Last week saw the nation’s highest numbers of new COVID-19 cases since the pandemic began; nearly 160,000 diagnoses were reported yesterday alone. But the week ushered in some positive news on the pandemic as well. This past Monday, a joint statement from New York–based pharmaceutical company Pfizer and German biotechnology company BioNTech announced that interim results from their Phase 3 clinical trial show their experimental vaccine to be more than 90% effective at protecting against SARS-CoV-2 infection. The news was met with surging stocks and hopes this could signal the beginning of the end for the historic pandemic. For Drew Weissman, a professor in Penn’s Perelman School of Medicine, it was also a major step forward for a pursuit decades in the making. Unlike most vaccines, which use a modified virus or viral protein to elicit an immune response, the Pfizer-BioNTech vaccine, as well as another leading vaccine candidate from Moderna, both use messenger RNA (mRNA) to instruct the body to begin defending itself against COVID-19. Fifteen years ago, Weissman’s lab at Penn, in collaboration with Katalin Kariko, a Penn faculty member at the time, made the key breakthrough that allowed for use of mRNA in this way. “When I first heard the news I had two reactions,” Weissman says. “The first was, ‘This is fantastic because I don’t remember a respiratory virus vaccine that has had an efficacy over 90%.’” But the scientist in Weissman couldn’t help but feel a little disappointed that the results weren’t even more impressive. “Just about every vaccine candidate, and we’ve probably done them for about 30 different pathogens in animal models, has been close to 100% effective.” Penn Today spoke with Weissman about the vaccine news, including the collaborative research that led to the novel approach, the pluses and minuses of using mRNA, and the outlook for a COVID-19 vaccine in the weeks and months to come. Here are five takeaways. Work on the vaccine started long before this coronavirus emerged After earning his MD and PhD from Boston University, Weissman pursued a fellowship at the National Institues of Health, working under none other than Anthony Fauci. Fauci gave his trainees tremendous scientific freedom in their work. When Weissman got to Penn in 1997, he began delving into vaccine biology. He got to know Kariko as they jockeyed over the copy machine, both eager to photocopy the latest journal articles. “She worked on RNA, and I worked on dendritic cells,” blood cells that digest foreign materials and present bits of them to the immune system, Weissman says. “So we decided to collaborate.” Kariko had been struggling to successfully use mRNA to deliver therapeutic proteins to treat and protect against a variety of diseases. The concept was sound. Injected messenger RNA that encodes a protein of interest would be taken up by cells, which would then “read” the RNA transcripts, and churn out the protein. Yet the mRNA injections made mice sick. Weissman and Kariko’s work revealed that the mRNA was provoking a major inflammatory response. To get around that, the scientists found that if they modified one of the RNA “letters,” or nucleosides, the transcripts could be delivered without causing harmful inflammation and still generate lasting protection. The body quickly degrades “naked” RNA, but encapsulating it in tiny lipid droplets allowed the transcripts to slip into cells in numbers great enough to elicit an immune response. Both BioNTech and Moderna licensed this modified mRNA technology for their vaccines, which use mRNA encoding the SARS-CoV-2 spike protein as the antigen target. RNA vaccines have unique benefits Many existing vaccines rely on inactivated virus or a viral protein to inspire the immune system to build up an arsenal of antibodies. But, because the body is generally so good at clearing invaders, the material that is actually injected is usually “gone within hours,” Weissman says. In contrast, human bodies are used to living with messenger RNA, and so the injected molecules can linger and generate protein for as long as two weeks. “And what we know about the immune system,” says Weissman, “is that you need to have long-lived protein to stimulate a good response.” mRNA-based vaccine technology is also far cheaper than protein-based therapeutics, and so far seems to be a safe approach, whereas protein drugs can sometimes cause dangerous side effects. One more advantage Weissman and colleauges found in their research was that mRNA vaccines induce a response from a type of immune cell called “helper T cells.” These helper cells activate B cells to produce antibodies that target the virus or other pathogens. They pose some challenges, too Messenger RNA-based vaccines require a deep freeze as part of the production process, and, once thawed, the vaccine is only good for as long as a week if kept refrigerated. This is true of many vaccine types, and the required “cold chain” to get the vaccine to billions of people might limit how accessible it may be in parts of the world that lack reliable electricity. The Pfizer-BioNTech and Moderna vaccines also require a booster shot in its current form. In previous laboratory studies of vaccines for other pathogens, Weissman notes that some confer protection with one shot, while others require two for the best defense against infection. His own lab is now trying to develop a more potent COVID-19 vaccine. Other vaccine candidates are still important Ideally, all 7.8 billion people on the planet would get quick access to a vaccine, once approved. “That’s a lot of vaccines that need to go to a lot of people,” Weissman says. Pfizer-BioNTech has announced it hopes to have 50 million doses by the end of 2020, and may be able to produce as many as 1.3 billion doses in 2021. That means it would still take years before the whole world was vaccinated, and that’s assuming long-lasting immunity. That’s one reason it’s good that other groups are all working on different versions of a COVID-19 immunization, says Weissman. “Some types of vaccines work better in certain groups,” he says. “The elderly might do better with one vaccine, young kids might do better with a different one, and people with immune deficiencies can’t take live virus.” There’s more to come in the weeks and months ahead The Pfizer-BioNTech results came from an interim check-in point of the Phase 3 clinical trial. The trial itself, Weissman says, “will go on for years,” but the U.S. Food and Drug Administration requires two months of safety monitoring after all participants get both immunizations before the agency will consider granting an emergency-use authorization. Assuming a vaccine is authorized or approved soon, Weissman predicts that it may be the middle of 2021 before it is widely distributed in the United States. And a vaccine that confers 90% protection gives us a good chance of achieving herd immunity. “The politicization of the vaccine has been criminal, in my opinion, and it’s made a lot of people nervous to take it,” he says. “But I think once a group of people has taken it first and others see that it’s safe, they will feel comfortable taking it later.” Meanwhile Weissman’s lab, in collaboration with that of Penn Medicine research assistant professor Norbert Pardi, has a variety of other irons in the fire, including work on a pan-coronavirus vaccine, one that could protect against potential pathogens yet to evolve. “There have been three coronavirus pandemics in the past 20 years,” Weissman says. “You have to expect that more are going to show up.” Drew Weissman is professor of medicine in the University of Pennsylvania’s Perelman School of Medicine. Source
