Yes, in the midst of a severe global surge in new cases and deaths, there are several genuinely good news items that we can pin our hopes on. Surely, you are aware of some of these, but I will attempt to put them in context.
As of yesterday, from the start of pandemic to the present, the number of total cases is 67,217,934, and the global mortality figure is 1,538,535. In the US, total cases number 14,769,353 and total deaths number 282,375. Globally, that’s a mortality rate of 2.32%, while the US mortality rate is a tiny bit lower at 1.98%. All of those numbers are inexact, of course – there are surely many, many more total cases, since not every single person with COVID-19 gets tested, either in the US or globally. But we have to go with something, and those figures are quite well substantiated. That difference between global and US mortality rate, about one-third of a percentage point, may not seem like much, but if the US mortality rate had been the same as the global mortality rate, we would have seen an additional forty thousand deaths or so.
The epidemiologists and infectious disease specialists have been unanimously grim in their warnings that there would be an uptick in cases after Thanksgiving, partly because Thanksgiving tends to be an occasion for large gatherings, and also because as the weather gets colder, more people will congregate indoors. My scrupulously careful spouse and I have had several excellent outdoor dinners, just the two of us, most recently about four weeks ago. Around here, many restaurants have created outdoor dining areas heated by propane heaters, but the season for that appears to be over. We will not be going to restaurants indoors, but lots of people are more willing to take risks. So, inevitably, there will be more COVID-19 cases and, sadly, more deaths.
In spite of that significant increase in cases and deaths, the past few weeks have seen a number of optimistic developments. The news about the Pfizer and Moderna vaccines has made the front pages, and there has been considerable discussion of the AstraZeneca/Oxford vaccine candidate. But there has also been news, received with measured optimism by Doc Gumshoe, having to do with ways of treating COVID-19 patients, which, while far from amounting to a cure, do seem to alleviate symptoms and prevent patients from experiencing the most severe forms of the infection.
And, besides those two definitely favorable news items, data have emerged that in persons who have recovered from the coronavirus infection, immunity persists much longer than had been previously thought, based on the waning of the antibody response. That is, although antibodies to the virus only last for a few months, the other mediators of immunity are able to recognize the virus and mount an immune response for years after the infection has cleared.
All of these developments bode well for hopes for an eventual end to the pandemic. At this point, no expert is predicting when this end will finally occur. The optimistic forecast seems to be “sometime next year.”
So let’s take a closer look at some of these developments.
What’s the scoop on vaccine development?
In the most recent Doc Gumshoe piece about COVID-19, I put in a late-breaking bit of news, namely that Pfizer had announced that its vaccine (with BioNTech) had attained an efficacy level of about 90%, which was considerably higher than anything that had been anticipated. That was about three weeks ago, a long time in the fast-breaking news world of COVID. The current news about the Pfizer/ BioNTech vaccine is even better.
Pfizer’s study enrolled 43,661 volunteers, approximately half of whom were given two doses of the vaccine three weeks apart. The other half were given placebo injections. There were a total of 170 cases of COVID-19 in the trial, of which 162 occurred in the placebo group, while in the group that received the two-dose vaccine there were 8 cases of COVID-19. The simple arithmetic tells us that, of the volunteers who became infected, just fewer than 5% were in the cohort that had received the vaccine. This produces an efficacy level of 95%. Another positive finding was that there were 10 cases of severe COVID-19 overall, but 9 of them were in the placebo group – only one severe case in the entire group that was vaccinated.
Data on side effects were also highly positive. These data were tracked in an 8,000 patient portion of the study. Only two severe side effects were observed in more than 2% of the subjects: fatigue, which occurred in 3.7%, and headache, which occurred in 2%. Older subjects had fewer and milder side effects than younger participants. Approximately 19,000 study subjects were followed for at least two months after the second dose of the vaccine.
The Pfizer study was able to report results much sooner than had been anticipated. That’s because of the sharp increase in the rate at which people were being infected with the coronavirus. Under certain circumstances in vaccine trials it is possible to vaccinate the subjects and then deliberately inoculate them with the pathogen that the vaccine is supposed to protect them from. This is possible only when there is a reliable way of treating the infected subjects. Obviously, this would not have been possible with SARS-CoV-2. Therefore the only course was to vaccinate the subjects and then wait and see who got infected. The rapid increase in new cases meant that meaningful results were available fairly quickly.
The results from the Moderna vaccine study came in a couple of weeks later and were quite similar to those in the Pfizer vaccine. The study of the Moderna vaccine, also a two-dose vaccine, enrolled more than 30,000 volunteers, half of whom got the vaccine while the other half got placebo. Of this total, 196 developed symptomatic cases of COVID-19. And, as in the Pfizer study, the great majority of the cases of COVID-19 occurred in the subjects who received the placebo, which was given to half the volunteers. Only 11 cases were seen in the subjects who received the actual vaccine, while 185 cases were in the placebo group. This translates to an efficacy level of about 94.1%. As with the Pfizer vaccine, the Moderna vaccine appears to be especially effective in preventing severe cases of COVID-19. There were 30 cases of severe COVID-19 in the subjects receiving placebo, but none at all in those who had the actual vaccine.
Safety data are continuing to be examined; however, there appear to be no serious safety issues. The most common adverse events included site pain, fatigue, muscle or bone pain, headaches, and redness at the injection site. These reactions were somewhat more serious in the vaccine group after patients received a second dose.
Both Pfizer’s and Moderna’s vaccines use messenger RNA, injected 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 body’s process of developing an acquired immune response.
Pfizer applied to the FDA for Emergency Use Authorization (EUA) for its vaccine on November 20. Moderna applied for EUA on November 30. Both applications are scheduled to be evaluated by the FDA’s Vaccines and Related Biological Products Advisory Committee in mid-December. Thus it is likely that some persons will be vaccinated before the end of the year.
The AstraZeneca/Oxford vaccine results – positive but puzzling
AstraZeneca and the University of Oxford announced some results of a trial of their vaccine candidate on November 23. On balance, the results were positive. In the study overall, the efficacy of the vaccine was calculated at about 70%. As with the Pfizer and Moderna vaccines, the AZ-Oxford vaccine is delivered in two doses given a month apart. However, in a subset of the study population – 2,741 subjects out of the total 11,363 – the first dose of the vaccine that they received was half of the full dose. This was followed by the full dose a month later. In this subset of the population, the efficacy was calculated at 90%, while in the remaining subset that received two full doses, the efficacy was only 62%. The 70% efficacy figure is an average of the 62% and 90% efficacy of the two dosing regimens.
An immunologist at Oxford’s Jenner Institute suggests that lower doses of vaccine might do a better job at stimulating the subset of immune cells called T-cells that support the production of antibodies. This is borne out by Hildegund Ertl, a viral immunologist at the Wistar Institute in Philadelphia. She says the results make sense in the light of some of her work on adenovirus vaccines in mice. She, too, has found that for a two-dose vaccine, a low first dose can lead to better protection than a high first dose. She thinks this is because a lower first dose leads more quickly to the establishment of memory immune cells that are triggered by a second-dose boost.
The AZ-Oxford vaccine is made from an adenovirus that is isolated from the stool of chimpanzees and modified so that it stops replicating, The adenovirus has been engineered to instruct human cells to produce the spike protein of the coronavirus, SARS-CoV-2, which then alerts the immune system of the human subject to recognize and attack the coronavirus itself, should it invade the subject. Trials of the AZ-Oxford vaccine are continuing in the US, South Africa, Japan and Russia.
The AZ-Oxford vaccine has some advantages over the Pfizer and Moderna vaccines. It can be stored at normal refrigeration temperatures for up to six months, which will make it easier to deploy in more settings than the ones from Pfizer and Moderna. These must be stored at ultra-low temperatures – the Pfizer vaccine at minus 94 degrees Fahrenheit, while the Moderna must be stored at minus 4 F. Once thawed, however, Moderna’s vaccine can be stored under normal refrigeration for a month.
Efficacy and effectiveness are not the same thing
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What we want the COVID-19 vaccines to accomplish is two-fold. Yes, we individually want to be protected from the coronavirus. But, at least equally important and possibly more important, we want the vaccines to be effective in putting an end to the pandemic. If I were to be vaccinated with one of those vaccines that are 95% efficacious, I would still have a one out of twenty chance of becoming infected with the coronavirus – unless, of course, a sufficient fraction of the population at large was also vaccinated. In that case, the number of people who could transmit the infection to me would be greatly diminished, and my chances of becoming infected would shrink a great deal.
For that to happen, the burden falls not on science but on logistics. Billions of doses of the vaccines will need to be manufactured, transported, stored, and administered to billions of people all over the world. And people need to be willing to accept vaccination. When the first reports of possible vaccines began to emerge, and when it was publicly stated that the FDA would consider efficacy figures as low as 50% possibly enough to gain approval, a great many people – perhaps about half of those surveyed – indicated that they would be reluctant to be vaccinated. The improved efficacy figures recently announced would probably increase the proportion of people willing to be vaccinated. But as you know, there are a great many anti-vaxxers in our midst. So the task ahead of us is far from easy.
Medical treatment options for persons with COVID-19
The absence of a cure for COVID-19 does not mean that there are no beneficial forms of treatment. In fact, a person who is infected with the coronavirus and develops symptoms has a pretty good chance of surviving the disease. In the US, as you read in the opening of this piece, the mortality rate is just under 2%. That mortality rate has improved significantly since the coronavirus started on its rampage this past March. That is probably because researchers and health-care workers have come up with a number of distinctly helpful treatment options.
One: a monoclonal antibody
In the first few days of November, Eli Lilly’s bamlanivimab became the first monoclonal antibody (mAb) to receive EUA from the FDA for the treatment of COVID-19 patients. Bamlanivimab is a recombinant monoclonal antibody targeting the SARS-CoV-2 spike protein. The drug is authorized for the treatment of mild-to-moderate COVID-19 in adult patients and in pediatric patients weighting at least 88 pounds. To be eligible, patients should be considered to be at risk of progressing to severe disease. However, the FDA stressed that bamlanivimab should not be given to patients who are already hospitalized or who require oxygen therapy. Lilly had a clinical trial going in this population and paused the clinical trial due to worse clinical outcomes in that cohort. The U. S. Department on Health and Human Services has contracted to buy 300,000 doses immediately and has an option to buy an additional 650,000 doses.
The FDA authorization was based on an interim analysis of a phase 2 trial in 465 non-hospitalized adults with COVID-19 symptoms, in which patients were randomized to 700, 2,800 or 7,000 mg of bamlanivimab or placebo within 3 days of testing positive for SARS-CoV-2. Effects on viral load, hospital visits and safety were similar in all three drug doses of the therapy, the agency said.
The FDA said it was particularly impressed with bamlanivimab’s effectiveness for the secondary endpoint of COVID-19 hospitalizations or emergency room visits within 28 days after treatment (3% in patients receiving the drug versus 10% in those getting the placebo). The primary endpoint was change in viral load from baseline to day 11, with most patients, including those in the placebo group, clearing the virus within that timeframe.
Two: a combination drug
Another promising treatment option employs a janus kinase (JAK) inhibitor in combination with remdesivir (Veklury, from Gilead), which was about the first drug that was thought to be useful in treating COVID-19. The JAK inhibitor, baracitinib (Olumiant, from Eli Lilly), was approved for the treatment of rheumatoid arthritis in 2018. Remdesivir has been approved for the treatment of hospitalized adults with COVID-19 and for the treatment of children with suspected or confirmed COVID-19. The combination of baracitinib and remdesivir received emergency use authorization by the FDA on November 18. The combination addresses an inflammatory response (the notorious “cytokine storm”) of the immune system that can overwhelm patients with COVID-19. I need to point out that as of November 20, the World Health Organization recommended against the use of remdesivir in COVID-19 patients, not on the grounds that it did any harm, but simply lack of sufficient evidence that it provided benefit.
FDA approval of the remdesivir-baracitinib combination was based on a clinical trial conducted by the National Institute of Allergy and Infectious Disease. The trial enrolled 1,033 subjects with moderate or severe COVID-19, 515 of whom received the combination drug and 518 received placebo with remdesivir. The patients on the combination recovered about one day earlier than the control group, and the odds of death or requiring ventilation were lower in the combination group. Odds of clinical improvement at day 15 were higher in patients receiving the combination drug than in those receiving the placebo combination.
Another trial of the remdesivir-baracitinib is underway. In this trial, the control arm will receive a combination of remdesivir and dexamethasone. Dexamethasone, which also targets the inflammatory response, was discussed fairly extensively in a previous Doc Gumshoe, which posted August 3.
Three: a selective serotonin reuptake inhibitor (SSRI)
One more drug that has demonstrated some effectiveness in treating COVID-19 is fluvoxamine, a well-known SSRI, originally marketed under the name Luvox. Fluvoxamine is widely used as an antidepressant and as a drug to relieve the symptoms of obsessive-compulsive disorder. A key mechanism of fluvoxamine is its high affinity for a protein that regulates cytokine production. As we have learned, the so-called “cytokine storm” is one of the ways in which infection with the coronavirus leads to severe harm in COVID-19 patients. Fluvoxamine has been shown to decrease the ill-effects of excessive cytokine release in mice.
A clinical trial was conducted in the St Louis area from April 10 to Augus