With the global supply of Covid-19 vaccine still woefully inadequate, vaccine makers are scouring the pharmaceutical landscape for partners to ramp up manufacturing, and civil society groups are pressing politicians to waive intellectual property protections in a bid to spur still more production.
But what if there was a simpler way? What if current supplies could be stretched, to vaccinate more people more quickly? What if the world is using more vaccine than it needs to on each person immunized, depriving people in the queue of a chance to be protected?
Reducing the size of a vaccine dose is an approach that has been used successfully before and ought to be explored, some scientists argue.
Several times in recent years the World Health Organization has recommended “fractionation” — using partial or fractional doses when supplies of critical vaccines have been limited. When a dangerous yellow fever outbreak in Angola and the Democratic Republic of the Congo threatened to exhaust the world’s stores of yellow fever vaccine, the WHO instructed countries to use one-fifth of a normal dose in their emergency vaccination efforts. (Research done during that 2016 outbreak suggested the lower dose protected those who received it.) The WHO has also recommended use of fractional doses of inactivated polio vaccine and meningococcal conjugate vaccines during periods of scarcity of those shots.
The idea of splitting doses of Covid vaccines is not universally supported, however; a number of experts contend that the vaccines should be used in the dose size tested during clinical trials and cleared for use by regulatory agencies. That route offers the best protection for individuals who are vaccinated, they insist. “The problem where I’m coming from is you have to prove fractional dosing works,” said Larry Corey, who co-led design of the trials of the Covid vaccines supported by the U.S. government. That hasn’t happened yet.
But Ben Cowling, an infectious diseases researcher at Hong Kong University, believes that a public health approach — one that focuses on what’s best for whole populations, not individuals — is what’s needed in a pandemic. He and two colleagues, Wey Wen Lim, of Hong Kong’s Laboratory of Data Discovery for Health, and Sarah Cobey, an associate professor of viral ecology and evolution at the University of Chicago, argued the case for using fractional doses of Covid vaccine in a commentary in Nature earlier this week.
“Think of the lives that would have been saved” if manufacturers geared their research to finding the smallest possible dose that was protective when they were testing their Covid vaccines, Cowling told STAT in an interview about fractionation.
It’s important to understand that when pharmaceutical companies set out to develop Covid vaccines in early 2020, they were in a race against time, with the SARS-CoV-2 virus sweeping the globe and infections and deaths rising rapidly. In such a scenario, there was no time to find a Goldilocks dose — the one that used just enough antigen to protect a person being vaccinated, but no more than was needed.
Settling on a vaccine dose in a situation like this is as much an art as it is a science. Most manufacturers tested a two-dose regimen, because the accumulated body of vaccine experience suggests that an immune system will need two introductions to a new pathogen to mount a good response against it. (The sole exception was Johnson & Johnson, which tested both a one-dose and a two-dose vaccine. The former has been authorized for use; study of the latter continues.)
On the question of how much antigen — the fluid that comprises each vaccine dose — was needed, each of the manufacturers quickly tested a small range of options. For instance, Pfizer and BioNTech, the partnership that brought the first vaccine to market in the U.S., tested doses of 10, 20, and 30 micrograms given in a two-dose regimen, and a single 100-microgram dose in its dose-finding study; Moderna tested doses of 25, 100 and 250 micrograms. Both opted for two-dose regimens with Pfizer selecting the 30-microgram dose and Moderna opting for 100 micrograms. (Moderna’s 250-microgram dose had caused too many side effects and was abandoned.)
The studies used to decide on those doses weren’t large enough to show whether the lower doses would have been protective. They only charted how tolerable the doses were — did they trigger too many unpleasant reactions? — and what the measurable immune responses were in the people who were vaccinated. For manufacturers, the priority was to find a vaccine dose that was effective, pushing them toward higher doses to be on the safe side.
(The cost of getting this wrong was evident when Sanofi, one of the world’s biggest vaccine makers, accidentally under-dosed people in one of its trials. Its Covid vaccine was not adequately protective and when Pfizer and Moderna were seeking emergency use authorizations last December, Sanofi announced it would have to redo its Phase 2 trial. While Pfizer and Moderna have been selling hundreds of millions of doses of vaccine, Sanofi still does not have an authorized product.)
A number of scientists have noted that the dose-finding studies for some of the vaccines suggest lower doses could have been used. In fact, the leadership of Operation Warp Speed — the Trump administration’s program to fast-track Covid vaccines, drugs and diagnostics — asked Moderna months ago to study whether it could halve its vaccine dose; Moncef Slaoui, the former chief adviser to Warp Speed, said on CBS in January that the responses generated by a 50-microgram dose was identical to that of the 100-microgram dose Moderna chose.
Slaoui didn’t cite a specific study, and the company sidesteps questions about whether it followed through on the Operation Warp Speed request. A Moderna spokesperson said via email that “the 100[-microgram] dose was selected for the pivotal Phase 3 study and this remains the only dose level for which we have demonstrated clinical efficacy.”
Cowling, Lim, and Cobey noted that the lowest dose Pfizer had tested, 10 micrograms, elicited immune responses that were comparable to the dose the company chose, which included three times as much antigen.
And a study from immunologists at La Jolla Institute of Immunology that was posted this week to a preprint server reported that people who received 25 micrograms of Moderna’s vaccine, the lowest dose the company studied, had immune responses that were on a par with people who had recovered from Covid infection.
One of the senior authors of that paper, Daniela Weiskopf, cautioned that because the world doesn’t yet know what levels and combinations of immune system armaments — Neutralizing antibodies? Binding antibodies? Activated B cells or T cells? — are needed to protect against the SARS-2 virus, it’s not clear if that would have been an effective vaccine.
(Multiple research groups, including scientists at Moderna, are working to try to establish so-called correlates of protection — what a protected immune system looks like. If the correlates of protection can be determined, a move to a lower dose might be considered, the company said, thought it would require regulatory approval.)
“What we don’t know … is if that is good enough,” said Weiskopf, an assistant research professor at La Jolla whose work focuses on the role of T cells in viral immunity. “Is that level of immune response enough to protect?”
Shane Crotty, an immunologist at La Jolla who was also a senior author of the paper, said he believes there would have been a measurable difference in efficacy if Moderna had opted for its lowest, rather than its highest, tested dose. But for a vaccine that showed 94% efficacy in its Phase 3 trial, would the difference have been great enough to significantly erode the effectiveness of the vaccine?
“Scientifically, there’s a reasonable chance it would be successful, but there’s also a really good reason we run Phase 3 clinical trials. It’s hard to predict those outcomes,” Crotty said.
Several countries that were having trouble accessing sufficient supplies of vaccine have asked Crotty’s advice about whether they could use fractional doses, he said. “I didn’t recommend it to anybody.”
When the WHO recommended fractional doses of yellow fever vaccine, it did so based on a study done in Brazil, which suggested the approach would work. Similar studies of Covid vaccines haven’t been conducted, Crotty said.
“We’re very interested in any evidence that is available on the performance of any of the vaccines at a dose other than the [current] dose,” said Kate O’Brien, director of the WHO’s department of immunization, vaccine, and biologicals. “The most important thing is we don’t make any recommendations that are absent data — you know, that are just data-free recommendations.”
Corey, a virologist at the Fred Hutchinson Cancer Research Center, admitted he isn’t a fan of the fractional dose idea. “It might work, but it may not work,” he said flatly.
“The best approach, of course, is to give the best vaccine at the effective dose,” he said. “Do you want to throw away 95% [vaccine efficacy] to get something to 80%? Will it still be as good against severe disease? Last as long?”
Even Cowling acknowledged that given that lower doses would need to be tested, the opportunity to go this route in this pandemic may be slipping from the world’s grasp. And he worries that even if the idea was adopted, fractional dose vaccines might be deemed as unacceptable in some countries; they might see it as sub-par product.
“One of my specific concerns is that, right now, if [WHO’s vaccine experts] were to convene to discuss fractionation for places like Africa or South America or parts of Asia that have had relatively low supply so far, that those places would be unhappy about the idea of using fractional doses when the developed world has been using full doses,” he said.
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