The last time global history was made in the German city of Mainz, it was Johannes Gutenberg fiddling around in a Late Medieval courtyard with a printing press equipped with moveable letters. This time, in the heart of the city – on a street with the promising name “At the Goldmine” – a vaccine candidate called BNT162b2 is fermenting in a bioreactor located safely behind security checkpoints and sterility barriers. It is a “nucleoside-modified messenger RNA” candidate that “encodes an optimized SARS-CoV-2 full length spike glycoprotein.”
In other words, it is perhaps the first legitimate coronavirus vaccine in the world.
It was developed under the leadership of Professor Dr. Ugur Sahin and his wife, Dr. Özlem Türeci. Both are the children of Turkish immigrants, quite an inspiring story in normal times. But that aspect of the narrative is getting short shrift in this period when daily infection numbers continue to spike around the world, and everyone is wondering: How can we stop the second wave? Will the fight against the pandemic soon be over? When will we conquer this virus?
United States President Donald Trump has already identified the day of victory. “We expect to have enough vaccines for every American by April,” he said in September. But it’s not quite that simple.
Journalists wishing to speak with Sahin these days are required to wear an FFP2 mask and are asked not to write exactly where in the building his office is located. Outside, in front of the entrance, a container has recently been installed for the muscular guards, while domestic security agents are doing what they can to protect the laboratory from virtual attacks. There is simply too much at stake, especially since the finish line has now come into view. Indeed, it could become clear already this week if a first, effective vaccine will soon be ready.
Sahin and the over 500 scientists at the company BioNTech are waiting – “on pins and needles” – for the initial results of the clinical study with 44,000 participants who in recent months have either received BNT162b2 or a placebo. If the results are overwhelmingly positive, then the company would apply for emergency approval. That would mean that vaccinations could begin within just a few weeks.
There could, of course, still be delays of several weeks, or even several months, if the data is insufficient or if the regulatory authorities need more time. Or if the vaccine doesn’t work as expected.
Around the world, there are currently 48 vaccines being tested in clinical studies, with 11 of them in the final trial phase. Experts agree that there will be a vaccine – many of them, in fact – and that we won’t have to wait much longer. The central question, though, is a different one: Will that be our longed-for salvation? Will everything go back to normal?
Or will it just take the edge off the drama, leading to fewer deaths and a lower caseload, but still requiring us to wear masks and observe social distancing guidelines for the next two years?
Never before has all of humanity focused so intently on the development of a medical remedy. Never before has so much money been invested in a serum in such a short amount of time. Never before have scientists, pharmaceutical companies and politicians been under such immense pressure to deliver.
All that has led to an achievement that few thought possible: the development of a new vaccine within just one year instead of the eight to 10 years it normally takes. It is an unbelievable accomplishment, but it is also a hint as to what is now in store for us. The vaccine, after all, will not be a silver bullet that can immediately put an end to the pandemic.
More likely is that it will initially be a moderately effective vaccine that primarily protects against the worst COVID-19 symptoms, but doesn’t eliminate the chance of infection. It’s not even certain for how long the vaccine will provide protection. Six months? A year? There won’t be an instant return to normalcy.
Indeed, the several months after the first vaccines begin receiving approval will likely be confusing and chaotic, with many questions left to be answered. How safe are the vaccines? How effective are they? How many doses will be available and who will be vaccinated first? How can you vaccinate an entire country?
Over the last several weeks, DER SPIEGEL went out on the search for answers to these questions. We visited three leading vaccine developers that are waiting for their candidates to be approved and we spoke with the president of the Paul Ehrlich Institute, which makes the final decision in Germany on vaccine approval. We interviewed the German health minister, who is responsible for organizing the inoculation of millions of people, and with the head of the German Ethics Council, who will help establish guidelines regarding who should be first in line.
The German biotech firm BioNTech, in cooperation with the pharmaceutical giant Pfizer, is developing what will likely be the first coronavirus vaccine in the world – and must defend itself from the U.S. president along the way.
Everything these days feels like a race against time. Against the second wave, against the hundreds of thousands of new infections each day around the world, and against the mounting death toll. “Every week counts,” says Ugur Sahin, which is why BioNTech has produced millions of vaccine doses in recent months. The hope is to get a head start, even if it isn’t clear yet whether the company’s candidate actually works. If it doesn’t, it will all have to be discarded.
It is a risky approach, even for a large pharmaceutical company. And it’s an even larger risk for a smaller company like BioNTech, even if the German government provided special funding that could ultimately amount to 375 million euros. There are no smokestacks and factory floors at BioNTech, just sterile, white laboratories where gene sequencers analyze enormous amounts of genetic material with the help of clever algorithms and fluids are injected into ampules using ultrasound. Artificial intelligence is relied on to calculate the results. Some of the rooms are almost completely devoid of humans, with automated, robotic platforms analyzing T-cells and blood samples.
The hundreds of scientists working in the five-floor complex have primarily concentrated on fundamental research in the past 10 years, relying largely on millions in funding from Thomas and Andreas Strüngmann, the founders of the major German pharmaceuticals company Hexal. The company has 20 medications in development, most of them cancer therapies. But none of them have been approved yet, in part because the technology is too new, too revolutionary and too untested.
The focus of BioNTech’s research is mRNA agents. The molecule is an important component of human biology, working as a messenger that essentially delivers assembly instructions from the cell’s genetic material to its protein factories. If mRNA can be synthesized and transported into the cells, then you suddenly have a direct impact on what happens in the body. Once researchers have figured out how to program these messengers, then they can theoretically deliver all kinds of instructions using the method, whether it is ordering T-cells to attack a specific tumor or commanding the immune system to launch an offensive against a virus.
Traditional vaccines, by contrast, are usually made using weakened viruses or virus parts, with even small amounts taking weeks to produce in a laboratory. BioNTech, though, only needed the genetic sequence of the coronavirus, which allowed researchers to produce the appropriate RNA within just two days and start experimenting. That’s what they did in January, well before the German government felt that the country was at risk from the pandemic. Even ahead of the March lockdown, BioNTech had come up with 20 vaccine candidates.
Many experts were surprised by the speed, as were some of the company’s own scientists initially. But much of that, Sahin realized, was the product of habits and expectations developed over the course of decades. Weeks of waiting for government agencies to respond to queries, for example, has long been commonplace, as has the wait of several months for fresh funding.
To speed the process up, a BioNTech team headed in February for Langen, the suburb of Frankfurt where the Paul Ehrlich Institute is located. The institute is responsible for approving new medications and vaccines in Germany, and BioNTech wanted to discuss the path forward. Their plan: a clinical study starting in the spring with the goal of having a fully developed vaccine by the end of the year. The Paul Ehrlich Institute agreed to support the aggressive timeline.
On April 19, BioNTech submitted its final application for the clinical study of several vaccine candidates. Approval arrived on April 22 and the first test subject was administered with a vaccine candidate on April 23.
Of the 20 initial candidates, two particularly promising ones remain. They both target the spike proteins that give the virus its distinctive appearance. “Should I sketch out the differences for you?” Sahin asks, as he heads toward a large whiteboard in his office without waiting for an answer. He draws the protein with a couple of quick lines before adding a few statistics and technical terms.
Essentially, though, his explanation boils down to the fact that one of the vaccine candidates focuses on just a part of the spike protein, while the other targets the entire length of the spike. Both approaches are able to deactivate the virus, but the first one triggers a slight fever for one or two days in 70 percent of the test subjects. The one that targets the entire protein, though, only triggers that side effect in 10 to 15 percent of test subjects.
Sahin is good at offering precise explanations of such complex processes, speaking quietly, insistently and without wasting words. He has been teaching at the University of Mainz for the last 15 years, most recently as a professor of oncology. Even in these rather tense times, he continues to supervise Ph.D. students, perhaps because he always wanted to be a scientist first and foremost, and not the head of a startup.
He has been considered one of the leading cancer researchers in the world for quite some time now, but his initial focus was immunology. One might think that COVID-19 and cancer don’t have all that much in common, but Sahin disagrees. “We see ourselves as immunity engineers,” he says. “We want to direct the immune system to protect us from certain illnesses.”
Sahin and BioNTech have a lot of experience with conducting research into new technologies. But they have never introduced a new medication to the world from scratch and developed a global production system. That’s why they sought out a partnership with Pfizer in the spring. The American pharmaceutical giant’s production facilities are to help produce a total of 1.5 billion doses of BNT162b2 by the end of 2021. Several hundred million doses have already been sold to the U.S., Japan and Canada.
Pfizer is assuming half of development costs and will pay BioNTech $748 million should the vaccine be successful. Analysts expect that the two companies will split the revenues, estimated to be around $3.5 billion in 2021. Critics say that it’s not a good deal for BioNTech and that the first COVID-19 vaccine is worth far more than that. But it’s only worth more if it is approved, and the path to approval is extremely expensive.
The clinical studies in particular cost hundreds of millions, sometimes even billions. They include three phases: Phase I focuses primarily on safety and tolerability. Phase II determines such things as the correct dosage. Combined, the first two phases require just a few hundred test subjects. It is Phase III where the drug’s broad and specific efficacy is explored along with its safety, and that requires tens of thousands of test subjects.
The phases can also be conducted concurrently, and BioNTech initially combined Phases I and II, recruiting around 200 volunteers in Germany, on whom the two candidates were tested in a variety of dosages, ranging from 10 to 100 micrograms. Identifying the correct dosage is critical: It must be high enough to be effective but low enough to preclude severe side effects. Pfizer copied the study later in the U.S. under the guidance of the German researchers.
After three months, on July 24, the results arrived. The vaccine candidate “elicited strong … T-cell responses against SARS-CoV-2 receptor binding domain.” In other words, the initial results looked good.
That same day, 60 staff members from BioNTech and Pfizer joined a video conference to discuss the next step: a combined Phase II and III study with at least 30,000 volunteer test subjects between the ages of 18 and 85, divided among 120 study centers, including sites in the U.S., Germany and Argentina. Each study participant would either receive the vaccine or a placebo. Neither BioNTech nor the test subjects nor the doctors involved would know who received what.
From that point on, Pfizer took over leadership of the study. Formally, though, BioNTech remains the contracting entity and will later have control over an approved vaccine. “It is our technology. The cooperation with Pfizer is an ideal partnership, allowing us to develop and distribute a possible vaccine in the shortest time possible,” Sahin says. Still, the partnership makes the approval process more vulnerable to political pressures, particularly since Pfizer is an American company.
The U.S. president, after all, has been saying from the very start of the pandemic that a vaccine is right around the corner. And after Phase I was completed so quickly and so successfully, BioNTech and Pfizer were quickly seen as the global frontrunners in the race for the first vaccine. Trump took notice.
What that means was on full display in the televised debate between Trump and his challenger Joe Biden. During that event, Trump told the millions of TV viewers that he had just spoken with Pfizer and that the vaccine would be finished in just a few weeks. “It’s a very political thing,” Trump said, seemingly hinting that approval was being slowed down to hurt him.
Pfizer CEO Albert Bourla wrote an open letter to company staff two days later in response to the accusation. Pfizer, he wrote, “would never succumb to political pressure.” The research results alone, he promised, would determine the pace of progress.
For many experts, that wasn’t enough. The studies must be more transparent, they are demanding, so that outside scientists can determine for themselves whether shortcuts have been taken or if development is going too quickly.
In mid-September, BioNTech and Pfizer gave in to those demands and released their study protocols, as did a number of other companies pursuing a vaccine. Those protocols are normally secret, since they essentially provide a blueprint for the entire clinical study. They describe which groups of test subjects are taking part, what safety standards have been applied and, most importantly, how and when the determination will be made regarding the efficacy of the vaccine.
To make such a determination, a minimum number of test subjects must have become infected with the coronavirus during the study’s run-time. The BioNTech/Pfizer study identified 164 cases as the threshold. Positive cases will be compared against the lists identifying who received the vaccine and who received a placebo. If all 164 positive cases are from the placebo group and none from the group of those who received the vaccine, efficacy would be defined as 100 percent.
But because it can take quite some time before so many test subjects become infected with the virus, all companies developing a vaccine have planned to release interim reports. BioNTech and Pfizer intend to make an initial check after 32 positive cases to see how many of them received the vaccine. With such a small number, though, the bar is much higher. “Overwhelming effectiveness” must be established. In Europe, it is up to the regulatory authorities to determine exactly what that means, but in the U.S., it is clearly defined: Efficacy in this case must be at least 77 percent, meaning that a maximum of six of the test subjects who tested positive can have received the vaccine.
Critics believe that an interim analysis on the basis of just 32 cases is too early and see it as a rushed attempt to gain approval as quickly as possible. “This is perhaps the most important clinical study in the world,” says Eric Topol, a leading biomedical researcher and head of the Scripps Institute in San Diego. “It should be done right and not stopped prematurely.”
The number is, in fact, “relatively low,” allows Sahin, and smaller numbers are “more prone to error.” For a statistically significant result, he says, vaccine efficacy must be extremely high. “But we wanted to have the opportunity to see early enough if the results really were very good.”
Pfizer CEO Bourla has repeatedly said in recent weeks that he thought the first interim results would be available by the end of October. That, in turn, has driven Trump to continue promising a vaccine before the election on Nov. 3.
Couldn’t the companies simply sidestep the entire political discussion by not releasing the interim results until after the election? Sahin doesn’t see that as an option and finds the entire discussion rather superfluous. Once the level of 32 positive cases has been reached, BioNTech will be automatically informed by the independent experts from the Data and Safety Monitoring Board, which is overseeing the study. The committee of doctors and statisticians will then lift the anonymity of the 32 test subjects to see which of them received the vaccine and which did not. “In the moment when we receive the information on efficacy, we cannot and will not withhold it,” says Sahin.
By now, of course, it is clear that no vaccine will be approved ahead of Election Day, even if the first study results arrive before then and are overwhelmingly positive. The Food and Drug Administration (FDA), the U.S. regulatory authority responsible for approving new medications, issued an edict in early October that it would only accept applications for emergency vaccine approval after all test subjects who received a full dosage of the vaccine had been under observation for at least two months. In the case of BioNTech and Pfizer, that would be mid-November. Trump tried hard to block the new FDA rule and described its implementation on Twitter as “just another political hit job!”
In Europe, approval before November would also be impossible. The regulatory authority European Medicines Agency (EMA) has allowed BNT162b2 to take part in its rolling review program. That means that study results are submitted to the regulatory authority bit by bit, and not all at once upon completion as is normally the case. That enables EMA to work through the data on a rolling basis and make its decision more quickly. Still, approval cannot take place overnight.
In any case, it will take months, or even years, to determine just how good a vaccine really is. Based on the research results thus far, though, Sahin is optimistic. “I think that vaccines should ideally accomplish two things: first, to prevent the illness or at least to weaken it; and second, to prevent the pathogen from jumping from person to person.” If it could do both, that would be an enormous success, he says, because it would stem the pandemic.
For the time being, though, only very few experts are as optimistic as Sahin. Studies thus far indicate that even those who have been vaccinated can pass along the virus, though they recover more quickly and thus infect fewer people. That, too, would help in the fight against the pandemic, but it would be far from over.
The American biotech company Moderna is receiving assistance from the U.S. military and sees the vaccine as just a first step toward a new palette of treatments.
Moderna is an extremely American company. Based in Cambridge, Massachusetts, where it was also founded, it has received a billion dollars in risk capital from U.S. investors and has become a star on the New York Stock Exchange. It has also developed the most promising candidate in the U.S. vaccination development program known as Operation Warp Speed. Still, the company is headed up by Stéphane Bancel, a gaunt, hard-bitten Frenchman who talks rapidly in heavily accented English. In the spring, he was invited to the White House, where Trump demanded that he produce a vaccine before the election.
The somewhat delayed answer to that request came a few weeks ago: Forget about it. The company said that its vaccine would be available in late November at the earliest. Well after Election Day.
Moderna is currently BioNTech’s greatest competitor and the Americans are using the same mRNA technology. And like the Germans, they see vaccines as just one of many possible offshoots on the path to an entirely new class of medicines.
“It’s a platform,” says Bancel. “Once we can reach directly into the cell, it opens up entirely new worlds for therapies to treat many diseases.” The company believes that mRNA is the key to rewriting “the software of life.”
That’s quite a claim, and perhaps a bit overstated, but after nine years as CEO, Bancel has become the most vocal champion of a technology that he initially thought was “impossible.” That was back in 2010, when stem-cell researchers at Harvard University were conducting initial experiments on mRNA technology and looking to start a company.
Bancel has since managed to convince many others. Moderna’s IPO in 2018 was the biggest ever for a biotech company and it is now developing treatments for cancer, AIDS and heart disease. And for infectious diseases. In the last two years, Moderna has joined forces with the National Institute of Allergy and Infectious Diseases (NIAID) to conduct research on the virus which causes Middle East Respiratory Syndrome (it is known as MERS and is also from the coronavirus family) in an effort to develop a preemptive weapon for the next pandemic. NIAID is led by Anthony Fauci, the U.S. government’s pandemic adviser.
Like BioNTech, Moderna received the DNA sequence of the novel coronavirus in January. Computers used that sequence to calculate its three-dimensional structure. Bancel immediately wrote to Fauci: “Do you see it too?” The spike proteins on the MERS virus and on the new coronavirus appeared to be almost identical. It looked as though it would be simple to develop an antigen, the vaccine element necessary to shut down a virus.
The vaccine’s design was finished just three weeks later, and on March 16, Moderna became the first to inject trial subjects with a coronavirus candidate vaccine. Phase III of the study has been going since July 27, organized in cooperation with Fauci’s NIAID. Still, the several month head-start the vaccine enjoys could ultimately evaporate if the thus-far unproven technology doesn’t produce the hoped-for results.
Conventionally designed vaccines will also be approaching approval early next year. The U.S. pharmaceutical company Johnson & Johnson is testing a vector-based vaccine on 60,000 subjects in a Phase III study, though it had to be paused in mid-October after one of the subjects became ill. It remains unclear if the illness was linked to the vaccine and the study is now set to resume.
A joint project involving the University of Oxford and the British-Swedish company AstraZeneca is using a harmless version of the cold virus as the basis for its vaccine. Their Phase III trial also had to be temporarily suspended after a test subject became ill, but it has since restarted. The pharmaceutical company Merck is working on a vector vaccine while Sanofi is using protein-based technology. Both companies have years of experience in creating vaccines, even if their candidates will only be ready for approval in about a year.
The U.S. government doesn’t particularly care which approach will be fastest. Washington has decided to help all of them get to the finish line. In April, Trump announced Operation Warp Speed, with the stated goal of having 300 million vaccine doses available by January 2021. The plan included funding of over $10 billion for eight companies.
The operation also includes centralized coordination among all U.S. government departments and agencies involved in vaccine production, from the Department of Health and FDA to the Department of Defense. The U.S. hasn’t seen such a centralized effort since the Manhattan Project, according to Trump, referring to the national effort during World War II to build the atomic bomb.
The comparison is not inaccurate, given the large role played by the military in Operation Warp Speed. Formally, the effort has two leaders. The first is Moncef Slaoui, the former head of GlaxoSmithKline’s vaccine division, who is responsible for vaccines and therapies. He is joined by Gustave Perna, a four-star general whose previous assignment was as head of Army Material Command, overseeing most of the army’s materiel logistics. In Operation Warp Speed, Perna is responsible for logistical aspects such as planning, equipment, production and distribution.
The organigram of Operation Warp Speed shows just how significant the military’s role is. Of the operation’s 90 leading staff members, around two-thirds of them are from the Defense Department or the military. The U.S. Army, the government insists, simply has the necessary experience with complex logistical challenges.
“Operation Warp Speed has proven to be very helpful,” says Bancel. Moderna is one of the companies that has received funding as part of the program. “We don’t have to worry about security or supplies. The Army is calling the companies every day until the stuff has arrived.”
When Moderna needed a new ventilation system for a production facility a few weeks ago, a military convoy escorted the supplier’s truck for several thousand miles from the Midwest to the East Coast. “It didn’t have to stop at any red lights,” Bancel says. In return, Moderna has pledged to deliver 100 million vaccine doses to the U.S. government in the coming months, worth $1.5 billion. Washington also has an option for 400 million more.
Despite the U.S. government’s direct involvement, no political pressure has been exerted on the companies, says Bancel. Shortcuts in the clinical studies, he says, are not an option.
Still, Moderna also intends to undertake an initial analysis of results prior to the end of the Phase III trial of its vaccine candidate mRNA-1273. Interim results will be examined once there are 53 positive coronavirus cases among the trial’s 30,000 test subjects, a benchmark expected to be reached in November.
Why not wait until the trial is concluded? “The figures show that if you want to wait untll next spring, we might lose over a million people on the planet,” Bancel says.
Since July, Moderna has been producing as many doses of mRNA-1273 as it can, and has established partnerships with production facilities around the world to do so. The hope is that 20 million doses will be available by the end of the year, with at last 500 million more doses to be produced next year. “Manufacturing is going be challenge fo everybody, not only for the next few months but the next 18 months,” says Bancel. The steady supply of regulated medical raw materials – such as cell cultures, enzymes and lipids – is particularly sensitive. If just a single component from one of the countless suppliers around the globe is missing, the entire production could come to a halt.
And even if everything works, says Bancel, including approval, production and delivery, there will still be a vaccine shortage for the foreseeable future. “In the first half of next year, at least, maybe until Labor Day next year,” says Bancel, “I anticipate that the world is going to be massively supply constrained, meaning not enough vaccine to vaccinate everybody.”
The Tübingen-based company Curevac is taking more time to develop a better vaccine. The company is also already busy working on a solution for the next pandemic – together with Elon Musk.
Curevac’s headquarters is located on a hill high above the university town of Tübingen. Large windows offer views deep into the Swabian Jura mountain range, and everything inside is so new that it still shines. Some taxi drivers don’t even know the way yet, though a new production facility is already under construction next door. Some 9,000 scientists from around the world have applied for jobs with the company this year alone.
Curevac, which was founded in 2000, is a pioneer in mRNA technology. Some of the first ground-breaking studies and important basic research into the field was carried out in Tübingen, which is home to one of Germany’s most prestigious universities. “The first to clear a path through the jungle and make a technology broadly applicable needs a bit of time and will collect some scratches along the way, whereas the others can just run right through,” says Curevac CEO Werner Haas.
Whereas Moderna in Cambridge was worth billions of dollars, Curevac in Tübingen has been financed for years solely through a single patron’s private coffers. SAP founder Dietmar Hopp has invested over 1 billion euros in promising German biotech companies since the turn of the millennium, largely because nobody else has shown much willingness to do so. Banks won’t touch anything that has to do with new medical products, and the government prefers to promote automobile technologies. It’s a typical German story. Basic research here is world class, but no one is transforming that into actual products because of a lack of money and faith.
Hundreds of new biotech and pharmaceutical companies have emerged in the United States and China over the past two decades, where they are developing new cancer drugs and gene therapies. Hopp, meanwhile, has been ridiculed for his investment in the sector in Germany, with people saying he’s just burning through his money.
That perception first started changing in 2015, at least a little bit. That’s when Bill Gates paid a visit to Tübingen and enthusiastically invested $100 million in Curevac. “Can you make vaccines for a dollar with your technology?” he asked. “In theory, we can,” they answered.
From that point on, everything could have gone much faster. Instead, Curevac spent years fighting with politicians and banks to build a factory for the industrial production of drugs – a billion doses of vaccine per year, for example. But the plant won’t be ready until 2022.
For a long time, German politicians showed little interest in the Tübingen company, but it did manage to attract attention elsewhere. In March, Donald Trump invited Curevac executives to the White House for a meeting with other leading vaccine manufacturers. A short time later it was reported that Trump had made a morally dubious offer to buy the company in order to secure its vaccine for America.
It turned out to be untrue and the company denied it, but in Tübingen, Curevac employees were spat on in the streets and disparaged as traitors. “That was a very difficult time for us and our employees,” says Haas.
A short time later, Curevac approached the German government, saying it needed money and support and asking if Berlin wanted to buy a stake in the company. In June, the German government acquired a 23 percent share of the company for 300 million euros. Economics Minister Peter Altmaier, of Angela Merkel’s center-right Christian Democratic Union (CDU) party, touted the investment, saying it served as a guarantee that not only would the vaccine stay in the country, but so too would the company and its technology.
Still, Curevac will not be among the first to get a vaccine approved. The clinical trial of the Tübingen company’s vaccine candidate is still in the first two phases: safety and dosage. Phase III is scheduled to begin at the end of this year. Possible approval, assuming everything works, would first come in March or April.
Curevac deliberately took more time. “The field is developing rapidly, and the first substances may not be the final ones,” says Mariola Fotin-Mleczek, Curevac’s chief technology officer. The company is targeting an agent that promises to be more effective, more efficient and also easier to transport, in that it will probably need to be stored only at refrigerator temperatures.
Curevac has long had its sights set on the next crisis, and they believe they’ve found the answer, in the form of a white box, as big as a living room cupboard. A pane of glass provides a view of what’s inside. Surrounded by a maze of tubes and pumps is silver egg, encased by a magnetic ring that moves up and down. It produces RNA. The gadget can be packed into a container and shipped around the world as a portable vaccine laboratory, ready to be set up in university hospitals and laboratories, where it can then begin producing the substance needed using online instructions. “If we had an RNA printer locally, we could produce the required substance in small quantities directly on site so that an outbreak could be controlled locally,” says CTO Fotin-Mleczek.
The device is still a prototype, but it should go into serial production within two years – with help from Elon Musk. The Tübingen-based researchers aren’t plant managers, so they have partnered with the mechanical engineering company Grohmann as their partner. The company was then acquired by Tesla, and Musk himself personally visited Tübingen over the summer to learn more about the mini-bioreactor, which now prominently features the Tesla logo. Musk was enthusiastic about the technology, but not about the German pace of development. “Guys, this has to go faster,” he said at the end of the visit, promising to provide his personal support.
“Musk has a point,” says Haas. “And now is the time to show what we can do.”
The president of the Paul Ehrlich Institute explains how and when approval for a vaccine is granted and how safe it must be.
If you’re looking for the antithesis of the chic corporate headquarters of the pharmaceutical companies and the optimistic stock market vernacular of their CEOs, it would be hard to find a better place than the Paul Ehrlich Institute (PEI), which could be a dilapidated school building in an industrial zone. A friendship plate from the Mongolian Health Ministry has been placed prominently in a glass case at the entrance. Displayed in the library on the second floor is the death mask of Paul Ehrlich, the man the institute is named after and the founder of modern chemotherapy.
PEI is one of two German drug regulatory authorities and is responsible for vaccines. For the past 11 years, the agency has been run by Klaus Cichutek, a 64-year-old professor of biochemistry and the global authority on gene therapy. “If the data meet the criteria of a favorable benefit-risk ratio,” he says, “it is possible that we will have approval for a COVID-19 vaccine in the first months of next year.” And more could follow. “I am very confident that we will have approvals for several vaccine products,” he says.
In recent months, officials at PEI have combined all available forces in the fight against the virus. Clinical trials were approved in an average of 12 days rather than the 65 days that had been the norm. Many vaccine developers were provided with scientific advice in advance to help them design their studies correctly. “We have advised some who are already in Phase II and III,” says Cichutek. The German institute enjoys worldwide expertise because it not only approves vaccines, but also conducts research in its own high-security laboratories.
Final approval is also set to go faster than normal. It’s possible that most vaccines for the coronavirus will initially be granted “provisional approval” and further data – on the long-term efficacy, for example – could then be submitted later.
Once a substance is approved, that authorization will apply for the entire European Union. Formally, the applications have to be submitted to the European Medicines Agency (EMA). For testing procedures, experts from the national authorities are then selected on the basis of their expertise. But Germany’s PEI, as a leader in vaccines, has done the most vaccine testing for Europe in the past two decades.
Of the 10 companies that are far along on the road to a vaccine, not all are likely to submit applications for approval in the EU for strategic reasons. Cichutek believes there will initially only be three or four applicants, but this doesn’t mean that doctors will have a wide choice of which vaccine to give their patients. It’s also quite possible that the FDA in the U.S. will consider a vaccine to be ready for the market because of the specific pandemic situation that the Europeans don’t think is ready – or vice versa. “The vaccine recommendation after authorization will also then focus on how to achieve the greatest benefit in containing the pandemic and how to protect certain particularly vulnerable risk groups. This could well vary around the world,” says PEI President Cichutek.
The U.S. authorities have said they would approve a COVID-19 vaccine if it has a 50-percent efficacy rate. Europe, though, hasn’t identified a specific benchmark. Could that then mean that a vaccine might be approved despite having only 40-percent efficacy, if it is particularly suitable for a certain group? Theoretically yes, says Cichutek. “We want to have the freedom to make our decisions based on the situation and on an evaluation of the entire product-specific data available and not put ourselves in a corset from the very start,” he says.
Cichutek again speaks somewhat abstractly of a “favorable benefit-risk ratio.” Benefits are commonly understood by the regulatory agencies as efficacy – i.e. preventing the most severe progressions of COVID-19 illness or the reduction of the death rate. At the moment, few are expecting the vaccines to produce what scientists call “sterile immunity,” meaning that they would not be able to prevent the infection from being passed on entirely.
As such, it’s likely that wearing masks is going to be part of our daily routines for some time to come. “We have to be aware of the possibility that we can still get infected with the virus, and in some cases, we can transmit it to non-immunized people,” says Cichutek. “But we will be protected from COVID-19 or the worst forms of illness it causes.”
On the other hand, vaccine safety is clearly defined: Temporary redness at the site of the injection or a slight headache after vaccination is considered acceptable by Cichutek, but harm to the body is not. In the medium term, vaccines against COVID-19 will likely become the best-researched drugs in human history because it’s possible that billions of vaccinations will ultimately be administered.
The chairwoman of the German Ethics Council is considering who should be vaccinated first and whether research has been conducted too quickly.
No one knows yet how many doses of vaccine will be available in Germany in the coming months. It is a certainty, however, that the supply will be vastly insufficient. There could be enough for 2 million or possibly up to 4 million people. In a country with over 83 million people, how should it be distributed?
“You have to distribute it as fairly as possible, taking into account exactly what the vaccine can do,” says Alena Buyx, a professor of ethics in medicine and health technologies and head of the Institute of History and Ethics in Medicine at the Technical University of Munich. She was elected chairperson of the German Ethics Council in May. Together with the experts at the German National Academy of Sciences Leopoldina and the Permanent Vaccination Commission (STIKO) of the Robert Koch Institute, the council advises the German government on who should be vaccinated and when in addition to addressing questions such as what is most important in a pandemic, protecting individuals or society as a whole.
German Health Minister Jens Spahn of the CDU asked the three organizations to join forces so that the federal government wouldn’t have to decide “in a vacuum” which groups would be given preference. “From an ethical point of view, the state may prioritize as long as there is a real shortage and there isn’t enough vaccine to go around to everyone,” says Buyx.
But she says that basic criteria must be applied. Self-determination, for example, so that not every nurse is forced to be vaccinated for the common good. Or equal treatment: If teachers are vaccinated first, then vocational school teachers shouldn’t be excluded.
Initial recommendations are to be presented this week in a joint report by the Ethics Council, Leopoldina and STIKO. But the groups can only be determined after the efficacy profiles of the vaccines have been presented. The experts can then use those profiles to develop computer-aided models that address important questions. For example: Does it make more sense to vaccinate elderly people because they are more likely to fall seriously ill or should the focus be on protecting the nursing staff in care homes?
The situation grows more difficult when children and adolescents are part of the equation. “Children aren’t little adults, they have a different physiology and need to be researched separately,” says Buyx. So far, though, only BioNTech and Pfizer are testing their vaccine candidate on 12- to 18-year olds.
Buyx isn’t concerned that development has been faster than normal. “I don’t see any indications that safety standards have been ignored,” she says.
But what if the companies in question appear to be closer to their goal, such as when BioNTech and Pfizer issue their interim report after just 32 positive corona cases? “Interim analyses are not in themselves a problem from the perspective of research ethics,” she says. But even if those reports are encouraging, she says, the studies should still be brought to full conclusion.
From the patient’s point of view, she says, it is quite positive if there are early results. This forces the researchers to measure their vaccine candidates against other vaccines that are already available rather than against placebos.
“Hopefully, we will be able to choose the best one in the future,” says Buyx. “And if we’re lucky, there may be one with very high efficacy in the next round.”
How the federal government plans to vaccinate millions of people
It’s an overcast October day in Berlin, with cold air streaming into the office of the German Health Minister Jens Spahn. He has opened the windows wide – a bit of a draught surely can’t hurt this morning. The number of new infections is increasing daily in Germany, as is the pressure on politicians, and Spahn is the face of the crisis. At this point, he doesn’t have any reason to suspect that he will soon be infected with the virus himself. (Spahn tested positive for the new coronavirus last week after the interview.)
Since the beginning of the pandemic, Spahn has been plagued by the lack of influence he has in Germany’s federal structure. In normal times, infection control policies are a matter for the states, and they’re also responsible for stockpiling vaccines for emergencies, at least as a rule. During the pandemic, the federal government has now taken over this responsibility. Given the magnitude of the crisis and the limited influence each state can exert on its own, Spahn has been haggling directly with pharmaceutical executives over prices, visiting production facilities and contemplating the right vaccination strategy.
In his interview, Spahn says he expects a vaccine for the German population “early next year.” He says it might be January, February, March – or even later. He’s trying hard not raise expectations. “Of course, it would be best if a vaccine could prevent new infections. But it would also be beneficial if it made the progression of the disease milder.”
The ministry expects the rush for vaccination will be significant. As soon as a vaccine is approved, the idea is to carry out vaccinations in large centers if possible. Spahn fears that general practitioners might initially be overwhelmed by the logistics.
The states and public health departments have begun looking for suitable locations, like exhibition halls. But transport and logistics have to be organized first. It’s likely that the vaccine will be distributed to 60 to 100 central warehouses. Special cold storage and refrigerated trucks will be needed. The vaccine will also come in bulk packages of dozens of doses rather than in individual ampoules. Once opened, they will have to be used within a few hours.
There isn’t much time left to get all that organized.
Most importantly, the halls will need to have plenty of space, especially should vaccinations begin in below-zero winter temperatures. People would be informed about the details of the vaccination in groups of 20 to 30 and then vaccinated in separate groups. Afterward, those who have been vaccinated must be placed under observation for at least a half-hour. “You need space for all that – the village gymnasium won’t be big enough,” says Spahn. Security personnel will also be needed to guard the scarce vaccine supplies. “In the beginning, it will certainly be the case that we have to turn people away if they come without an appointment.”
The vaccine will be paid for by the federal government and not by the statutory health insurance companies in Germany. “We can’t have a situation where people at the vaccination centers first have to go through the time-consuming process of proving whether or not they are covered by public or private insurance,” says Spahn.
The federal government is also currently steering the development of several digital applications: a solution for appointment management, which, according to Spahn, is “quite banal, but very important.” Statistical data must also be collected, particularly for RKI. Another app is being developed to make it easy to record side effects. “In an ideal world, all this would belong in one big digital tool,” the health minister says. “But the experience of the past few months has shown that these things quickly go wrong when there is time pressure,” which is why the government is developing “several stand-alone solutions.”
In return, the states have been asked to take care of the smaller things, particularly the procurement of the supplies needed to administer vaccinations, like band aids, needles and syringes. “If states are smart, they are already securing supplies,” Spahn says in what sounds like a pointed warning. Spahn himself failed in his efforts in the spring to obtain even the cheapest protective gear. The complete lack of masks available in Germany at the start of the COVID-19 outbreak is still considered the government’s greatest failure in the crisis.
And who will be the first to get vaccinated? Spahn is waiting for the proposals from the joint commission. “Nurses, doctors and health care professionals have to be at the top of the list,” he says. It’s very likely that vaccines in the first half of the year will have to be rationed and prioritized.
The government is planning an educational campaign to explain the procedure. “We don’t want to encourage people to get a corona vaccination only to then find out that there is no vaccine available for them,” says Spahn.
There is no plan for when a critical mass of people in Germany will have been vaccinated. Spahn says everything is contingent on how many vaccines get approved in the coming months and how many doses are available. As soon as enough vaccine is available, Spahn says it might be possible to “vaccinate a large number of those who want to” within six or seven months.
The U.S. has already defined more precise targets. “At the beginning of the year, we could vaccinate 30 to 40 million people,” says Moncef Slaoui, the head of Operation Warp Speed. After that, in pure logistical terms and if enough doses were available, 80 million Americans could be vaccinated each month.
But Spahn has refused prescription targets like that. “There won’t be any compulsory vaccination requirement,” he says. “That’s why there is no point in setting targets.”
The German government has committed the country to the European Vaccine Initiative, under which the European Commission in Brussels is negotiating with manufacturers on behalf of the entire EU. The doses would then be distributed based on the population sizes of the EU member states. The more inhabitants a country has, the more vaccine doses it will get.
Some of the negotiations have been dragging on for months, including those with BioNTech and Pfizer. Spahn is growing impatient and has trouble hiding that in his interview. Under existing contracts, Germany is entitled to at least 150 million doses, which are expected to be delivered in monthly tranches as soon as they are available.
Millions more doses are to come from BioNTech and Curevac independently of the EU, which have been guaranteed through hundreds of millions of euros in funding the companies have received from the German government.
“We are securing considerably more vaccine than will be needed,” says Spahn. If anything is left over, Germany could still sell it on to other countries or donate it to poor countries, he says. “But vaccine development is far too complex for us to rely on just one candidate. We need alternatives.”
There’s one thing, in particular, that the German government wants to avoid at all costs: Betting on a single horse that collapses shortly before it reaches the finish line.