Vaccine Development, Covid-19, and mRNA vaccines

Vaccine Development, Covid-19, and mRNA vaccines | The Incidental Economist

In this last episode of our six-part series on vaccinations, supported by the National Institute for Health Care Management Foundation, we cover vaccine development – particularly in the context of the current global pandemic. We discuss the timeline of Covid-19 vaccine development and the mRNA vaccine approach.

A negative Covid-19 test isn’t an all-clear

What is the probability of testing positive for Covid-19 before you get symptoms? Scientists really don’t know. 

Vice President Mike Pence has not tested positive for SARS-CoV-2, the virus that causes Covid-19. But he’s been in close contact, in recent days, with people with confirmed Covid-19 infections. And he debated Sen. Kamala Harris last night. Was this a good idea?

In a word: No. Per the Centers for Disease Control and Prevention’s own guidelines, Pence should have been quarantining, not debating, even if he’s testing negative. (That said, CDC director Robert Redfield had cleared Pence to debate.)

Since the Trump administration’s actions over the last 11 days have muddied the message from public health experts, let’s be clear: A negative test is not an all-clear for doing risky activities during the pandemic.

Scientists don’t yet understand exactly when a person who is infected with the coronavirus will start testing positive for the virus. There are situations when a person could test negative, actually be infected, and also be contagious. It’s also possible — since this virus multiplies itself exponentially in the body very, very quickly — that someone could test negative in the morning (and not be contagious), but by the afternoon test positive (and be very contagious).

Confusing? Yes, it is. But the bottom line is that Covid-19 diagnostic tests (both the slower, more common, viral genetic test — called RT-PCR— and the more rapid viral protein test, called an antigen test) are most useful, and most accurate, when used on people experiencing symptoms.

“One of the huge gaps now in the data is: What is the probability of testing positive before you get symptoms?” Benny Borremans, a disease ecologist at UCLA, says. Right now, scientists just don’t know for sure.

Why testing is less accurate before symptoms begin

There are several reasons scientists are unsure about when in an infection people will start testing positive for SARS-CoV-2. To understand why, and to make this less confusing, it’s helpful to think through all the things that have to happen for a Covid-19 test to come back positive.

First, the virus needs to take its time to establish itself in a person’s body. This is called the incubation period, and it can take upward of two weeks. On average, this happens in about five or six days. During the incubation period, a person might not test positive for the virus because there’s not enough virus in their body to detect in a test.

“The virus particles, day by day, will multiply,” Muge Cevik, a virologist and physician at the University of St. Andrews, says. “The virus needs to reach a threshold for the PCR [i.e. viral genetic] tests to pick it up.” PCR is the more common Covid-19 diagnostic test because it requires a lower threshold of the virus to test positive; rapid antigen tests would require a higher level of virus to register a positive test.

Testing positive should coincide with being contagious. But not always.

Generally, a person can start being infectious for the virus around two days before they start to show symptoms, in what’s known as the presymptomatic phase.

And, generally — but not always — scientists would expect that if a person is contagious, they’d test positive. After all, if they’re spewing enough virus out to get another person sick, they’re probably spewing enough virus out for a diagnostic test to pick up on.

But there are a few wrinkles here: When exactly a person makes the jump from testing negative and being non-infectious to testing positive and being infectious is hard to predict.

“If everything works as it should, the test should be positive if you are infectious at the very moment of the test, as there must be virus present then,” Justin Lessler, an epidemiologist at Johns Hopkins University, says. “However, you could easily test negative then become infectious a day, or even hours, after the test.” Unless you’re testing every hour, it’s impossible to get a fine-grained view on when the infectious period truly begins. (Also possible, but probably rarer: A person tests positive before they start to be contagious.)

Even if a person is contagious, they may not test positive. It could come down to where the sample for testing was taken from.

In general, “we consider the gold standard to be the nasopharyngeal swab,” Bobbi Pritt, the director of clinical microbiology at the Mayo Clinic, says. “That’s the deep nasal swab that goes all the way back into the back of your nose. Whereas other specimens — like a throat swab or just the very outer edge of your nose, like right inside your nostril — that’s not going to contain as much virus.”

Early on in the infection, a person who is incubating the virus is expected to test negative. Over the summer, Johns Hopkins researchers — including Lessler — published a paper estimating the likelihood of a false negative test in the first few days after being exposed to the virus. On the first day, they found the chance of a false negative is near 100 percent. No test is going to find the virus so early. Through the first four days, that rate drops to 67 percent on day four, on average, but with a very large range of error. On the day people first reported symptoms, there’s still a significant false negative rate, at 38 percent.

What does this all add up to? “What we’re saying is don’t test anyone in less than four days after exposure,” Cevik says. It’s not going to tell you much about the person’s status. Or if a person is tested in that time, they ought to be retested a few days later.

“In general, five to eight days after exposure is the best time to test,” Cevik says. “Or day three after symptom onset.” That’s when the genetic RT-PCR tests are most likely to reveal a true positive.

Because nothing about Covid-19 can be simple, here’s another thing to consider: The antigen tests that produce quick results have a shorter window in which you’d expect a person would test positive.

They are also slightly less accurate. But if used correctly, they can be very useful: They’ll test positive in the window when a person is most likely to be contagious. With repeated use, scientists hope these quick tests could help stop outbreaks from growing out of control.

The White House, on the other hand, has been using another rapid test, Abbott’s ID Now, to screen asymptomatic people. We just don’t know how good these tests — or any tests, for that matter — are at screening asymptomatic, or presymptomatic, people. “The FDA would be the first ones to tell you that they don’t know how the test is going to perform in that population,” Pritt says.

A negative test without symptoms might not mean much. Keep your mask on.

Here’s the bottom line: “We don’t know when one will test positive pre-symptom onset for PCR or antigen tests,” epidemiologist A. Marm Kilpatrick writes in an email. If you have symptoms, you’re likely to test positive the day you start feeling ill, but not guaranteed. The first few days after starting to feel sick, you have a very high probability of testing positive.

We could learn more in the months ahead about testing asymptomatic and presymptomatic people with studies following people after they have been exposed to the virus, and testing them repeatedly over a few weeks to determine the likelihood of testing positive before symptoms begin. “We have a lot of data from symptom onset onwards, but we don’t have data in terms of pre-symptoms,” Cevik says.

This is why testing is no replacement for other Covid-19 mitigation measures, like quarantining people exposed to the virus, mask-wearing, and social distancing.

“Testing negative is not like a passport for people to go out and do whatever they want to do,” Cevik says. If you might have been exposed to the coronavirus, like Vice President Pence was, you should quarantine for two weeks, regardless of what your test says.

What you need to know about the COVID-19 vaccine

What you need to know about the COVID-19 vaccine | Bill Gates

Humankind has never had a more urgent task than creating broad immunity for coronavirus.

One of the questions I get asked the most these days is when the world will be able to go back to the way things were in December before the coronavirus pandemic. My answer is always the same: when we have an almost perfect drug to treat COVID-19, or when almost every person on the planet has been vaccinated against coronavirus.

The former is unlikely to happen anytime soon. We’d need a miracle treatment that was at least 95 percent effective to stop the outbreak. Most of the drug candidates right now are nowhere near that powerful. They could save a lot of lives, but they aren’t enough to get us back to normal.

Which leaves us with a vaccine.

Humankind has never had a more urgent task than creating broad immunity for coronavirus. Realistically, if we’re going to return to normal, we need to develop a safe, effective vaccine. We need to make billions of doses, we need to get them out to every part of the world, and we need all of this happen as quickly as possible.

That sounds daunting, because it is. Our foundation is the biggest funder of vaccines in the world, and this effort dwarfs anything we’ve ever worked on before. It’s going to require a global cooperative effort like the world has never seen. But I know it’ll get done. There’s simply no alternative.

Here’s what you need to know about the race to create a COVID-19 vaccine.

The world is creating this vaccine on a historically fast timeline.

Dr. Anthony Fauci has said he thinks it’ll take around eighteen months to develop a coronavirus vaccine. I agree with him, though it could be as little as 9 months or as long as two years.

Although eighteen months might sound like a long time, this would be the fastest scientists have created a new vaccine. Development usually takes around five years. Once you pick a disease to target, you have to create the vaccine and test it on animals. Then you begin testing for safety and efficacy in humans.

Safety and efficacy are the two most important goals for every vaccineSafety is exactly what it sounds like: is the vaccine safe to give to people? Some minor side effects (like a mild fever or injection site pain) can be acceptable, but you don’t want to inoculate people with something that makes them sick.

Efficacy measures how well the vaccine protects you from getting sick. Although you’d ideally want a vaccine to have 100 percent efficacy, many don’t. For example, this year’s flu vaccine is around 45 percent effective.

To test for safety and efficacy, every vaccine goes through three phases of trials:

  • Phase one is the safety trial. A small group of healthy volunteers gets the vaccine candidate. You try out different dosages to create the strongest immune response at the lowest effective dose without serious side effects.
  • Once you’ve settled on a formula, you move onto phase two, which tells you how well the vaccine works in the people who are intended to get it. This time, hundreds of people get the vaccine. This cohort should include people of different ages and health statuses.
  • Then, in phase three, you give it to thousands of people. This is usually the longest phase, because it occurs in what’s called “natural disease conditions.” You introduce it to a large group of people who are likely already at the risk of infection by the target pathogen, and then wait and see if the vaccine reduces how many people get sick.

After the vaccine passes all three trial phases, you start building the factories to manufacture it, and it gets submitted to the WHO and various government agencies for approval.

This process works well for most vaccines, but the normal development timeline isn’t good enough right now. Every day we can cut from this process will make a huge difference to the world in terms of saving lives and reducing trillions of dollars in economic damage.

So, to speed up the process, vaccine developers are compressing the timeline. This graphic shows how:

In the traditional process, the steps are sequential to address key questions and unknowns. This can help mitigate financial risk, since creating a new vaccine is expensive. Many candidates fail, which is why companies wait to invest in the next step until they know the previous step was successful.

For COVID-19, financing development is not an issue. Governments and other organizations (including our foundation and an amazing alliance called the Coalition for Epidemic Preparedness Innovations) have made it clear they will support whatever it takes to find a vaccine. So, scientists are able to save time by doing several of the development steps at once. For example, the private sector, governments, and our foundation are going to start identifying facilities to manufacture different potential vaccines. If some of those facilities end up going unused, that’s okay. It’s a small price to pay for getting ahead on production.

Fortunately, compressing the trial timeline isn’t the only way to take a process that usually takes five years and get it done in 18 months. Another way we’re going to do that is by testing lots of different approaches at the same time.

There are dozens of candidates in the pipeline.

As of April 9, there are 115 different COVID-19 vaccine candidates in the development pipeline. I think that eight to ten of those look particularly promising. (Our foundation is going to keep an eye on all the others to see if we missed any that have some positive characteristics, though.)

The most promising candidates take a variety of approaches to protecting the body against COVID-19. To understand what exactly that means, it’s helpful to remember how the human immune system works.

When a disease pathogen gets into your system, your immune system responds by producing antibodies. These antibodies attach themselves to substances called antigens on the surface of the microbe, which sends a signal to your body to attack. Your immune system keeps a record of every microbe it has ever defeated, so that it can quickly recognize and destroy invaders before they make you ill.

Vaccines circumvent this whole process by teaching your body how to defeat a pathogen without ever getting sick. The two most common types—and the ones you’re probably most familiar with—are inactivated and live vaccines. Inactivated vaccines contain pathogens that have been killed. Live vaccines, on the other hand, are made of living pathogens that have been weakened (or “attenuated”). They’re highly effective but more prone to side effects than their inactivated counterparts.

Inactivated and live vaccines are what we consider “traditional” approaches. There are a number of COVID-19 vaccine candidates of both types, and for good reason: they’re well-established. We know how to test and manufacture them.

The downside is that they’re time-consuming to make. There’s a ton of material in each dose of a vaccine. Most of that material is biological, which means you have to grow it. That takes time, unfortunately.

That’s why I’m particularly excited by two new approaches that some of the candidates are taking: RNA and DNA vaccines. If one of these new approaches pans out, we’ll likely be able to get vaccines out to the whole world much faster. (For the sake of simplicity, I’m only going to explain RNA vaccines. DNA vaccines are similar, just with a different type of genetic material and method of administration.)

Our foundation—both through our own funding and through CEPI—has been supporting the development of an RNA vaccine platform for nearly a decade. We were planning to use it to make vaccines for diseases that affect the poor like malaria, but now it’s looking like one of the most promising options for COVID. The first candidate to start human trials was an RNA vaccine created by a company called Moderna.

Here’s how an RNA vaccine works: rather than injecting a pathogen’s antigen into your body, you instead give the body the genetic code needed to produce that antigen itself. When the antigens appear on the outside of your cells, your immune system attacks them—and learns how to defeat future intruders in the process. You essentially turn your body into its own vaccine manufacturing unit.

Because RNA vaccines let your body do most of the work, they don’t require much material. That makes them much faster to manufacture. There’s a catch, though: we don’t know for sure yet if RNA is a viable platform for vaccines. Since COVID would be the first RNA vaccine out of the gate, we have to prove both that the platform itself works and that it creates immunity. It’s a bit like building your computer system and your first piece of software at the same time.

Even if an RNA vaccine continues to show promise, we still must continue pursuing the other options. We don’t know yet what the COVID-19 vaccine will look like. Until we do, we have to go full steam ahead on as many approaches as possible.

It might not be a perfect vaccine yet—and that’s okay.

The smallpox vaccine is the only vaccine that’s wiped an entire disease off the face of the earth, but it’s also pretty brutal to receive. It left a scar on the arm of anyone who got it. One out of every three people had side effects bad enough to keep them home from school or work. A small—but not insignificant—number developed more serious reactions.

The smallpox vaccine was far from perfect, but it got the job done. The COVID-19 vaccine might be similar.

If we were designing the perfect vaccine, we’d want it to be completely safe and 100 percent effective. It should be a single dose that gives you lifelong protection, and it should be easy to store and transport. I hope the COVID-19 vaccine has all of those qualities, but given the timeline we’re on, it may not.

The two priorities, as I mentioned earlier, are safety and efficacy. Since we might not have time to do multi-year studies, we will have to conduct robust phase 1 safety trials and make sure we have good real-world evidence that the vaccine is completely safe to use.

We have a bit more wiggle room with efficacy. I suspect a vaccine that is at least 70 percent effective will be enough to stop the outbreak. A 60 percent effective vaccine is useable, but we might still see some localized outbreaks. Anything under 60 percent is unlikely to create enough herd immunity to stop the virus.

The big challenge will be making sure the vaccine works well in older people. The older you are, the less effective vaccines are. Your immune system—like the rest of your body—ages and is slower to recognize and attack invaders. That’s a big issue for a COVID-19 vaccine, since older people are the most vulnerable. We need to make sure they’re protected.

The shingles vaccine—which is also targeted to older people—combats this by amping up the strength of the vaccine. It’s possible we do something similar for COVID, although it might come with more side effects. Health authorities could also ask people over a certain age to get an additional dose.

Beyond safety and efficacy, there are a couple other factors to consider:

  • How many doses will it be? A vaccine you only get once is easier and quicker to deliver. But we may need a multi-dose vaccine to get enough efficacy.
  • How long does it last? Ideally, the vaccine will give you long-lasting protection. But we might end up with one that only stops you from getting sick for a couple months (like the seasonal flu vaccine, which protects you for about six months). If that happens, the short-term vaccine might be used while we work on a more durable one.
  • How do you store it? Many common vaccines are kept at 4 degrees C. That’s around the temperature of your average refrigerator, so storage and transportation is easy. But RNA vaccines need to be stored at much colder temperature—as low as -80 degrees C—which will make reaching certain parts of the world more difficult.

My hope is that the vaccine we have 18 months from now is as close to “perfect” as possible. Even if it isn’t, we will continue working to improve it. After that happens, I suspect the COVID-19 vaccine will become part of the routine newborn immunization schedule.

Once we have a vaccine, though, we still have huge problems to solve. That’s because…

We need to manufacture and distribute at least 7 billion doses of the vaccine.

In order to stop the pandemic, we need to make the vaccine available to almost every person on the planet. We’ve never delivered something to every corner of the world before. And, as I mentioned earlier, vaccines are particularly difficult to make and store.

There’s a lot we can’t figure out about manufacturing and distributing the vaccine until we know what exactly we’re working with. For example, will we be able to use existing vaccine factories to make the COVID-19 vaccine?

What we can do now is build different kinds of vaccine factories to prepare. Each vaccine type requires a different kind of factory. We need to be ready with facilities that can make each type, so that we can start manufacturing the final vaccine (or vaccines) as soon as we can. This will cost billions of dollars. Governments need to quickly find a mechanism for making the funding for this available. Our foundation is currently working with CEPI, the WHO, and governments to figure out the financing.

Part of those discussions center on who will get the vaccine when. The reality is that not everyone will be able to get the vaccine at the same time. It’ll take months—or even years—to create 7 billion doses (or possibly 14 billion, if it’s a multi-dose vaccine), and we should start distributing them as soon as the first batch is ready to go.

Most people agree that health workers should get the vaccine first. But who gets it next? Older people? Teachers? Workers in essential jobs?

I think that low-income countries should be some of the first to receive it, because people will be at a much higher risk of dying in those places. COVID-19 will spread much quicker in poor countries because measures like physical distancing are harder to enact. More people have poor underlying health that makes them more vulnerable to complications, and weak health systems will make it harder for them to receive the care they need. Getting the vaccine out in low-income countries could save millions of lives. The good news is we already have an organization with expertise about how to do this in Gavi, the Vaccine Alliance.

With most vaccines, manufacturers sign a deal with the country where their factories are located, so that country gets first crack at the vaccines. It’s unclear if that’s what will happen here. I hope we find a way to get it out on an equitable basis to the whole world. The WHO and national health authorities will need to develop a distribution plan once we have a better understanding of what we’re working with.

Eventually, though, we’re going to scale this thing up so that the vaccine is available to everyone. And then, we’ll be able to get back to normal—and to hopefully make decisions that prevent us from being in this situation ever again.

It might be a bit hard to see right now, but there is a light at the end of the tunnel. We’re doing the right things to get a vaccine as quickly as possible. In the meantime, I urge you to continue following the guidelines set by your local authorities. Our ability to get through this outbreak will depend on everyone doing their part to keep each other safe.