For mRNA vaccines, we should stick to the schedule

Vaccines are our best hope for controlling Covid-19. But they should be delivered in ways that we know are effective

The Covid-19 pandemic has been fraught with uncertainty and missteps, and for every scientific advancement that has moved us forward, failures to appreciate and clearly communicate the nuances have set us back. This month, we received the welcome news that mRNA vaccines are safe and protective against symptomatic Covid-19. As part of their submissions to the United States FDA for emergency use authorisation, both Pfizer/BioNTech and Moderna included a compelling finding: that the vaccines provided some protection just 14 days after the first shot.

Based on these observations, academics and lawmakers have been seduced by the idea of reducing the two-dose schedule for mRNA vaccines to just one dose, delaying the second dose until more people receive the initial immunisation, or even decreasing the dose of vaccine by half, all with the goal of getting more shots into more arms as quickly as possible. The notion of maximising the number of vaccinated people by these methods has rapidly gained support. In a time of crisis, regulators might be justified in making a decision such as this with little data in order to make the most of limited vaccine supplies and protect as many people as possible. However, in this case, they are not, both because it’s not supported by the data that we do have, and because it doesn’t address the actual problem currently facing the UK, the US, and Canada, which is the distribution of existing supplies.

In the UK, the Joint Committee on Vaccination and Immunisation has expanded the timeframe for a second dose of the Pfizer/BioNTech mRNA vaccine from three weeks – the spacing used in the clinical trials that showed 95% efficacy in protecting against Covid-19 – to up to 12 weeks. (A second dose of the AstraZeneca vaccine, which is the other jab authorized in the UK, can also be administered up to 12 weeks after the first, a practice with some support from clinical trial data.) In the US, Ron DeSantis, the governor of Florida, is reported to have suggested that one dose could be enough. In Ontario, Rick Hillier, who has been charged with vaccine distribution in Canada’s most populous province, has asked regulators to look into allowing the Moderna vaccine to be administered as a single dose. And Dr Moncef Slaoui, the scientific adviser for the US’s vaccination program Operation Warp Speed has proposed decreasing the dose of Moderna vaccine by half. In these and other instances, the thinking goes: if we could vaccinate more people, that would save more lives and bring the pandemic to a close more quickly, right?

Probably not. According to the trial data, vaccine efficacy drops to around 50% after a single shot for both mRNA vaccines. While this estimate includes the 14 days immediately after the primary shot (before the maximum immune response is expected to kick in), it suggests that a single-shot regimen would provide substantially less protection. Even if the first 14 days are excluded, after which efficacy is estimated to be over 90%, the confidence intervals – or what scientists estimate is the range of the true efficacy – indicate that this protection could vary by nearly 30%.

This also is at odds with data obtained from earlier studies with mRNA vaccines against both Sars-CoV-2 (the cause of Covid-19) and its cousin, Mers-CoV. Studies of Sars-CoV-2 infections in monkeys suggest that for a single mRNA vaccine shot to be protective, the dose must be higher. Phase 1 clinical trials designed to assess tolerability and immune responses in healthy volunteers to different doses showed that higher ones were associated with more serious side-effects. It’s questionable whether a single-shot vaccine could be both protective and safe.

The argument that the second (booster) shot of an mRNA vaccine could be delayed is also not supported by the science. Because of the expedited trial process, we don’t yet have information on immune durability, that is, the length of time that protective immunity endures. Typically booster shots are intended to provide the immune system with advanced “training” to make better antibodies, and to hardwire immune memory so that vaccine protection lasts.

Some vaccines don’t require a booster for this to occur, but these typically use vaccine platforms that include harmless replicating viruses, either weakened (so-called live-attenuated vaccines), or used as a vehicle to carry bits of protein from the target virus (viral-vectored vaccines). The Johnson & Johnson vaccine, which is expected to conclude phase 3 clinical trials in January, is a viral-vectored vaccine and is being evaluated as a single shot. These types of vaccines can stimulate the immune system more robustly and for a longer period of time than mRNA vaccines (although this is not always the case, as with the Oxford/AstraZeneca vaccine, which is a viral-vectored vaccine that requires two doses).

mRNA is essentially a rapidly degrading set of instructions for cells to make the spike protein of Sars-CoV-2, which is what the immune system responds to. When the mRNA degrades, the cell will stop making the spike protein and the immune system will stop responding to it. mRNA is a notoriously unstable molecule, which is why the vaccines must be stored in ultracold freezers prior to use, so there is just a short window of time for the immune system to mount a response after a shot. Hence a booster shot being necessary to “remind” the immune system about the protein it had briefly encountered.

There is a significant risk that a single shot would be inadequate, particularly for elderly people, the group most in need of protection. It is well-known that age diminishes the duration and magnitude of immune responses, and we cannot gamble the safety of the most vulnerable based on an intriguing preliminary result. It is not worth risking an untested vaccine regimen when we are so tantalisingly close to having enough vaccines for everyone, especially when we know the current two-shot regimen is broadly protective.

Another concern about using altered vaccination schedules or regimens is that this may result in exposing circulating virus to low levels of antibodies, leading to evolutionary selection of variants that may be able to bypass those antibodies. The spectre of these “escape” mutants has been invoked by the simultaneous independent emergence of variants with mutations in the receptor-binding domain of the spike protein, a key target for antibodies, in the UK, South Africa and elsewhere. We don’t yet know how changing vaccination regimens will affect the emergence of similar or even more worrisome variants, but there is the possibility that this could fan the flames.

Vaccination remains our best hope for controlling Covid-19. But fiddling with the vaccination schedule or dose risks undermining public confidence in the rigorous nature of development, testing and regulatory oversight of the vaccines. Rather than risk these effects, we need to redouble our efforts to scale up vaccine production and administration. Currently, only a fraction of available vaccine doses have been administered, owing to distribution bottlenecks of various kinds in different countries.

The development and rigorous evaluation of safe and highly efficacious vaccines to a novel pathogen in record time is a true triumph of modern science. We must not snatch defeat from the jaws of victory by administering vaccines in any way besides that for which they were carefully evaluated. Of course we must find ways to increase vaccine accessibility, but not at the expense of the long-term goal: ending the pandemic once and for all.

  • Angela Rasmussen is a virologist at the Georgetown Center for Global Health Science and Security. Ilan Schwartz is an infectious diseases doctor at the University of Alberta, Canada

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