When it comes to remdesivir, Anthony Fauci has described the drug as bringing “a clear-cut, significant, positive effect in diminishing the time to recovery.” And those results came in a genuine medium-scale, random trial — meaning they’re enormously more important than the kind of observational “we gave it to someone and they got better” anecdotal reports about many potential treatments.
Skies are not entirely blue for the anti-viral. First of all, it’s not clear that remdesivir reduces the fatality of COVID-19. In the study cited by Fauci, 8% of those taking the drug still died, meaning there was no statistically significant improvement over those not taking remdesivir. Also, shortly after Fauci stood up to praise the drug, British medical journal The Lancet published another study from China in which remdesivir “was not associated with a difference in time to clinical improvement” and the trial was stopped early because some patients reported adverse effects and researchers had difficulty getting additional volunteers (Note: This is the same report which was accidentally released in pre-print form, then withdrawn, by the World Health Organization, so if that detail sounds familiar you may really have heard it before).
Why such a difference in the two studies? Well, to start with there was a different in scale. The U.S. trial included giving remdesivir to over 1,000 patients, while the Chinese trial had 158. Also, the Chinese study had limited access to patients at different stages of the disease. Finally, there were differences in how and when the drug was administered, age-ranges of patients … there were a lot of differences. All of this could be settled by the results of a global study being conducted as part of the “Solidarity” trials for COVID-19 treatments arranged by the WHO. But in the meantime, the U.S. results are encouraging enough that the drug, originally developed as a treatment for Ebola, is likely to be widely used, at least in the United States.
Behind remdesivir is another antiviral called leronlimab. The developer of the drug, CytoDyn, has reported ‘impressive results’ in a small trial of COVID-19 patients. Leronlamab is interesting for two big reasons. One, it attacks the mechanism through which viruses are able to reproduce themselves in human cells. Second, it can supposedly block the overwhelming immune response known as a “cytokine storm” that were thought to be responsible for most deaths during the 1918 flu epidemic and are known to be involved in some COVID-19 deaths. Being able to both fight the virus directly, and fight a potential cytokine storm is a big deal.
However, there are reasons Anthony Fauci isn’t yet standing up to make leronamib standard treatment. First, the results CytoDyn is promoting came from small-scale phase 1/2 trials in which only a total of around 25 patients have actually received the drug. Second, though the fact that leronamib was developed as an HIV treatment (and is being studied for use against metastatic breast cancer) rather than for Ebola may make it seem like it might be available in greater quantities, but in fact it is still in clinical trials for use against HIV. Finally, there have so far been few published results from the initial trials that allows objective review of the results.
In any case, the results from early trials of leronamib have been exciting enough that researchers have already jumped into a number of larger trials. And, in part because clinical trials for leronamib with HIV have shown limited side effects, it’s being used on patients with mild or moderate symptoms in addition to those with severe forms of COVID-19. In other words, loronamib might turn out to be a treatment that is given broadly to anyone showing symptoms, rather than just those on the border of critical conditions. Big emphasis on might.
But there do seem to be indications that general antivirals, like remdesivir and leronamib, can have an impact on COVID-19. And that’s a very good thing. The way in which viruses work, by hijacking the mechanisms of the cells they invade, means that fighting them can be extremely difficult. There is a reason there are many, many more antibiotics and antivirals.
Not every antiviral has proven effective against COVID-19. Part of the WHO Soldarity trials includes testing HIV treatment lopinavir—ritonavir. These trials have so far not demonstrated any positive results. The same appears to be true when this interferon is added to the treatment.
When the first case of H1N1 flu was uncovered in a California hospital in April 2009, the CDC kicked into high gear. It developed a test within two weeks. It deployed 25% of the nation’s stockpile of protective gear and antivirals to the states before the first death. Two days after that first death, the FDA announced that it had already secured a facility to begin growing seed materials for a vaccine. That same day, test kits were available in every state. On October 14, the first 11 million doses of vaccine became available.
That, people, is what a sound response by a fact-driven White House looks like.
In any case, since Donald Trump spent January, February, and early March splitting his time between the critical actives of golf and rallies, the schedule for when we might see a COVID-19 vaccine has often included the phrase “12 to 18 months.” And there have been a frightening number of articles, not all of them clickbait, indicating that such a vaccine may never be available (though really … such articles are 98% clickbait).
So the news that Oxford University researchers had completed animal trials of a potential vaccine and were moving on to a large scale trial in humans was very (x10) exciting. And when some of those researchers indicated that the vaccine might be ready as soon as September, it became an announcement that generated a worldwide sigh of enormous relief.
The reason Oxford has a lead is because it was already involved in coronavirus research and had already done some preliminary testing on a delivery mechanism showing that it could make coronavirus vaccines safely. By grabbing genetic components of the SARS-CoV-2 virus and plugging them into their existing vaccine, the Oxford team took advantage of that research lead and convinced the British government to begin a trial that will involve over 6,000 people by the end of May. That’s a large enough group that it should be a good test of both the vaccine’s effectiveness and its safety.
In fact, the biggest obstacle to the test is that researchers are not allowed, for very good reasons, to expose people to the virus on purpose. So they have to wait for their volunteers to go out there and mingle with the virus-laden public, in hopes that some of them should get sick, but don’t. Some of the researchers have even expressed concern that social distancing in the U.K. may even be effective enough to interfere with the trial. Which … yes, we should hope social distancing is effective. Please, yes. But selfishly, please not effective enough that they can’t compile good results.
In any case, it seems that the U.K. government may launch into the kind of pre-results vaccine manufacturing that the U.S. did in 2009, which could make the first round of doses available in September. It’s unlikely that the first batch would wash up on this side of the Atlantic, but any effective vaccine is a win and, assuming everything goes well, the U.S. could see benefits from this study before year’s end.
The Oxford news was exciting, but it’s far from the only team making progress toward a COVID-19 vaccine. Chinese company SinoVac has also reported that their vaccine generates a strong immune response in monkeys and protects them from COVID-19 infection. And in case you’re wondering a number of sad monkeys in the control groups, both at SinoVac and Oxford, did develop symptoms of disease. Monkeys have not developed the most severe symptoms of COVID-19 seen in humans, but this may be a factor of how many monkeys have been tested, which is still only in double digits.
In any case, the results would seem to put the Chinese company on par with the Oxford study … except that SinoVac doesn’t have the years of product safety research to leverage. Also, the number of monkeys in their test (< 10) really suggests that this team needs to do more animal research before moving on to human trials.
The name SinoVac may not generate the kind of good vibes that come from hearing “Oxford.” But they are an experienced manufacturer of vaccines for both animals and people. That includes being one of the companies with vaccines against H5N1 “bird flu.” Even so, there is not yet the kind of large scale testing that the Oxford group is conducting and SinoVac has already raised warning flags about their ability to manufacture vaccine in the kind of quantities needed for COVID-19.
But SinoVac isn’t the only game in town. Or at least, not the only game in China.
There are also a vaccines trial underway from CanSino. If SinoVac wasn’t all that reassuring, the fact that CanSino is conducting its research in partnership with both the Beijing Institute of Biotechnology and the Chinese Academy of Military Medical Sciences makes this one seem a little concerning, even for those not prone to leaping at every Evil China Virus conspiracy theory. And for folks outside the ranks of Chinese military medical researchers, the phase 1 trials of CanSino’s vaccine have been somewhat opaque. However, they apparently began work on this vaccine in January and announced plans in mid-March to proceed to phase 2 trials and to move forward rapidly. Hopefully, more details to come.
BioNTech / Pfizer Vaccine
Another vaccine that has recently gotten some positive attention is the one being developed by German firms Pfizer Pharmaceuticals and BioNTech. The reason this vaccine is getting special attention, including from the White House podium, is because it’s about to enter Phase 2 trials in the United States.
It’s already had very limited human trials in Germany, with 12 patients receiving doses of the vaccine candidate last week. The next phase will look at 200 healthy adults in the U.S., with testing focusing on safety and appropriate dosage. To support these tests, the FDA has kicked out a quartet of Emergency Use Authorizations that allow the partners to bypass some of the safety stages usually included in vaccine trials.
And, as with the Oxford vaccine and that H1N1 vaccine back in 2009, Pfizer—the big manufacturing part of this partnership—seems prepared to being manufacturing vaccine even before all the results are in. They’re not promising that they’ll have doses as early as the Oxford team has indicated, but they could have hundreds of millions of doses available by the end of the year.
Again, that requires every possible thing to go right. There could be safety concerns. There could be negative responses. The vaccine may flat out be ineffective, or effective for only a subset of the population. For most drugs, the idea of some small amount of problems may be acceptable, but with a vaccine going out to a large part of the population, it really doesn’t take that high a percentage of problems to generate calls for a do-over.
In the best of all possible worlds, the BioNTech vaccine is available before the end of the year, and the Oxford vaccine is available. Because with any vaccine, there are sure to be reasons why it isn’t appropriate for some group.
And then there’s the American upstart in this arena. If you watch this March 2 White House roundtable on COVID-19, in which Trump meets with pharmaceutical executives, you can spot the moment in which is profoundly uninterested in a whole line of big American pharmaceutical execs promising a vaccine in a year … maybe two.
Then the CEO of biotech firm Moderna declares that he’s not just working on a vaccine, he’s already sent it to Anthony Fauci at the NIH. Game over. Thank you everyone for playing.
Of course, CEO Stephane Bancel then backs away a little as he mentions that it will take some time to get into phase two. And more time to get into phase three. And … basically, he’s laying out the same thing that all the other CEOs were saying when they talked about a year. But Bancel did it in a way that definitely caught Trump’s attention and turn Moderna into the go to hope for a fast vaccine.
So, two months later, how is that going? Well, the vaccine did enter limited phase 1 human testing in late March, but since then very little has been released on how the trials are going. What has been released is announcements by Bancel that Moderna could begin production on vaccine in July and announcements that it has already licensed the vaccine to a European manufacturing partner.
That July date makes it seem that Moderna, whose whole “encapsulated mRNA” vaccine represents a fundamentally different approach than some competitors, might even beat the Oxford crew to your local pharmacy, but the details are a little less exciting. Limited phase 2 trials are beginning in May. Moderna doesn’t expect to have large phase 3 trials—like the one Oxford now has underway—until an unspecified date in the fall.
Moderna could still get in under the wire with a 2020 vaccine. If they begin manufacturing in July, they could be ready to roll as soon as results are in on the Phase 3 trial, and considering the eagerness for an answer, it would not at all be surprising to see a big White House announcement that this U.S. firm was coming to market with the world’s salvation … say, sometime around Mid-October, a couple of weeks before the election.
Sorry, there are around 70 other vaccine candidates in some stage of development, but this isn’t a real thing. I just wanted to mention that, after being on this beat since January, I’m going to be away for a couple of weeks. Well … you know, not away, away. Not even away from my keyboard, because I’m hoping to use the time to finish a novel in progress. But away from Johns Hopkins, WorldOMeters, and CovidTracking. Away from fretting over the daily uselessness of the IHME model, and absolutely away from watching the daily indulgence at the White House.
So … see you soon, keep social distancing, and drop me a note if you want to chat about bees, bread, or the book. Take care.