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As the world fell victim to the coronavirus pandemic early this year, the field seemed wide open for the scores of pharmaceutical companies and universities that rushed todevelop vaccines to curb Covid-19. But now thatPfizer Inc. and its partnerBioNTech SE are rolling out a coronavirus shot, with rivalModerna Inc. not far behind, dozens of drugmakers further back in the development pack are suddenly facing a sobering possibility: The window to develop a successful vaccine before the field becomes crowded could be closing. That may leave some laggards unable to easily enroll enough volunteers in the trials needed to win regulatory authorization. In fact, drugmakers that are too many months behind might find themselves locked out of the vast U.S. market, which also is usually the most lucrative.
The problem is the stunning success of the early leaders’ inoculations.Pfizer andModerna last month announced their vaccines achieved efficacy levels of around 95% in trial results, stoking optimism that the world will soon have potent weapons to stop a contagion that’s killed more than 1.5 million people. And, despite confusion surrounding its findings,AstraZeneca Plc appears to have anotherpromising contender.
While that’s good from a public-health standpoint—multiple products will undoubtedly be needed to immunize the world’s almost 8 billion people—the exceptional effectiveness of the early leaders’ vaccines is raising the bar and shrinking the pool of candidates for challengers such as Merck, Novavax, andSanofi and its partner,GlaxoSmithKline, along with more than 200 other research teams.
One problem is that getting volunteers to sign up for or remain in clinical studies where as many as half are given placebos could become difficult if they think they can simply wait and gain access to a guaranteed, effective vaccine such as Pfizer’s. The challenge will become more acute in late winter and early spring, as significant swaths of the population likely become eligible for vaccines that have been cleared by U.S. or other global regulators.
“If you’ve enrolled in a study, or your plan is to enroll in a study, and you’ve suddenly got an email saying, ‘Hey, you are eligible for the Pfizer vaccine next week,’ my guess is you’d probably take the latter,” says Daniel Mahony, a health-care fund manager with Polar Capital in London. That could prolong the time it takes to conduct a robust trial, pushing latecomers even further back in the pack.
After initial difficulties assembling enough trial enrollees,Johnson & Johnson said it should be able to get results in January. Sanofi and Glaxo plan to launch the last phase of their trials this month, whileNovavax Inc. expects to begin large tests in the U.S. and Mexico soon. Many others hope to get into late-stage trials sometime next year.
There’s a need for multiple approaches for many reasons, beyond the overwhelming challenge of vaccinating the entire world in the shortest time possible—a feat never before attempted. It’s uncertain how long the shots will confer protection and whether they’ll need to be given repeatedly. Evidence has emerged that immunity may wane even in people who were previously infected.
While the mRNA vaccines from Pfizer and Moderna, which turn cells into tiny vaccine-making factories, produced superlative short-term protection, it’s unclear if the benefit may ebb. They also can cause side effects such as headaches and fatigue, especially after the second dose. That could give second-generation vaccines an opening to deliver a better tolerated or longer-lasting entry.
That prospect of a robust and persistent market is likely to compel some vaccine stragglers to take different approaches to testing than those used by Pfizer and Moderna, which conducted traditional large-scale trials of their vaccines compared to placebo in areas where outbreaks were raging.
One approach to the problem of the crowded U.S. market is to avoid it altogether. That’s what German vaccine makerCureVac NV is doing. The late-stage trial of its Covid-19 mRNA vaccine will take place in Europe and Latin America. “We are not planning to run the clinical trial in the U.S., because the U.S. is well covered with vaccines for the pandemic,” Chief Executive Officer Franz-Werner Haas said on a Nov. 30 investor call.
Likewise, avoiding the U.S. may be the best strategy for smaller biotechs.Arcturus Therapeutics Holdings Inc., for example, signed supply deals with the governments of Israel and Singapore but has no funding from the U.S. government. “We don’t need a billion-dose transaction to move the needle,” CEO Joseph Payne said in October.
Novavax believes it will be able get enough people for its U.S. and Mexican trial since only high-risk health-care workers and the elderly initially will be eligible for the Pfizer and Moderna vaccines in the U.S. “The availability of any authorized vaccines will still be very limited when we initiate our trial,” Gregory Glenn, the company’s president of research and development, said in an email. Since most virus cases are still occurring among groups that aren’t on high-priority lists for the vaccine rollout, “we believe that we will be able to fully enroll the trial.” Novavax already has a big trial underway in the U.K.
There are also other options, including granting trial participants placed in a placebo group priority access to a vaccine, according to Moncef Slaoui, chief scientific adviser toOperation Warp Speed, the U.S. program to combat coronavirus. That incentive would ease volunteers’ fears that they wouldn’t be protected from the virus in a timely fashion.
That’s J&J’s approach. At a Dec. 8 media briefing, Paul Stoffels, chief scientific officer, said the company is working on a plan to alert people in the trial if they fall into a high-priority category that would allow them early access to the Pfizer or Moderna vaccines. The goal is to “find a way to inform them and do everything necessary so they can participate” in the rollout of other vaccines, he said.
Another possibility is to conduct studies comparing the vaccines that have been authorized to those that are still experimental in what’s called a head-to-head trial, ensuring that everyone will be inoculated in some form, though such studies are expensive and time-consuming, Slaoui says.
The U.K. is planning a way that might get around the issue, using so-called challenge studies that deliberately expose people to the coronavirus. The results could allow scientists to compare the efficacy of competing vaccines and speed research, and the first such trials could occur next year.
There’s still plenty of room for innovation, and second-generation vaccines could have an edge.Merck & Co. and J&J plan to provide protection with one shot instead of two, making the vaccine simpler to distribute, administer, and generate full protection, while others may be cheaper to produce or easier to deploy in developing nations. Pfizer and BioNTech’s vaccine has to be kept at about -70C (-94F), colder than winter in Antarctica.
None of the vaccine companies wanted to talk in detail about their plans to get second-generation inoculations to the market. Some are still waiting for initial results that will determine how they proceed, and others don’t want to divulge what could become key tactical strategies. With more than 200 different vaccines in development, and just 52 now in human studies, according to the World Health Organization, it’s a challenge that many will face.
“We will continue to work with regulatory agencies on the design and implementation of our larger studies,” Merck said in an emailed statement.
Glaxo has said its adjuvants—substances that enhance the body’s immune response—could play an important role in protecting the elderly. And rather than delivering a vaccine through an injection, other scientists are hoping to generate superior immune responses with inhaled vaccines that directly target the airway cells the virus invades.
The world would benefit from having a number of options, says Gregory Poland, director of the vaccine research group at the Mayo Clinic. Moderna and Pfizer can’t produce enough doses to meet demand in a short enough period of time, and it’s likely the coronavirus will continue to persist and circulate throughout the population, requiring vaccination for years to come, he says.
There’s ample precedent for delivering improvements in almost all vaccine-preventable diseases, he says, as companies work to make their products faster to produce and easier to take. “There is zero possibility of the field closing down around two vaccines,” Poland says. “There will always be a next generation of vaccines.”
The trailing companies are counting on there being a need for different methods to fight the virus. It’s unclear if a seasonal vaccine will be needed at the end of the pandemic, Glaxo, which has partnerships with companies in addition to Sanofi, said in a statement. “Our strategy is to have multiple shots on goal.”
The prospects are good for companies that are already in the final phase of testing and aren’t still racing to enroll participants in their trials, says Mahony, the fund manager. Ultimately, the world is likely to need at least five or six different vaccines, he says.
The challenge will be greater for products that are further back in the pipeline, as vaccination programs wipe out much of the circulating virus. In that situation, even having a placebo group in the trial wouldn’t help tease out the efficacy of a new approach, Poland says.
Eventually, scientists will be able to evaluate how well the vaccines work without tracking infection rates in thousands of people. The most likely approach will be to compare the amount of neutralizing antibodies produced against the coronavirus. If novel shots yield similar or higher levels of the protective antibodies as approved vaccines, they may be just as effective, Poland says. The process also takes less time and significantly less money than a traditional efficacy trial.
Supplies of vaccines that successfully cross the finish line will be limited in the initial months, and already there are concerns that some countries may not be able to get as much of the Pfizer and Moderna shots as they would like. That would open the door for trials that are testing novel approaches. The U.S., which has ordered enough from each company to inoculate a total of100 million people before it will need more, declined multiple offers from Pfizer to reserve additional doses, the Washington Post reported.
U.S. officials have disputed reports that the government declined to lock up more of Pfizer’s doses, suggesting the drug giant refused to provide a concrete timeline for when when it could deliver additional supply. The U.S. is in active talks with Pfizer about exercising options for more doses, they said.
Still, the Mayo Clinic’s Poland says that vaccine makers that can innovate have the most chance of winning long term, regardless of their current status, as most of the world still awaits protection. “The idea that the window is closing for new coronavirus vaccines is completely wrong and counterintuitive,” he says. “The window is closing for manufacturers who think they can do things in the same old ways.” —With Cristin Flanagan, Riley Griffin, Suzi Ring, and Tim Loh
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