Early coronavirus vaccine data leave many questions, but some lessons, too
In the early months of this year, scientists at drugmakers and universities in the U.S., U.K., China and Germany began work decoding the new coronavirus, recognizing early on what's become a desperate need for a vaccine.
Their hunt led to four experimental candidates quickly thrust into early clinical testing and, in an unprecedented timeframe, early data on whether their shots appear to work as intended.
Moderna, the Cambridge, Massachusetts-based biotech that's led the way in the U.S., and China's CanSino Biologics, were first to share preliminary trial results in May. Over three weeks in July, both delivered more substantive updates, while researchers at the University of Oxford in the U.K., and Pfizer, working with the German drug developer BioNTech, gave first glimpses at data from their initial vaccine studies.
More remains unknown than known about the four vaccines developed by each group. The Phase 1 studies, meant to show first and foremost whether candidates can be safely given to healthy adults, do not prove whether the vaccines can protect against coronavirus infection or development of COVID-19. And several of the trials are not yet complete, with outcomes only available for certain groups.
But the datasets offer several early lessons and help to provide a yardstick for assessing what comes of the 20 other experimental vaccines now in human testing. Here are three findings, along with the next questions that will need to be answered before anyone can be sure a vaccine will be available soon.
The vaccines have proven safe, but fever-like side effects are common
The first hurdle for developing any vaccine is determining whether it can be safely given. Phase 1 studies test that in healthy adults, usually aged 18 to 55, who are at low risk of serious complications.
Because approved vaccines are given to large groups of people who are otherwise healthy, the bar is set high for advancing an experimental candidate.
So far, results for the four vaccines have shown each to be generally well tolerated, with no side effects severe or unexpected enough to forestall further study. That's no small feat, given each candidate was designed and developed in previously unheard-of timelines, and some of them are based on unproven technology.
Still, the shots resulted in fever-like symptoms, headache or fatigue for good portions of the volunteers who were vaccinated in all of the trials. These effects were mostly mild or moderate in nature, and quickly resolved.
In a few cases, though, there were more severe reactions to high vaccine doses. Moderna, for example, observed three cases of severe systemic side effects at the highest dose it evaluated in its Phase 1 study, leading it to choose a lower, yet still promising dose for large Phase 3 trials. CanSino made a similar decision when it advanced its candidate from Phase 1 into Phase 2.
In choosing a dose, developers must strike a balance — too high and the immune system could overreact, leading to unwanted side effects; too low and the immune response elicited may be too weak to protect against viral infection.
Next question to be answered: Can the vaccines be safely given to older adults, who are considered most at risk from coronavirus infection? Side effects that may be tolerable or mild in younger, healthy adults could pose more of a problem in a more elderly population or those with weaker immune systems.
Further down the road, drugmakers will have to ensure there aren't any rare side effects only detectable in large clinical trials, or over longer periods of time.
The vaccines can spur immune responses similar to those experienced by recovered patients
Vaccines train the immune system by showing it enough of a virus that it recognizes the real thing later on. Drugmakers have come up with a number of ways to do this. Some, more established methods deliver shots of inactivated versions of the actual virus. Other, newer technologies rely on strips of genetic code to coax the body's cells into making tell-tale parts of the virus.
The first signs an experimental vaccine is doing its job are the emergence of antibodies — immune proteins that can seek out, bind to and neutralize viral pathogens. So far, Phase 1 results have shown each of the four candidates capable of eliciting, to varying degrees, antibodies specific to the SARS-CoV-2 virus.
Since the four candidates are built with two newer vaccine technologies — messenger RNA and viral vectors — their success on that score is encouraging.
Moderna, BioNTech and Pfizer, and Oxford, teamed with AstraZeneca, have compared the immune responses from their respective shots to what's been observed in tests of people confirmed to have been infected with SARS-CoV-2.
While the means of measuring differ, the three were all able to generate neutralizing antibodies at or above the levels found in the blood of patients who have recovered from COVID-19, suggesting the vaccines can mimic the effects of an actual infection. CanSino did not compare its results to convalescent sera, as the blood samples are known.
Moderna's and BioNTech's shots appeared the most potent, resulting in neutralizing antibody levels several times that of their respective convalescent sera comparator, while Oxford and AstraZeneca's appeared slightly less effective.
Next question to be answered: How much of an immune response is required to confer protection, and does the type of immune response matter? Scientists view convalescent sera as a rough guidepost, one that's potentially predictive of whether a vaccine might be protective. But, as with many things involving SARS-CoV-2, there's no clear answer yet as to what level of neutralizing antibodies are needed.
Antibodies are likely only part of the story, too, as immunity involves cellular components like T cells. Data on those measures are only just starting to be generated.
Booster shots will be critical
Moderna's vaccine, as well as the vaccine developed by BioNTech and Pfizer, are administered via two shots, spaced several weeks apart.
Results from each group's Phase 1 study showed immune responses generally didn't kick in until a couple weeks after the first injection, as is typical of vaccines, and only reached their highest point after a second "booster" shot. Even then, antibody levels didn't peak until a week or more after that second shot. In other words, four to six weeks passed before the strongest immune response emerged.
The Oxford and AstraZeneca team hope to develop a single shot version of their vaccine, which uses a viral vector loaded with DNA, rather than mRNA like Moderna and BioNTech. But in their Phase 1 study, they explored a two-dose regimen in ten participants. Data showed those individuals reached higher neutralizing antibody levels, prompting the researchers to expand plans for testing the two-shot approach further in later stages.
CanSino's vaccine is given via a single injection.
Whether a vaccine is given by one shot or two could have consequences for how much supply becomes available should a candidate be successfully proven safe and effective.
Next question to be answered: How durable are the immune responses observed to date? Will subsequent vaccinations be needed for any of the candidates being developed?
Results from studies of Moderna and Pfizer/BioNTech's vaccines showed antibody levels began to fall somewhat after peaking post second injection. It's not clear yet whether the immune responses elicited will persist and, indeed, whether a sustained response matters for protection. Looking further, people may also need further vaccinations one or two years after their first.
Article top image credit: National Institute of Allergy and Infectious Diseases. (2020). "Novel Coronavirus SARS-CoV-2" [Micrograph]. Retrieved from Flickr.