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Stanford Team Profiling Omics of COVID-19 Vaccine Response

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NEW YORK – Researchers at Stanford University are using multiple omics approaches to profile the response of individuals to COVID-19 vaccination.

Led by Michael Snyder, a professor of genetics at Stanford, the project will collect information including proteomic, metabolomic, and antibody data on subjects at several time points before and after vaccination with the goal of understanding the dynamics of the body's response to the vaccine as well as potentially giving insight into factors underlying differences in response between individuals.

The researchers have just begun enrolling patients and are looking to sample at least 500 individuals spanning a range of ages and geographies. They also hope to get enough recipients of each of the different vaccines to be able to look at how response profiles might differ with the type of vaccine received, said Ryan Kellogg, one of the leaders of the project and a postdoc in Snyder's lab.

The Stanford team is collecting blood samples from subjects using the Mitra microsampling device from sample collection firm Neoteryx. It will use mass spectrometry to make proteomic, lipidomic, and metabolomic measurements in these samples and Luminex-based immunoassays to measure antibodies, autoantibodies, and cytokines.

The researchers are also collecting stool samples, which they will use to look at changes in subjects' microbiomes and their immune cell profiles over the course of the study.

"You gut is your largest immune organ, and so we are going to see if there are microbiome changes with immunity that develop following the vaccine, and also look at changes in immune cells in the gut, which we can measure from the stool," Kellogg said.

They will collect samples shortly before vaccination to get baseline measurements and then at seven additional points over the first year following vaccination, Kellogg said.

He said the researchers are particularly interested in getting a better understanding of the dynamics of the antibody response to COVID-19 vaccination at the individual level as well as determining if there are molecular markers that could identify people at risk of experiencing adverse effects from the vaccines.

Snyder's lab has conducted a number of omics studies longitudinally profiling subjects, including previous efforts looking at the effects of vaccination. Last year, he and his colleagues published a study in Nature looking at individuals' multi-omic profiles and the relationship between viral infections and type 2 diabetes that included omics data tracking subjects' responses to the flu vaccine.

"Obviously there was much more severe response, with cytokines and everything else, with a regular illness than with the vaccination, but there was an effect from vaccination," Snyder said.

He said he and his colleagues are particularly interested to see the molecular response to the COVID-19 vaccine given the reports of fairly strong side effects.

He noted that the omics of infectious disease has a particular personal relevance for him as in another of his profiling studies he was able to detect in himself the onset of type 2 diabetes following what he described as a "particularly nasty respiratory syncytial virus infection."

"So we're very interested in general about the relationship between viral infections and their long-term effects," he said.

Snyder and his team have previously explored microsampling as a tool for facilitating their longitudinal omics profiling studies, but he noted that the shutdowns necessitated by the COVID-19 pandemic have made them shift even more to the approach.

"We haven't been allowed to [collect samples] in person," he said. "They are just starting to open up again and let us run studies where we can bring people in to draw blood. [Microsampling] has totally enabled us to run studies when we were otherwise shut down."

Snyder said that the convenience of microsampling makes it a particularly useful approach for studies like his that aim to collect longitudinal samples from a large number of subjects across a range of geographies. He also noted that microsampling allows researchers to collect samples more frequently than they could using traditional blood draws.

"You can't take 75 [milliliters] of blood from someone every day," he said. "The fact that you can [with microsampling] take a lot of samples through a time course with like vaccination or what-have-you… it really lets us do studies that we wouldn't otherwise be able to do."

Kellogg said the lab currently has around a dozen studies either ongoing or planned that will use microsampling and added that he imagined most of the studies will involve a microsampling component in the future.

"It allows more participants, more geographic distribution, more time points, you don't have the collection costs associated with phlebotomy, and it's much less burdensome on the patient," he said. "We imagine that it can allow us to scale to much larger cohorts sizes and more frequent time points that will capture more of the dynamics of biology over time. If you have, say, a drug intervention or some health fluctuation, we can capture that change … in real time … rather than waiting several days later for a blood draw."

Companies like Torrance, California-based Neoteryx and West Lafayette, Indiana-based Novilytic are working to improve upon the dried blood spots (DBS) most commonly used for microsampling applications.

"We started with dried blood spots, and to be honest, they don't work nearly as well as the Neoteryx [product]," Snyder said, noting that a particular problem with dried blood spots is normalizing volumes across samples.

The Mitra device uses a fixed volume capillary to ensure that all subjects collect the same volume of blood. This isn't a perfect solution, either, because people are differently hydrated, which can impact the contents of their sample, but, Snyder said, it is significantly better than approaches for normalizing DBS volumes, which commonly involve using hemoglobin measurements.

He said that his team is able to measure on the order of hundreds of proteins, metabolites, and lipids from the blood microsamples as well as around 60 to 70 cytokines.

James Rudge, technical director at Neoteryx, said that the company has seen an uptick in interest from researchers since the pandemic began a year ago. "The pandemic has certainly brought new awareness to the value of remote microsampling in both research and healthcare," he said.

Rudge noted that over the last year the company's devices had been used for sample collection for a study of the prophylactic efficacy of hydroxychloroquine in COVID-19, as well as a serology study run by the National Institutes of Health that analyzed around 8,500 samples collected using the Mitra device to assess the prevalence of SARS-CoV-2 in the early months of the pandemic.

The devices have also seen adoption in some clinical settings due to the pandemic. For instance, in the UK, Nottingham Children's Hospital began using remote sampling to monitor pediatric kidney transplant patients to assess their blood creatinine levels and levels of the immunosuppressant tacrolimus, which is used following organ transplants to lower risk of rejection. At the end of 2020, London's Guy's Hospital began using the device for remote sampling of its adult transplant patients.

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