Blood Test From Stanford-led Team Could Predict Vaccine Durability

Original from: 360dx

A transcriptional signature in blood cells called megakaryocytes following vaccination correlates with the strength of an individual's antibody response months later, according to new research.

The finding, from a study published today in Nature, suggests that this particular molecular signature may be used to estimate how long a vaccine may remain effective for a given person.

Waning antibody responses and loss of protective efficacy over time are limitations common to many vaccines. To investigate this, a group led by researchers affiliated with the Stanford University School of Medicine conducted a clinical trial at the Emory Vaccine Center of Emory University, in which they profiled the immune responses of 50 healthy volunteers aged 21 to 45, who received two doses of the H5N1 bird flu vaccine either with or without ASO3, an adjuvant that enhances the immune response to an antigen but does not induce one on its own.

They analyzed the genes, proteins, and antibodies found in blood samples collected from each volunteer at a dozen time points over the first 100 days after vaccination and used a machine-learning program to identify patterns within the resulting dataset.

Using gene set enrichment analysis (GSEA), the researchers uncovered transcriptional pathways related to cell adhesion and expressed primarily in platelets that became active over the first week following vaccination. This signature appeared faster and was more pronounced in the group that received ASO3 than in the unadjuvanted group.

Importantly, this signature appeared to predict the durability of antibody responses to vaccines beyond just the H5N1 vaccine, suggesting the existence of a conserved mechanism underlying vaccine durability. An analysis of publicly available datasets containing both transcriptional information and long-term, post-vaccine antibody titer measurements taken roughly between three months and two years showed evidence of similar responses to vaccines against COVID-19, malaria, and meningococcal and pneumococcal diseases.

To pinpoint the cellular origin of the observed transcriptional responses, the scientists performed CITE-seq (cellular indexing of transcriptomes and epitopes by sequencing) to construct single-cell protein and transcriptome landscapes of peripheral blood mononuclear cells (PBMCs).

The analysis zeroed in on platelets as key contributors to the vaccine durability transcriptional program. As platelets lack nuclei, however, the researchers traced the origin of these platelets to precursor cells called megakaryocytes, which are found in the bone marrow. To further examine how megakaryocytes contribute to the platelet-mediated vaccine response, the team activated them with the growth factor thrombopoietin and observed that this enhanced the durability of vaccine-induced antibody responses.

Digging deeper, the scientists found evidence that megakaryocytes enhanced vaccine response durability largely by helping to sustain the survival of bone marrow plasma cells, which are key producers of vaccine antibodies.

"The platelets are a bellwether for what is happening with megakaryocytes in the bone marrow," Bali Pulendran, professor of microbiology and immunology at Stanford and the study's senior author, said in a statement.

Importantly, the platelet-associated signature appeared predictive even in PBMC samples with few platelets, suggesting that changes in platelet-expressed genes might be detected across various sample types, opening up new avenues for vaccine response monitoring in the future.

Pulendran and his colleagues have been investigating the ASO3 adjuvant and vaccine durability for some time. In 2021, they published a study showing that epigenetic changes in monocytes after both seasonal flu and H5N1 vaccinations triggered changes that conferred increased resistance to the unrelated Zika and dengue viruses.

The next year, they published a separate study in which they identified a "universal" transcriptomic signature predictive of early antibody response to several vaccines. That signature, however, could not predict how long antibody responses would last.

Pulendran is now planning further studies to probe why certain vaccines might spur higher levels of megakaryocyte activation in the first place. Potentially, this could help researchers develop vaccines that impart more durable antibody responses by better activating megakaryocytes.

In the meantime, the Stanford team is applying its newly discovered transcriptional signature to develop tests to determine how long a vaccine is likely to last. Their hope is that this could accelerate vaccine clinical trials that often take months to years to determine durability, as well as advance research into personalized vaccines.

"We could develop a simple PCR assay — a vaccine chip — that measures gene expression levels in the blood just a few days after someone is vaccinated," Pulendran said in a statement. "This could help us identify who may need a booster and when," adding that vaccine durability is likely affected by a number of complex factors in addition to megakaryocytes.

Pulendran said that his team is currently carrying out studies in support of developing such a test and that Stanford has filed a patent application on the proposed assay but is not yet at a stage to attract commercial interest. 

"I certainly hope that we can develop a blood test to assess vaccine durability that would have broad utility across the world," Pulendran said.

Source: Blood Test From Stanford-led Team Could Predict Vaccine Durability