Summary List PlacementAs the first coronavirus vaccines are rolling out, the 200-plus additional candidates in development face immense challenges in ever reaching the public.
Despite the uncertainty, investor enthusiasm has remained. The vaccine ambitions of many small biotechs have resulted in their stocks surging to all-time highs. But as safe and highly effective shots start to be distributed, the challenges of running massive clinical studies and ramping up manufacturing will only grow more daunting.
“Most of these companies are kind of making it up as they go along,” SVB Leerink industry analyst Geoffrey Porges told Insider. “They haven’t developed products before; they don’t have a lot of organizational expertise in the execution of these very large trials. It’s almost certain that a lot of value is going to be destroyed in these late-to-market vaccine programs.”
Even still, experts told Insider there are many reasons to carry on with next-generation vaccine programs. Future vaccines could have milder side effects, provide better protection against certain viral mutations, and carry a simpler distribution profile with either being given as a single dose or not needing to be stored in extremely cold temperatures.
As it stands, US regulators have OK’d two vaccines from Pfizer and Moderna. Other vaccine candidates, developed by British, Russian, Indian, and Chinese companies and researchers, are also being rolled out in other countries around the globe.
What could come in the short-term is fairly clear. Johnson & Johnson is expected to present pivotal data by the end of January on a single-dose vaccine candidate. And two more vaccine programs led by Novavax and AstraZeneca are in the final stage of US-based clinical trials, which could produce definitive data by the spring.
But beyond that, the future becomes far more hazy, with dozens of smaller biotechs hurrying to advance their research. The vast majority of these programs are still in the early stages of research, either in small-scale human trials or still being tested on the lab bench and in animals first.
Some of these biotechs, like Arcturus Therapeutics, are prioritizing a single-dose jab. Others, like VBI Vaccines, are hoping to develop a shot that can protection against multiple coronaviruses, hopefully boosting efficacy against future mutations. And others, like VaxArt and AltImmune, are developing vaccines given by pill or nasal spray rather than a syringe.
The sluggish start to vaccinating the world’s population — with some projections showing widespread availability for all countries won’t come until 2023 or 2024 — means the door is open for many more vaccine developers to play a role.
“We are going to need tons of vaccines because the human species is doing such a lousy job of vaccinating,” said Porges, a longtime Wall Street analyst who previously worked in the pharmaceutical giant Merck’s vaccine business.
Read more: What’s coming next for COVID-19 vaccines? Here’s the latest on 11 leading programs.
Pharma giants have largely disappointed, leaving vaccine work to small biotechs
Most of the companies working to develop vaccines are small biotechs that have never brought a medicine to market before.
The vaccine space is dominated by four industry giants — Pfizer, Merck, GlaxoSmithKline, and Sanofi — primarily due to the high barriers of entry in maneuvering the regulatory requirements and building the manufacturing plants needed to mass-produce doses.
These giants have disappointed, with the notable exception of Pfizer’s work with the German biotech BioNTech to develop the first COVID-19 shot to win US authorization, Porges said.
“Merck is nowhere, GSK has been a passive participant, and Sanofi is certainly not in the frontline,” he said. “That’s disappointing because I would have thought these companies have a public obligation, as well as a profit opportunity and incentive for pushing ahead, and it’s been pretty limited.”
Instead, the second-generation vaccine landscape may be best summed up by a January 19 announcement. A tiny California biotech called Gritstone Oncology announced its plans to develop a COVID-19 vaccine, a radical departure from the company’s cancer-focused pipeline. That program has yet to even start an initial human trial narrowly focused on safety, and the long-term strategy on reaching market is unclear.
Despite those concerns, the cancer-focused biotech’s stock shot up more than 350% on the week, now commanding a market value of about $1.3 billion.
Read more: A top biotech venture capitalist said he saw the pandemic coming. He shared his prediction for how the coronavirus will shape 2021.
Pivotal clinical trials likely will look radically different in 2021
The leading COVID-19 vaccines were developed with record speed in 2020 for a variety of reasons. A critical accelerator was Operation Warp Speed, the Trump administration’s vaccine initiative that committed more than $11 billion directly to drug companies to fund research and manufacturing.
Warp Speed’s support took financial risk off the table, allowing the selected companies like Moderna, Johnson & Johnson, and Novavax to run multiple studies in parallel and start ramping up production before knowing whether or not the shots work.
A key element of Warp Speed’s program was funding and designing massive, late-stage clinical trials in the US and abroad. These studies, each recruiting 30,000 or more volunteers, randomly gave people either the experimental vaccine or placebo injections.
Placebo-controlled trials aren’t likely to have much success in the US in 2021. Already, the Warp Speed-backed program by Novavax has run into difficulties with its Phase 3 study that started last December. Older volunteers are dropping out at increasing rates, especially as many states have started offering the elderly FDA-authorized vaccines, The Washington Post reported.
Vaccine trials in 2021 will look different, with the potential of going abroad to recruit volunteers or leaning on antibody measurements as a likely indicator of efficacy.
“We’re proceeding with a different strategy completely,” Arcturus Therapeutics CEO Joseph Payne told Insider.
The San Diego-based biotech is aiming to start a placebo-controlled Phase 3 study in the second quarter of 2021, one that could produce pivotal results before the end of the year. Payne said he expects this will be a placebo-controlled study, but that will mean recruiting volunteers outside the US. The ex-US focus could make it easier to enroll volunteers in areas with high rates of infections who accept a chance of receiving a placebo, he said.
Payne said one approach would be to negotiate with other countries and give discounted prices in exchange for funding the pivotal research.
Payne said noted there was “very high demand” among countries he’s talked to for a single-dose vaccine, which Arcturus is pursuing.
A critical potential shortcut to these burdensome trials could come in 2021 from vaccine regulators. Experts are eagerly waiting for guidance from the Food and Drug Administration to see if they can identify a certain level of immune response that is likely to protect people.
These so-called correlates of protection would be a game-changer in simplifying future studies, experts said. Trials would likely be able to proceed without a placebo group, meaning all volunteers would get the experimental shot. If the typical immune response is strong enough, that may be sufficient for authorization.
“It would be incredibly wonderful to have likely correlates of protection,” Dr. Jesse Goodman, an infectious-disease physician at Georgetown University and former FDA chief scientist, told Insider. “That could be meaningful in terms of expediting trials, picking the best candidates, and in terms of regulatory use. That is critically important.”
Porges said he expects clarity in the couple of months from the FDA. It’s also unclear how many people these trials may need. If regulators want to see that these next shots are as safe as the first vaccines, they still may need to test well over 15,000 volunteers with their shot.
Read more: Inside Moderna’s historic coronavirus vaccine program that transformed the biotech upstart into a $55 billion drug industry powerhouse
Even with success, barriers to success will likely only grow
The bar for what is a useful vaccine is high and will likely only get higher.
Before pivotal study readouts late last year, infectious-disease experts had set the realistic hope to have a vaccine that is 70% or 80% effective at preventing COVID-19. The leading shots from Pfizer and Moderna were respectively 95% and 94% effective in late-stage trials.
Even if a biotech produces a solid vaccine, say 70% effective, that may help meet global demand but could also raise thorny ethical questions if poorer nations wind up with the less potent shots.
Regulators could set a higher bar for the next wave of vaccines. 2021 could bring non-inferiority trials, or studies designed to show an experimental shot is at least as good as, if not better, than what has already been authorized. With Moderna’s and Pfizer’s programs showing efficacy exceeding 90%, that would be a daunting task for competitors.
Many vaccine developers are touting other ways to stand apart, such as single-dose options or not relying on extremely cold storage. But Johnson & Johnson could make those advantages moot if its vaccine succeeds, with definitive results due by the end of January for its single-dose shot that can be kept stable for months with typical refrigeration.
The frontrunners aren’t sitting still either. Both Pfizer and Moderna have touted the ability to quickly tweak their vaccine in response to new viral mutations if needed. Experts anticipate more robust testing will happen on multiple strains of the coronavirus to see if the vaccines hold their high levels of efficacy across variants.
Pfizer also hopes to address one of the key limitations on its shot with the need for extra-cold storage. A powder version that could be kept at typical fridge temperatures is expected to be rolled out sometime in 2021.Join the conversation about this story » NOW WATCH: COVID-19 vaccines are making their way around the world, but global immunity is still far off