, I vote to accord each side considerably more than a grain of truth.   You are right, and you are right also.

Gilead sets a fairly reasonable price for remdesivir

On June 29^th, Gilead ended speculation on what it would charge for remdesivir.   The figure is surprisingly low.   Gilead will charge all governments in the developed world $2,340 for a five-day course of the drug.   US insurers, including Medicare and Medicaid, will be charged 33% more, bringing the cost for a five-day course to $3,120.   In addition to this, countries in the developing world will be able to get the drug at a greatly reduced price, through generic manufacturers to which Gilead has licensed production.

Although from the perspective of a COVID-19 patient, $3,120 is not chicken feed, the price Gilead has set for this drug is a reversal of the usual pharmaceutical practice of pricing a drug to represent the manufacturer’s total investment, including a share of the maker’s total costs for research and development.   Many critics of the pharmaceutical industry characterize such prices as “whatever the market will bear,” and without doubt, prices are set with an eye to the overall market.   The question is whether Gilead, which has been criticized for its high prices for HPV and HIV drugs, will find it difficult to return to its usual pre-COVID practices, and also whether the remdesivir pricing structure will be used by critics of the pharmaceutical industry to hammer down drug prices in general. 

And just a day ago (as I write this) researchers at Vanderbilt and the University of North Carolina together with Gilead reported that remdesivir strongly inhibited the novel coronavirus SARS-CoV-2, which causes COVID-19, in human lung cell cultures and that it also improved lung function in mice infected with that virus.

This kind of laboratory evidence of the mechanism of action through which remdesivir acts to support the health of persons infected with COVID-19 is an important step in understanding the way the drug could best be used in human patients.

* * * * * * *

As you see, this pandemic, along with being a constant nagging worry to all of us, is also a constant source of news.   Doc Gumshoe tries to keep at least one eye on what’s going on in the health-care field in general, while the other eye stays firmly focused on COVID-19.   Could this effort make me cross-eyed?   I hope not!   But I will continue to pay attention to the going-on in health-care beyond COVID-19 and report it to the faithful on Planet Gumshoe.   And please know that I am grateful for all comments.   Be well and stay well, 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.]