LONDON – The U.K. is moving on to the next phase of testing mixed dosing schedules for COVID-19 vaccines, launching a study in which it will assess the effect of using Moderna Inc. or Novavax Inc.’s products as the second dose in a heterologous prime boost trial.
Starting next Monday, April 19, it is planned to recruit 1,500 adults over the age of 50 who have had their first, or prime, vaccination in the past eight to 12 weeks. These volunteers, who will have received either Astrazeneca plc or Pfizer Inc./Biontech SE’s vaccine, will be randomly allocated to receive either the same vaccine for their second dose, or a dose of the Moderna or Novavax products.
The study is designed to show noninferiority compared to the licensed schedules of two doses of the same product, look for any adverse reactions and access antibody and T-cell responses to the new combinations of vaccines.
If equivalent safety and efficacy is demonstrated, new vaccination regimens would need to be approved by the U.K. Medicines and Healthcare products Agency (MHRA) and given the go-ahead from the independent Joint Committee on Vaccines and Immunization, before being rolled out. The Novavax vaccine is yet to be approved in the U.K., though it is currently under rolling review by the MHRA, and commercial manufacturing is underway in northeast England.
“The question is, ‘Are you any worse off if you get a different booster,’ compared to the same booster, and we will look at any side effects,” said Matthew Snape, associate professor in pediatrics and vaccinology at Oxford University, who is chief investigator in the trial. “The aim is to generate greater flexibility in case of shortage of any vaccine,” he said.
France and Germany already have mandated mixed dosing schedules in younger people who received a first dose of Astrazeneca’s vaccine, despite an absence of clinical trial data showing that will be safe and effective. The move is a response to the reports of rare and unusual blood clots, which the EMA now considers are side effects of the adenoviral vectored product.
Before the French announcement that it would mix dosing schedules, 500,000 people under the age of 55 had received a first dose of the Astrazeneca vaccine. On April 9, the regulator Haute Autorité de santé (HAS) said it “now recommends completing the vaccine schedule for this population with an mRNA vaccine within 12 weeks after the first injection.”
The HAS said there are “many arguments in favor” of heterologous prime boost, which has proved more effective than using two identical injections in HIV, for example. But it was forced to admit data supporting the approach with COVID-19 “are still limited.”
The French agency recommended setting up a study to gather real-world evidence of the immune response conferred by the mixed vaccination strategy.
For Snape, the main risk of this approach is not of a fresh safety concern, but that the immune responses are suboptimal. “I personally would be very surprised if that happens,” but he said, “France and Germany are going into a mixed schedule in advance of any evidence.”
The benefit of the U.K. study is that it is randomized and controlled. “We will be able to look at antibody levels and make a direct comparison with the licensed schedules that have been effective in clinical trials,” Snape said.
First mixed schedule data coming soon
Data showing what the immune response is when people get Astrazeneca vaccine’s followed by Pfizer/Biontech are due in the next one or two weeks, when the first part of the mixed dosing schedule study that began in February reports initial results.
That part of the study took only two weeks to recruit 830 participants, who were randomized to get two doses of either Astrazeneca or Pfizer, or one of each. The doses were administered either four weeks apart, as prescribed on the label, or 12 weeks apart, as the U.K. decided to proceed in order to be able to give as many people as possible some level of protection, as quickly as possible.
Snape said there have been no concerns about the Astrazeneca vaccine from trial participants. Only two people dropped out and 99% turned up for the subsequent blood tests. “We had fantastic retention,” said Snape. Unlike other vaccines studies in the U.K., ethnic minorities were well represented and 55% of volunteers had one or more co-morbidity.
The plan to test heterologous prime boost was drawn up at the end of 2020, before the U.K. vaccination program began. The study design allows for any of the seven vaccines the U.K. has procured to be administered in any combination with any other, although it is now unlikely all possible combinations can be assessed.
“Originally in drawing up the plan, we had all combinations of all vaccines. But it came down to looking at what was most important for U.K. policy, and most [people] have had Astrazeneca or Pfizer,” said Snape. “What is special is the foresight. It was anticipated there may be some issues at some point, with some vaccines,” he said.
In addition to testing antibody and T-cell responses, the blood samples taken in the trial will be tested against emerging variants of SARS-CoV-2, to see if the immune response remains sufficient. “The serum will be stored and T cells will be tested against new variants. It’s not funded yet, but we will need to do that study,” said Snape.
Another study in the works will look at administering a third, booster dose of vaccine later in the year. Snape said the results of the current trials will inform what combinations are assessed as third doses.