Tinkering with vaccine dosage and timing makes a mockery of clinical trials
What happens when the protocols aren’t followed? What about the risk of a lower level of immunity? Or future mutations with global implications?
Every country that is imposing varying degrees of lockdowns because of rising coronavirus infection rates — as the UK did on Monday — is trying to reduce the burden of the disease on its population, health-care systems and economy. The best solution, of course, is vaccines, and three shots have proved in trials to offer protection against disease. That’s assuming they are administered based on data generated from clinical trials.
But what happens when the protocols aren’t followed?
The UK, in its desire to vaccinate as many people as possible as fast as possible, has taken the unprecedented step of implementing a vaccine regimen that hasn’t been tested in rigorous clinical trials and doesn’t have solid efficacy data backing it: it’s stretching the period between the first and second “booster” shot for the two vaccines it has so far approved — developed by AstraZeneca and University of Oxford, and Pfizer and BioNTech — to 12 weeks from as few as three.
The UK is not alone in considering changes to vaccination schedules, with Germany also mulling the same and Denmark already doing it. There is also discussion in the US about taking a similar approach or changing dosage levels to allow the current vaccine stockpiles to get to more people faster.
These decisions are being made or discussed by highly respected experts who have reason to believe the tweaks may help in the inoculation effort without unduly increasing risks. I am not sure there is sufficient data to back these decisions.
The reason tinkering with dosage regimens has even come up is because some countries have put themselves into a tight corner in this latest dire stage of the pandemic. The UK is grappling with a rapid rise in infection rates as well as a new, potentially more transmissible variant that is fast taking over as the dominant version of the virus. The US, meanwhile, continues to set records in cases, hospitalisation and deaths and, like other countries, has found evidence of the same variant as in the UK now spreading within its own borders.
Both are paying the price for bad policy decisions in recent months, such as allowing indoor dining, leaving gyms open and generally not enforcing mask-wearing and limits on public gatherings. While the UK has finally admitted that it needs a severe lockdown similar to the one in spring of 2020, the US is unlikely to take a similar step, leaving it vulnerable as it rolls out vaccines.
Companies and regulators have worked hard to make sure the clinical trials of vaccines are large and conducted with utmost care. They have worked on protocols to test the efficacy of the shots as quickly as possible without compromising safety. The 21- and 28-day inoculation intervals used in the Pfizer-BioNTech and Moderna vaccine trials, respectively, are shorter than those generally used against other diseases, with the majority at two months.
The companies did not have the luxury of testing longer dosing schedules, and while it’s possible that, like other vaccines, a longer interval can work just as well as — or even better than — the short ones tested, there is no data to back this view. (The intervals used in AstraZeneca’s trials ranged from five to 10 weeks.)
The UK’s joint committee on vaccination and immunisation based its decision for the 12-week schedule on exploratory analyses and cross-trial comparisons, even using data from trials of the Moderna vaccine — which has not yet been approved in the country. The use of data from the Moderna trial is flawed, though, because it is based on short-term analysis and produced from a small, non-randomised subgroup, with no information on how long immunity lasts.
A parallel discussion in the US about using just one dose of the Moderna vaccine — half for the first shot and half for the second — is based on antibody analysis that has yet to be proven to be a good surrogate for protection and disease prevention in the case of the SARS-CoV-2 virus that causes Covid-19.
Beyond the risks involved in tinkering with the dosage regimen, there is the question of how much faster the UK can actually vaccinate its population using a 12-week schedule compared with a shorter one of, say, four weeks. Let’s take the AstraZeneca vaccine as an example: it is aiming to supply 2-million doses a week.
This means that by June, 26-million individuals could have two jabs of the vaccine using either dosing schedule. But with the 12-week interval, about 26-million people could have had a single jab by the end of March, compared with roughly 18-million with a four-week interval. It would take just two more months to get to 26-million with the shorter regimen. Every single day of reduced infections may mean many lives saved, assuming one dose has a big enough impact.
But does this warrant the risk of potentially giving a meaningful percentage of vaccinated people a lower level of immunity, increasing the odds of future variants with global implications?
Chances to mutate
The risk of developing new variants is the biggest worry. It is theoretically possible that giving a suboptimal dose of vaccine or a long interval before the booster shot increases the chances that the virus finds a way to mutate away from the potentially less mature antibody and cellular immunity induced in some people.
While this may not be an issue if we were dealing with low levels of infections, it carries a higher risk given that the virus is still spreading quickly. Indeed, one way used in the laboratory to force virus evolution is to expose it to low antibody pressure.
On top of all this, the AstraZeneca vaccine had lower efficacy than Pfizer-BioNTech’s and Moderna’s, potentially because of the design of the vaccine itself. It also appeared to induce lower antibody levels in early trials, though methodological differences make it difficult to draw firm conclusions.
It’s impossible to know whether a 12-week interval is enough to give the virus the opportunity to develop some resistance to the vaccine in individuals who do not develop a strong immune response to it, but it’s likely that viral evolution is more probable than it would be under a shorter two-shot schedule.
The UK’s decision to impose a severe lockdown should help to reduce viral transmission and the associated increased risk of the virus’s evolution, but it won’t eliminate that risk entirely. Let’s hope that infection rates fall quickly enough for this not be an issue.
My sincere hope is that the tweaked dosage timing, combined with the new restrictions on activity, will have proved to be a stroke of genius leading the UK out of the pandemic faster than most other countries. But we should also watch out for the nightmare scenario in which the UK ends up being the source of the first virus variant that escapes the vaccine.
It’s little consolation that it has one of the best, if not the best, genomic sequencing efforts, which should allow it to detect any such variant quickly.
As for the US, any decision to change the way vaccines are delivered in such a way that increases the chances of inadequate immune protection — such as cutting doses in half or just using a single dose of vaccine — would leave the population vulnerable, given the rapid rise in infections. Without the science to back it up, or other precautions put in place, it’s not worth the risk.
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