Benefits and pride at stake, the race for a vaccine intensifies



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WASHINGTON – Four months after a mysterious new virus began its deadly march around the world, the search for a vaccine has taken on an intensity never seen before in medical research, with huge implications for public health, the global economy and politics.

Seven of the approximately 90 projects carried out by governments, pharmaceutical manufacturers, biotech innovators and academic laboratories have reached the stage of clinical trials. With political leaders, especially President Trump, increasingly pressing for progress, and with huge potential gains at stake for the industry, drug makers and researchers have signaled that they are moving at speeds never seen before.

But the entire company remains concerned about the uncertainty of whether any coronavirus vaccines will be effective, how quickly it could be available to millions or billions of people, and whether in a hurry, compressing a process that can take 10 to 10 years. months, it will sacrifice security.

Some experts say the most immediate promising field could be developing treatments to speed up the recovery of Covid-19, an approach that has generated some optimism in the past week by initially encouraging the results of research on remdesivir, an antiviral drug previously tested in the fight against Ebola.

“Biomedical research has long been a focus of theft, especially by the Chinese government, and vaccines and treatments for coronavirus are the holy grail of today,” Deputy Attorney General for Homeland Security John C said Friday. Demers. “Commercial value aside, it would be very important to be the first to develop a treatment or vaccine. We will use every tool we have to safeguard American research.”

The intensity of the global research effort is such that governments and companies are building production lines before they have something to produce.

“We are going to start increasing production with the companies involved,” said Dr. Anthony S. Fauci, director of the National Institute of Allergy and Infectious Diseases and the federal government’s leading expert on infectious diseases, this week. “Don’t wait until you get a response before you start manufacturing.”

Not to be outdone, UK-based pharmaceutical giant AstraZeneca said this week that it was working with a vaccine development project at Oxford University to manufacture tens of millions of doses by the end of this year.

With demand for such a strong vaccine, there are increasing calls for “human challenge trials” to speed up the process: tests in which volunteers are injected with a potential vaccine and then deliberately exposed to the coronavirus.

Because the approach involves exposing participants to life-threatening illness, challenge trials are ethically charged. But they could be faster than simply inoculating human subjects and waiting for them to be exposed along with everyone else, especially as the pandemic comes under control in large countries.

Even when promising solutions are found, there are major challenges in expanding production and distribution. Bill Gates, the founder of Microsoft, whose foundation is spending $ 250 million to help stimulate vaccine development, warned of a critical shortage of a mundane but vital component: medical glass.

The magnitude of the problem and the demand for a quick fix are bound to create tensions between the profit motives of the pharmaceutical industry, which generally struggles hard to get the most out of its investments in new drugs, and the public’s need for action. fast to effectively vaccinate as many people as possible.

So far, much of research and development has been supported by governments and foundations. And much remains to be resolved when it comes to patents and what national governments will demand in exchange for their support and promises of swift regulatory approval.

George Q. Daley, dean of the Harvard Medical School, said that thinking in country-by-country terms rather than global terms would be unwise since “it would involve wasting the first few doses of the vaccine on large numbers of people at low risk, instead of covering as many high-risk individuals globally “- healthcare workers and older adults -” to stop the spread “worldwide.

Given the proliferation of vaccine projects, the best result may be that none of them emerge as a clear winner.

“Let’s say we get a vaccine quickly, but we can only get two million doses by the end of next year,” said Anita Zaidi, who heads the Bill and Melinda Gates Foundation’s vaccine development program. “And another vaccine, just as effective, comes three months later, but we can do a billion doses. Who won that race?

The answer, he said, “is that we will need many different vaccines to cross the finish line.”

At 1 a.m. on March 21, 1963, a 5-year-old girl named Jeryl Lynn Hilleman woke up her father. She had fallen with the mumps, which had made her miserable with a swollen jaw.

As it happened, his father, Maurice, was a vaccine designer. Then she told Jeryl Lynn to go back to bed, drove to her laboratory in Merck to pick up some equipment, and rubbed her throat again. Dr. Hilleman refrigerated his sample in his laboratory and soon began to work weakening his viruses until they could serve as a mumps vaccine. In 1967, it was approved by the F.D.A.

For vaccine manufacturers, this story is legendary. Dr. Hilleman still holds the record for the fastest delivery of a vaccine from the laboratory to the clinic. Vaccines typically take 10-15 years of research and testing. And only six percent of the projects scientists launch reach the goal.

For a world in the hands of Covid-19, on the other hand, this story is a nightmare thing. No one wants to wait four years to receive a vaccine, while millions die and economies remain paralyzed.

Some of the top contenders for a coronavirus vaccine now promise to have the first batches ready in record time, early next year. They’ve sped up their schedules by collapsing the standard vaccine timeline.

They are combining trials that used to be done one after another. They push their formulations into production, despite the risk of trials failing, leaving them with millions of useless doses.

But some experts want to do even more to speed up the conveyor belt. Writing last month in Vaccines magazine, vaccine developer Dr. Stanley A. Plotkin and Dr. Arthur L. Caplan, a bioethicist at NYU Langone Medical Center, proposed to infect volunteers vaccinated with the coronavirus, the method known as challenge trials. The procedure could cut months or years from development, but would put test subjects at risk.

Dr. Caplan said limiting the trials to healthy young adults could reduce the risk, since they were less likely to suffer serious complications from Covid-19. “I think we can let people make the decision and I have no doubt that many would,” he said.

In Congress, Representative Bill Foster, Illinois Democrat and physicist, and Representative Donna E. Shalala, Florida Democrat and the former secretary of the Department of Health and Human Services, organized a bipartisan group of 35 legislators to sign a letter asking regulators to approve such lawsuits.

Some scientists caution that truly informed consent, even by willing volunteers, may not be possible. Even medical experts still don’t know all the effects of the virus. Those who seemed to recover could still face future problems.

Even without challenge testing, accelerated testing can risk losing potential side effects. One dengue fever vaccine, and one for SARS that never made it to market, were abandoned after making some people more susceptible to severe forms of the diseases, not the least.

“It will be extremely important to determine that that does not happen,” said Michel De Wilde, a former senior vice president for research and development at Sanofi Pasteur, a vaccine maker in France.

When it comes to the risks of faulty vaccines, China’s history is instructive.

The Wuhan Biological Products Institute was involved in a 2018 scandal in which ineffective vaccines against diphtheria, tetanus, pertussis, and other conditions were injected into hundreds of thousands of babies.

The government confiscated the “illegal income” from the Wuhan Institute, fined the company and punished nine executives. But the company was allowed to continue operating. He is now running a coronavirus vaccine project, and together with two other Chinese groups, he has been allowed to combine his safety and efficacy trials.

Several Chinese scientists questioned the decision, arguing that the vaccine must be shown to be safe before testing how well it works.

In the early days of the crisis, Chinese billionaire Hui Ka Yan approached Harvard. He arranged to give approximately $ 115 million to be shared between Harvard Medical School and its affiliated hospitals and the Guangzhou Institute of Respiratory Diseases for a collaborative effort that would include the development of vaccines against coronavirus.

“We are not competing with each other, we are competing with the virus,” said Dr. Dan Barouch, director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center and a professor at Harvard Medical School who is also working with Johnson and Johnson. “What we need is a global vaccine, because an outbreak in one part of the world puts the rest of the world at risk.”

That all-for-one sentiment has become a mantra among many researchers, but it’s hardly universally shared.

The tension between those who believe that a vaccine should go where it is most needed and those who face pressure to supply their own country first is one of the defining characteristics of the global response.

The Trump administration, which in March introduced a German biotech company to either acquire its vaccine research or move it to the United States, has awarded grants of nearly half a trillion dollars each to two US-based companies. UU., Johnson & Johnson and Moderna.

Johnson & Johnson, although based in New Jersey, conducts its research in the Netherlands.

Paul Stoffels, the company’s vice president and chief scientific officer, said in an interview that the Department of Health and Human Services understood that “we cannot take up our research and move it” to the United States. But he made sure the company teamed up with Emergent BioSolutions, a Maryland biological production company, to produce the first large batches of any vaccine approved for the United States.

“The political reality is that it would be very, very difficult for any government to allow a vaccine made in its own country to be exported as long as there was a major problem at home,” said Sandy Douglas, a researcher at the University of Oxford. “The only solution is to make a large number of vaccines in many different places.”

In China, the government instinct is to show the growth of the country in a technological power capable of defeating the United States. There are nine Chinese Covid-19 vaccines in development, involving 1,000 scientists and the Chinese military.

China’s Center for Disease Control and Prevention predicted that one of the vaccines could be in “emergency use” in September, meaning that in the midst of the US presidential election, Trump could see television footage of citizens. Chinese queuing for injections

“It’s a scenario we’ve thought about,” said a member of Trump’s coronavirus task force. “No one wants to be around that day.”

The more than 90 different vaccines in development work in radically different ways. Some are based on designs used by generations. Others use genetics-based strategies that are so new that they have not yet resulted in an approved vaccine.

“I think in this case it is highly advisable to try different platforms,” ​​said Dr. De Wilde.

The traditional approach is to make vaccines from viruses.

When our bodies find a new virus, they begin to learn how to make effective antibodies against it. But they are in a race against the virus as it multiplies. Sometimes they produce effective antibodies fast enough to clear an infection. But sometimes the virus wins.

Vaccines give the immune system an advantage. They teach you how to make antibodies before infection.

The first vaccines against diseases such as rabies were made from viruses. Scientists weakened the viruses so that they could no longer make people sick.

Several groups are weakening the coronavirus to produce a vaccine against Covid-19. In April, the Chinese company Sinovac announced that its inactivated vaccine protected monkeys.

Another approach is based on the fact that our immune system produces antibodies that precisely bind to viruses. When scientists came to understand this, it occurred to them that they did not have to inject a whole virus into someone to activate immunity. All they needed was to deliver the fragment of a viral protein that was the precise target.

Today, so-called viral subunit vaccines are used against hepatitis B and herpes zoster. Many vaccines from the Covid-19 subunit are now being tested.

In the 1990s, researchers began working on vaccines that enrolled our own cells to help train the immune system. The basis of these vaccines is typically a virus called adenovirus. Adenovirus can infect our cells, but it is altered so that it does not make us sick.

Scientists can add a gene to the virus adenovirus they want to fight, creating what is known as a viral vector. Some viral vectors then invade our cells, stimulating the immune system to produce antibodies.

Researchers from the University of Oxford and the Chinese company CanSino Biologics have created a viral vector vaccine for Covid-19, and have started safety trials on volunteers. Others, including Johnson & Johnson, will launch their own tests in the coming months.

Some groups, including the American company Inovio Pharmaceuticals, are taking a totally different approach. Instead of injecting viruses or protein fragments, they inject pure DNA, which is read by the cell’s machinery, making a copy like an RNA molecule. The RNA is then read by the cell’s protein-building factories, producing a viral protein. The protein in turn leaves the cell, where the immune cells collide with it and make it an antibody.

Other teams are creating RNA molecules instead of DNA. Moderna and a group at Imperial College London have launched safety trials for RNA vaccines. While experimental, these gene vaccines can be quickly designed and tested.

It is one thing to design a vaccine in record time. It is a completely different challenge to manufacture and distribute one on a scale never attempted before: billions of doses, specially packaged and transported at sub-zero temperatures, to almost every corner of the world.

“If you want to give a vaccine to a billion people, it had better be very safe and effective,” said Dr. Stoffels of Johnson & Johnson. “But you also need to know how to do it in amounts we’ve never seen before.”

So the race is about to get ahead of huge logistical problems, from basic manufacturing capacity to a shortage of medical glass and caps that Mr. Gates and others have warned of.

Johnson & Johnson researchers are trying to make a five-dose vial to save precious glass, which could work if a smaller dose is enough for inoculation.

Each potential vaccine will require its own customized production process in special “clean” facilities for drug manufacturing. Building from scratch can cost tens of millions of dollars per plant. Equipping an existing facility could easily cost $ 5 million to $ 20 million. Ordering and installing the necessary equipment can take months.

Governments, as well as organizations like the Gates Foundation and the nonprofit Coalition for Outbreak Preparedness Innovations are bringing money to production facilities long before a particular vaccine is proven to be effective.

In addition, some vaccines, including those being tested by US companies Moderna and Inovio, are based on technology that has never before produced a drug licensed for use or mass-produced.

But even traditional processes face challenges.

Due to staff illness and social estrangement, this spring’s pandemic reduced productivity by 20 percent at the MilleporeSigma facility in Danvers, Massachusetts, which supplies many drug manufacturers with the equipment used to make vaccines.

Then, about three weeks ago, the first clinical trials began for the proposed new vaccines. Urgent calls from customers around the world. Even before the first phase of the first tests, the manufacturers were struggling.

“The demand went through the roof, and everyone wanted it yesterday,” said Udit Batra, executive director of MilleporeSigma, which has expanded production and asked other clients to accept delays to avoid becoming a bottleneck.

Even as the world awaits a vaccine, a potential coronavirus treatment is already here, and more may be on the way.

Remdesivir showed modest success in a federally funded clinical trial, slowing disease progression, but without significantly reducing mortality rates.

Drug studies tend to move faster than vaccine trials. Vaccines are given to millions of people who are not yet sick, so they must be extremely safe. But in the sickest people, that calculation changes, and side effects can be an acceptable risk.

As a result, clinical trials can be conducted with fewer people. And because the drugs are tested on people who are already sick, the results can be seen more quickly than in vaccine trials, where researchers must wait to see who gets infected.

Public health experts have warned that there will likely be no magic pill. Rather, they expect incremental breakthroughs that will make Covid-19 less deadly.

“Almost nothing is 100 percent, especially when it comes to a virus that really wreaks havoc on the body,” said Dr. Luciana Borio, former director of medical preparedness and biodefense for the National Security Council under President Trump. .

Many in the medical community closely watch the development of antibody drugs that could act to neutralize the virus, either once someone is already ill or as a way to block the infection in the first place.

Dr. Scott Gottlieb, a former F.D.A. commissioner, and others said that by the fall, the Covid-19 treatment image may look more hopeful.

If its efficacy is demonstrated in additional trials, remdesivir may be more widely used. One or two antibody treatments may also be available, providing limited protection for healthcare workers.

Even without a vaccine, Dr. Borio said, a handful of early treatments could make a difference. “If you can protect people who are vulnerable and can treat people who contract the disease effectively,” he said, “then I think it will change the trajectory of this pandemic.”

David E. Sanger reported from Washington, David D. Kirkpatrick from London, Carl Zimmer and Katie Thomas from New York and Sui-Lee Wee from Singapore. Denise Grady and Maggie Haberman contributed reporting.

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