Even as companies rush to develop and test vaccines against the new coronavirus, the Bill and Melinda Gates Foundation and the National Institutes of Health are betting that scientists can do even better than what’s now in the pipeline.
If, as seems quite possible, the Covid-19 virus becomes a permanent part of the world’s microbial menagerie rather than being eradicated like the earlier SARS coronavirus, next-gen approaches will be needed to address shortcomings of even the most cutting-edge vaccines: They take years to develop and manufacture, they become obsolete if the virus evolves, and the immune response they produce is often weak.
With Gates and NIH funding, the emerging field of synthetic biology is answering the SOS over Covid-19, aiming to engineer vaccines that overcome these obstacles. “It’s all of us against the bug,” said Neil King of the University of Washington, who has been part of the hunt for a coronavirus vaccine since 2017.
Although the Gates Foundation is spreading its bets among several cutting-edge vaccine platforms, including those using genetic material, one based on synthetic biology has real promise. “We may need an approach that can get you millions and even billions of doses,” said immunologist and physician Lynda Stuart, who directs the foundation’s vaccine research. Gates announced last month that it will funnel $60 million to Covid-19 research, including vaccines.
A vaccine created through the tinkering of synbio looks not only scalable to a level of billions but also like it will work without the need for refrigeration. All that, Stuart said, “will be super important to protect people from coronavirus who are otherwise left behind, such as those in sub-Saharan Africa.”
King and his synbio colleagues knew there would be another coronavirus epidemic, like the SARS and MERS outbreaks before this one, he said, “and there will be another one after this,” perhaps from yet another member of this virus family. “We need a universal coronavirus vaccine.”
Achieving that is so high on scientists’ to-do list that when President Trump visited NIH last week, his tour included the lab that’s collaborating with UW’s, and researchers showed him a mock-up of what synthetic biology can do: Design and build nanoparticles out of proteins and attach viral molecules in a repetitive array so that, when the whole thing is packed into a vaccine, it can make people resistant to the new coronavirus. (The human immune system has evolved to interpret repetitive arrangements of molecules as a sign of danger: bacterial cell walls have repetitive chemical groups on them.)
With a few tweaks, the nanoparticle can be studded with molecules from additional coronaviruses to, scientists hope, protect against all of them — the original SARS virus, MERS, and, crucially, a mutated form of the Covid-19-causing virus, called SARS-CoV-2.
Even compared to the DNA and RNA vaccines against Covid-19 that Moderna Therapeutics, CureVac, and Inovio Pharmaceuticals are speeding toward human testing, the synbio approach has advantages. These companies’ experimental vaccines contain synthetic (that is, lab-made) strands of RNA or DNA that code for protein molecules on the virus’s surface. Once the vaccine delivers the genetic material into cells, the cells follow the genetic instructions to churn out the viral protein. The idea is that the body would see that as foreign, generate antibodies to it, and if all goes well thereby acquire immunity to the virus. But safety tests of mRNA vaccines have turned up adverse events, and it’s not clear how potent they’ll be. Moderna plans to begin safety testing in healthy volunteers next month.
With all due respect to nature, synthetic biologists believe they can do better. Using computers, they are designing new, self-assembling protein nanoparticles studded with viral proteins, called antigens: these porcupine-like particles would be the guts of a vaccine. If tests in lab animals of the first such nanoparticle vaccine are any indication, it should be more potent than either old-fashioned viral vaccines like those for influenza or the viral antigens on their own (without the nanoparticle).
The first step toward the molecule that was presented to Trump is to “play Legos with proteins,” as King put it.
That starts with the nanoparticle — the body of the porcupine. Its shape and composition must be such that the protein’s building blocks not only spontaneously self-assemble and stick together but also turn into something that can display the viral antigens in a way the immune system will strongly respond to. Using a computational protein-design algorithm, scientists might determine that, for instance, a nanoparticle 25 nanometers across and made of 60 identical pieces is ideal for presenting the antigens sotheir most immunity-inducing side faces outward, where the immune system can most easily “see” it.
“We might try 1 million variants on the computer” before finding the optimal shape and protein composition, meaning which protein sequence will spontaneously form the ideal nanoparticle, King said.
The next step is to take lab-made DNA that codes for the designed protein, stick it into E. coli bacteria, and wait for the bugs to follow the genetic instructions, manufacturing the desired protein like a tiny, living assembly line. Extracted from the bacteria, purified, and mixed together in a test tube, the proteins spontaneously self-assemble into the bespoke nanoparticle.
“When it works, we get exactly the protein we designed by computer, with every atom where we want it,” King said.
The next step is to stick the quills onto the porcupine. For the virus that causes Covid-19, the quills are the “spike protein,” a molecule that fits into receptors on cells and ushers the virus inside. Scientists led by UW’s David Baker predicted the structure of this antigen from the virus’s genome, and scientists at the University of Texas, Austin, and NIH confirmed it with a Nobel-winning form of electron microscopy.
King and his colleagues then scrutinize the spike protein to see which part of it might work best in a vaccine and how to position multiple copies of it. “It turns out that if you stick 20 of them onto your nanoparticle in an ordered, repetitive array, you can get a stronger immune response than with the [spike] protein alone,” Baker said — another reason why the nanoparticle approach might prove more effective than RNA and DNA vaccines. NIH and the UW groups have begun testing the antigen-studded nanoparticles in mice to see what kind of immune response they trigger.
Making nanoparticles the core of a vaccine “does a number of useful things,” Stuart said. It reduces or eliminates the need for an adjuvant, an ingredient that boosts the immune response; the nanoparticle is enough on its own. Sticking antigens on it makes the whole complex so tolerant of heat (“you could almost boil it,” Stuart said) that refrigeration isn’t necessary, a crucial feature for vaccines to be deployed in resource-poor countries. And because the nanoparticle can be studded with antigens from several viruses, she said, “you could get a pan-coronavirus vaccine.”
They’re cautiously optimistic because of a recent success. An experimental vaccine against respiratory syncytial virus (RSV), the main cause of pneumonia in children, is also made of a computer-designed nanoparticle that self-assembles from protein building blocks and is studded with an engineered version of RSV’s key antigen. When tested in mice and monkeys, it produced 10 times more antibodies than an experimental RSV vaccine based on traditional technology, King’s team reported last year in Cell. The Seattle biotech start-up Icosavax is moving the vaccine toward clinical trials. (King chairs its scientific advisory board.)
It was the first time the structure and other characteristics of an antigen had been designed at the atomic level and incorporated into a vaccine, scientists at vaccine giant GSK wrote, hailing the work as “a quantum leap” in vaccine design.
The Gates Foundation, in addition to supporting the research, is working to pair the scientists with manufacturers, Stuart said: “We want to identify the people who can manufacture these at scale.”
As Covid-19 spreads, “scale” is looking larger than anyone imagined.