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High-throughput single-cell technology is unearthing the genotype-phenotype relationships that enrich immune repertoires.
FREMONT, CA: Antibody discovery is riding a single-cell wave, enabling massive numbers of B (and T) cells to be individually interrogated for several parameters while also retaining their antigen receptor chain pairing. This could have taken half a year, but now be accomplished in a day or a week, at a throughput that was unimaginable previously. This was the focus of the Deep Sequencing and Single Cell Analysis for Antibody Discovery conference.
Vaccines against viruses are usually designed to mimic infection in a way that's safe for the healthy recipient, leveraging an attenuated or killed virus, for instance, or perhaps selected portions of the native virus to elicit an immune response that will guard against a real challenge. But the typical approach doesn't always work. The concept is to find the kind of antibody response that is trying to elicit and then work backwards to a vaccine immunogen that will elicit it.
The vaccine protein or group of proteins might not necessarily look like the virus very much. The native antibodies must undergo several rounds of mutation and selection against HIV before they can bind and neutralize the virus. Those mature antibodies that can identify HIV don't bind the antigens that their unmutated precursors do and vice versa. The idea is to look out for the rare B cells that make the rare antibodies that have the potential to mature into broadly neutralizing antibodies. The process involves computationally inferring what the germline antibody sequences looked like, and engineering proteins utilizing yeast display directed evolution approaches to find what they bind.
The wave of single-cell technology being harnessed for therapeutic antibody discovery usually breaks down into two camps, those that do on-chip genomics, and those that do on-chip phenotypic assays. All the sequencing is done based on a single cell that has already passed some sort of metric, like functional status.