Guiding SARS-CoV-2 vaccine development with single-cell RNA sequencing

The road to an improved coronavirus vaccine is complex. Yet, it is one of the most pressing challenges in the effort to protect against COVID-19. This blog describes how single-cell RNA sequencing helps map out the small steps toward vaccine improvement.

The ongoing COVID-19 pandemic is far from an end. Vaccines are at the basis of the fight against COVID-19, and although current vaccines are already very effective, the scientific world is taking on the challenge to improve them further.

One of the main goals of SARS-CoV-2 vaccination is to create neutralizing antibodies and memory B cells that protect against future infection. So, understanding the human B cell response to SARS-CoV-2 could accelerate vaccine redesign.

Single-cell RNA sequencing helps identify B cells in the SARS-CoV-2 response

Single-cell RNA sequencing can be used to explore adaptive and innate immune cell diversity, for example B cell diversity. It can characterize the immune response to infection or treatment on single-cell resolution.

In this study, researchers from the Amsterdam UMC and The Scripps Research Institute of La Jolla, USA, investigated the B cell population in people not previously exposed to the virus or vaccine. Even when you’re unexposed to the coronavirus, some of your B cell receptors and antibodies already recognize the spike protein. The researchers could isolate those particular B cells using stained coronavirus spike proteins. Then, they used flow cytometry and single-cell RNA sequencing to describe the spike protein-reactive B cell repertoire.

10x Genomics reveals which B cell receptors react with the spike protein

The researchers used the single-cell RNA sequencing platform 10x Genomics‘ Next GEM technology for single-cell immune profiling. This technique allows for high throughput and so identifies even rare subpopulations. In this case, the researchers studied 8000 live B cells on a single-cell resolution. They combined 10x Genomics with the Feature Barcoding technique, allowing them to profile the B cell receptors. This way, the researchers could make a reliable analysis of the compartment to which the B cells belonged (naïve or memory) ánd which B cell receptors are present in the population that binds to the SARS-CoV-2 spike protein.

The results came back with a fundamental find that could guide vaccine optimization.

In unexposed individuals, the SARS-CoV-2 spike protein mainly elicits the response of one type of antibody. It is derived from the B cell receptor IGHV1-69/IGKV3-11, so named because of the heavy chain and light chain that make up the antibody. This B cell receptor is overly present in the naive B cell repertoire. Moreover, some unexposed people already have memory B cells that respond to SARS-CoV-2 with this receptor too.

The antibody that is derived from IGHV1-69/IGKV3-11 is non-neutralizing. That’s important. Non-neutralizing antibodies help signal to the immune system that there’s viral danger, and they can also help mediate the response and prevent dangerous auto-immune reactions. But they cannot block viruses from spreading, the way neutralizing antibodies can. It would mean that, in the vaccine, an IGHV1-69/IGKV3-11 B cell response might best be replaced by a response that favors neutralizing antibodies.

Stability of the spike protein affects the B cell response

The researchers revealed that the non-neutralizing antibody mainly targets a part of the spike protein that is usually unexposed unless the spike protein becomes unstable. If the vaccine could prevent instability or replace the spike protein with a more stable version, it could create a more neutralizing immune reaction. Indeed, some of the approved vaccines already contain a more stable S-2P spike protein variant.

3D reconstruction and electron microscopic images of three antibodies that target the stable version of the spike protein.
Image: 3D reconstruction and electron microscopic images of three antibodies that target the unstable spike protein variant. It is adapted from the published study by Mathieu Claireaux et al.

Does this improve the SARS-CoV-2 vaccine? It is not entirely sure. Non-neutralizing antibodies do have an effect in the immune response. They may still play a role in clearing SARS-CoV-2 from the body. And they may also be important in preventing long-term effects from infection or vaccination by their mediating powers on the immune system.

The next step on the road to improved vaccines

Is the vaccine improved if the IGHV1-69/IGKV3-11 response it elicits is decreased? A next step on the road toward a better vaccine would be to tackle this question. In the intricate struggle to improve the SARS-CoV-2 vaccine, it’s great to have a roadmap like that.

Improvement of a SARS-CoV-2 vaccine isn’t the only way Single Cell Discoveries hopes to aid the anti-COVID-19 effort. For example, we’re helping develop nasal airway epithelial cell cultures for high-throughput drug development. In the past, we also contributed to an organoid-derived bronchioalveolar model to study alveolar response to SARS-CoV-2 infection by providing the data that confirmed the model’s likeness to real tissue. Another collaborative study showed that SARS-CoV-2 can infect gut organoids for the first time, to which our data also contributed. We hope to support more projects in the future.

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