Covid-19 vaccination: What’s the evidence for extending the dosing interval?

On 30 December the four UK chief medical officers announced that the second doses of the covid vaccines should be given towards the end of 12 weeks rather than in the previously recommended 3-4 weeks. The BMJ’s Gareth Iacobucci and Elisabeth Mahase look at the questions this has raised

Why has the government taken the step to delay the second dose?

In a letter sent to healthcare staff on 30 December NHS England said the decision had been taken to prioritise giving the first doses of vaccine (whether the Pfizer and BioNTech one or that of Oxford University and AstraZeneca) to as many people as possible on the priority list to “protect the greatest number of at-risk people overall in the shortest possible time.”1 Delaying the second dose meant that the prioritisation process “will have the greatest impact on reducing mortality, severe disease and hospitalisations and in protecting the NHS and equivalent health services,” it said.

Why was this decision taken?

In a letter to the profession sent on 31 December laying out the “scientific and public health rationale” for the change to the dosing schedule,2 the chief medical officers said that vaccine shortages were a major reason for the shift in approach. “We have to ensure that we maximise the number of eligible people who receive the vaccine. Currently the main barrier to this is vaccine availability, a global issue, and this will remain the case for several months and, importantly, through the critical winter period. The availability of the AZ [AstraZeneca] vaccine reduces, but does not remove, this major problem. Vaccine shortage is a reality that cannot be wished away.”

What’s the evidence for changing the schedule?

There isn’t much for the Pfizer-BioNTech vaccine, as trials did not compare different dose spacing or compare one with two doses. The trials of the Oxford-AstraZeneca vaccine did include different spacing between doses, finding that a longer gap (two to three months) led to a greater immune response, but the overall participant numbers were small. In the UK study 59% (1407 of 2377) of the participants who had two standard doses received the second dose between nine and 12 weeks after the first. In the Brazil study only 18.6% (384 of 2063) received a second dose between nine and 12 weeks after the first.3 The combined trial results, published in the Lancet,4 found that vaccine efficacy 14 days after a second dose was higher in the group that had more than six weeks between the two doses (65.4%) than in the group that had less than six weeks between doses (53.4%).

In their joint statement the chief medical officers said that data provided to the Medicines and Healthcare Products Regulatory Agency (MHRA) showed that, although optimal efficacy was achieved through two doses, both vaccines “offer considerable protection after a single dose, at least in the short term.”

Stephen Evans, professor of pharmacoepidemiology at the London School of Hygiene and Tropical Medicine, said, “In an ideal world, decisions about treatments would only be made within the exact parameters of the trials which have been conducted. In the real world, this is never so . . . We know that vaccinating only half of a vulnerable population will lead to a notable increase in cases of covid-19, with all that this entails, including deaths. When resources of doses and people to vaccinate are limited, then vaccinating more people with potentially less efficacy is demonstrably better than a fuller efficacy in only half.”

How effective is just one dose?

A paper published in the New England Journal of Medicine stated that the efficacy of the Pfizer-BioNTech vaccine was 52.4% between the first and second dose (spaced 21 days apart).5 However, in its “green book” Public Health England said that during the phase III trial most of the vaccine failures were in the days immediately after the first dose, indicating that the short term protection starts around day 10.6 Looking at the data from day 15 to 21, it calculated that the efficacy against symptomatic covid-19 was around 89% (95% confidence interval 52% to 97%). Meanwhile, Pfizer has said that it has no evidence that the protection lasts beyond the 21 days.

In the case of the Oxford-AstraZeneca vaccine, PHE said, “High protection against hospitalisation was seen from 21 days after dose one until two weeks after the second dose, suggesting that a single dose will provide high short term protection against severe disease . . . An exploratory analysis of participants who had received one standard dose of the vaccine suggested that efficacy against symptomatic covid-19 was 73% (95% CI 48.79-85.76%).”

What do the manufacturers say?

In a joint statement Pfizer and BioNTech said, “The safety and efficacy of the vaccine has not been evaluated on different dosing schedules as the majority of trial participants received the second dose within the window specified in the study design . . . There is no data to demonstrate that protection after the first dose is sustained after 21 days.”

The European Medicines Agency has said that the gap between the first and second doses of the Pfizer-BioNTech vaccine should not exceed 42 days. “Any change to this would require a variation to the marketing authorisation as well as more clinical data to support such a change, otherwise it would be considered as ‘off-label use,’” the agency said.7

AstraZeneca did not reply to a request for comment from The BMJ.

How have doctors responded?

The BMA has called the government’s decision “unreasonable and totally unfair” and said it could cause “huge logistical problems” for general practices and vaccination centres.8 GPs and clinical leaders have told the BMA that delaying already promised second doses “will have a terrible impact on the emotional wellbeing of their most vulnerable, at-risk patients.”

Richard Vautrey, chair of the BMA’s General Practitioners Committee, said, “The decision to ask GPs, at such short notice, to rebook patients for three months hence will also cause huge logistical problems for almost all vaccination sites and practices. For example, to make contact with even just 2000 elderly or vulnerable patients will take a team of five staff at a practice about a week, and that’s simply untenable.”

He said that bookings for the oldest and most vulnerable members should be honoured.

Will the consent forms still be valid?

GPs told The BMJ that patients consent to the two doses of the vaccine during their appointment for the first dose but could not specify what these changes would mean for that consent. They said that patients were understandably worried about the change and called on the government to provide them with a clear explanation as to why this has happened.

What are patients told about their behaviour after one dose?

Patients are given a leaflet when attending vaccine appointments,9 and this has been updated to reflect the latest changes to dosing. It tells patients that it takes one to two weeks for protection to build after the first dose. It advises, “Like all medicines, no vaccine is completely effective, so you should continue to take recommended precautions to avoid infection. Some people may still get covid-19 despite having a vaccination, but this should be less severe.”

How do other countries view the policy change?

The US news site STAT referred to the move as “effectively turning [the UK] into a living laboratory.”10 It accused the UK of basing its new vaccination schedule “on small slices of evidence mined from ‘subsets of subsets’ of participants in clinical trials . . . and on general principles of vaccinology rather than on actual research into the specific vaccines being used.” It added, “If the efforts succeed, the world will have learnt a great deal. If they fail, the world will also have gained important information, though some fear it could come at a high cost.”

But Andrew Pollard, the head of the Oxford Vaccine Group and chief investigator into the trial of this vaccine, said that extending the gap between vaccines made biological sense. “Generally, a longer gap between vaccine doses leads to a better immune response, with the second dose causing a better boost. (With HPV vaccine for girls, for example, the gap is a year and gives better responses than a one month gap.) From the Oxford vaccine trials, there is 70% protection after the first dose up to the second dose, and the immune response was about three times greater after the second dose when the second dose was delayed, comparing second dose after four weeks versus second dose after 2-3 months,” he told The BMJ, referring to the MHRA’s summary of product characteristics.11

“With the Pfizer vaccine, there are no published data comparing shorter and longer gaps between doses because all participants had the second dose at 3-4 weeks. However, the biology is straightforward and will be the same as with all vaccines . . . The immune system remembers the first dose and will respond whether the later dose is at three weeks or three months.”

In a statement the British Society for Immunology said, “Most immunologists would agree that delaying a second ‘booster’ dose of a protein antigen vaccine (such as the two approved covid-19 vaccines) by eight weeks would be unlikely to have a negative effect on the overall immune response post-boost. We also would not expect any specific safety issues to arise for the individual due to delaying the second dose, other than an increased potential risk of disease during the extended period due to lowered protection.”

However in a BMJ Opinion article John Robertson, professor of surgery at the University of Nottingham, and colleagues, warned that less was known about the behaviour of the Pfizer vaccine because of the novel mRNA technology it uses.12 “Maximising coverage with the first dose as intended by the CMOs could come at increased risk to already high risk/priority groups,” they said. They called for the second dose of this vaccine to be provided at day 21 “until the MHRA and/or JCVI [Joint Committee on Vaccination and Immunisation] make the data on which the JCVI recommendation is based publicly available for independent scientific review” and for randomised controlled trials to compare the dosing schedules.

A spokesperson for the Department of Health and Social Care for England said, “As agreed by all four UK chief medical officers and the medical experts at the independent Joint Committee on Vaccination and Immunisation, the data provided by the manufacturers demonstrated that both vaccines offer considerable protection for patients after the first dose.

“This measure will have the greatest impact on reducing mortality, severe disease, and hospitalisations, helping to protect the NHS and save lives.”

Are any other countries going to do the same?

German health minister Jens Spahn has reportedly asked the Robert Koch Institute, the country’s disease control agency, to look into extending the period between the first and second vaccine dose, according to the Guardian.13 Meanwhile, in Denmark the infectious disease institute has said it was closely monitoring the UK situation and was considering a three to six week interval between doses.

Could the gap lead to vaccine resistant strains of SARS-CoV-2?

Paul Bieniasz, a retrovirologist from Rockefeller University who is studying how the virus can acquire mutations, has warned that the UK was taking a gamble that risked fostering vaccine resistant forms of the virus. He told the news site STAT, “My concern, as a virologist, is that if you wanted to make a vaccine-resistant strain, what you would do is to build a cohort of partially immunized individuals in the teeth of a highly prevalent viral infection.”14

When asked about this concern, a Department of Health and Social Care spokesperson did not directly answer the question, saying rather that it was “vital we do everything we can to quickly and safely protect as many vulnerable people as possible from this virus” and that data from manufacturers showed considerable protection for patients after the first dose.

What are the implications of this move for vaccine uptake?

Some experts are concerned that having large numbers of people only partially protected for several months could lead to some individuals contracting covid while they wait for the second dose, which could dent people’s confidence in the effectiveness of vaccines.

The British Society for Immunology has called on the government’s advisory committee on vaccines to make the “full evidence for decisions around covid-19 vaccines available immediately” to build public trust. “Having access to the evidence and rationale behind the public health decisions taken is important,” it said in a statement.15 “The government have confirmed that openness and transparency are vital. The British Society for Immunology will continue to monitor and advocate for this.”

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