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Choose your own vaccine adventure – The Ken

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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:

Quote

One sometimes finds what one is not looking for. When I woke up just after dawn on Sept. 28, 1928, I certainly didn’t plan to revolutionize all medicine by discovering the world’s first antibiotic, or bacteria killer. But I guess that was exactly what I did.

Alexander Fleming, Discoverer of Penicillin

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%.

Meanwhile, in the United States more than 20 companies were working round-the-clock on penicillin. John L. Smith was a vice-president at Charles Pfizer & Co., then a little-known chemical manufacturer. He had warned his superiors that the penicillin mold was “as temperamental as an opera singer” and implored them to “think of the risks.” But Smith himself was soon gambling the company on deep fermentation of penicillin.

Penicillin : Wonder drug of World War II, HistoryNet

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?

Nothing.

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.

In the same way that during my Microsoft career I talked about the magic of software, I now spend my time talking about the magic of vaccines. Vaccines have taken us to the threshold of eradicating polio. They are the most effective and cost-effective health tool ever invented.

I like to say vaccines are a miracle. Just a few doses of vaccine can protect a child from debilitating and deadly diseases for a lifetime. And most vaccines are extremely inexpensive.

My Annual Letter : Vaccine miracles, Bill Gates

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.
 
The first method is a technique called mRNA.

Without getting too technical, this is how The New York Times described the mRNA technique back in April 2020.

If you talk about vaccines long enough, a new type of vaccine, called Messenger RNA (or mRNA for short), inevitably comes up. There are hopes it could be manufactured at a record clip. Mr. Gates even included it on his Time magazine list of six innovations that could change the world. Is it the miracle we’re waiting for?

Rather than injecting subjects with disease-specific antigens to stimulate antibody production, mRNA vaccines give the body instructions to create those antigens itself. Because mRNA vaccines don’t need to be cultured in large quantities and then purified, they are much faster to produce. They could change the course of the fight against Covid-19.

“On the other hand,” said Dr. van Exan, “no one has ever made an RNA vaccine for humans.”

How long will a vaccine really take? The New York Times

A few pharmaceutical companies that were pursuing research for a vaccine decided to bet on the mRNA technique. This included two American pharma companies. The first was a small Boston-based company called Moderna, which had a great deal of expertise in mRNA.

The second was the most powerful pharmaceutical company in the world—Pfizer.

In The New York Times story I linked above, some experts are quoted on whether the mRNA technique could work.

“Could it work? Yeah, it could work,” said Dr. Fred Ledley, a professor of natural biology and applied sciences at Bentley University. “But in terms of the probability of success, what our data says is that there’s a lower chance of approval and the trials take longer.”

The technology is decades old, yet mRNA is not very stable and can break down inside the body.

“At this point, I’m hoping for anything to work,” said Dr. Iwasaki. “If it does work, wonderful, that’s great. We just don’t know.”

The fixation on mRNA shows the allure of new and untested treatments during a medical crisis. Faced with the unsatisfying reality that our standard arsenal takes years to progress, the mRNA vaccine offers an enticing story mixed with hope and a hint of mystery. But it’s riskier than other established approaches.

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.

Oxford University.

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.

Prof. Bell says he was told the meeting went well, so with the Merck deal all but dead and few prospective partners left, he called AstraZeneca executives on a Saturday morning. AstraZeneca isn’t a giant in vaccines, making it a less-obvious choice. But it was global, British and willing to move quickly.

After 10 days of talks, AstraZeneca agreed to commit to global distribution that wouldn’t favor any one country or region. It also agreed to provide the vaccine at cost during the pandemic, or at least until next summer, pending terms they were still hashing out. U.K. government officials worked on a deal to pay up-front for doses.

A successful vaccine could prove profitable for AstraZeneca in the long run, while burnishing the reputation of the company.

Oxford developed Covid vaccine, then Scholars clashed over money, The Wall Street Journal

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.

The skeptics have strong reasons to be concerned: This week’s “promising” results are nothing like the others that we’ve been hearing about in November—and the claims that have been drawn from them are based on very shaky science.

The problems start with the fact that Monday’s announcement did not present results from a single, large-scale, Phase 3 clinical trial, as was the case for earlier bulletins about the BNT-Pfizer and Moderna vaccines. Instead, Oxford-AstraZeneca’s data came out of two separate studies: one in the UK that began in May, and another in Brazil, which got started at the end of June.

These two studies were substantially different from one another: They didn’t have standardized dosing schemes across the trials, for one thing, nor did they provide the same “control” injections to volunteers who were not getting the experimental Covid vaccine. The fact that they may have had to combine data from two trials in order to get a strong enough result raises the first red flag.

The AstraZeneca Covid Vaccine Data Isn’t up to Snuff, WIRED

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.

Quote

The reason we had the half-dose is serendipity

Mene Pangalos, Head of AstraZeneca’s non-oncology research and development

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.”

Foul play suspected in private firm’s deal to supply Russian vaccine to Nepal, Kathmandu Post

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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Take care.

Regards,
Praveen Gopal Krishnan

The Nutgraf by The Ken

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