Should we change Covid-19 vaccine doses to reach more people?

The first Covid-19 vaccines have arrived, and the race is on to get them into as many arms as possible as soon as possible. But vaccination rates have fallen frustratingly short of what is needed to turn the tide of this pandemic, which continues to claim thousands of lives every day. The currently authorized vaccines are meant to be given in two doses. To speed things up, some scientists have floated the idea of delaying the second dose, only giving people only a single dose or halving the dose size. UK regulators have prioritized giving as many individuals their first dose of the Pfizer and AstraZeneca vaccines as possible — even if that means waiting up to 12 weeks for the second shot. Other countries are also considering changes to their vaccine dosing regimens.

Some experts say there are not enough data on the amount and length of protection these altered dosing schedules provide, however. They argue that the bigger problem is distributing the existing vaccine supply and that changing the schedules without rigorous evidence could compromise public trust in vaccines.

“We should really think long and hard any time we advise people to deviate from what the evidence actually shows in terms of efficacy, which has only been tested for those standard dosing regimens,” says Angela Rasmussen, a virologist at Georgetown University’s Center for Global Health Science and Security. “Before we start tinkering with the vaccine regimens, we should worry about making sure that we can actually give people the vaccines that we already have.”

The US Food and Drug Administration has said it does not support changing vaccine dosing or schedules, calling such actions “premature and not rooted solidly in the available evidence.” This week President Donald Trump’s administration recommended immediately opening up vaccinations to everyone older than 65. The Department of Health and Human Services also said it would release all available vaccine doses instead of holding back the second ones. That assertion was made just days after President-elect Joe Biden announced similar plans once he takes office next week. The Biden administration has said it does not intend to skip second doses and expects that companies will be able to manufacture enough vaccine by the time people need their second round.

Here’s what the data suggest about tweaking vaccine doses.

Delaying the second dose

The Pfizer-BioNTech and Moderna vaccines — both of which involve viral genetic material known as mRNA — were given to clinical trial participants in two doses (a “prime” dose followed by a “booster” three or four weeks later). After both doses, the Pfizer vaccine was found to be 95 per cent effective in preventing Covid, and Moderna’s came in at 94.1 per cent.

In the trials, the Pfizer vaccine provided partial immunity about two weeks after the first dose, with an efficacy of 82 per cent. But there are no data on whether protection lasts longer than three weeks, when the second dose was given. Immunological evidence suggests the antibody response to the vaccine increased substantially after the second dose as well.

“While decisions on alternative dosing regimens reside with health authorities, Pfizer believes it is critical to conduct surveillance efforts on any alternative schedules implemented and to ensure each recipient is afforded the maximum possible protection, which means immunization with two doses of the vaccine,” the company said in a statement shared with Scientific American. Rasmussen agrees. “The bottom line is that there’s not really any efficacy to support a delayed second dose, at least of [the] Moderna and Pfizer [vaccines],” she says.

A World Health Organization advisory group called SAGE (Strategic Advisory Group of Experts on Immunization) concluded that the two doses of the Pfizer vaccine should ideally be given three to four weeks apart but that countries “experiencing exceptional epidemiological circumstances” could consider delaying the second dose by up to six weeks in order to vaccinate more people.

Moderna’s clinical trial included a relatively small, nonrandom group of people who received only a single dose. Among these individuals, one dose was found to be 80.2 per cent effective in preventing Covid when researchers followed up with them about a month later. There are no data on whether protection lasts longer than that, however. Moderna did not respond to a request for comment.

The vaccine developed by AstraZeneca and the University of Oxford involves an adenovirus and is authorized in the UK, India and other countries. It was given to clinical trial participants in two doses between four and 12 weeks apart. The vaccine’s clinical trial data have been somewhat confusing, however: An interim analysis indicated an efficacy of 70.4 after two doses. But a further breakdown of the data showed that the efficacy was 62.1 per cent when given in two full doses — and, surprisingly, 90 per cent in a subset of participants who mistakenly received a half-dose followed by a full one. Scientists are still puzzled as to possible reasons for the latter result. Some speculate that it may be linked to the longer interval between doses in the half-dose group.

According to an AstraZeneca spokesperson, an exploratory analysis found the vaccine’s efficacy was 73 per cent after a single dose, for a dose interval between 22 days and 12 weeks. Nevertheless, the UK’s Medicines and Healthcare Products Regulatory Agency recommends two doses, given at an interval between four and 12 weeks.

Data on participants’ immune response showed antibodies increased after the second dose and also did so if there was a longer interval between doses. Preliminary data (which are yet unpublished) suggest the increased immune response with longer dosing intervals could result in increased efficacy, the company’s spokesperson says.

This is not surprising, says Shane Crotty, a professor at the La Jolla Institute for Immunology’s Center for Infectious Disease and Vaccine Research. “Whether the booster immunization is given a day, 21 days, 28 days or 12 weeks [after the first shot], if you take a population of people six months after that and ask, ‘How are they doing?’ I would expect all of those to be relatively the same — or, if anything, the 12-week booster group to be doing even better,” he says. The bigger problem is the window of vulnerability between doses because it is not clear how long protection from the first dose lasts. “The reason to give people second immunizations faster is definitely not that it gives a better immune response,” Crotty adds. “It’s that you get the person protected faster.”

Skipping the second dose

Some have also suggested skipping the second dose altogether. But given the lack of data on how long protection from a single dose lasts, many experts are wary of this idea.

“I don’t think a single dose with mRNA [which the Pfizer and Moderna vaccines rely on] makes any sense,” Crotty says. “There’s clearly a substantial increase in immune response after the booster immunization.”

Natalie Dean, a biostatistician at the University of Florida, agrees. “I think every company would have preferred to have a one-dose vaccine if it worked similarly well. But they made [the decision to have two doses] based on what was most likely to work and what they saw in the immunological data,” she says. The only way to truly know whether a single dose would work is to run a clinical trial, Dean notes. Doing so would likely require a lot of time and resources that are in short supply, however. By the time the trials would yield data, other vaccines might have been authorized and could alleviate the shortage.

On Twitter, Florian Krammer, a professor of microbiology at Mount Sinai’s Icahn School of Medicine, pointed out another concern with giving only a single dose: the possibility that it might cause a weak immune response, which could make the virus more likely to mutate and potentially make the vaccine ineffective. That is a possibility but may not be a huge concern, Crotty says.

Halving doses

Perhaps the most plausible suggestion put forth to extend the vaccine supply is to halve the dose of certain vaccines. Earlier this month, Moncef Slaoui, chief adviser of the Trump administration’s vaccine effort Operation Warp Speed, said officials were contemplating giving half-doses of the Moderna vaccine to Americans between the ages of 18 and 55. (This week Slaoui resigned from his position, but he will remain for 30 days.) In clinical trials, he said, people who received half of the Moderna vaccine’s 100 microgram dose had an identical immune response to those who received a full dose. But he added that it would ultimately be up to the FDA to decide whether to authorize such a change in dosing. Additionally, the data on half-doses were from a phase II clinical trial — so there is not sufficient evidence that half-doses prevent disease, Crotty notes.

Ultimately, the risks of altering data-backed vaccine-dosing strategies could outweigh the benefits. Discussions of changing the dosing regimen with no data to support them could create doubt and skepticism about the process and lead to increased vaccine hesitancy, Rasmussen says.

Crotty agrees. “In emergency situations, I think it’s reasonable to have [this] dialogue,” he says. “But in the end, I think it’s important to go with what’s proven.”