StemCell Therapy

As a mystery illness started spreadingin China in late December, researchers at Inovio Pharmaceuticals were keeping aclose eye on what was happening, even before anyone knew the cause was acoronavirus.

The company, based in San Diego, is nostranger to the viruses. After MERS, which is caused by a different coronavirus, emergedin 2012, Inovio was one of the first to develop a still-experimental vaccinefor the disease. In the new outbreak, as soon as Chinese researchersposted the genetic makeup of the virus, dubbed SARS-CoV-2, the companysscientists sprang into action.

Wed all hoped that there would beenough overlap that our previously developed MERS vaccine would be helpful inthis case, says Kate Broderick, Inovios senior vice president for researchand development. Like MERS and SARS, the new virus is a coronavirus that usesRNA as its genetic material.

But in-depth analysis revealed that thetwo coronaviruses are too different for a vaccine against MERS, also known asMiddle East respiratory syndrome, to take down the new virus. So thecompanys researchers set about designing a new vaccine.

That design relies on a relatively newapproach to vaccine creation, one that the researchers used to develop the MERSvaccine. Traditional vaccines are composed of weakened or killed forms ofviruses or parts of viruses, including purified proteins. When injected into aperson, the immune system recognizes the virus as an invader and producesantibodies to stave off future invasions. But growing enough debilitated virusesor purifying enough proteins to make vaccine doses for millions of people can takemonths or even years.

So Inovio and other companies havedeveloped ways to make vaccines much more quickly. For their SARS-CoV-2 vaccine,Inovio scientists convert the viruss RNA into DNA and select pieces of thevirus that computer simulations have suggested will prod the immune system intomaking antibodies. Those selected bits of DNA are then inserted into bacteria,which produce large quantities of protein snippets to be used in the vaccine. Thisapproach drastically shortens the time it takes to make a vaccine. Atraditional vaccine takes two to three years to develop. For Inovios product,it took three hours to design and about a month to manufacture, Broderick says.

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Inovio started testing the vaccine inanimals at the beginning of February and hopes to begin safety tests in peopleby early summer.

Even so, Inovios vaccine is still atleast a year away from being widely used. As the number of cases of the novelcoronavirus disease, or COVID-19, continues to rise, several other groups are alsoracing to develop vaccines and therapeutics that take nontraditional approachesto fight the virus.

Researchers at the U.S. National Institute of Allergy and Infectious Diseases, working with the Cambridge, Mass.based biotechnology company Moderna, are developing a messenger RNA, or mRNA, vaccine that will stimulate the body to produce vaccine components. Messenger RNAs are copies of protein-making instructions encoded in the DNA of genes. Cellular machinery reads the mRNA instructions to build proteins.

Scientists have selected portions of SARS-CoV-2that may spark a vigorous immune reaction against the virus, says KizzmekiaCorbett, a viral immunologist at the NIAIDs Vaccine Research Center inBethesda, Md. The mRNA vaccine will tell human cells which viral proteins tomake, she says.

Were literally giving the cells agenetic code of our vaccine design, delivered as RNA that will tell cells, Hey,make this protein, says Corbett, who is the scientific lead on the centerseffort to develop the vaccine.

Those proteins Corbett wouldnt saywhich viral proteins will then prod the immune system to make antibodies toprotect against the virus. Since the body does all of the protein-productionwork with the mRNA vaccine, researchers can skip the time-consuming and costlystep of manufacturing vaccine proteins.

This strategy could be used to designvaccines against future coronaviruses or other emerging infectious diseases,Corbett says. What we feel we have developed is a universal strategy, beingable to quickly deploy a vaccine if another novel coronavirus should pop up,Corbett says. Other mRNA vaccines against MERS and other diseases are still inthe testing phase.

Corbett would not specify a timeline for her teams mRNA vaccine, but Anthony Fauci, director of NIAID, has said the mRNA vaccine could be ready for initial safety testing within months. But the researchers have yet to find a pharmaceutical company to manufacture the large quantities of mRNA doses that would be necessary for use by the general public, Fauci said February 11 in Washington, D. C., at a discussion of the new coronavirus at the Aspen Institute, a nonprofit organization.

Inovios experience with its MERSvaccine is one example of just how long it typically takes to make sure avaccine is safe and effective. Inovio conducted initial safety testing of theMERS vaccine in a PhaseI clinical trial from February 2016 to May2017. There were noserious side effects among the 75 healthy adult participants, theresearchers reported in 2019 in theLancet Infectious Diseases. The vaccine moved into a PhaseII trial in August 2018 to test safety in a larger number of people anddetermine whether the vaccine spurs the immune system to make protectiveantibodies. That trial is expected to wrap up later this year.

Even if everything goes swimmingly, theMERS vaccine must still pass Phase III safety and effectiveness testing beforebeing considered for approval by the U.S. Food and Drug Administration. Itsthe same gauntlet that all new vaccines and drugs must run.

Inovio and the NIAID/Moderna partnershiphave both received funding from the Oslo-based Coalition for EpidemicPreparedness Innovations. CEPI is also funding yet another type of novelvaccine development. CEPI and researchers from the University of Queensland inBrisbane, Australia, have found a way to clamp down on the coronavirus to keepit from infecting cells.

The Queensland group had already beenworking with CEPI on molecular clamp vaccines against other viruses for about ayear, says Trent Munro, a biotechnologist involved in the work. A molecularclamp is a protein stitched onto another protein, in this case the coronavirusspike protein. With SARS and MERS, spike proteins work a bit like malleablelock picks, changing shape to interact with a protein on the surface of humancells and gain entry into them. The 3-D structure of SARS-CoV-2s spike protein,reported online February 19 in Science,confirms the protein is also a shape-shifter.But the new coronavirus spike protein clings10 to 20 times as tightly to its target on human cells as the SARS versiondoes. Holding on tighter may help the new virus spread more easily from personto person, researchers say.

The molecular clamp the Queensland teamdevised keeps the spike protein from shape-shifting, locking it in a form that triggersantibody production and thus making it a potent vaccine, Munro says.

The team uses mammalian cells to producethe vaccine, and a specialized machine determines which cells are churning outclamped protein. With the machine, researchers can do things that would havetaken weeks before in just days, Munro says. Laboratory testing may start within weeks.Safety testing in people may begin in months, but it will take much longer for thevaccine to be ready for general use. When the Queensland group began workingwith CEPI to develop a molecular clamp vaccine, we thought it would take threeyears as a test case, Munro says. But the emergence of the new coronavirusforced the researchers to accelerate their efforts. Still, Munro estimates itwill be at least a year before the vaccine will be ready.

I know the timeline feels long, he says.I imagine it feels just unacceptable to those folks who are in areas ofserious outbreak, but at least we have a way of . . . pushing things forward asfast as possible.

CEPI has calls out for additionalvaccine development proposals. On January 31, the organization announced thatit would work with CureVac AG, based in Tbingen, Germany, to develop anothermRNA vaccine targeting the novel coronavirus.

Vaccines help keep people from gettinginfected with disease-causing organisms but may not help once someone isalready infected. But a shortcut to getting protection a shot of theprotective antibodies themselves may both prevent infections and treat them.

People who have recovered from infectionsretain antibodies in their blood against the virus or bacteria that caused theillness, often for years or decades. Such antibodies may give some protectionwhen the person encounters a similar infectious organism later on. But,crucially, these antibodies can also protect others. And quickly.

It can take weeks to months for vaccinesto prod the immune system into making protective levels of antibodies, says ChristosKyratsous, vice president of infectious disease research and viral vector technologiesat Regeneron Pharmaceuticals. Ebola vaccines, for example, take at least a weekto stimulate antibody production, but shots of antibodies offer immediateprotection, Kyratsous says. (Regeneron Pharmaceuticals,headquartered in Tarrytown, N.Y., is a major financial supporter of Society forScience & the Public, which publishesScience News.)

In studies conducted by other researchers,blood serum containing protective antibodies taken from people who hadrecovered from Ebola helped infected people recover from the disease. Doctorsand scientists in China have already begun using blood plasma from people whohave recovered from COVID-19 to treat people who are ill with the disease.

But giving people antibodies fromsurvivors doesnt always work. Regeneron and other companies have developedantibodies that can more reliably offer protection. Thecompany is already testing antibodies against Ebola and the MERS virus. Clinicalstudies and laboratory work with the companys MERS antibodies suggests thatthey can help protect against infection and treat established infections, Kyratsoussays.

The company isnow developing antibodies against the new coronavirus. We have learneda lot of things from the MERS project that we can now apply to the novelcoronavirus project, Kyratsous says.

For instance, the team has learned moreabout which viral proteins and parts of proteins make the best antibodytargets. Proteins on the surface of the virus that are needed for infection,such as the spike protein, are generally the best bets, he says.

Regeneron researchers have madeSARS-CoV-2 proteins in the lab and injected them into mice that have humanversions of antibody-producing genes. These humanized mice make fully humanantibodies, Kyratsous says, and could provide a ready supply. As soon as thoseantibodies are available, the company hopes to test their efficacy against thevirus in the lab. If that works, safety testing in animals and people may startsoon.

The team also hopes to work with peoplewho have recovered from COVID-19 to get antibody-producing cells from theirblood. But, Kyratsous says, harvesting antibodies from people isnt somethingthat can be easily scaled up.

Still, despite the rapid reaction ofthese and other scientists, vaccine and antibody protection for most people isstill far off.

In an acute situation, youre not justgoing to pull a vaccine out of your pocket, NIAID director Fauci said at theAspen Institute discussion. If the current outbreak proves to be really bad, theFDA may be able to authorize emergency use of promising vaccines that haventcompleted full safety and efficacy testing. But researchers wont know for atleast six months whether any of the vaccines in development help against SARS-CoV-2.

Other strategies to fight the new virus, including repurposing existing drugs used against other diseases, including HIV and hepatitis C, are also under way. But theres no clear winner yet among those candidates. For now, people exposed to the virus must rely on their own immune systems and supportive care from doctors and nurses to fight off the disease.

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To tackle the new coronavirus, scientists are accelerating the vaccine process - Science News

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