When children receive their second dose of the measles-mumps-rubella vaccine between 4 and 6 years, the protection against the three viruses lasts most of their lives. Meanwhile, the effectiveness of an influenza vaccine lasts only for one flu season. Scientists were perforated by why few vaccines induce immunity for decades while others wear off after mere months.
Now, a new study by researchers at Stanford University could finally answer. The study, published in Nature Immunology, has indicated that the variation in vaccine durability is linked to a type of blood cell called megakaryocytes, typically involved in blood clotting.
The lead author, Bali Pulendran, says, “The question of why some vaccines induce durable immunity while others do not has been one of the great mysteries in vaccine science. Our study defines a molecular signature in the blood, induced within a few days of vaccination, that predicts the durability of vaccine responses and provides insights into the fundamental mechanisms underlying vaccine durability.”
The study led by Bali Pulendran initiated the experiment with the H5N1 bird flu vaccine given with an adjuvant. The adjuvant is a chemical mixture that improves the immune response to an antigen.
Researchers collected blood samples from 50 healthy volunteers with two doses of the bird flu vaccine with the adjuvant or two without the adjuvant. The team used machine learning to conduct in-depth analyses of genes, proteins, and antibodies in each sample.
Since the blood samples were first 100 days after vaccination, the program identified a molecular signature in the blood associated with the strength of a person’s antibody response months later. This molecule signature was mostly embedded in RNA within platelets.
Platelets are derived from megakaryocytes. When platelets break off from megakaryocytes, they enter the bloodstream and often take small pieces of RNA from the megakaryocytes with them. Since the activity of megakaryocytes can’t be tracked down easily, platelets with RNA act as proxies.
“What we learned was that the platelets are a bellwether for what is happening with megakaryocytes in the bone marrow,” Pulendran said.
To confirm the effect of megakaryocytes on vaccine durability, researchers injected mice with the bird flu vaccine. They also added Thrombopoetin drug to boost the number of activated megakaryocytes in the bone marrow. This drug led to a sixfold increase in anti-bird flu antibodies two months later.
Experiments showed that activated megakaryocytes produce key molecules that increase the survival of the bone marrow cells, which are responsible for making antibodies. When these molecules were blocked, antibodies had a lower survival rate in the presence of megakaryocytes. Researchers hypothesize that megakaryocytes provide a nurturing, pro-survival environment for plasma cells in the bone marrow.
Similar trends were shown for other vaccines, including influenza, yellow fever, malaria, and COVID-19. The molecular signature could predict which vaccines will last longer and which vaccine recipients will have a longer-lasting response.
In the upcoming experiments, Pulendran and his colleagues plan to probe why some vaccines spur higher levels of megakaryocyte activation. These findings could enable researchers to develop vaccines that effectively activate megakaryocytes.
Journal Reference
- Cortese, M., Hagan, T., Rouphael, N. et al. System vaccinology analysis of predictors and mechanisms of antibody response durability to multiple vaccines in humans. Nature Immunology. DOI: 10.1038/s41590-024-02036-z
