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Good Morning Dear Reader,
Nearly every weekend, immediately after this newsletter is published, I receive a lot of emails from subscribers. Once in a while, I get feedback that’s usually a variant of this:
“This was a wonderful edition! But why are you so negative and pessimistic all the time about everything?”
My reply is usually something like this:
“We’ve been in a global lockdown for nine months. My friends have either separated, gotten married or had babies—all on Zoom. Some have done all of the above. I tried watching Netflix to relax but got anxiety attacks because nobody was wearing any masks. So now I only watch Darth Vader supercut videos on YouTube.
Instead, why don’t you tell me how you are so positive and optimistic all the time?”
However, I decided to take this feedback to heart. And I’ve come up with a slightly different edition for you today.
Today’s edition is about something that has dominated the headlines for the past week or so—the Covid-19 vaccine. Success numbers have been touted. Amazement has been registered. And in many, many ways, it’s one of the best things to have happened this year. And when the world finally goes back to the way it was, I suspect we’ll probably remember it as one of humanity’s greatest achievements in modern history.
That’s one way to look at it—the positive, optimistic side. We can admire. We can marvel. We can read a story that tells us a happy ending, the one where we fought something we had never seen before, which made us do things we’d never done.
But there’s another side. The critical, pessimistic perspective.
This story has a slightly different ending. It’s about what happens afterwards because, in this perspective, there are no happy endings. Only the beginning of newer problems.
Today, I’ll tell the story.
You can pick the ending you prefer.
Let’s dive in.
Oxford does not want to make the same mistake twice
Our story begins not in 2020, but nearly a century earlier.
In 1928, a Scottish lab technician at St Mary’s Hospital in London left some bacterial cultures in a few petri dishes and went on a two-week vacation. When he got back, he found something extraordinary. Mould had collected in one of the petri dishes that he had left open by mistake. No bacteria were to be found.
He thought this was interesting and published his findings.
Several years later, the lab technician was quoted as saying:
You can look up any article, listicle or documentary about serendipity i.e medical discoveries made by accident, and Alexander Fleming’s discovery will almost certainly be on it.
And what happened in 1928 immediately after Fleming published his discovery that revolutionised all medicine?
Nothing. Nobody cared. Not scientists. Not the general public. Even Fleming himself stopped studying it and moved on to other things.
The world’s most important discovery remained hidden and ignored for the next twelve years.
Finally, in 1940, at the peak of the Second World War, a team of researchers at the University of Oxford in the United Kingdom started paying some attention to penicillin. The reason why these researchers were interested in it was because they had found that penicillin was very effective against a range of pathogens, including bacteria that caused gangrene.
Gangrene, essentially caused by bacteria that infected open wounds, was one of the leading causes of death during the Second World War. It killed so many soldiers during the war that it was routine for doctors and nurses to triage and decide to treat only those soldiers whose wounds were clean, because once gangrene set in, it was hopeless.
However, the Oxford team had a problem. They knew that penicillin worked, but they also struggled to manufacture it. The best they could do was grow tiny films of it, which barely served their experimental needs.
Finally, in 1941, the team at Oxford decided that they needed help, and turned to the greatest manufacturing powerhouse in the world at the time—the United States pharmaceutical industry.
The pharmaceutical industry quickly grasped the power and potential of penicillin.
By 1942, there was enough penicillin manufactured in the United States to treat maybe 10 patients.
By June 1945, 21 pharma companies were producing 650 billion units of penicillin every month.
It’s hard to estimate how many lives penicillin saved during the war. One estimate says it’s about 100,000 soldiers. Another suggests that it reduced the mortality rate by 12-15%.
By the late 40s, American pharma companies would be producing half of the world’s pharmaceuticals. The manufacture of penicillin as part of this war effort is what catapulted them into global corporations over the next several decades. Pfizer, for instance, recorded $52 billion in revenue just last year.
And what about Oxford University, which actually took the trouble to extract penicillin and bring it to the attention of the American pharma companies? How much did they make from all this?
The Oxford team that manufactured penicillin didn’t even patent it, believing that it would be unethical to do so. After all, they didn’t even create it—it was discovered serendipitously, by a stroke of luck.
Meanwhile, Americans had patented processes of manufacturing penicillin at an industrial scale.
Oxford University never forgot this.
It’s part of their University lore—how they created the most important discovery of the century, only to hand it away to American pharma companies, and got nothing in return.
Perhaps you are wondering what any of this has to do with the Covid-19 vaccine.
It has everything to do with it.
Two methods. Two bets.
Back in 2011, Bill Gates, the founder of Microsoft and noted philanthropist, wrote this in his blog.
It’s true. Vaccines are miracles.
But it’s not easy to create this miracle.
Conventionally, there has been just one way to create a vaccine. In a grossly oversimplified form, it looks something like this: they trick your immune system into creating antibodies to fight an infection by ‘fooling’ your body into thinking that it is under attack by a pathogen. Vaccines do this by either introducing weaker forms of a deadly virus or bacteria in your body or through inactivated versions of it.
This isn’t foolproof. Sometimes it works. Sometimes it doesn’t and results in adverse effects. If a pathogen is deadly, there’s no guarantee that a weaker form of it is less deadly for everyone. You need to isolate, test, wait. Then isolate it in another way, test, wait. At some point, the right combination triggers the right level of immune response across all cohorts of humans.
This is why vaccine development takes years and years.
The record for the fastest vaccine ever produced is four years.
So when the Covid-19 pandemic hit, researchers decided that the conventional method was far too time-consuming. Instead, they decided to try out two other experimental methods.
Without getting too technical, this is how The New York Times described the mRNA technique back in April 2020.
That’s the first technique. mRNA.
The second technique is even more interesting.
It’s called the adenovirus vector method. In this method, the genetic material of the Covid-19 virus is coded into another harmless virus and injected into a body. This acts somewhat like a Trojan horse and causes the body to fight back with antibodies.
This isn’t easy to do. You need a lot of experience to understand how to make this work. Ideally, you need to have done it before for another flu virus, preferably a coronavirus. And you need a team that has deep, institutional knowledge about vaccines.
In 2020, there was only one organisation in the world that checked all these boxes. It was the same entity that had successfully synthesised penicillin nearly 80 years ago.
The right partner
The details of how Oxford University found itself as a frontrunner in the race to create the vaccine isn’t that relevant. However, if you’d like, you can read this fantastic Bloomberg story that describes how they had tried the adenovirus technique for the Ebola virus and MERS earlier, and about the team that did it.
The bottom line was that Oxford University was the team to beat. By April, they had crunched a process that normally took five years into less than four months. When one member of the team testified before the UK Parliament about what Oxford University was going to do, the effort was described as “going into a shed and coming out with a jet engine”.
Soon, it was quite evident that Oxford University would have a vaccine before anyone else. The problem was that Oxford University didn’t have any manufacturing capabilities.
It was like penicillin all over again. Oxford University needed a manufacturing partner.
And this time, they found themselves in a dilemma.
Oxford University’s academics and researchers believed that the vaccine needed to be available to the broadest population across the world, especially to those who could not afford it. That’s why they needed a manufacturer who could create it at scale.
But they also didn’t want someone else to get all the financial gain either.
Oxford University needed a partner to help them achieve both.
At first, they spoke to the pharma giant Merck. But talks quickly broke down over concerns whether Merck could supply to low-income countries. Then, a new partner emerged.
There were other aspects to the deal. AstraZeneca guaranteed to sell three billion doses at no profit. It also promised to make the vaccine available to low- to middle-income countries at no profit in perpetuity.
In return, Oxford University would receive 6% of royalties for every vaccine sold after the pandemic ends. The University said that the funds will be placed into a new Pandemic Preparedness and Vaccine Research Centre that Oxford is developing “in collaboration with AstraZeneca”.
Oxford University had crafted the dream agreement. It got nearly everything it wanted.
A guarantee to give away the vaccine for free in perpetuity automatically makes the world root for you over your competition. But, there was another reason why the world was rooting for Oxford University’s vaccine.
RNAs are more unstable than DNA. The mRNA vaccine, when it’s developed, will need to be stored and transported at minus 20 degrees celsius. Most commercial freezers aren’t built for that. This makes the distribution and logistics of the mRNA vaccine a nightmare, which is something that Pfizer and Moderna will have to solve for.
On the other hand, the Oxford vaccine—which is built on DNA— can be stored and transported in any refrigerator.
Long story short, the world really, really needs the Oxford vaccine to work.
And more than anyone else, one country has really gone all-in on the Oxford vaccine.
Source : Bloomberg
Finally, over the last two weeks, the results of the Phase III trials rolled in for all the vaccines.
The results and the choice
Phase III trials are the last and the most important phase of vaccine development. In this phase, a significant set of the population—often nearly thousands and thousands of people—is broken into two groups. One group gets the vaccine, and the other group gets the control, which is usually just a salt solution. Then both groups are tracked for months to see how many of them get the coronavirus. Rates are compared across both cohorts. A percentage effectiveness is given.
No vaccine is 100% effective. In fact, even a 50-60% effectiveness is often seen as promising.
Pfizer and Moderna were the first to report their results.
Both of their vaccines were found to be over 90% effective.
Dr Anthony Fauci, the US’ leading infectious disease expert and a man not easily surprised, termed it as ‘just extraordinary’. Pfizer shared its findings with regulators and applied for an emergency use authorisation that would enable it to manufacture the vaccine immediately.
But the result that everyone was waiting for was the AstraZeneca Oxford vaccine.
Last week the numbers came in.
AstraZeneca-Oxford reported an efficacy rate of 70%—lower than that of Pfizer and Moderna, but still quite effective.
Immediately, instead of treating the news with jubilation, the share price of AstraZeneca fell.
Because experts noticed something others hadn’t.
So what happens next?
At this point, as the reader, you have a choice.
You can choose to read the optimistic scenario or the pessimistic one. We don’t know the definitive ending yet, because this is still a work in progress, but we do have some indications on how things will turn out.
Just remember that your choice reflects your preference on how you want this to end.
Here it is.
Choice A : The Optimistic Ending
Let’s understand a bit about the fuss about Oxford’s methodology.
Now, it’s important to understand that AstraZeneca and Oxford aren’t being accused of doing fraud or making up numbers. The criticism is about the methodology itself. Instead of having one uniform Phase III trial, Oxford chose to do two separate trials and combine the results, even though both trials had different operating conditions.
This isn’t ideal, but it isn’t fraud. Not by any stretch.
In fact, let’s break down the two trials.
The first trial gave two full doses of the vaccine. This trial showed an efficacy of 62%.
The second trial is where it gets interesting.
Participants were given a half dose and a full dose. And the efficacy rose to 90%.
I know what you are thinking. How is half a dose more effective than a full dose?
Nobody really knows.
According to the Financial Times, Dr. Sarah Gilbert, an Oxford professor who’s at the forefront of the vaccine’s manufacturing, thinks that it’s possible that “a smaller initial dose primes the immune system in a way that better mimics natural infection”. Dr. Gilbert was the same person who had testified before the UK Parliament. She was the one who was expected to emerge with a jet engine.
In any event, AstraZeneca and Oxford have promised to conduct fresh trials. There’s reason to remain optimistic that all will go well, and we’ll soon have an effective vaccine in our hands.
But there’s something even more bizarre. And also quite poetic.
The half-dose trial that gave a 90% effective result was not a deliberate strategy, but a result of an accident.
AstraZeneca prefers to use another word to describe it.
It’s a word we’re quite familiar with.
Choice B : The Pessimistic Ending
If you think about it, the point isn’t whether the AstraZeneca-Oxford vaccine has high efficacy but whether the efficacy matters at all in the first place.
Several countries have already tied themselves to one manufacturer or the other. They are attempting to get vaccines for their populations, no matter the effectiveness. And right now, everyone is getting desperate and hitching their wagons to whatever they can find.
Take Sputnik, the Russian vaccine. Despite strong doubts about its methodology and its claimed efficacy by scientists, here’s what happened in Nepal.
Public health experts and some government officials have suspected foul play in the purported deal between Russian Direct Investment Fund and a private Nepali firm to supply the Russian vaccine for the coronavirus to Nepal.
Reports on Tuesday suggested that Russian Direct Investment Fund, Russia’s sovereign wealth fund, would supply 25 million doses of its potential Covid-19 vaccine to Nepal through Trinity Pharmaceuticals.
“It looks like some government officials’ ploy to help a private company benefit,” an official at the Department of Health Services told the Post requesting anonymity because he feared retribution. “It reminds of an earlier deal in which the government had asked Omni Business Corporate International Pvt Ltd to import medical equipment to fight the pandemic.”
And right now, developers of the Sputnik vaccine are asking AstraZeneca to combine their vaccine into theirs.
It’s easy to envision a scenario where months from today, people just pick the vaccine they can afford. The rich and the privileged go to a private hospital and get themselves a vaccine with a high efficacy rate… because they can.
And the others get the low efficacy rate vaccine, because… what choice do they have?
And vaccines, which started off as miracles, become another luxury good.
If you still have doubts about what human beings can do with medical technology — even those considered as miracles, and how it can lead to unforeseen consequences, let me end with a final story.
We’ll end where we began — with penicillin.
On the question of how penicillin changed the course of the war, one incident stands as an ironic postscript to the story about Churchill’s recovery from pneumonia: On July 20, 1944, German Führer Adolf Hitler suffered burns and abrasions when a bomb planted by one of his own officers exploded in a room where he was meeting with staff. A spattering of wood splinters posed the most serious threat, from septicemia, or blood poisoning, according to molecular biologist Milton Wainwright in his 2004 article “Hitler’s Penicillin.”
Hitler’s doctors recalled what had happened to Reinhard Heydrich, “the Butcher of Prague,” who had been one of Hitler’s personal favorites. Heydrich survived a 1942 bombing attack by resistance fighters only to develop a bacterial infection from the splinters, leather and horsehairs blasted into his body from his car’s upholstery. In the absence of penicillin, Heydrich soon succumbed to blood poisoning.
But by 1944 Hitler’s personal physician, Theodor Morell, not only knew about penicillin but also had somehow obtained a quantity of it, either from captured Allied soldiers or from Germany’s own faltering attempts at manufacturing the drug.
He did not administer the precious drug to General Rudolf Schmundt, another victim of the bombing, who later died of his injuries.
Morell did give it to Hitler, who lived.
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