Scientists at Fred Hutchinson Cancer Research Center have found laboratory evidence that patients who have been infected with the COVID-19 virus and are subsequently vaccinated against it mount a stronger immune defense than those who were vaccinated but never infected with the virus.

In a paper posted online on March 25 by the journal Science, a Fred Hutch team led by Drs. Leo Stamatatos, Julie McElrath and Andrew McGuire report that a single shot of either the Moderna or Pfizer-BioNtech vaccines boosted participant immune responses against SARS-CoV-2 by as much as 1,000-fold.

Infection-fighting proteins called antibodies roused by the vaccine in the blood of these patients targeted not only the year-old virus from the first-known cases, but also reacted strongly to the variants of concern first found in South Africa. They even reacted modestly against the spike proteins of the related SARS virus that appeared in 2003, whose key spike surfaces vary as much as 50% from those of SARS-CoV-2.

The vigorous antibody response in previously infected people who received one dose of vaccine exceeded the levels of neutralization a measure of how well antibodies completely block the virus found in unexposed donors who received two doses. That is impressive because the two-dose regimen is already known to protect against symptomatic disease in 95% of those immunized.

Curiously, a second dose of vaccine in the previously infected did not improve upon the strong performance elicited by the first dose a finding that suggests that just one dose may be all that most survivors of COVID-19 may need to avoid a new infection. That could come in handy at some point if there is a need to stretch vaccine supplies.

The laboratory study was made possible by Seattle-area volunteers who participated in a trial developed by McElrath, who is senior vice president and director of the Hutchs Vaccine and Infectious Disease Division. Holder of the Joel D. Meyers Endowed Chair, McElrath leads the Seattle COVID Cohort Study, which seeks out local volunteers who have already contracted the disease or are at high risk of doing so.

The team obtained blood samples from 15 participants in the study who were previously infected and from 13 others who were never infected. Samples were collected before and after each of them had their first and second doses of vaccine. The sera a fluid containing just the antibodies was mixed in test tubes with harmless, nonreplicating viruses that were engineered to carry spikes from several isolates of the coronavirus, including variants of concern that arose in South Africa.

In the laboratory, the researchers tested how well various concentrations of these antibodies prevented infection of cultured human cells featuring the ACE-2 receptor, which the coronavirus latches onto and uses as a gateway to infect the cells in the human nose and lungs.

The work showed that those who had recovered from natural coronavirus infection had the most powerful neutralizing antibody response against the new variants after vaccination.

McGuire said it was encouraging to see the immune response against variants. He was also intrigued to see that the immune systems of these previously infected COVID-19 patients were able to mount a response to the SARS virus (SARS-CoV-1), a virus that first appeared 18 years ago and has a spike structure markedly different from the current coronavirus. This cross-reactivity is a potentially powerful trait that underscores the broad scope of the human immune systems ability to block infection.

We picked SARS-1 because it is fairly divergent from SARS-CoV-2, he said. The rationale was that there are these emerging variants of concern, and we dont know what the next one will look like.

The Science publication followed early releases of the data in February and March on the online preprint server MedRxiv, which provides an opportunity for papers be discussed by scientists prior to formal peer review. The research was funded by donations to theFred Hutch COVID-19 Research Fund, as well asthe Paul G. Allen Family Foundation, the Joel D. Meyers Endowed Chair, the National Institutes of Allergy and Infectious Diseases, and Sanofi Pasteur.

While the study shows that having a previous infection may significantly improve the response to subsequent vaccination, McGuire cautioned that two of the previously infected participants who never showed symptoms of COVID-19 did not have the same robust protection after vaccination as those who had been diagnosed with symptoms of the disease.

There may be a way to stretch the vaccine supply, if it is done in the right way, McGuire said. It maybe something like delaying the second vaccine, if you are giving to someone who already tested positive but youve got to be careful about it.

In a separate study posted on March 24 on the preprint server BioRxiv, Stamatatos and colleagues including McElrath and McGuire tested the neutralizing ability of 198 different antibodies found in blood samples donated by four different COVID-19 patients. The study expanded on work the team had done last year sifting antibodies from a single patient infected in the first month of the pandemic. From these four people, the researchers identified 14 antibodies that neutralized the COVID-19 virus. A dozen of those neutralizing antibodies target the receptor binding domain, the sweet spot on the tip of the coronavirus spike where it latches onto the ACE2 receptor on human cells.

Three of those 12 potent antibodies, and a fourth that targeted a second site on the spike, were also found to block the South African variant as well as the much older SARS strain from 2003. As such, these cross-neutralizing antibodies could help inform the design of a universal human coronavirus vaccine..

These studies highlight the deep dive that virus researchers are taking to analyze how the human immune system is responding to the vaccine and variants of the virus, and points to the possibilities for adapting to future changes as the current threat evolves.

I think it is encouraging that you can harness immune memory to SARS-CoV-2 and potentially neutralize forthcoming variants, McGuire said.