LONDON – The latest tranche of data from an array of large-scale COVID-19 studies running in the U.K. provides real-world evidence that vaccines have a dramatic effect in preventing hospitalization and death, but that there are a very small number of vaccine failures.

The data cover 3,842 people who received a vaccine and subsequently were admitted to the hospital between Dec. 8, 2020, when the national vaccination rollout began, and the data cutoff of April 10, 2021.

Just over 70% of vaccinated patients admitted to the hospital had developed their symptoms within 14 days of receiving the vaccine, before they were likely to have mounted a protective immune response.

But 526 of the hospitalized patients had developed their symptoms more than three weeks after being vaccinated, meaning they would be expected to have had immunity to SARS-CoV-2 infection. A total of 113 those patients died.

“This is real-world data showing that the vaccines work, but it is not unexpected that it also shows some vaccine failure, mostly in the frail, elderly population,” said Calum Semple, professor of Child Health and Outbreak Medicine at Liverpool University. “We’re saying the vaccines do work. This is good real-world evidence, but there are some vaccine failures.”

The 3,842 vaccinated people admitted to the hospital represent 7.3% of 52,280 patients hospitalized with COVID-19 from Dec. 8 – April 10 who were enrolled into a study run by the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC), of which Semple is co-lead.

ISARIC was set up in 2012, with the aim of providing rapid early data for policymakers, to help in dealing with serious disease outbreaks. This particular analysis of ISARIC data was commissioned by the U.K. government’s scientific advisory group on emergencies.

“Our role is to give the earliest signs using dirty real-world data,” Semple said, noting the nature of the study means lots of questions are left hanging.

There are not enough data as yet to discern if immunity wanes over time. Nor is it possible at this stage to say how individual vaccines performed, because it is not known which product the patients had received. Semple said it is hoped to link back to the national immunization database to see if patients had been given Astrazeneca plc’s or Pfizer Inc./Biontech SE’s vaccine.

Similarly, it is not clear if the data mirror what was seen in the clinical studies of the vaccines, but Semple said that “from a public health policy perspective the deaths seen are to be expected, given what was seen in the trials.”

There have been community studies in the U.K. and Israel demonstrating vaccines are effective in preventing hospitalization. What is notable about vaccinated patients who are admitted to the hospital is that their outcomes are the same as non-vaccinated counterparts.

In order to be in the hospital, patients have to meet a “threshold of sickness” that is the same “if they are vaccinated or non-vaccinated,” said Annemarie Docherty, critical care consultant and a co-author of the study. “They look as sick as non-vaccinated patients. We’re only comparing patients that are sick enough to come into hospital, and then there is no difference in how well they do,” she said.

Peter English, retired consultant in communicable disease control, who was not involved in the research, said that is not surprising given the natural history of the disease, where the initial viral infection can trigger a destructive immune response. “Once the immune overreaction starts – and it is usually this that causes illness severe enough to require hospital admission – the presence of the virus is no longer a factor in the subsequent course of the illness,” English said.

Understanding vaccine failure

In the U.S., reports to CDC show there had been 7,157 cases of vaccine breakthrough infection as of April 20, 2021, at which time more than 87 million people had received two doses of vaccine.

Of the 7,157 cases, 498 people were hospitalized and there were 88 deaths. The CDC said those reported cases will represent an undercount because the surveillance system depends on voluntary reporting from state health departments.

In the case of the U.K. cohort of vaccinated patients admitted to the hospital, only 140 had received two doses of vaccine.

The CDC is in the midst of transitioning from monitoring all cases of vaccine breakthrough to identifying and investigating only those infections that result in hospitalization or death.

That will be key to understanding the circumstances in which a vaccine fails. Semple said it is not possible to say at this stage what those factors might be from the U.K. study. “There is some suspicion about vaccine data,” he said. “The science community really are trying hard to understand vaccine failure; we’re doing follow-up.”

Viral samples from vaccinated patients who ended up in the hospital are being sequenced to see if infections were caused by variants of concern.

Semple noted also that the absolute numbers of vaccine failures are low, and continue to fall as the likelihood of exposure to the virus reduces. That will lead to under-representation of the signal of vaccine failure, he said.

No vaccine is 100% effective in stopping disease, said Deborah Dunn-Walters, chair of the British Society for Immunology COVID-19 taskforce and professor of immunology at Surrey University. “A very small number of people were hospitalized 21 days post-vaccination, and it’s these people that we need to examine in more detail to understand why the vaccine did not afford them full protection,” she said.

Understanding the correlates of protection, or what effective immunity against COVID-19 looks like at the cellular level, will help provide answers to this, Dunn-Walters said.