The threats from more transmissible variants are “a huge topic with everybody in the White House and everyone wants to make sure we have viable strategies,” Andy Slavitt, the White House senior adviser on the covid-19 response, said in an interview. “But part of it is we need to learn more.”
Among the unknowns: Will one variant — for instance, the highly transmissible version that shut down the United Kingdom — become dominant here, or will the number of mutant strains expand? Will existing vaccines, and others on the runway, offer sufficient protection against the new variants? And if not, should companies target the most worrisome strain, or develop an injection that covers several of them?
Perhaps the trickiest question of all: If vaccines need to be switched, when should companies and government officials pull the trigger?
Drug companies already have started working on updating their vaccines against new, more transmissible variants — a move encouraged by government officials.
“What we are saying is, ‘Go ahead and study them, get them ready to go,'” said a health official who spoke on the condition of anonymity to discuss the message conveyed to manufacturers. “You do a construct for the 351 variant [first detected in South Africa], test it in people and get all the information. If you need it a few months from now, you have it. You essentially hold them in the freezer” until needed.
While the current shots by Pfizer-BioNTech and Moderna use a new technology that allows for speedy modifications, changing vaccines adds wrinkles to manufacturing and distribution schemes that are already complex.
“It’s a big decision to have a strain change,” said Kathleen Neuzil, director of the Center for Vaccine Development at the University of Maryland School of Medicine. “It has to be a very thoughtful approach.”
The next few months are shaping up as a pivotal chapter in what could be a long-running contest between coronavirus vaccines and variants, including those first detected in South Africa and Brazil, as well as the United Kingdom. Even as coronavirus infections and hospitalizations have plunged in recent weeks, experts worry upstarts could spoil an improving picture. Studies in lab dishes have shown that while the Pfizer-BioNTech and Moderna vaccines appear to be highly effective against the U.K. variant, officially known as B.1.1.7, they had a decreased ability to neutralize the South African version, or B.1.351.
Pfizer, in a statement responding to the studies, said it doesn’t believe the data translates into “a significant reduction in protection” against B.1.351, but the company is taking steps “to be in a position to develop and seek authorization for an updated mRNA vaccine or booster” if needed.
RNA viruses, such as the novel coronavirus, are notorious for mutating. The Centers for Disease Control and Prevention says more than 1,500 cases of covid-19 have been caused by the three variants, mostly, the U.K. one — a number that is almost certainly an undercount given the dearth of genetic sequencing in this country. The speed and scale of the mutations have surprised some scientists, who say that the uncontrolled spread of the virus gives it ample opportunities to replicate and change in ways that benefit its survival.
Trevor Bedford, a computational biologist at Fred Hutchinson Cancer Research Center, said he assumed last year that coronavirus vaccines would need to be reformulated every five years or so to counter mutations. Now he thinks the shots will need to be altered annually, like influenza vaccines. “It’s obviously not what I would have wanted to see, but it’s not the end of the world,” he said.
Bedford believes the U.K. variant, which may be more lethal as well as more transmissible, will become dominant in the United States in April. But he thinks there may not be a resulting spring surge, partly because of seasonal factors and also because growing numbers of people have been vaccinated or have had covid-19 and developed natural immunity. Others, however, are predicting a rise in cases in the spring. Bedford said he is more worried the B.1.351 variant or a similar one could cause a wave of cases next fall, when the weather cools.
Experts say it is important to have updated vaccines ready by then — or even before, if existing shots turn out to be less effective than needed against rapidly spreading variants. The CDC is ramping up genomic sequencing from abysmally low levels to try to track the variants and their effects. Meanwhile, the Food and Drug Administration is preparing to spell out how vaccine makers can apply for clearance of revamped vaccines. And high-level administration officials are huddling about how to secure supplies of re-engineered shots if they eventually are needed.
Most experts agree the shift would likely be prompted by evidence that variants are causing serious covid-19 illness in those who have already been vaccinated. Such “breakthrough” infections would indicate the vaccines are not shielding people from the most feared outcome — hospitalization and death.
“If we start seeing people who got full doses of vaccines and are getting severely ill from a variant, that to me would be a real trigger point,” said William Moss, executive director of the International Vaccine Access Center at the Johns Hopkins Bloomberg School of Public Health.
Even if updated vaccines are not needed in the next few months, work on updating the vaccines can be a dry run for something many industry officials and regulators believe will ultimately be needed.
One bright spot is that the Pfizer-BioNTech and Moderna vaccines, which late last year were found to be about 95 percent effective against the prevailing strain, both use genetic material called messenger RNA. It can be rapidly changed to meet mutation challenges by swapping out elements of their genetic codes. In that way, the vaccines can be uniquely tailored to create a variant spike protein that will train the immune system to meet the new threat.
Both companies are preparing to test new versions of their vaccines in small clinical trials, something they have framed as a precautionary step. Pfizer said this week it is studying the potential for a revised vaccine that would target original and new strains of the virus, as well as a stand-alone booster aimed at the South Africa variant and possibly others. It also plans to test how effective a third shot of the current two-dose vaccine would be at quelling infection by the variants if given at either six or 12 months. Moderna said late last month it plans to test an additional booster to its original vaccine and another one targeting the B.1.351 variant.
`What variants are going to appear next'
A prime inventor of the technology behind mRNA vaccines, Drew Weissman, of the University of Pennsylvania, said he has been told by the leader of BioNTech that it could take as little as six weeks to formulate a new mRNA payload and manufacture it to target a variant. Pfizer chief executive Albert Bourla told investors earlier this month that he anticipates that a variant-specific vaccine could be approved in 100 days, including clinical testing and regulatory reviews.
Even if existing vaccines offer some protection against the variants, “my concern is what variants are going to appear next,” Weissman said. “I would assume that at some point in time, if we let this pandemic rage on, there will be variants that the vaccine doesn’t work against.”
The best approach to creating new shots would be to pack multiple mRNA strands tailored for various mutations into a single shot, he said.
Such an approach would have the additional benefit of not stressing production capacity. Existing manufacturing lines could be switched to producing one kind of shot, instead of being split between two, Weissman said.
But the drug companies first have to create an effective vaccine against a single variant, to be able to test it in isolation, before it can be combined, John Grabenstein, a consultant and former executive director of medical affairs for vaccines at Merck and a former Department of Defense immunologist, said during a media briefing last week by COVAT, a group of vaccine experts.
“You need to know that vaccine induces an immune response, and then you can combine a one-two product,’’ he said.
The next vaccine likely to get emergency authorization from the FDA — Johnson & Johnson’s — was shown to be 57 percent effective against moderate and severe covid-19 in its late-stage clinical trial in South Africa, where B.1.351 is prevalent. The results were even more impressive against severe disease — the company said the vaccine was 89 percent effective in South Africa in preventing hospitalizations and deaths.
J&J also said that inoculation may be effective against the U.K. and Brazilian variants. It is studying whether it could add a new mutation target to its existing vaccine, which uses a harmless virus to introduce instructions to create a spike protein.
“We realize … at this kind of unique time we can’t wait, that we should do those things in parallel,” J&J’s chief executive Alex Gorsky told CNBC on Feb. 9.
South Africa said this month it was suspending the rollout of AstraZeneca’s vaccine after researchers found that it provided “minimal protection” against mild-to-moderate coronavirus infections there after the variant became prevalent. Whether it protects against severe disease remains unknown, according to the researchers.
Sarah Gilbert, a professor of vaccinology at the University of Oxford who conducted the initial research on the AstraZeneca vaccine, said in a statement that “efforts are underway to develop a new generation of vaccines that will allow protection to be redirected to emerging variants as booster jabs, if it turns out that it is necessary to do so.”
Novavax, another company that has received U.S. government support to develop a vaccine, is conducting a late-stage clinical trial in the United States of its original vaccine candidate, while also developing a version against the South African variant. It said in January that its original vaccine showed diminished effect against the variant in lab dishes but was still protective.
‘We can’t just lay on our laurels’
Many are optimistic the industry and regulators can successfully respond to a changing coronavirus — if the government vastly improves the tracking of the pathogen and takes other steps. “We have to have an adaptive and quick process, we can’t just lay on our laurels and say this is over,” Slavitt, the White House senior adviser, said on CNN Thursday night.
The CDC announced this week that it will invest $200 million in scaling up the nation’s lagging genomic sequencing efforts with a goal of increasing sequencing to about 25,000 positive virus samples per week in an effort to identify variants in real time. It is asking commercial labs, for example, to sequence every 10th coronavirus isolate, which will result in “thousands and thousands” more sequenced samples, according to an agency scientist who spoke on the condition of anonymity because he was not authorized to discuss the subject. Legislation pending in Congress would allocate $1.75 billion for sequencing.
If vaccines need to be changed, the system for approving annual influenza shots provides at least a partial guide, public health experts say. The World Health Organization makes recommendations about which three or four strains to include in a vaccine, and individual countries make the final decisions. In the United States, the FDA has the final say but almost always concurs with the WHO.
As with the flu, experts say, global consultations on the coronavirus are necessary, and U.S. health officials already are talking to their WHO counterparts. But while the FDA doesn’t require human trials for updated flu shots, because of decades of experience with that vaccine, it will require studies of 300 to 400 people to test for the safety of revised coronavirus vaccines and the resulting immune response, officials have said. The original Pfizer-BioNTech and Moderna trials each had 30,000 enrollees.
Any final decision on changing vaccines is likely to come after discussions involving the manufacturers, the FDA, other government health experts and perhaps the White House, said one administration insider who spoke on the condition of anonymity because he was not authorized to discuss the issue.
“This will be among the most important decisions you can make for national security,” he said.
Lena H. Sun contributed to this report.