Researchers pinpoint 'correlates of protection' for Moderna vaccine

Findings may make it easier to test COVID-19 vaccine updates to protect against variants
A nurse prepares to give a COVID-19 vaccination
A scientific team has developed a set of laboratory measurements known as correlates of protection that may simplify and speed up future studies of vaccine efficacy. Getty Images stock photo

Editor's note: This story was originally published on Aug. 11, 2021, based on a preprint posted on medRxiv. It has been updated in the study's publication Nov. 23, 2021, in the peer-reviewed journal Science.

In the race to develop new and better vaccines and boosters to block COVID-19, scientists are eagerly seeking laboratory tests that can measure immune responses to quickly show how well these shots are working, instead of waiting months for results of clinical trials involving tens of thousands of people.

Now, a group of top scientists, including Dr. Peter Gilbert, a biostatistician at Seattle’s Fred Hutchinson Cancer Research Center, are reporting that they have defined such measurements — or correlates of protection — for the widely used Moderna mRNA vaccine.

Correlates of protection are laboratory-derived numbers that are widely used to measure performance and update vaccines against dozens of common diseases ranging from whooping cough to influenza.

Results of the study were published Nov. 23 in the journal Science. They were originally released as a non-peer-reviewed preprint on medRxiv on Aug. 10.

The vaccine research community had been eagerly awaiting these results since April. That is when Gilbert and his colleagues began processing immune system-response data collected from 1,391 participants in blood draws during last year’s huge, 30,000 person clinical trial for the Moderna COVID-19 vaccine.

Four tests using blood samples from trial

That trial found it 94% effective in preventing symptomatic COVID-19 disease, leading the Food and Drug Administration to issue an Emergency Use Authorization in December 2020. As of June, Moderna has shipped 217 million doses of that vaccine to the U.S. government.

Using methods developed in collaboration with Gilbert’s team, researchers at Oxford University have developed similar correlates of protection for the COVID-19 vaccine produced by AstraZeneca, which has yet to be approved in the United States. Their results, published in medRxiv in June, are being used in further studies of that vaccine.

The newly released research on the Moderna vaccine involved four different tests on samples of blood from the participants. Two of the tests measured concentrations of antibodies — tiny immune proteins induced by the vaccine — that latch onto the notorious spike proteins that dot the surface of the coronavirus. The two other tests measure the concentration of antibodies needed to block, or neutralize, the virus from infecting via its chosen target, a protein called ACE2 found on the surfaces of human cells in the lung and nose, among other locales.

Each of the four tests yielded numbers that were higher in vaccine recipients who did not experience COVID-19 than in vaccine recipients who did. Data from these tests therefore helped researchers find specific levels of antibody activity that correlated with the level of protection from disease afforded by the vaccine at set points in time after each dose.

Equipped with tools to measure whether future vaccines or boosters have raised the level of protection in the blood of volunteers, vaccine developers using these correlates might obtain early evidence on whether and how well a new formulation might work against a new COVID-19 variant.

Dr. Peter Gilbert
Fred Hutch biostatistican Dr. Peter Gilbert is lead author of the medRxiv paper and is principal investigator for the Statistical Data Management Center for the HIV Vaccine Trials Network. Fred Hutch file photo

In medical research parlance, these test results would be “surrogate markers” of vaccine effectiveness, replacing the need for the cold calculus of counting and comparing those who became infected against those who did not. Surrogate marker trials could be shorter and quicker.

For a two-dose vaccine like that of Moderna, a trial using similar surrogate marker tests might be able to generate sufficient data from each participant as early as two months after the first dose. From first participant to final analysis, such a trial might demonstrate that a vaccine is meeting correlate benchmarks in three to five months, depending on how many tests are ultimately required and how often the participants are tested. Importantly, fewer participants would be needed.

“We’re talking hundreds, not thousands, of vaccinees,” Gilbert said in an interview about the findings.

Since all four tests performed equally well, Gilbert said it is conceivable that a single assay, likely the neutralization test involving ACE2, might be sufficient in the future to predict how effective a vaccine will be.

“There is precedent for delineating just one marker,” Gilbert said. “Typically, you specify a benchmark for what equals success and get the regulators to agree that it is appropriate. Usually, it’s based on a single assay.”

Follow-up will be crucial

Surrogate marker trials would not be permitted unless the FDA approves them, and while scientists want to develop correlates of protection, there is no consensus yet to adopt them in trials of new vaccines against rapidly evolving SARS-CoV-2, the virus that causes COVID-19.

The correlates of protection used to measure neutralization of the virus did not involve testing with a live virus, but rather used a harmless “pseudovirus” studded with the same spike proteins found on SARS-CoV-2. While pseudovirus testing is commonly employed in virology, some experts may advocate for live virus testing if these markers are used in critical tests of vaccines.

Nevertheless, Gilbert is optimistic that these surrogate markers could be used to test the efficacy of vaccines — both current and future. Even though they were developed against viruses circulating last year, they could become useful in evaluating vaccine efficacy against variants. That includes the worrisome delta variant, which is more readily transmissible than others and has quickly come to dominate COVID-19 infections in the U.S.

“I think it is realistic to suspect that success will occur. There are many historical examples where, for pathogens with multiple variants, the correlates did apply across them. Yet it remains crucial that we also follow up any provisional decisions based on such assays with direct verification that the vaccines benefit individuals and the public against COVID-19,” Gilbert said.


Sabin Russell is a former staff writer at Fred Hutchinson Cancer Center. For two decades he covered medical science, global health and health care economics for the San Francisco Chronicle, and he wrote extensively about infectious diseases, including HIV/AIDS. He was a Knight Science Journalism Fellow at MIT and a freelance writer for the New York Times and Health Affairs. 

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