An electron microscope image of SARS-CoV-2 viruses (blue): "The speed of vaccine development depends, among other things, on doing things in parallel."
AFPNeal Browning, a 46-year-old software engineer at Microsoft, isn't the kind of person who enjoys taking risks. He has a good-sized wine collection with several hundred bottles at his home north of Seattle and he enjoys cooking for his neighbors. His favorite way of preparing steak is with a sous vide machine.
But on Monday, he took on a new role - that of American hero. That's the day he became test-subject No. 2 in the very first vaccine study in the fight against the respiratory disease COVID-19, which is currently changing life as we know it all around the world.
At a clinic in Seattle, he was given an injection in his upper arm at shortly after 9 a.m. on Monday. It contained several micrograms of a substance known as mRNA-1273. This possible vaccine from the U.S. company Moderna is designed to reprogram human cells for the controlled production of coronavirus proteins.
The idea is to simulate an infection with the novel pathogen so that the immune system can learn how to fight the virus – but without the sometimes-severe symptoms of a real coronavirus infection. A total of 45 subjects are to receive the test-vaccine in the next several weeks – but it will be months before it is known whether it actually works or not.
Browning learned of the study via Facebook at the end of February and says he was immediately interested. He spoke about it with his girlfriend, a nurse, and then he volunteered to take part, receiving $1,100 for his participation. At the time, there was just a single confirmed case of the disease in the state of Washington, though now there are over 1,000. "I thought about my two daughters," Browning says, "how important it is for them to have their flu shots and how a vaccine against coronavirus could protect them."
Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, says it will likely take between 12 and 18 months until a vaccine against the novel coronavirus is widely available. And many experts now believe that only a vaccine can help defeat the virus and put an end to the global disruptions.
Accelerating Development
A model published a few days ago by Imperial College London indicated that it would be possible to loosen quarantine measures once the exponential rise of COVID-19 infections begins to slow. But once that happened, a renewed increase in the number of infections would be unavoidable, according to the forecast, which could again lead to school closures, limitations on travel and event cancellations.
Initially, any new vaccine would be used to protect doctors, nurses and those most at risk, such as the elderly and people with pre-existing conditions, like high blood pressure or diabetes. But efforts would also be made to make it available to everybody as soon as possible. "Even in low-risk groups like young, healthy people, there is still some risk of severe disease," says Caitlin Rivers, epidemiologist at the Johns Hopkins Bloomberg School of Public Health. "So a vaccine is important in any case."
Test subject Neal Browning: "I thought about my two daughters."
TED WARREN / APThe international vaccine organization Coalition for Epidemic Preparedness Innovations (CEPI), which also receives funding from the German Ministry of Education and Research, is thus doing everything it can to accelerate the development of a coronavirus vaccine. Thus far, CEPI is supporting eight research teams and companies with a total of $29.2 million, in addition to sharing their own expertise. Moderna is one of the companies they are funding, as is the Tübingen-based vaccine company CureVac.
"We help developers to avoid the bottlenecks," says Melanie Saville, director of vaccine development at CEPI. "The speed of vaccine development depends, among other things, on doing things in parallel."
Still, it won't be easy to develop a vaccine against the novel coronavirus. "It is vital that the vaccine leads both to the production of antibodies and the activation of certain immune cells," says Volker Gerdts, director and CEO of the Canadian vaccine organization VIDO-InterVac, which has been working on developing a coronavirus vaccine since January. "Only then can we expect it to be effective."
Modern Methods of Vaccine Development
The standard method that has been successfully relied on for decades – that of simply using a deactivated virus as a vaccine – could actually lead to particularly severe symptoms in the case of coronavirus. There is a risk that the vaccine could actually create antibodies that would make it easier for pathogens to find their way into healthy cells. Weakening the novel virus enough that it could be used in a vaccine will also likely prove to be a challenge.
That is why there are only two vaccine candidates listed by the World Health Organization (WHO) that are taking this traditional approach. In total, the WHO list includes 41 research groups and pharmaceutical companies currently working as fast as they can to develop a vaccine – and all of the remaining 39 have chosen one of three modern methods for vaccine development.
With so-called vector-based vaccines, virus DNA is introduced into human cells with the help of a different virus. Researchers in Munich, for example, are trying to use a smallpox vaccine to transport DNA from the novel coronavirus – a method that has already been tested in a small study aimed at the related virus MERS-CoV.
Kate Broderick, senior vice president of research and development at Inovio
The new vaccine is to be ready for testing by the end of the year in an initial study involving 30 test subjects at the University Clinic Eppendorf (UKE) in Hamburg. "Vector vaccines often trigger robust immune responses," says Marylyn Addo, head of the infectiology department at the UKE.
Scientists at the German Center for Infection Research (DZIF) are looking to use a measles vaccine as a coronavirus vehicle, while researchers at the University of Hong Kong are relying on a weakened flu virus. Janssen Vaccines, a subsidiary of the U.S. pharmaceutical company Johnson & Johnson, is using a virus that causes the common cold.
Massive Expansion of Productive Capacity
"We have applied the same platform in different programs, such as in our Ebola vaccine or in HIV treatments," says Hanneke Schuitemaker, head of vaccine discovery and translational medicine at Janssen Vaccines. The company is planning to launch its first coronavirus vaccine trial in October and is expecting first solid data by early 2021.
At the moment, the factory in Leiden has the capacity to produce 300 million doses of vaccine per year. "But we are aware that that won't be enough," says Schuitemaker. The company is currently working toward a massive expansion of its production capacity.
There are also several research groups and companies working on the development of so-called subunit vaccines, which involve the injection of fragments of virus proteins. Researchers at the U.S. company Novavax are currently in the process of reverse engineering the so-called spike-protein, also called s-protein, of the novel coronavirus. It is the main ingredient of the vaccine they are seeking to develop.
Gregory Glenn, the president of research and development, is hoping that the vaccine would continue to protect people even if the virus were to mutate and the s-protein were slightly changed. "Think about when you're in a packed subway train. The only thing you see is people's tops, their haircut," Glenn says. "If they change it, you may not recognize them anymore." His vaccine, he says, will ensure that immune systems develop antibodies for the entire protein. "It's as if the immune system could also remember the color of their ties and jackets," he says.
Just like Novavax, Gerdts is also hoping for broad effectiveness. "We are hoping that this vaccine will allow us to vaccinate against several different coronaviruses at the same time," he says.
30,473 Characters
Likely the newest method for developing vaccines, though, is one that relies on nucleic acids – essentially the virus's DNA. That is the approach being taken by the Tübingen-based company CureVac and the American companies Inovio and Moderna, which produced the vaccine being used in the Seattle study.
Their vaccine candidates primarily consist of the genetic information from coronavirus proteins. If you inject the nucleic acid strands into the human body, cells begin producing the necessary antigens themselves. It is an elegant idea, but one with significant uncertainties.
Kate Broderick, senior vice president of research and development at Inovio, received the most important information for the development of such a vaccine by email. It arrived at the company's research center in San Diego on Jan. 10 and contained the new virus's entire genetic sequence. Chinese scientists had managed to decode the sequence in record time. On her monitor, Broderick saw an apparently random series of the four letters A, C, G and T – a series that extended for 30,473 characters.
The molecular geneticist loaded the series of letters into a special program and three hours later, the computer delivered the results: a design for a nucleic acids vaccine – essentially instructions for the production of virus building blocks.
With the help of bacteria cultures, laboratory staff produced a liter of the new vaccine within just a few days. They performed experiments in cell cultures and planned trials on lab animals. When these initial results were analyzed, the company tightened its timeline and announced that it would begin an initial study on healthy people in April. When Broderick got home from work, she had dinner with her children, took them to bed and sat down at her desk again. She only slept three hours that night. "An epidemic like this is everything I personally ever trained for," she says. "This will probably define my whole career."
"A Very Aggressive Timeline"
Nucleic acids vaccines have a significant advantage in that millions of doses can be produced relatively quickly. But the technology does have a disadvantage: Thus far, not a single such vaccine has ever made it to the market. A potential Inovio vaccine against the respiratory illness MERS managed to trigger the production of the necessary antibodies in only 50 percent of the patients it was administered to.
Vaccine researcher Peter Hotez from Texas Children's Hospital, who participated in the development of a possible vaccine against the coronavirus SARS, is thus rather skeptical when it comes to the startup's promises. "The idea that it works within a year seems like a very aggressive timeline."
The Tübingen-based company CureVac, which is also developing a similar type of DNA-based vaccine, has thus far only ever tested a rabies vaccine on humans in a small study. The development of a MERS vaccine was no longer pursued once the epidemic subsided.
Now, though, CureVac intends to begin human trials of a coronavirus vaccine in Germany and Belgium in early summer. If it works, says Chief Production Officer Florian von der Mülbe, the company would be able to produce up to 10 million doses in a short amount of time. Additionally, the EU has pledged the company 80 million euros in funding so that production capacity could be ramped up to 2 to 4 billion doses.
The drama that can be triggered by the distribution of vaccines was on full display when reports began circulating that the U.S. government was trying to buy out the German company.
In early March, CureVac was the only company from outside the United States that was invited to a coronavirus summit with Donald Trump in the White House. The U.S. president was extremely enthusiastic, it was said after the meeting – so much so that he allegedly wanted to buy CureVac for a billion dollars. An uproar was the result. "Germany is not for sale," said German Economics Minister Peter Altmaier. The company itself has insisted it knew nothing of the offer.
Whether there ever actually was a concrete offer from the U.S. is ultimately unimportant. Berlin, after all, has the ability to stop foreign takeover bids. To prevent "security threats," the Economics Ministry can examine foreign purchases of German companies and, should they feel it necessary, block them. And it is clear, say sources in Berlin, that German security interests are involved when it comes to the production of a coronavirus vaccine.
Taking New Risks
The tug-o-war is likely only to get worse. But it remains unclear if companies that are currently in competition with one another will ultimately join forces to produce vaccines together. And it has become more obvious than ever what a bad idea it was to suspend the development of a SARS and MERS vaccine once the dangers presented by those viruses subsided.
"In a crisis like the one we are seeing with COVID-19, every scientist wants to test as many therapies and vaccines as possible," says Ulrich Strych from the Center for Vaccine Development at Texas Children's Hospital. "But once the crisis seems to have passed, interest levels quickly fall."
In order to develop a vaccine as rapidly as possible, scientists, regulatory authorities, pharmaceutical companies and politicians must now take the kind of risks that were inconceivable only a short time ago. At a meeting of the World Health Organization (WHO) in mid-February, representatives of public research facilities and pharmaceutical companies agreed that human trials should begin before all animal testing had been completed – representing the breaking of a strict taboo. National agencies charged with approving new drugs and vaccines do not have to abide by that decision, but the decision sends a clear message, nonetheless. Neal Browning also received his vaccine dose even as important animal tests were still ongoing.
The decision taken at the WHO meeting triggered a heated discussion in the science magazine Nature. Animal testing, after all, can make a key contribution to determining early on if a potential vaccine has dangerous side effects.
"I think we should proceed cautiously," says vaccine researcher Hotez. "It's not clear whether some biotechs just use the coronavirus as a means to get their technology out there."
Klaus Cichutek, president of the Paul Ehrlich Institute, which is the German agency responsible for the approval of vaccines, is taking a more relaxed approach. "The important thing is that an approved vaccine is safe and effective," he says. "Already, we have a number of measures at our disposal that we can apply as needed to accelerate the approval process while observing the necessary diligence."
Depending on the data available, for example, it would be possible, he says, to apply for approval under extraordinary circumstances. "Should it take longer," Cichutek says, "it won't be because of us. Rather, it will be because the development of the vaccine simply isn't yet complete."
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