With record-setting speed, vaccinemakers take their first shots at the new coronavirus – Science Magazine

Jennifer Haller receives the first administration of an mRNA vaccine, made by the biotech firm Moderna, against the pandemic coronavirus.

By Jon CohenMar. 31, 2020 , 5:15 PM

Sciences COVID-19 reporting is supported by the Pulitzer Center.

The coronavirus that for weeks had been crippling hospitals in her hometown of Seattle changed Jennifer Hallers life on 16 Marchbut not because she caught it. Haller, an operations manager at a tech company in the city, became the first person outside of China to receive an experimental vaccine against the pandemic virus, and in the days since, she has been flooded by an outpouring of gratitude. Theres been overwhelming positivity, love, and prayers coming at me from strangers around the world, Haller says. We all just feel so helpless, right? This was one of the few things happening that people could latch on to and say, OK, weve got a vaccine coming. Disregard that its going to take at least 18 months, but its just one bright light in some really devastating news across the world.

The vaccine Haller volunteered to test is made by Moderna, a well-financed biotech thathas yet to bring a product to market. Moderna and Chinas CanSino Biologics are the first to launch small clinical trials of vaccines against coronavirus disease 2019 (COVID-19) to see whether they are safe and can trigger immune responses. (The CanSino vaccine trial also began on 16 March, according to researchers from the Chinese militarys Institute of Biotechnology, which is collaborating on it.) An ever-growing table put together by the World Health Organization now lists 52 other vaccine candidates that could soon follow. This is a wonderful response from the biomedical community to an epidemic, says Lawrence Corey, a virologist at the Fred Hutchinson Cancer Research Center who has run vaccine trials against a dozen diseases but is not involved with a COVID-19 effort. Its both gratifying and problematic in the sense of how do you winnow all this down?

Broadly speaking, these vaccines group into eight different platformsamong them old standbys such as inactivated or weakened whole viruses, genetically engineered proteins, and the newer messenger RNA (mRNA) technology that is the backbone of the Moderna vaccineand their makers include biotechs, academia, military researchers, and a few major pharmaceutical companies. On 30 March, Johnson & Johnson (J&J) announced what it said could bea $1 billion COVID-19 vaccine project, with about half the money coming from the U.S. Biomedical Advanced Research and Development Authority if milestones are met.

Many viruses, including HIV and hepatitis C, have thwarted vaccine developers. But the new coronavirus, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), doesnt appear to be a particularly formidable target. It changes slowly, which means its not very good at dodging the immune system, and vaccines against the related coronaviruses that cause SARS and Middle East respiratory syndrome (MERS) have worked in animal models. Corey heads the United Statess HIV Vaccine Trials Network, which has seen one candidate vaccine after another crash and burn,is optimistic about a SARS-CoV-2 vaccine. I dont think this is going to be that tough.

One concern is whether people develop durable immunity to SARS-CoV-2, which is crucial given that vaccines try to mimic a natural infection. Infections with the four human coronaviruses that typically cause minor colds dont trigger long-lasting immunity. Then again, researchers have found long-lasting immune responses to the viruses causing SARS and MERS, and genetically they are far more like SARS-CoV-2. And unlike cold-causing viruses, which stay in the nose and throat, the new coronavirus targets the lower respiratory tract, where the immune response to a pathogen can be stronger, says Mark Slifka, an immunologist who studies vaccines at the Oregon National Primate Research Center. When you get an infection in the lungs, you actually get high levels of antibodies and other immune cells from your bloodstream into that space.

Even with this all-out effort, Anthony Fauci, director of the U.S. National Institute of Allergy and Infectious Diseases (NIAID), predicts getting a vaccine to the public is going to take a year, a year and a half, at least. And Fauci adds at least because side effects, dosing issues, and manufacturing problems can all cause delays. Already some are calling for an ethically fraught shortcut to speed up clinical trials: giving people candidate vaccines and then intentionally attempting to infect them to see whether theyre protected.

A new vaccine might also be made available to health care workers and others at high risk even before phase III efficacy trials are completed. And Stanley Perlman, a veteran coronavirus researcher at the University of Iowa, suggests a vaccine that only offers limited protection and durability could be good enoughat first. In this kind of epidemic setting, as long as you have something that tides us along and prevents a lot of deaths, that may be adequate, he says.

On 13 January, 3 days after Chinese researchers first made public the full RNA sequence of SARS-CoV-2, NIAID immunologist Barney Graham at sent Moderna an optimized version of a gene that would become the backbone of its vaccine. Sixty-three days later, the first dose of the vaccine went into Haller and other volunteers participating in the small trial at the Kaiser Permanente Washington Health Research Institute. In 2016, Graham had made a Zika virus vaccine that went from lab bench to the first volunteer in what he then thought was a lightning-fast 190 days. We beat that record by nearly 130 days, he says.

The effort benefited from lessons Graham learned from his past vaccine efforts, including his work on respiratory syncytial virus (RSV). The search for an RSV vaccine has a checkered past: in 1966, a trial of a candidate vaccine was linked to the death of two children. Later studies identified the problem as vaccine-triggered antibodies that bound to the surface protein of the virus but did not neutralize its ability to infect cells. This antibody-viral complex, in turn, sometimes led to haywire immune responses.

The World Health Organization has tallied dozens of vaccine candidates, based on a variety of technologies. Two have started human safety trials (*).

Studying the 3D structures of the RSV surface protein, Graham discovered that the dynamic molecule had different orientations before and after fusing with the cell. Only the pre-fusion state, it turned out, triggered high levels of neutralizing antibodies, so in 2013 he engineered a stable form of the molecule in that configuration. It was so clear at that point that if you didnt have structure, you didnt really know what you were doing, Graham says. An RSV vaccine that built on this concept hasworked wellinearly trials.

The experience came in handy in 2015, when a member of Grahams lab made a pilgrimage to Mecca, Saudi Arabia, and came back ill. Worried that it might be MERS, which is endemic in Saudi Arabian camels and repeatedly jumps into humans there, Grahams team checked for the virus and instead pulled out a common cold coronavirus. It was relatively easy to determine the structure of its spike, which then allowed the team to make stable forms of the spikes for the SARS and MERS viruses, and, in January, for SARS-CoV-2s. Thats the basis of the Moderna COVID-19 vaccine, which contains m RNA that directs a persons cells to produce this optimized spike protein.

Still a new strategy, no mRNA vaccine has yet reached a phase III clinical trial, let alone been approved for use. But producing huge numbers of vaccine doses may be easier for mRNA vaccines than for traditional ones, says Mariola Fotin-Mleczek of the German company CureVac, which is also working on mRNA vaccine for the new coronavirus. CureVacs experimental rabies vaccine showed a strong immune response with a single microgram of mRNA. That means 1 gram could be used to vaccinate 1 million people. Ideally, what you have to do is produce maybe hundreds of grams. And that would be enough, Fotin-Mleczek says.

Many companies are relying on time-tested techniques. Sinovac Biotech is making a SARS-CoV-2 vaccine byinactivating whole virus particles with formaldehyde and adding an immune booster called alum. Sinovac used the same strategy for a SARS vaccine it developed and tested in a phase I clinical trial 16 years ago, says Meng Weining, a vice president at Sinovac. We immediately just restarted the approach we already know. The companys SARS vaccine worked in monkeys and although there were concerns that an inactivated coronavirus vaccine might trigger the sort of antibody enhancement disease that occurred with the RSV vaccine, Meng stresses that no such problems surfaced in their animal studies.

Florian Krammer, a virologist at the Icahn School of Medicine at Mount Sinai, says inactivated virus vaccines have the advantage of being a tried-and-true technology that can be scaled up in many countries. Those manufacturing plants are out there, and they can be used, says Krammer, who co-authored a status report about COVID-19 vaccines that appears online inImmunity.

CanSino is now testing another approach. Its vaccine uses a nonreplicating version of adenovirus-5 (Ad5), which also causes the common cold, as a vector to carry in the gene for the coronavirus spike protein. Other vaccine researchers worry that because many people have immunity to Ad5, they could mount an immune response against the vector, preventing it from delivering the spike protein gene into human cellsor it might even cause harm, as seemed to happen in a trial of an Ad5-basedHIV vaccine made by Merck that was stopped early in 2007. But the same Chinese collaboration produced an Ebola vaccine, which Chinese regulators approved in 2017, and a company press release claimed its new candidate generated strong immune responses in animal models and has a good safety profile. I think pre-existing Ad5 immunity and HIV vaccine risk are not a problem, Hou Lihua, a scientist working on the project at the Institute of Biotechnology, wrote in an email to Science, noting that the Ebola vaccine trial results adds to their confidence that these will not be issues.

Disregard that [a vaccine is] going to take at least 18 months, but its just one bright light in some really devastating news across the world.

Other COVID-19 vaccine platforms include a laboratory-weakened version of SARS-CoV-2, a replicating but harmless measles vaccine virus that serves as the vector for the spike gene, genetically engineered protein subunits of the virus, a loop of DNA known as a plasmid that carries a gene from the virus, and SARS-CoV-2 proteins that self-assemble into viruslike particles. J&J is using another adenovirus, Ad26, which does not commonly infect humans, as its vector. These different approaches can stimulate different arms of the immune system, and researchers are already challenging vaccinated animals with SARS-CoV-2 to see which responses best correlate with protection.

Many researchers assume protection will largely come from neutralizing antibodies, which primarily prevent viruses from entering cells. Yet Joseph Kim, CEO of Inovio Pharmaceuticals, which is making a DNA COVID-19 vaccine, says a response by T cellswhich clear infected cellsproved a better correlate of immunity in monkey studies of the companys MERS vaccine, which is now in phase II trials. I think having a balance of antibody and T cell responses probably is the best approach.

Kim and others applaud the variety of strategies. At this early stage, I think it makes sense to try anything plausible, he says. As Stephan Bancel, CEO of Moderna, says, Nobody knows which vaccines are going to work.

Spurring many of the efforts in the nascent COVID-19 field has been the Coalition for Epidemic Preparedness Innovations (CEPI), a nonprofit set up to coordinate R&D for vaccines against emerging infectious diseases. So far, CEPI has invested nearly $30 million in vaccine development at Moderna, Inovio, and six other groups. We have gone through a selective process to pick the ones that we think have the greatest likelihood of meeting our goalswhich we think ought to be the worlds goalsof speed, scale, and access, says CEPI CEO Richard Hatchett.But he is rooting for other candidates as well. We dont want to be in a situation where we have [one] successful vaccine and we have a contamination event [during manufacturing] and suddenly we dont have any vaccine supply.

CEPI invests in manufacturing facilities at the same time it puts money into staging clinical trials. By doing things in parallel rather than in serial fashion, we hope to compress the overall timelines, Hatchett says. After reviewing phase I data and animal model data, CEPI plans to move six of the eight products into larger safety studies to arrive at three that are worthy of full-scale efficacy trials that enroll perhaps 5000 participants.

CEPI has less than $300 million in its coffers for the effort, and Hatchett estimates the price tag at $2 billion. He says CEPI hopes to raise this money from governments, private philanthropies, industry, and the United Nations Foundation.

Seth Berkley, who heads Gavi, the Vaccine Alliance, arguedin an editorial in the 27 March issue ofSciencethat the world needs to come together even more to streamline the search for a COVID-19 vaccine. If ever there was a case for a coordinated global vaccine development effort using a big science approach, it is now, Berkley wrote, stressing that there must be extraordinary sharing of data, coordination of clinical trials, and funding. You cant move 100 vaccines forward, he says.

Moderna and J&J both say that if everything goes perfectly, they could launch an efficacy trial with about 5000 people by late November and determine by January 2021 or so whether the vaccine works. Meng says that, depending on approval from Chinese regulatory agencies, Sinovac could move its vaccine through small phase I and II tests by June. But, because of Chinas success at controlling its epidemic, the company may have to find another country that has high transmission of SARS-CoV-2 to stage an efficacy trial quickly.

Haller has had no serious side effects from the mRNA injected into her arm but realizes that the phase I study will not determine whether the vaccine is effective. The chances of the one that I got being really anything? I dont know, Haller says. This is just the first of many, many vaccines, and its just stupid luck that I was the first one.

With reporting by Kai Kupferschmidt.

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With record-setting speed, vaccinemakers take their first shots at the new coronavirus - Science Magazine