Home >Science >health >Inside the race to crack the Covid-19 vaccine

Something strange happened. On Monday, 18 May, Moderna, a biotech company based in the US, held a press conference in which it released positive preliminary data on its ongoing vaccine program for covid-19. Its stock price reached stratospheric heights.

The following day, perhaps suffering from the hangover of the initial euphoria, with the sobering realization that there is still a long way to go before any vaccine can be deemed successful, Moderna’s share price started to slide.

We really need a vaccine. SARS-CoV-2, the pandemic coronavirus that causes covid-19 has infected over five million people globally. Ravaging much of Asia, Europe, and North America, it is now intensifying in South America and Africa. Because it is a new virus that spreads like wildfire, the only hope of ending the pandemic lies in a substantial portion of the global population developing some form of immunity.

Such immunity can come from fighting and clearing the virus, but at least half of the world’s population, and perhaps up to 70% would need to be infected to acquire such “herd immunity". And because of the significant lethality of the disease especially among certain vulnerable populations, experts believe the loss of life that would occur in order to get to herd immunity quickly would make this option broadly undesirable.

There’s another way to beat the virus with a much softer landing: a vaccine. That’s why there has never been a push for a vaccine like this in human history, using so many different, unique platforms. And all vaccine-makers want something called “sterilizing immunity" in which the vaccine prevents infection altogether.

An engineer taking samples of monkey kidney cells as he tests an experimental vaccine for covid-19 at the Sinovac Biotech facilities, Beijing
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An engineer taking samples of monkey kidney cells as he tests an experimental vaccine for covid-19 at the Sinovac Biotech facilities, Beijing

The contenders

Vaccine-watchers can take heart in knowing that there are now ten different vaccine candidates being tested on healthy volunteers. A further 114 are in earlier stages of development (including a handful by Indian companies).

The top ten vaccines are in the stage where they’re being tested to see if they’re safe, and if they actually can get an immune response. Then, more people will be vaccinated to see if the vaccines actually work. In the last hurdle, even more people will be tested to get a clearer picture of whether the vaccine works in a diverse population. No vaccine has passed the second hurdle, or gotten near the third hurdle yet, but the news so far is promising.

Four of the ten are inactivated vaccines, which contain actual virus particles that have been killed by chemicals. This is the basis for traditional vaccines that you and I have received for other diseases. Because they use actual viruses, the safety protocol is extensive. Of these four inactivated vaccines (all led by Chinese institutions), Sinovac Biotech Ltd has one which seems to be the furthest along the way.

The other six vaccines use experimental platforms that don’t actually need the virus. The downside is they’re very new and none of them have resulted in commercially-available vaccines yet. So, there’s more limited experience with working with these systems.

On Monday, Novavax, a US-based company announced they had started testing their candidate in Australia. This vaccine uses new technology in which virus protein is made in large vats, packed into nanoparticles, and injected into the body. The immune system recognizes these virus parts are “alien" and makes antibodies against them.

Other next-generation vaccines use genetic information to get human cells to create the virus parts. The idea is getting deoxyribonucleic acid (DNA) or better yet, ribonucleic acid (RNA) into the body where it can serve as a blueprint for the cellular machinery to make parts of a virus that launch the immune response.

Inovio Pharmaceuticals is going the route of a vaccine with a virus gene inserted into a piece of DNA in the shape of a garland. Moderna and its collaborators are skipping a few steps altogether and using a kind of RNA that cells can use to make virus proteins that trigger the immune system.

Finally, there are two that contain the DNA blueprint inserted into the shell of a dead common cold virus. One of these is by CanSino Biologics of China, along with Beijing Institute of Biotechnology. On Friday, in The Lancet, they showed their candidate vaccine is safe and generates antibodies in humans.

The other vaccine of this kind has a DNA blueprint in a chimpanzee virus-shell. This vaccine by the University of Oxford team in the UK, in conjunction with AstraZeneca partially works in rhesus macaque monkeys: the vaccine is safe, and prevents serious pneumonia, but doesn’t block onward spread. But the crucial proof will be whether it works in people.

The headquarters of Moderna, which is also working on a vaccine, in Cambridge, Massachusetts
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The headquarters of Moderna, which is also working on a vaccine, in Cambridge, Massachusetts

How it works

How would a vaccine work? If infection with SARS-CoV-2 results in immunity, then we can hope that vaccination might do the same. So it’s important to track the immune responses in the body.

The crucial missing information right now is how many antibodies that stop the virus are needed to get a pretty good immune response. There are reports that people who have mild infections don’t generate many antibodies naturally. The good news is that recent reports indicate that natural infection with SARS-CoV-2 provides some level of protection from reinfection in most other people.

The other really good news is that recovering patients generate T cells: these cells can be thought of as the conductors of the immune response orchestra. So, we should expect a robust vaccine to stimulate T cells and antibodies like in a natural infection. Though, we don’t yet know the duration of immunity, if SARS-CoV-2 is anything like SARS coronavirus and MERS coronavirus, it might be expected to last 2-3 years.

For a completely new virus, a vaccine takes 10 years or more to develop. Even for ebola, which was fast-tracked, it took 5 years to progress into clinical trials. Vaccine development is moving at warp speed, counting in days from when the genome was sequenced in January.

Steps in the process of vaccine development have been accelerated and contracted. Assumptions have been made about a covid-19 vaccine based on experience with other vaccine development programmes, and on the biology of other coronaviruses like SARS and MERS. And perhaps, most importantly new experimental technologies and platforms are being used.

Like for SARS coronavirus and MERS coronavirus, the spike protein, which gives SARS-CoV-2 its sun-like appearance, is absolutely vital for infection. The spike protein is like a key that helps the virus open the lock of the cell, called an “ACE2 receptor". The ACE2 receptor is a protein that normally functions to regulate blood pressure, but the virus uses it to get into cells. If the spike protein of the virus can be blocked, there’s no infection.

With SARS-CoV-2, researchers didn’t wait for the shape of the spike protein, or all the steps in infection to be elucidated: they figured that the spike protein, and specifically a piece of it involved in opening the lock, needed to be obstructed by antibodies. There are many candidate vaccines, but almost all of them are trying to do one thing: latch on to the spike protein so it can’t “open" the ACE2 receptor.

The timelines

Vaccine development follows a standard timeline. Once a candidate vaccine is developed, it is tested in animals that recapitulate infection and immunity. The toxicity of the vaccine is noted and the animal is “challenged" to see if infection occurs. Researchers then have an early idea of whether the vaccine might stand a chance of even working.

When the genome of SARS-CoV-2 was released in January, there were no model animals for covid-19. So, most vaccine programmes went into human trials based on data on previous vaccines, while animal models were developed. It took a few months, but now researchers have non-human primates (rhesus macaque monkeys), transgenic mice, and ferrets. We are now getting reports of how candidate vaccines work in animals.

After that it’s on to people. The first stage of clinical trials in humans, known as phase I, tests the safety of the vaccine and whether any antibodies at all (not necessarily ones that prevent infection) are created. And as part of phase I, vaccine programmes check for safety, ability to generate antibodies, and possible dosage for broader trials in healthy human volunteers.

This is the furthest any candidate vaccine has progressed so far, and this is vital to remember to set expectations. We won’t actually know if a vaccine works in people, until it goes into phase II, which checks for effectiveness. And phase III, is when the vaccine is dosed in a larger, more diverse population. Many vaccines drop out at each step of the way, and that’s by design.

There’s a lot of sensitivity to the use of vaccines, starting with safety. Unlike with a drug administered to those who are sick and need it, vaccines are mass-produced to be given to large populations of those who are healthy. Therefore, it is absolutely vital to get it right.

Also, more than 99% of people infected with SARS-CoV-2 will clear the virus on their own and will produce antibodies. Some researchers believe that improper vaccines can generate antibodies that are weak, or which can actually help coronavirus infect cells, something called immune enhancement.

Something like that shouldn’t happen with a vaccine given to millions of people. What everyone agrees is that even in the middle of a pandemic, the adverse effects of a vaccine should not be comparable or worse to the actual disease.

The status report

As things stand, there is sufficient cause for cautious optimism. So far, many of the candidate vaccines that have made it through animals and phase I are on track, and we should watch them closely.

Moderna has arguably generated the most praise and heat so far. Last week in their press release, they highlighted preclinical and partial phase I data. In mice, their vaccine stops SARS-CoV-2 from making more copies of itself, something that we want to see in an animal study.

In humans, Moderna’s data indicated that their vaccine is safe in low doses. There were some minor reactions at higher doses, but those won’t be used. There’s never been a commercially available RNA vaccine before. What Moderna’s observation tells us is that even if this particular vaccine fails, this class of vaccine might work.

Moderna also met another goal of their phase I to see if antibodies (not just ones that stop infection) can be generated in people. Moderna saw that the amount of the immune response increased with the dose of the candidate vaccine, something you would want to see in a trial.

Finally, Moderna was able to use the trials to tweak the dosage. The early results were successful in showing what a trial of this nature is supposed to show, though criticisms that they didn’t publish all of their data are valid.

Unfortunately, none of these data generated as much excitement as the very preliminary observation that the first eight volunteers that received the vaccine that they tested had not only broad antibodies but specific ones, which could defeat the virus in the lab. What are we to make of this data? Well, as you probably figured: we can’t conclude anything yet. Eight people is still too few, and we don’t have a benchmark for how much of these antibodies are needed to prevent infection.

It’s still too early to crack open champagne bottles, because we don’t have a clear indication yet of which vaccines, if any, will work in people. But there are promising early signs that a vaccine that will defeat SARS-CoV-2 might be possible.

There are long months ahead, and getting a vaccine that works is only half the battle, however. We also have to ensure that 8 billion people, of which 1.4 billion are Indians, can get vaccinated rapidly.

Fortunately, India has some of the leading vaccine-makers in the world. Serum Institute of India, the world’s largest, is working on a candidate vaccine of its own with Codagenix, a company in the US. This hasn’t made it to human tests, so there’s not a lot to talk about yet. But they’re also collaborating with the Oxford/AstraZeneca team: should either vaccine work, they will rapidly create hundreds of millions of doses for India’s population.

Anirban Mahapatra trained as a microbiologist and is assistant director at the American Chemical Society. These are his personal views.

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