Monday, May 21st, 2018

Time	Event
2:59p	A single-injection vaccine for the polio virus A new nanoparticle vaccine developed by MIT researchers could assist efforts to eradicate polio worldwide. The vaccine, which delivers multiple doses in just one injection, could make it easier to immunize children in remote regions of Pakistan and other countries where the disease is still found.  While the number of reported cases of polio dropped by 99 percent worldwide between 1988 and 2013, according to the Centers for Disease Control, the disease has not been completely eradicated, in part because of the difficulty in reaching children in remote areas to give them the two to four polio vaccine injections required to build up immunity. “Having a one-shot vaccine that can elicit full protection could be very valuable in being able to achieve eradication,” says Ana Jaklenec, a research scientist at MIT’s Koch Institute for Integrative Cancer Research and one of the senior authors of the paper.   Robert Langer, the David H. Koch Institute Professor at MIT, is also a senior author of the study, which appears in the Proceedings of the National Academy of Sciences the week of May 21. Stephany Tzeng, a former MIT postdoc who is now a research associate at Johns Hopkins University School of Medicine, is the paper’s lead author. “We are very excited about the approaches and results in this paper, which I hope will someday lead to better vaccines for patients around the world,” Langer says. Global eradication There are no drugs against poliovirus, and in about 1 percent of cases, it enters the nervous system, where it can cause paralysis. The first polio vaccine, also called the Salk vaccine, was developed in the 1950s. This vaccine consists of an inactivated version of the virus, which is usually given as a series of two to four injections, beginning at 2 months of age. In 1961, an oral vaccine was developed, which offers some protection with only one dose but is more effective with two to three doses. The oral vaccine, which consists of a virus that has reduced virulence but is still viable, has been phased out in most countries because in very rare cases, it can mutate to a virulent form and cause infection. It is still used in some developing countries, however, because it is easier to administer the drops than to reach children for multiple injections of the Salk vaccine. For polio eradication efforts to succeed, the oral vaccine must be completely phased out, to eliminate the chance of the virus reactivating in an immunized person. Several years ago, Langer’s lab received funding from the Bill and Melinda Gates Foundation to try to develop an injectable vaccine that could be given just once but carry multiple doses. “The goal is to ensure that everyone globally is immunized,” Jaklenec says. “Children in some of these hard-to-reach developing world locations tend to not get the full series of shots necessary for protection.” To create a single-injection vaccine, the MIT team encapsulated the inactivated polio vaccine in a biodegradable polymer known as PLGA. This polymer can be designed to degrade after a certain period of time, allowing the researchers to control when the vaccine is released. “There’s always a little bit of vaccine that’s left on the surface or very close to the surface of the particle, and as soon as we put it in the body, whatever is at the surface can just diffuse away. That’s the initial burst,” Tzeng says. “Then the particles sit at the injection site and over time, as the polymer degrades, they release the vaccine in bursts at defined time points, based on the degradation rate of the polymer.” The researchers had to overcome one major obstacle that has stymied previous efforts to use PLGA for polio vaccine delivery: The polymer breaks down into byproducts called glycolic acid and lactic acid, and these acids can harm the virus so that it no longer provokes the right kind of antibody response. To prevent this from happening, the MIT team added positively charged polymers to their particles. These polymers act as “proton sponges,” sopping up extra protons and making the environment less acidic, allowing the virus to remain stable in the body. Successful immunization In the PNAS study, the researchers designed particles that would deliver an initial burst at the time of injection, followed by a second release about 25 days later. They injected the particles into rats, then sent blood samples from the immunized rats to the Centers for Disease Control for testing. Those studies revealed that the blood samples from rats immunized with the single-injection particle vaccine had an antibody response against poliovirus just as strong as, or stronger than, antibodies from rats that received two injections of Salk polio vaccine. To deliver more than two doses, the researchers say they could design particles that release vaccine at injection and one month later, and mix them with particles that release at injection and two months later, resulting in three overall doses, each a month apart. The polymers that the researchers used in the vaccines are already FDA-approved for use in humans, so they hope to soon be able to test the vaccines in clinical trials. The researchers are also working on applying this approach to create stable, single-injection vaccines for other viruses such as Ebola and HIV. The research was funded by the Bill and Melinda Gates Foundation. (Comment on this)
3:00p	Chemists synthesize millions of proteins not found in nature MIT chemists have devised a way to rapidly synthesize and screen millions of novel proteins that could be used as drugs against Ebola and other viruses. All proteins produced by living cells are made from the 20 amino acids that are programmed by the genetic code. The MIT team came up with a way to assemble proteins from amino acids not used in nature, including many that are mirror images of natural amino acids. These proteins, which the researchers call “xenoproteins,” offer many advantages over naturally occurring proteins. They are more stable, meaning that unlike most protein drugs, they don’t require refrigeration, and may not provoke an immune response. “There is no other technological platform that can be used to create these xenoproteins because people haven’t worked through the ability to use completely nonnatural sets of amino acids throughout the entire shape of the molecule,” says Brad Pentelute, an MIT associate professor of chemistry and the senior author of the paper, which appears in the Proceedings of the National Academy of Sciences the week of May 21. Zachary Gates, an MIT postdoc, is the lead author of the paper. Timothy Jamison, head of MIT’s Department of Chemistry, and members of his lab also contributed to the paper. Nonnatural proteins Pentelute and Jamison launched this project four years ago, working with the Defense Advanced Research Projects Agency (DARPA), which asked them to come up with a way to create molecules that mimic naturally occurring proteins but are made from nonnatural amino acids. “The mission was to generate discovery platforms that allow you to chemically manufacture large libraries of molecules that don’t exist in nature, and then sift through those libraries for the particular function that you desired,” Pentelute says. For this project, the research team built on technology that Pentelute’s lab had previously developed for rapidly synthesizing protein chains. His tabletop machine can perform all of the chemical reactions needed to string together amino acids, synthesizing the desired proteins within minutes. As building blocks for their xenoproteins, the researchers used 16 “mirror-image” amino acids. Amino acids can exist in two different configurations, known as L and D. The L and D versions of a particular amino acid have the same chemical composition but are mirror images of each other. Cells use only L amino acids. The researchers then used synthetic chemistry to assemble tens of millions of proteins, each about 30 amino acids in length, all of the D configuration. These proteins all had a similar folded structure that is based on the shape of a naturally occurring protein known as a trypsin inhibitor. Before this study, no research group had been able to create so many proteins made purely of nonnatural amino acids. “Significant effort has been devoted to development of methods for the incorporation of nonnatural amino acids into protein molecules, but these are generally limited with regard to the number of nonnatural amino acids that can simultaneously be incorporated into a protein molecule,” Gates says. After synthesizing the xenoproteins, the researchers screened them to identify proteins that would bind to an IgG antibody against an influenza virus surface protein. The antibodies were tagged with a fluorescent molecule and then mixed with the xenoproteins. Using a system called fluorescence-activated cell sorting, the researchers were able to isolate xenoproteins that bind to the fluorescent IgG molecule. This screen, which can be done in only a few hours, revealed several xenoproteins that bind to the target. In other experiments, not published in the PNAS paper, the researchers have also identified xenoproteins that bind to anthrax toxin and to a glycoprotein produced by the Ebola virus. This work is in collaboration with John Dye, Spencer Stonier, and Christopher Cote at the U.S. Army Medical Research Institute of Infectious Diseases. “This is an extremely important first step in finding a good way of rapidly screening complex mirror image proteins,” says Stephen Kent, a professor of chemistry at the University of Chicago, who was not involved in the research. “Being able to use chemistry to make a library of mirror image proteins, with their high stability and specificity for a given target, is obviously of potential therapeutic interest.” Built on demand The researchers are now working on synthesizing proteins modeled on different scaffold shapes, and they are searching for xenoproteins that bind to other potential drug targets. Their long-term goal is to use this system to rapidly synthesize and identify proteins that could be used to neutralize any type of emerging infectious disease. “The hope is that we can discover molecules in a rapid manner using this platform, and we can chemically manufacture them on demand. And after we make them, they can be shipped all over the place without refrigeration, for use in the field,” Pentelute says. In addition to potential drugs, the researchers also hope to develop “xenozymes” — xenoproteins that can act as enzymes to catalyze novel types of chemical reactions. The research was funded by DARPA and a STAR Postdoctoral Fellowship from Novo Nordisk. (Comment on this)

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