Contribute Try STAT+ Today

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.

advertisement

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.”

advertisement

Support STAT: If you value our coronavirus coverage, please consider making a one-time contribution to support our journalism.

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.

Trump - National Institutes of Health's Vaccine Research Center
President Trump is shown a vaccine model during a tour of the National Institutes of Health’s Vaccine Research Center in Bethesda, Md., on March 3. BRENDAN SMIALOWSKI/AFP via Getty Images

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.

  • Does scientist try all the antibiotics to cure this COVID-19 Virus? Did they try Clarithromycin Antibiotic? Clarithromycin is used to treat many different types of bacterial infections affecting the skin and respiratory system.

    • Why would someone use an antibiotic to treat a viral infection..?

  • It difficult to produced vaccination like HIV . Covid 19 genes modified
    vaccination being hybrid in nature genetically Dr. V. B BORADE. Frof. MEDICINE. LECTURES GIVEN ON Vaccinations.

  • Vaccine development is an old piece of science and has’nt progressed very much. Where is modern technology? These days with the introduction of robotics, computing, etc, many cannot even thing logically any longer. Very sad state of affairs.

  • What if instead of synthesizing antigens, we’d biosynthesize nanoparticles which would enable human cells to constantly pyrolyze viral RNA without needing to elicit an identify and attack response from the immune system the way vaccines do, but would instead prevent transcription through the same protective mechanism provided by some secoiridoid phenols like oleuropein, or by targeting viral glycoprotein to inhibit viral interaction with receptor cells the same way some polyphenols do?

    • Both SARS-CoV-2 and SARS-CoV before it enter human host cells via the ACE-2 receptor. There has been some research into preventing this interaction ever since SARS-CoV’s mechanism of cell entry was discovered. It’s been a neglected area for years, but has gotten some renewed interest for the past couple of months.

      As for inhibiting viral RNA – siRNA would be the closest thing to what you are suggesting. However the technology has its problems (difficulty of targeting, difficulty of delivery into cells, and an immune response against the siRNA by the body). The important thing to realize about this kind of technology is that it cannot stop the virus, only slow it down (you won’t block all RNA translation). But it buys your immune system some time to fight the infection. A vaccine remains important.

  • If coronvirus changes its genetic material in response to possible treatment then why can’t scientists or biologists produce a vacvine or drug that can inhibit its growth in all its possilbe changing genetic forms

    • Immunology is all about shapes. The immune system recognizes small specific, often repetitive, shapes on viruses, and makes antibodies that attach to those shapes.

      When a virus mutates it changes its shapes. That makes it impossible for the old antibodies to recognize it. There are so many permutations of how a shape can change that it is impossible to anticipate what the mutation will be (think of all the possible combinations on a rubix cube for example).

  • All hopeful but Human biological interaction with medical solutions beyond the computer simulation stage don’t always go to plan so human trials are where the rubber meets the road and hopefully success

  • I love the phrase of “synthetic biologists” in the title–android researchers are going to rescue us . . .

  • If this R&D delivers, its technology could also address the dire global shortfall in developing anti-microbials, anti-fungals, antibiotics. The minuscule bugs are beating their human hosts, evidenced by the global SARS-CoV2 spread. The current global emergency response is long overdue, and advanced cyber tech could deliver permanent R&D against these powerful tiny killers.

  • This approach can likely avoid / correct any negative side effects of vaccines (many caused by adjuvants). The Bill and Melinda Gates Foundation is on a tech-track speeding up direly needed research & solutions for a “universal” coronavirus vaccine for broad-scale use, likely far more effective than any currently around. Count our lucky stars for this tremendous progress.

    • i am no scientist but it seems to me a lot could be learned from going back to the virus source in bats and study of the immune system of the baby bats and stem cell research to study their immune system and the corona virus and the development of vaccines that target the cause of the virus first from the hosts and its transmission to the human race perhaps then when a vaccine is found and developed a world wide effort to immunize the corona virus in bats as the source letting their own breeding cycle eradicate the disease globally would be beneficial to the human race instead of letting this virus mutate with more deadly strains in humans ,,,, just a thought to a sensible scientific approach ,,,,,,,,,,,,,,,,,,,,,,,,, kind regards ,,,,, james booth

Comments are closed.