Blood Test Can Predict How Long Vaccine Immunity Will Last

A study led by researchers at Stanford Medicine has shown that variation in vaccine durability can, in part, be attributed to a type of blood cell called megakaryocytes, typically implicated in blood clotting. In the study, Bali Pulendran, PhD, a professor of microbiology and immunology, and colleagues, initially studied an experimental H5N1 bird flu vaccine given with an adjuvant — a chemical mixture that enhances the immune response to an antigen but, on its own, does not induce an immune response. The researchers followed 50 healthy volunteers who received either two doses of the bird flu vaccine with the adjuvant or two doses without the adjuvant. They collected blood samples from each volunteer at a dozen time points over the first 100 days after vaccination and carried out in-depth analyses of the genes, proteins and antibodies in each sample. Then, they used a machine-learning program to evaluate — and find patterns within — the resulting dataset.

The program identified a molecular signature in the blood in the days following vaccination that was associated with the strength of a person’s antibody response months later. The signature was mostly reflected in tiny bits of RNA within platelets — small cells that form clots in the blood. Platelets are derived from megakaryocytes, cells found in the bone marrow. Platelets, when they break off megakaryocytes and enter the bloodstream, often take small pieces of RNA from the megakaryocytes with them. While researchers can’t easily track the activity of megakaryocytes, platelets carrying RNA from megakaryocytes act as proxies. “What we learned was that the platelets are a bellwether for what is happening with megakaryocytes in the bone marrow,” Dr. Pulendran said.

To confirm whether megakaryocytes were affecting vaccine durability, Dr. Pulendran’s research group simultaneously gave mice the bird flu vaccine and thrombopoetin, a drug that boosts the number of activated megakaryocytes in the bone marrow, which led to a six-fold increase in levels of anti-bird flu antibodies two months later. Further experiments showed that activated megakaryocytes produce key molecules that increase the survival of the bone marrow cells responsible for making antibodies, or plasma cells. When these molecules were blocked, plasma cells survived less in the presence of megakaryocytes. “Our hypothesis is that megakaryocytes are providing this nurturing, pro-survival environment in the bone marrow for plasma cells,” Dr. Pulendran said.

The scientists tested whether the trend held true for other vaccine types. They looked at previously collected data on the responses of 244 people to seven different vaccines, including vaccines against seasonal influenza, yellow fever, malaria and COVID-19. The same platelet RNA molecules — signs of megakaryocyte activation — were associated with longer-lasting antibody production for the various vaccines. The molecular signature could predict which vaccines lasted longer, as well as which vaccine recipients would have a longer-lasting response.

Dr. Pulendran and his colleagues plan to conduct studies that probe why some vaccines might spur higher levels of megakaryocyte activation in the first place. Those findings could help researchers develop vaccines that more effectively activate megakaryocytes and lead to more durable antibody responses. In the meantime, the scientists want to develop tests to determine, using their newly discovered molecular signature, how long a vaccine is likely to last. That could help speed up vaccine clinical trials — in which researchers often must follow people for months or years to determine durability — but also could yield personalized vaccine plans.