A key potential new coronavirus vaccine Bottazzi’s research group is working on is derived from the new coronavirus’s spike protein. (The group is actually building upon previous work they did on a vaccine for SARS-CoV, Bottazzi explains.) The spike protein is on the outside of the virus and gives the pathogen its name; the proteins look like the spikes of a crown. “These spike proteins are what the virus utilizes to bind to a human cell receptor,” Bottazzi says. The spike protein binding allows the virus to enter the cell and replicate. So, if you block spike proteins from binding to receptors, you can stop the virus from attaching in the first place and prevent the infection.
“Most of the [new coronavirus] vaccines that are being developed focus on trying to block this [protein],” Bottazzi says. Falzarano agrees. “We are pretty sure that we need to use the spike protein as the vaccine antigen,” he says.
Researchers also have to figure out how much of the antigen they can use to produce the right level of an immune response. Too little of the antigen might not stoke the immune system enough, whereas too much of it might create such an intense immune reaction that it inadvertently causes damage to the animal or person being tested. It’s a fine line. What Bottazzi’s group has done is focus on a piece of the spike protein called the receptor-binding domain, breaking it down into smaller and smaller pieces “until we found the minimal amount that we needed to … induce a very robust immune response but without that immune enhancement [that harmed the host],” she explains.
Once researchers have decided on an antigen to use and how much of it, they then have to determine how to produce the antigen so they can include it in vaccines, says Falzarano. “There are lots of different ways to do this,” he explains, including producing the antigen in bacteria, yeast, insect cells, mammalian cells, and even plant cells. Many vaccines that are not only proven to be safe and effective but also relatively cheap to mass-produce are made using proteins that organisms like bacteria and yeast synthetically produce, Bottazzi says. This is how other vaccines on the market, including the Hepatitis B vaccine, protect against various infectious diseases. “Therefore we favor vaccines that use the same systems to be produced as other proven vaccines already in the market,” she says.
After that, researchers need to decide on the best way to deliver the antigen to the host, which will first be animals, then humans. There are lots of ways to do this, like as live attenuated vaccines (which contain weakened yet technically living antigens) and as inactivated vaccines (which contain dead antigens), says Falzarano.
There are pros and cons to every delivery method. For example, live attenuated vaccines often lead to longer-lasting immunity but can be tougher to transport and administer than other forms; inactivated vaccines are often safer but don’t usually produce as robust an immune response.
“We know various ways that we can deliver [the spike protein] antigen,” Falzarano says. “But we don’t really know the best way to do so.”
The first new coronavirus vaccine currently undergoing human clinical trials uses novel antigen delivery technology that has never resulted in a licensed vaccine. That technology involves mRNA (messenger RNA), molecules that carry DNA codes that the body uses to make various proteins. (Neither expert I spoke with for this piece is involved in developing this vaccine.)
Once researchers decide on the antigen delivery method, they can start testing on animals to see if the vaccine creates the immune response they’re looking for. Do the animals make antibodies that can fight off the virus? Do the antibodies stop the virus from infecting cells? (If so, these are called “neutralizing antibodies.”) After some observation, they can give the vaccinated animals the virus (“challenge” them with it, in science parlance) to see if the vaccine actually protects them against infection, or at least makes it less serious or deadly, Falzarano explains.