LONDON – A single dose of Pfizer Inc./Biontech SE’s COVID-19 vaccine does not promote a strong enough immune response to provide protection against variants of SARS-CoV-2, including the Kent variant B.1.1.7, which as of April 29 had caused 226,635 confirmed infections in the U.K.

A single dose of the vaccine also is not effective against the South Africa variant B.1.351, and most likely the P1 variant that arose in Brazil, and the latest threat, the “double mutant” B.1.617, first reported in India, according to in-depth immune profiling of blood samples from U.K. health care workers.

After single-dose vaccination, 90% of individuals – who were known not to have been previously infected with SARS-CoV-2 – showed no detectable neutralizing antibodies against B.1.1.7, though they did show demonstrable responses to the wild-type Wuhan SARS-CoV-2 virus.

In contrast, in all participants who were known to have contracted the infection, a single dose acted as a booster, and they had substantially enhanced antibody responses, neutralizing not just Wuhan SARS-CoV-2, but also the B.1.1.7 and B.1.351 variants of concern.

That is significant because previous analyses of blood samples from the cohort of health care workers have shown natural infection alone did not protect against variants of concern.

Previously infected health care workers had “really, really majorly enhanced responses” after a single dose of the Pfizer vaccine, said Rosemary Boyton, professor of immunology and respiratory medicine at Imperial College London, who led the research, published in Science. Neutralizing antibody levels were 43-fold higher than the values recorded after two doses of vaccine in the phase I trial of Pfizer’s vaccine.

“People who have had their first dose of vaccine and who have not previously been infected with SARS-CoV-2 are not fully protected against the circulating variants of concern,” Boyton said. “This study highlights the importance of getting second doses of the vaccine rolled out to protect the population.”

That is a particularly resonant message in the U.K., where it was decided to extract the maximum public health benefit from limited supplies of vaccines by administering the two doses 12 weeks apart, rather than after a three- or four-week interval, as in the clinical trials.

As of the end of April, 34 million of a population of 67 million people in the U.K. had received a single dose, and more than 14 million had received two doses, of either Pfizer or Astrazeneca plc’s COVID-19 vaccine.

Despite the fact that people who were previously infected with the virus mounted an effective immune response against the Kent and South Africa variants, there was a 11- to 25-fold drop in the level of neutralizing antibodies compared to that seen with the Wuhan strain, against which the vaccines were designed.

However, the majority remained within a “protective threshold,” which was not the case for vaccinated infection-naïve individuals, the researchers said.

That result was mirrored in memory B cells, which were lower in number in vaccinated naïve individuals compared to vaccinated post infection individuals.

There was mixed picture in terms of T-cell responses, where the mutations in the Kent and South Africa variants resulted in reduced, enhanced or unchanged levels of T-cell immunity, compared to the Wuhan strain.

“You can have a weak T-cell response that stays weak, or some respond better to variants than to the Wuhan [strain],” said Danny Altmann, professor of immunology at Imperial College. The T-cell response appears to be dictated by HLA (human leukocyte antigen) type, he said.

Taken overall, people who have had a prior infection and one dose of the Pfizer vaccine are “well protected” against variants, but while vaccinated naïve people are well protected against the Wuhan virus by one dose of Pfizer vaccine, “they are looking exposed to variants,” said Altmann.

At odds with real world data

Altmann and Boyton have been following the cohort of 731 health care staff who work at the Barts and Royal Free hospitals in London, since March 2020. The volunteers have had weekly PCR testing for SARS-CoV-2, providing detailed understanding of when and who had been infected by the virus. This piece of research involved 51 people, 25 of whom had contracted the virus 39 weeks earlier, before any variants of concern were known to have emerged, and 26 who were virus naïve.

The research fills an important gap in showing how people who had a natural infection respond to vaccination, since all the volunteers in clinical trials were screened to make sure they were SARS-CoV-2 naïve.

Boyton and Altmann recognize their immunological data are at odds with what is happening in reality, where the U.K. national vaccination program prioritizing administration of as many first doses as possible has resulted in a sharp fall in serious COVID-19 infections, hospitalization and deaths.

That occurred in the context of the rapid spread of the Kent variant across the U.K. from December 2020 to February 2021.

The clinical trials of the Pfizer vaccine “would say one dose doesn’t work very well,” but “real life data shows there’s been an enormous impact,” Altmann acknowledged. “All I can say, is it’s not reflected in a very strong immune response,” he told a press briefing.

“One dose in terms of measurable parameters really does look very feeble, especially against variants. But it is at odds with the real world data,” Altmann said.