The science behind the race to develop a coronavirus vaccine

A vaccine for Covid-19 is soon to be injected into healthy volunteers in Seattle, US. The National Institutes of Health in the US will run these tests with a vaccine made by biotech firm Moderna.

"This was reputedly prepared and ready for testing in 42 days, which is an incredibly rapid response," says Prof Kingston Mills, immunologist at Trinity College Dublin. "Under normal circumstances to make a vaccine and have it approved for use could take 10 to 15 years."

Traditional vaccines are often made from live weakened viruses or viral proteins manufactured in cells. A big advantage with the new vaccine is that it is made from RNA, a simple biomolecule that is easier and faster to synthesise.

The RNA is placed inside a minuscule lipid particle. RNA is the code that the coronavirus inserts into our cells. Normally DNA is copied into messenger RNA in our cells, which is the blueprint to make proteins. The coronavirus hacks into this system to manufacture new coronaviruses.

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The RNA inside lipid is injected and gobbled up by patrolling immune cells in our bodies. These chop up and stick pieces of virus protein on their surface to alert and teach other immune cells about the virus.

German company CureVac is also advancing a RNA vaccine for Covid-19. CEO Ingmar Hoerr says they will make 10-gram batches of RNA, which is enough for thousands of vaccine doses. He says with more funding there is nothing to stop them making millions or even billions of doses.

However, there is no RNA vaccine approved for any disease yet. CureVac had an RNA vaccine for rabies in clinical trial, but is refocusing now on the coronavirus. It is expected that drug regulators will fast-forward approval for a pandemic vaccine.

“It could be ready in 12 to 18 months from now. That is great if it happens,” says Prof Mills.

Spikes

There are also DNA and protein vaccines. The target proteins are invariably the spikes that give the virus a crown-like appearance under an electron microscope – hence their name coronavirus.

Remarkably, Chinese scientists released the entire RNA sequence of the Covid-19 virus by early January. Scientists around the world then raced to copy the blueprint of all or some of the spike protein to make vaccine.

The spike is what the virus uses to harpoon on to a receptor (ACE2) on cells in our mouth, throat, lungs and gut. The immune cells and antibodies of a vaccinated person would be expected to spot the spike protein and neutralise the virus. Moderna’s vaccine encodes the entire spike protein.

Prof Robin Shattock at Imperial College London is now testing his own RNA vaccine based on the spike protein in lab animals. "With the right funding we hope to do first-in-human studies this summer to see if it induces the right antibody response in people," he says.

What will take time is people testing. "The science of what will make a good vaccine will happen very fast," predicts Prof Michael Farzan at the Scripps Institute in Florida – the scientist who first reported that SARS hooked on to ACE2 receptors in lung cells. "The problem is that production, distribution and testing can take a year or more."

Three steps

Testing happens in three steps. The first sees a small number of healthy adults given the vaccine to ensure it is safe, which may last two months. The Seattle trial will enrol 45 adults. Phase II trials test safety in a larger group of people and look for expected effects in the body.

Then comes the big one. “The stringent testing is in phase III. You are normally talking about tens of thousands of people being tested,” says Prof Mills. “They may change the rules when there’s a pandemic.”

It will be in the hands of the European Medicines Agency in Europe and the Food and Drug Administration in the US to decide if the vaccine can be licensed. This might be based on more limited safety and efficacy testing than normally required for a new vaccine.

While regulators might speed up decision-making, Prof Mills is adamant they will not bend the rules. “They will not regulate a vaccine unless happy it is safe and effective.”

He acknowledges frustration among the public that they cannot get a drug such an an antiviral or a vaccine. “But if you put something on the market that doesn’t work or causes side effects then you lose the confidence of the public,” says Prof Mills. “It has to be tested appropriately.”

Drug trials involve thousands of patients partly because small groups of people may turn out to be at risk of rare side effects, perhaps because of their age, or genetic makeup or underlying health conditions.

On the upside, the SARS-CoV-2 virus is not expected to change much. It has a very large genome and “a better proof reader” than other RNA viruses, such as influenza, which tends to make lots of mistakes (ie mutations).

“It tends to evolve slower than other RNA viruses,” says Prof Farzan. “So we should be in reasonable shape with vaccines based on early versions of the spike protein.”

Flu mutates so much that a new vaccine is needed every winter, and even then it is a best guess as to the dominant strains.

“I would say HIV is the hardest, flu is intermediate, and something like this coronavirus is relatively straightforward to develop a vaccine for,” Prof Farzan adds.

It may even be possible to make a vaccine against many of the coronaviruses in bats that might again jump to people and threaten another pandemic.

Immune response

Asked if a vaccine for just older people might be feasible, Prof Shattock at Imperial College London says this is unlikely. It could take longer to show a vaccine is effective in those aged over 65 as their immune response is not as strong.

“That said, vaccination of care givers and medical staff would do a lot to prevent exposure to the more vulnerable.”

Prof Mills does not think that a vaccine will be available by summer. There may be value to having a vaccine by 2021. We don’t know if this coronavirus will be seasonal like the flu, meaning that infections drop off during the summer when the weather warms up. “If it behaves like the flu then there is risk that it might come back in the autumn,” Mills notes.

There may be a vaccine available for the winter of 2021. There are plenty of intense efforts to generate one.

Inovio is a US biotech company developing a DNA vaccine for Covid-19. The DNA begets viral RNA and viral proteins. A group in Australia is developing stable viral protein as parts of its vaccine, and Novavax is working on a protein vaccine. All are funded by the Coalition for Epidemic Preparedness Innovations (CEPI), which also supports CureVac and a group at Oxford University.

CEPI was established in 2017 to speed vaccine development for new diseases. It was funded by governments in Germany, Japan and Norway, as well as the Bill & Melinda Gates Foundation and the Wellcome Trust. Its sense of emergency about the risk of a global pandemic caused by flu or a novel coronavirus has proven to be entirely justified.