The invention of Covid-19 vaccines will be remembered as a milestone in the history of medicine, creating in a matter of months what used to take a decade. But Dr. Kayvon Modjarrad, director of the Section for Emerging Infectious Diseases at the Walter Reed Army Research Institute in Silver Springs, Maryland, is not satisfied.
“This is not fast enough,” he said. More than 2.3 million people worldwide have died and many countries will not have full access to vaccines for another year or two: “Fast – really fast – it’s getting there on the first day.”
There will be more outbreaks of coronavirus in the future. Bats and other mammals are full of strains and species of this abundant virus family. Some of these pathogens will inevitably cross the species barrier and cause new pandemics. It’s only a matter of time.
Dr. Modjarrad is one of many scientists who have been calling for a different type of vaccine for years: one that can work against all coronaviruses. These calls were largely ignored until Covid-19 demonstrated how disastrous coronaviruses can be.
Now researchers are beginning to develop prototypes of a so-called pancoronavirus vaccine, with some promising, albeit early, results of animal experiments. Dr. Eric Topol, professor of molecular medicine at the Scripps Research Institute in San Diego, thinks that scientists should join another large-scale vaccine project immediately.
“We have to get a real workforce to accelerate this, so that we can have this year,” he said. Dr. Topol and Dennis Burton, an immunologist at Scripps, called for this project on coronavirus vaccines on Monday in the journal Nature.
After coronaviruses were first identified in the 1960s, they did not become a high priority for vaccine manufacturers. For decades, it seemed that they caused only mild colds. But in 2002, a new coronavirus called SARS-CoV emerged, causing a deadly pneumonia called severe acute respiratory syndrome, or SARS. Scientists struggled to make a vaccine for him.
Since no one had made a coronavirus vaccine for humans before, there was a lot to learn about its biology. Finally, the researchers chose a target for immunity: a protein on the surface of the virus, called pico. The antibodies that adhere to the peak can prevent the coronavirus from entering cells and stop an infection.
Public health officials in Asia and elsewhere did not expect the invention of a SARS vaccine to start working, however. Its quarantines and other efforts have proved remarkably effective. In a matter of months, they eliminated SARS-CoV, with only 774 deaths along the way.
The danger of coronaviruses became even clearer in 2012, when a second species spread from bats, causing yet another deadly respiratory disease called MERS. The researchers began to work with MERS vaccines. But some researchers wondered whether making a new vaccine for each new coronavirus – what Modjarrad calls a “bug, drug approach” – would be the smartest strategy. Wouldn’t it be better, they thought, if a single vaccine could work against SARS, MERS and any other coronavirus?
That idea hasn’t gone anywhere for years. MERS and SARS caused relatively few deaths and were soon eclipsed by outbreaks of other viruses, such as Ebola and Zika.
In 2016, Maria Elena Bottazzi, a virologist at Baylor College of Medicine, and her colleagues requested support from the US government to develop a vaccine against pancoronavirus, but did not receive it. “They said there is no interest in pancorona,” recalls Bottazzi.
His team even lost funding to develop a SARS vaccine after it was shown to work in mice, was non-toxic to human cells and could be manufactured on a scale. A coronavirus that had disappeared from view was simply not a priority.
Without enough money to start clinical trials, scientists stored their SARS vaccine in a freezer and went on to further research. “It has been a struggle,” said Bottazzi.
Dr. Matthew Memoli, a virologist at the National Institute of Allergy and Infectious Diseases, views these decisions as a huge mistake. “It is a failure of our science system,” he said. “Funders tend to chase shiny objects.”
Three years later, a third dangerous coronavirus emerged: the SARS-CoV-2 strain that causes Covid-19. Although this virus has a much lower mortality rate than its cousins that cause SARS and MERS, it does a much better job of spreading from person to person, resulting in more than 106 million documented cases worldwide and still increasing.
All the lessons the researchers learned about coronaviruses helped them to act quickly to make new vaccines against SARS-CoV-2. Dr. Bottazzi and her colleagues used the technology they created to make vaccines against SARS to make one for Covid-19, which is now in the first clinical trials.
Other researchers have used even newer methods to move faster. The German company BioNTech created a genetic molecule called messenger RNA that encodes the spike protein. In partnership with Pfizer, the companies received authorization from the US government for their vaccine in just 11 months. The previous record for a vaccine against chickenpox was four years.
Although the Covid-19 pandemic is far from over, several researchers are calling for preparations for the next deadly coronavirus.
“This has already happened three times,” said Daniel Hoft, a virologist at Saint Louis University. “It is very likely that it will happen again.”
Researchers at VBI Vacines, a Cambridge-based company, took a small step toward a pancoronavirus vaccine last summer. They created virus-like shells studded with peak proteins from the three coronaviruses that caused SARS, MERS and Covid-19.
When the researchers injected this three-pointed vaccine into mice, the animals produced antibodies that worked against the three coronaviruses. Interestingly, some of these antibodies can also attach to a fourth human coronavirus that causes seasonal colds – although the peak proteins from that virus have not been included in the vaccine. Scientists have made this data public, but have not yet published it in a scientific journal.
David Anderson, VBI’s scientific director, said it was unclear why the vaccine worked this way. One possibility is that an immune cell presented with several versions of a protein at the same time does not produce antibodies against just one. Instead, it creates a compromise antibody that works against them all.
“You are educating this,” said Anderson, although he warned that this was speculation for now.
Last month, Pamela Bjorkman, a structural biologist at Caltech, and her colleagues published a more extensive experiment with a universal coronavirus vaccine in the journal Science. The researchers attached only the tips of the peak proteins from eight different coronaviruses to a protein nucleus, known as a nanoparticle. After injecting these nanoparticles into mice, the animals generated antibodies that could attach to all eight coronaviruses – and four other coronaviruses that scientists did not use in the vaccine.
Dr. Modjarrad is leading a team at Walter Reed in the development of another vaccine based on a nanoparticle studded with protein fragments. They anticipate the start of clinical trials in volunteers next month. Although the vaccine currently uses protein fragments only from SARS-CoV-2 peaks, Dr. Modjarrad and his colleagues are preparing to reformulate it as a vaccine against pancoronavirus.
Dr. Hoft of Saint Louis University is working on a universal vaccine that does not depend on antibodies to the peak protein. Collaborating with Gritstone Oncology, a California-based biotechnology company, he created a vaccine that stimulates cells to produce surface proteins that can alert the immune system as if a coronavirus – any coronavirus – is present. They are now preparing a clinical trial to see if it is effective against SARS-CoV-2.
“We are interested in perhaps developing a third generation vaccine, which is on the shelf and ready for the future outbreak,” said Hoft.
Dr. Topol believes that scientists should also explore another strategy: researching antibodies against pancoronavirus produced by our own body during infections.
Researchers studying HIV and other viruses have found, among the billions of antibodies produced during an infection, rare types that act against a wide variety of related strains. It may be possible to create vaccines that induce the body to produce abundant amounts of these widely neutralizing antibodies.
Coronaviruses are similar to each other, said Topol, which may not be so difficult to build vaccines that produce widely neutralizing antibodies. “This is a family of viruses that are easy to eliminate,” he said.
The search for a pancoronavirus vaccine may take longer than Dr. Topol’s expectations. But, even if it takes a few years, it can help prepare the world for the next coronavirus that will jump the species barrier.
“I think we can have vaccines to prevent pandemics like this,” said Memoli. “None of us want to go through this again. And we don’t want our children to go through this again, or our grandchildren, or our descendants 100 years from now. “