COVID Transmissions for 4-12-2022
CORBEVAX approval and public data
Greetings from an undisclosed location in my apartment. Welcome to COVID Transmissions.
It has been 847 days since the first documented human case of COVID-19. In 847, Vikings landed in Brittany and began attacking the region—and extorting protection money from the locals. Duke Nominoe wasn’t able to beat them in battle, but he was able to bribe them to go away. The age of the Vikings is upon us.
Meanwhile, in the world of COVID, we haven’t be able to bribe it to go away. But we have been able to develop some vaccines against it that are very effective.
Today I will focus in on CORBEVAX, a low-cost vaccine candidate that is highly desirable as a candidate to vaccinate the world. Its creators, Dr. Peter Hotez and Dr. Maria Bottazzi, have been suggested as candidates for the Nobel Prize. Vaccine equity is a huge problem the world over, and a low-cost vaccine may be just what we need to continue to get the most vulnerable people vaccinated.
The problem is, very little data were available publicly when the vaccine was approved for use in India, and by now, 20 million people have been given doses. Was this process appropriate? Does the vaccine work? We’ll delve in, today.
Before that, a couple of notes on newsletter operations:
I’ll be changing the day that the second issue of the week comes out. We will now be on a Tuesday and Friday schedule here at COVID Transmissions.
Many of you will have received last Thursday’s issue twice; this was due to some kind of technical problem at Substack that affected many newsletters.
Bolded terms are linked to the running newsletter glossary.
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Now, let’s talk COVID.
CORBEVAX is now in 20 million patients; let’s look at the publicly available data
Some time ago I covered here the story of CORBEVAX, the inexpensive COVID-19 vaccine created by famed physician Dr. Peter Hotez, a personal hero of mine, and his longtime collaborator Dr. Maria Bottazzi.1 At the time, scant data were available in the public record and there were some questions as to the path to approval in India given the lack of public data.
In the intervening time, the vaccine has been approved in India and more data have become available publicly. The order of these events has left many concerned, and I must admit a certain amount of reservation as well, personally—the approval of a vaccine should, in my opinion, always be made based on data that can be scrutinized publicly. I will not be shy about criticizing the Indian government for approving this vaccine in a non-transparent way.
However, in a pandemic emergency where global vaccine equity is lagging substantially, there is an argument for getting a vaccine out to as many people as possible as soon as you have the data to support doing that, without waiting for the manuscript to be fully formatted and published online first. The world is really behind on getting everyone vaccinated, and this is as much a biosecurity weakness as it is a failure of human compassion.
So, in the last couple of months, 20 million adolescents have been vaccinated with CORBEVAX:
More vaccinees will be following in these footsteps. Given the questions over publicly available data, I asked Dr. Hotez directly what safety and efficacy data were available in the public domain at this point to support his team’s vaccine.
Dr. Hotez is the kind of person who, despite being internationally famous and extremely busy, takes the time to respond to requests like that. He sent me the following preprints:
I will point out here that Dr. Hotez is not an author on the two papers linked in that tweet. While his team created the vaccine, trials were run by the company Biological E and the Indian government.
The tweet only has one preview, which makes this a bit confusing, but here are the results linked:
Phase 1/2 and Phase 2 open-label safety-focused trials: https://www.medrxiv.org/content/10.1101/2022.03.08.22271822v1
Phase 3 single-blind study: https://www.medrxiv.org/content/10.1101/2022.03.20.22271891v1
The first preprint’s studies, like many Phase 1 and 2 trial setups, was looking to identify the best safe formulation for the vaccine for use in the Phase 3 trial. In general Phase 1 and 2 trials are used to determine the design of the big Phase 3 trials—and ensure that it will be safe to proceed to these larger trials.
In that first preprint, we see a lot of data about immune responses, and these data are interesting, but in my opinion because of the open label nature of those trials and the absence of a comparator, it is not fair or meaningful to assess efficacy in that study. However, assessing safety is quite reasonable based on the data found there, and overall, the rates of any adverse event with any of the formulations being tested were extremely low. In the Phase 1/2 trial, fewer than 12% of patients had any adverse event, and in the Phase 2 trial this was approximately 27%. There were no adverse events classified as serious. We are looking at data in 460 total patients here. Based on this finding, and the fact that there were detectable and robust immune responses, I am confident that the decision to proceed to a Phase 3 trial was a wise one. I just wish this paper had come out before the vaccine was approved in India on February 22nd, 2022—instead of on March 8th, 2022, when it was released.
The Phase 3 is the second preprint, and it’s where I’d like to focus most of my attention. It was released on March 22, 2022—a full month after approval in India. I will note at this stage that the preprint itself is of relatively unpolished quality. It contains errors of English, and very oddly, a “Confidential” flag icon within the text, suggesting that an internal draft was not adequately cleaned before Biological E made it available to the public on MedrXiv. That’s not the most egregious thing I’ve ever seen in a preprint, but it does raise an eyebrow.
In this trial, CORBEVAX was compared with COVISHIELD, an active, rather than placebo, control. COVISHIELD is the Indian local brand name for the AstraZeneca-Oxford vaccine that we have discussed in this newsletter many times.
I want to point something out here about study design. While I may ultimately criticize the design of this Phase 3 in key ways, one thing that I have to commend here is that the choice to use an active control is the only ethical option. There are now vaccines against COVID-19 that are highly effective, and to conduct a trial where some patients are administered a placebo instead of one of those vaccines means you are choosing to put those patients at risk. So, the designers of this study made the ethical choice to give a real, active vaccine as their competitor.
This is a risky choice in study design, because your product has to be at least as good as your active control for your trial to be considered successful. But, it is the right thing to do.
2140 patients were randomized in this study, but only 639 of those were in the “immunogenicity” arm (that is, the population where they assessed whether the vaccine yielded an immune response). That means that at least 320 patients got a vaccine that the trialists knew would work before the trial was started. Definitively, that is a good thing. The other ~1800 patients got CORBEVAX, by the way—which the Indian government says works! So if they are correct—and we will examine that here—then they got a pretty good deal too. As a note, 319 patients got CORBEVAX in an immunogenicity-assessment population, and the remaining 1500 patients received CORBEVAX but were evaluated for safety only. This design was presumably due to resource limitations; measurement of immunogenicity requires intensive laboratory work and is not cheap, on top of the costs of running the clinical portion of the trial. It is not cheap either to assess clinical safety, but I suppose it is less expensive than also running lots of lab assessments on all those patients.
Regardless, though, this immunogenicity population is rather small for a Phase 3 trial. However we have the advantage of knowing a lot more about what is indicative of a protective response against COVID-19 these days than we did when the first vaccine trials were conducted.
Anyway, let’s discuss some results. With regard to safety, 20-40% of the CORBEVAX patients had adverse events and of these, the most common were things like injection site pain or fatigue. With COVISHIELD, in the small number of patients dosed, the rates were around 40%.
There were only two “serious adverse events” reported, and neither were judged to be related to study vaccines.
Overall, we are looking at a safety profile that is comparable to a well-known vaccine like COVISHIELD. While large population data could always reveal rarer events, these data suggest a vaccine that is generally tolerable and not at all out of the ordinary.
The real question, though, is this: does it work?
The best we have to go on here is neutralizing antibody titers. The levels of these neutralizing antibodies are thought to be correlated with protection, though currently there is still debate over what level corresponds to what amount of protection. We do not have any data that tell us whether one vaccine prevented more infections than the other, or whether infection rates, disease rates, or death rates were similar among the two vaccinated groups. All we have to go on is the antibodies—but since we know one of the vaccines works, the antibodies may be a meaningful indicator of efficacy. I am not sure I can promise that they are, though.
Anyhow, these are the neutralizing antibody levels, in a graph with incredibly obtuse labeling:
The differences between the two vaccines here look quite small, but part of that is because the graph is on a logarithmic scale. Regardless, we see robust neutralizing antibody titers that the statistics said were significantly higher with CORBEVAX. This looks promising. COVISHIELD is not my favorite vaccine available, but it prevents serious outcomes and death meaningfully, and CORBEVAX yields a better neutralizing antibody titer, at least initially.
Now here is where I have to get a bit critical. This paper does not have a lot of patients. There is still a lot we do not know about immunity to COVID-19. There are no actual anti-disease efficacy results reported. All of these things give me a certain amount of pause—but, considering that we continue to be in a pandemic emergency, and there are data here indicating a favorable risk-benefit profile is at least likely, I can’t second guess the decision to approve the vaccine based on the data I have so far. I do not see a huge difference in practical terms between the data presented here and the pediatric vaccination data, also based on immune response only, that have been made public by Pfizer and Moderna for their mRNA vaccines.
I understand that there are additional data coming. It is possible that the Indian government also had access to these data, even though we do not, and this further enhanced the case for approval. I will not speculate about that—instead I will say that I am relatively OK with making the decision to distribute this vaccine in one of the world’s most populated countries, because with 60% of the population fully vaccinated, there is still an unvaccinated population in India that is bigger than the entire population of the United States. If all of those people got COVID-19, I would expect a minimum of 4 million of them to die, and that’s just one of many negative outcomes. And if we need a selfish reason, the more wholly susceptible people there are out there, the more human test subjects the virus has to explore its evolutionary space in search of the next devastating variant. In this situation, public health can impact your personal health.
That said, I have many questions. Does this vaccine impact infection rate, disease rate, hospitalization rate, or death rate? How durable are the antibody titers that are observed? Will a booster vaccination for CORBEVAX be needed? Does CORBEVAX perform well when it is given in a mixed-brand regimen?
These are all questions that have been answered for the older vaccines, and I think they ought to be answered for CORBEVAX too. I do think that the regulatory approval process for CORBEVAX was not the idealized process that I prefer, but ultimately, having seen these data, I am left with the sense that this vaccine is definitely better than no vaccine, and it may in fact be quite a lot better. In light of that, I’m glad it’s out there.
But…I want more data.
Part of science is identifying and correcting errors. If you find a mistake, please tell me about it.
Though I can’t correct the emailed version after it has been sent, I do update the online post of the newsletter every time a mistake is brought to my attention.
No corrections since last issue.
What am I doing to cope with the pandemic? This:
Brooklyn Botanic Garden
My family and I visited the Brooklyn Botanic Garden this past weekend! It was a bit cold, but I love that place (and, it has some great cherry blossoms, to follow on another story that appeared in this section recently).
It was great! Here’s a photo I took there:
Reader Rachel Manija Brown made the following comment on my hepatitis C virus origins piece:
I think there's a simpler explanation for blood-borne human-animal transmission than shared grooming tools or a horse and rider getting wounded in battle together. It's very easy to cut your finger when chopping raw, bloody meat. And for societies that don't eat horses, it would also be easy to tend a horse or donkey's injury when you have a small cut on your hand.
It’s a good point, and I wanted to share it here with you.
You might have some questions or comments! Join the conversation, and what you say will impact what I talk about in the next issue. You can also email me if you have a comment that you don’t want to share with the whole group, or if you are unable to comment due to a paywall.
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Please know that I deeply appreciate having you as readers, and I’m very glad that if we must be on this pandemic journey, at least we’re on it together.
Dr. Bottazzi lives a less public life than Dr. Hotez, but is nonetheless an incredible scientist.