Where Are We in the COVID-19 Pandemic? – March 2021

Four, maybe Five Vaccines, Treatment and Herd Immunity news, and other COVID updates

By Michael Jorrin, "Doc Gumshoe", March 1, 2021

This piece was going to be titled “COVID Continued.” Then I thought, “what a depressing title. Nobody wants to read about the continuation of the pandemic. A much more attractive title would be “COVID Terminated.” That’s the headline we want to see. Or, better, that’s the headline we want to believe.

How close are we to the point where such a headline would be somewhere close to accurate? Dr Fauci has said that in the US the pandemic will likely have diminished to the point of no longer being a major concern sometime before the end of this year. That will, of course, depend of how many people have been vaccinated, as well as how many people have become infected and recovered, with some degree of immunity.

In an online talk Dr Fauci gave, sponsored by the Harvard T. H. Chan School of Public Health and the New England Journal of Medicine, Dr Fauci said, “Let’s say we get 75%, 80% of the population vaccinated. If we do that, if we do it efficiently enough over the second quarter of 2021, by the time we get to the end of the summer, i.e., the third quarter, we may actually have enough herd immunity protecting our society that as we get to the end of 2021, we can approach very much some degree of normality that is close to where we were before.”

Dr Fauci’s calculation omits the part of herd immunity that results from the percentage of the population that has been infected with the coronavirus and recovered, thereby acquiring a degree of immunity. Robust evidence is now emerging that a person who was infected with SARS-CoV-2 almost a year ago still has antibodies to the virus and thus has some immunity, without even taking into account the other immune agents such as T-cells and memory B-cells. At the present rate at which new cases are being reported, it is likely that about 40 million persons in the US will have been infected by the end of third quarter – more than 10% of the total population.

Adding that 10% to the percentage of the population (about 70%) that has expressed willingness – and actually desire – to be vaccinated and we come close to the percentage of the total population with some degree of immunity that is needed to achieve herd immunity. There is a bit of overlap in those two percentiles; perhaps about 10% of people in that 70% of the population are likely to be COVID-19 survivors. But if vaccination proceeds according to plan, we’ll surely get close to herd immunity before the end of the year.

So, first let’s see what’s happening on the vaccine front.

The World Health Organization formally authorizes the AstraZeneca vaccine

That announcement came on Monday, February 14th. It may not be hugely significant to those of us who live in the more prosperous and developed parts of the planet, but it is likely to make a major difference in the trajectory of the disease in the less-developed parts. That is because the AstraZeneca vaccine, developed in collaboration with the University of Oxford in the UK, is less expensive than other vaccines and does not require the kind of extreme and expensive refrigeration that is necessary for the Pfizer vaccine in particular. That vaccine is manufactured by AstraZeneca and also by The Serum Institute, a drug manufacturer in India that will likely supply much of the vaccine to be used in the poorer parts of the world.

The efficacy of the AstraZeneca vaccine varies to some degree depending on the coronavirus variant that is prevalent in the clinical trial cohort. Data from Oxford show that the efficacy of the vaccine against non-variant strains was 84%. Against the B.1.1.7 strain of the coronavirus that has become the dominant strain in the UK, efficacy after two doses of the Oxford-AstraZeneca vaccine was 74.9%.

The B.1.351 variant, which was first identified in Nelson Mandela Bay, South Africa in October 2020, is now becoming a predominant strain in several countries in Southern Africa, and some cases have since been detected outside of that region. A small clinical trial in South Africa recently failed to show that the AstraZeneca/Oxford vaccine could keep people from being infected with the coronavirus and getting mild cases of COVID-19 caused by that B.1.351 variant. However, in other trials, that same vaccine had protected all participants against severe disease and death and may yet prevent severe disease and death caused by the variant first detected in South Africa.

The AstraZeneca trials reported another interesting – although somewhat puzzling – result. Volunteers in the trial were asked to swirl a swab inside their nostrils every week during the trial to test for signs of infection, using the polymerase chain reaction test to detect the virus. This was the only instance of a vaccine study in which that step was a part of the protocol. The results were a bit contradictory.

What they found was that a single dose of the vaccine cut positive test results by two-thirds (67%). But after two doses, the positive results did not decline further. In fact, they increased to 49.5%. How could one dose be more effective than two doses?

The study authors do not venture an answer to that question. However, this particular finding reminds me of the finding back in November last year that there was a considerable difference in the efficacies of two different dosing regimens of the AstraZeneca vaccine. As with the Pfizer and Moderna vaccines, the AstraZeneca vaccine is delivered in two doses given about a month apart. However, in a subset of the study population – 2,741 subjects out of a total of 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 study population, the efficacy was calculated at 90%, while in the remaining subset that received two full doses, the efficacy was only 62%. An immunologist at Oxford’s Jenner Institute suggests that the lower doses of vaccine might do a better job of stimulating the production of T cells and thus boosting the immune response.

However, the general conclusion is reasonably robust. Whether the single-dose or the two-dose data are to be relied on, we can conclude that the vaccine not only reduces severe disease and death by large margins, but that the vaccine also reduces transmission. Some authorities have questioned that conclusion, pointing out that the trial demonstrated only a reduction in virus-shedding (which is the term for sneezing, spitting, or breathing out virus particles) and not a reduction in transmission. But a logical person would conclude that if there were a significant reduction in virus shedding, which the trial appeared to demonstrate at least to some degree, then there would be a concomitant reduction in transmission. Unless some virus is being shed or expelled, the likelihood of transmission is tiny.

A finding that might seem puzzling is that, even though the overall efficacy of the AstraZeneca vaccine does not come near the efficacy of the Pfizer or Moderna vaccines, the AstraZeneca vaccine is highly effective in preventing the most severe consequences of infection. In several trials, there have been very few cases requiring hospitalization or intubation, and no fatalities. Trial subjects have become infected, and in some cases developed mild or moderate cases of COVID-19. But the vaccines (and this is not limited to the AstraZeneca vaccine) have induced immunity such that the subjects were able to fight off the worst consequences of the virus – perhaps not the immediate rejection that might be the result of a quick attack on the virus by autoantibodies, but an effective delayed response by other agents of the subjects immune system.

The AstraZeneca/Oxford vaccine uses an adenovirus – the chimpanzee adenovirus Oxford 1 (ChAdOx1) as a vector for the genetic information of SARS-CoV-2. 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, and when used in a vaccine given to a human subject, they can trigger the same immune response as the coronavirus itself.

Positive results reported in a trial of the Johnson & Johnson vaccine

The Johnson & Johnson vaccine also uses a neutralized adenovirus, which delivers DNA containing instructions for the SARS-CoV-2 spike protein into the body. That causes the body to produce that same spike protein and generates the immune response that protects against the coronavirus. On Friday, February 12, J & J reported successful results of its Phase 3 clinical trial of a vaccine developed in the lab of Harvard Medical School Professor Dan Barouch at Beth Israel Deaconess Medical Center. 

The J & J vaccine is a one-dose vaccine and can be stored at higher temperatures than the Pfizer or Moderna vaccines, greatly reducing some of the logistical obstacles to widespread vaccination.

J & J announced that the trial demonstrated strong protection against severe disease, hospitalization, and death from COVID-19. Overall efficacy was somewhat less robust. It was reported by J & J that 28 days after vaccination, the vaccine protected against moderate-to-severe COVID-19 with 72% efficacy in the US, 66% efficacy in Latin America, and 57% efficacy in South Africa, where the B.1.351 strain, which is more transmissible and has shown some ability to escape the immune response, has become the dominant train.

However, the J & J vaccine’s protection against severe disease and death was much stronger. At 28 days after the single shot, the vaccine conferred 85% protection against severe disease in all regions where it was tested. This degree of protection rose to 100% by 49 days after the single shot. It also demonstrated complete protection against hospitalization and death at 28 days and no allergic reactions in those who received it.
Dr Barouch, in whose laboratory the J & J vaccine originated, was asked about the prospect that J & J would offer a two-shot version of the vaccine, and whether it would be more effective than the one-shot version. His answer was as follows:

“The results reported today are the results from a single-shot trial. We have a second Phase 3 study that’s ongoing, it’s currently still enrolling, and it’s a two-shot version of the vaccine. So the question is: Will the two-shot version of the vaccine be better than the current single-shot vaccine? We know that a single-shot vaccine has enormous practical and logistic advantages. I mean, who wouldn’t rather have a once-and-done vaccine than one where you have to go back for a booster shot three or four weeks later? But we also know that a second shot of this vaccine can substantially increase the antibody responses by at least three- to fourfold. And so it is very likely that a two-dose version of this vaccine will have higher efficacy. And quite honestly, we’ll just have to look at the numbers when they come out. If it’s a marginal increase, then the one-shot vaccine is the way to go because of its convenience. If the two-shot vaccine really has a substantial increase in efficacy, then it will really be dealer’s choice. And some people might prefer to get a two-shot version or some people might prefer to get a one-shot version.”

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Dr Barouch was also asked whether the J & J vaccine could be modified in such a way as to be equally effective against the variant strains of the coronavirus. His answer was:

“Nucleic-acid vaccines, including the RNA vaccines as well as the vector vaccines, are particularly well-suited for revision over time. All you need to do is make a tweak of the genetic sequence of the insert. It’s a relatively straightforward process to remanufacture the vaccine with those circumstances. So does it take effort? Yes, but it certainly will be much easier to revise the vaccines than to develop them initially.”

Dr Barouch’s answer applies not only to the J & J vaccine, but also to the AstraZeneca vaccine (a vector vaccine) and to the Pfizer and Moderna vaccines, which are RNA vaccines. If I may venture an opinion, this is excellent news!

And on February 27th, the FDA granted emergency use authorization to the J & J vaccine.

What about the Russian vaccine, cunningly named “Sputnik V”?

The “V” stands for “vaccine,” not for the fifth iteration of the space capsule. Back in August last year, Vladimir Putin announced in a cabinet meeting that Russia had granted approval to this vaccine, which had been developed from scratch in about five months. At that time, the results of the Phase 1 and Phase 2 clinical trials had not been published, and the Phase 3 trial wasn’t yet underway. Putin also casually dropped a mention that his own daughter had been vaccinated with Sputnik V, had had a couple of days of mild side effects and then went back to feeling just fine. The development of this vaccine fits right in with Russia’s proud boast that they had launched the first space satellite. Now they claimed to have succeeded in the development of the first vaccine against the coronavirus that causes COVID-19.

Sputnik V was developed at the Gamayela Research Institute of Epidemiology and Microbiology in Moscow, starting from scratch in February 2020. Previously, Gamayela had produced vaccines for Ebola and MERS. However, neither of these vaccines were ever approved for use anywhere but in Russia. There were many questions about these two vaccines. For example, doses of the Ebola vaccine were sent to Guinea for a planned Phase 3 trial which never took place, because by the time the vaccine got to Guinea for the planned trial, there were not enough new Ebola cases to conduct the trial, so the actual efficacy of that vaccine was never reliably verified. The MERS vaccine also never reached a Phase 3 trial.

Questions immediately arose whether Sputnik V was really a bona fide vaccine, or the result of a “pedal-to-the-metal” and therefore probably unreliable scientific research. The director of the Gamaleya Institute has asserted that Sputnik V was about 90% effective. The basis for his assertion is that the vaccine triggers the production of antibodies in persons who have been vaccinated. This assertion has also been questioned, since some vaccines, including a prospective HIV vaccine, can result in the generation of antibodies, but without conferring immunity to the invading virus.

As with the AstraZeneca/Oxford and Johnson & Johnson, Sputnik V is a vector vaccine. It employs two different strains of the adenovirus. For the first dose, it uses the same strain as the J & J vaccine, and for the second dose, it employs a more common adenovirus strain. The purpose of using different adenovirus strains is to lessen the chance that the recipient of the vaccine might develop immunity to the adenovirus rather than to the coronavirus.

An overall comment: if four effective vaccines – and possibly five, if Sputnik V is really effective! – against a brand-new virus can be developed and put to use in a year’s time, we can conclude that medical science is working pretty well.

Fortunately, SARS-CoV-2 does not mutate as fast as the flu virus

As it happens, the coronavirus has an enzyme that is able to correct some of the random errors that are made as the virus replicates. These random errors in transcription could be characterized as “typos.” The great majority of these errors make no difference whatever. Some are detrimental to the survival of the virus. A few are helpful to the survival of the virus. Those are the mutations that result in harm to the host that has been invaded by the virus.

The enzyme I mentioned acts as a sort of spellcheck. It can correct some of those typos; i.e., it can prevent some of those mutations. As a result, it has a lower mutation rate than some other RNA viruses such as the influenza virus.

Also, the genome of the coronavirus is not segmented. It is a single piece of RNA. Influenza, on the other hand, has a segmented genome, such that if a person happens to get infected with two different influenza virus particles, those genome segments can get shuffled together in unpredictable ways. That allows new variants to emerge very quickly.

That does not happen with coronaviruses. However, because there has been so much transmission of the coronavirus that causes COVID-19, it has had many opportunities to replicate. Still, it does not mutate as fast as the flu virus.

Children who have had the flu vaccine have milder COVID-19 symptoms

Doc Gumshoe alluded to this in a previous piece, but now there is confirmation. Researchers at the University of Missouri School of Medicine reviewed the medical records of 905 pediatric patients diagnosed with COVID-19 between February and August last year. COVID-19 positive children who had received the flu vaccine in the current season had about 51% lower odds of experiencing symptoms, respiratory problems, or severe disease (P = 0.010). The same relationship was found in children who had had the pneumococcal vaccine. (Padwardhan A. Cureus. Jan 13(1):e12533)

Dr Anjali Padwardhan, professor of pediatric rheumatology and child health observed that “It is known that the growth of one virus can be inhibited by a previous viral infection. This phenomenon is called virus interference, and it can occur even when the first virus invader is an inactivated virus, such as the case with the flu vaccine.”

A drug used to treat RA has some benefit it preventing COVID-19 mortality

Tocilizumab (Actemra, from Roche) in combination with dexamethasone has been reported to reduce mortality by about one-third for COVID-19 patients requiring oxygen and by almost one-half for patients requiring a ventilator. This is based on results from the RECOVERY (Randomised Evaluation of COVID-19 Therapy) trial in the UK, which was established in March, 2020, to investigate treatments for COVID-19. The trial has previously shown that hydroxychloroquine, lopinavir-ritonavir, azithromycin and convalescent plasma have no benefits for patients hospitalized with COVID-19. The trial is currently investigating aspirin, anti-inflammatory drugs baricitinib and colchicine as well as Regeneron’s antibody cocktail.

Tocilizumab is one of a class of drugs called monoclonal antibodies (mAbs). It is an inhibitor of interleukin-6 (IL-6) which can trigger an inflammatory response that contributes to rheumatoid arthritis (RA). It is widely used in the treatment of RA.

In the RECOVERY trial, 2,022 hospitalized patients were randomly selected to receive tocilizumab and were compared with 2,094 patients randomly selected to receive standard care alone. The researchers said 82% of the patients were also taking a steroid such as dexamethasone. It was reported that 596 patients in the tocilizumab group died within 28 days compared with 694 patients in the standard care group. According to the authors, that means for every 25 patients treated with tocilizumab, one additional life would be saved.

The drug increased the probability of discharge within 28 days from 47% to 54%, according to the researchers. The benefits were seen in all patients, including those requiring mechanical ventilators in an intensive care unit. Among patients not on a ventilator before entering the trial, tocilizumab reduced the chance of progressing to invasive mechanical ventilation or death from 38% to 33%.

The absolute percentages noted above may not seem like much of a benefit for tocilizumab. The relative percentages are somewhat more encouraging. For example, 47% of hospitalized COVID-19 patients in the cohort that did not receive tocilizumab treatment were released within 28 days, but that percentage went up to 54% in those that did receive tocilizumab. That’s almost a 15% relative increase, not trivial. The relative benefit in terms of the reduction of the chance of mechanical ventilation or death was a bit more than 13%.

As I was writing about tocilizumab/Actemra, the Infectious Disease Society of America (IDSA), a very influential body, has recommended that mAb for the treatment of patients with COVID-19.

What about monoclonal antibodies in general?

Like other monoclonal antibodies, tocilizumab is made by cloning one specific white blood cell and multiplying that cell. Monoclonal antibodies are structured to bind to a specific receptor on an antigen; in the case of tocilizumab, the antigen is interleukin 6, which is involved in the pathology of rheumatoid arthritis. This particular mAb does not specifically target the coronavirus; that it appears to affect the coronavirus is accidental. But it may be possible to construct mAbs that specifically bind to any substance, including SARS-CoV-2.

Some mAbs now being used to treat COVID-19 patients in the US aren’t great at attaching to some of the new SARS-CoV-2 variants. But scientists are betting that the same survival characteristics that nudged the virus to become less susceptible to certain treatments will also guide ongoing development efforts. To be sure, the immunity offered by vaccines will last longer than the temporary virus-fighting boost of monoclonal antibodies, but there could still be an important role for these synthetic copies of potent natural defenses – if scientists can outwit the virus. “The thing we’ve learned is, this will be a cyclical war of attrition with the virus. The virus will change, we’ll come forward with new antibodies,” said Andrew Adams, Chief Scientific Officer at Eli Lilly.

In fact, Eli Lilly’s bamlanivimab was the first mAb to be given emergency use authorization (EUA) in November of 2020. Later than same month, bamlanivimab was followed by a combination of casirivimab and imdevimab from Regeneron. Then on February 9, the FDA granted EUA to Eli Lilly’s bamlanivimab/etesevimab combination product. However, these authorizations are limited to outpatient use in mild-to-moderate cases judged to be at high risk of progressing to severe disease.

And then, on February 23, the NIH’s COVID-19 Treatment Guidelines Panel issued the following statement:

“The Panel recommends the use of bamlanivimab 700 mg plus etesevimab 1,400 mg for the treatment of outpatients with mild to moderate COVID-19 who are at high risk of clinical progression as defined by the EUA criteria. Treatment should be started as soon as possible after the patient has received a positive result on a SARS-CoV-2 antigen or nucleic acid amplification test and within 10 days of symptom onset. …

The Panel recommends against the use of bamlanivimab 700 mg plus etesevimab 1,400 mg for patients who are hospitalized because of COVID-19, except in a clinical trial. However, bamlanivimab 700 mg plus etesevimab 1,400 mg should be considered for persons with mild to moderate COVID-19 who are hospitalized for a reason other than COVID-19 but who otherwise meet the EUA criteria.”

The terms of these authorizations have been criticized as being excessively limited. For example, although these mAbs were specifically not authorized for hospitalized patients or those on oxygen therapy for any underlying comorbidity, they have to be given as one-hour infusions to be followed by one hour of monitoring.

Dr Martin Makary of Johns Hopkins, a frequent commentator on the impact of regulatory decisions, observed that the strict limits on the EUA would likely tend to undermine the capacity to give these drugs in hospitals for cases in which it would make sense to use them. He pointed out that although bamlanivimab failed in patients with severe COVID-19 in the ACTIV-3 trial, the detrimental effects of the drug were seen in ICU patients who were already critically ill.

Dr Makary said, “By excluding any hospitalized patients, we missed out on the opportunity to more broadly give this life-saving therapy to select patients with early COVID disease in a hospital where infusions are far more feasible than scheduling a newly infected patient in an outpatient setting. While it can be given off-label in a hospital, the overly narrow FDA EUA discouraged clinicians from doing so.”

He added that emergency departments may still be able to administer it to patients who are not yet admitted, but the confusion has presented a barrier. “In the ER, that’s where people should have been getting it – people walk in with mild disease all the time.”

That strikes me as one more example of excessive rule-making getting in the way of common sense.

What’s this about colchicine as a treatment for COVID-19?

The information about colchicines and COVID-19 comes from the Montreal Heart Institute, which conducted a study (the COLCORONA trial) in about 4,500 outpatients with COVID-19 who had one or more high-risk features such as fever, diabetes, coronary heart disease, obesity, or respiratory disease. Subjects were assigned either to oral therapy with colchicine or placebo for a period of 30 days.

Most of the findings in the study favored colchicine, but by narrow margins mostly failed to meet the standard for statistical significance. For example, 4.7% of the patients on colchicine died or were hospitalized, compared with 5.8% in the placebo group. Serious adverse events were about 5% in both groups. Overall adverse events were somewhat higher in patients on colchicine than in those taking the placebo, 24% versus 14%.

Colchicine has been around for a long time. In the form of the autumn crocus (whence this drug originated) it has been used as early as 1500 BCE to treat joint swelling. These days it is mostly used to treat gout and Behçet’s disease, although (particularly in the treatment of gout) the drugs of choice would likely be NSAIDs or steroids.
The potential side effects associated with colchicine include GI upset, diarrhea, neutropenia, and with higher doses, damage to bone marrow and anemia. Deaths have resulted from colchicine overdoses.

The Montreal Heart Institute Research Center Director and COLCORONA trial principal investigator Dr Jean-Claude Tardif said: “Our research shows the efficacy of colchicine treatment in preventing the ‘cytokine storm’ phenomenon and reducing the complications associated with C