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 1st. 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 1st, IHME projected that the fatality rate in the US would reach 72,500 by August 1st. 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 25th. 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 1st?
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.
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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.