The concept of viral escape from antibody neutralization seems intimately familiar in our post-COVID world—it’s the reason that we wait in line for new iterations of vaccines while dreadingthe inevitable arrival of new viral variants which can evade those vaccines. It’s a stark reminder that as our immune systems, scientists, and governments fight this virus, the virus fights back. In a recent preprint posted to bioRxiv, Timothy Yu, a graduate student in the lab of Dr. Jesse Bloom, and colleagues report efforts to predict viral escape from complex mixtures of neutralizing antibodies. In doing so, they hope to leverage state-of-the-art experimental and computational techniques to stay ahead in the arms race between virus and man, while potentially gaining new insight into how antibody mixtures interact with viral antigens on a fundamental level.
First, some vocabulary: antibodies are small proteins produced by our immune system whose job it is to bind viral proteins called antigens (for example, the spike protein on the surface of SARS-CoV-2) and neutralize or prevent them from invading our cells. To get more specific, any given antibody only binds a specific portion of its corresponding antigen—this region is called an epitope. We would like to imagine a simple scenario, whereby a viral infection causes your body to produce a single antibody type targeting a specific epitope, which the virus will slowly mutate to disrupt antibody binding and escape neutralization. However—as is usually the case in biology—reality is more complicated. Viral infection or immunization causes your body to produce a mixture of antibodies which recognize many different epitopes. While this is thought to increase the durability of anti-viral responses, we know from experience that viruses are still able to escape from these ‘polyclonal’ mixtures of antibodies by accumulating mutations in multiple antigenic regions (multiple epitopes). Understanding how viruses manage this escape—and developing tools to predict when they will—is of prime public health and basic science importance.
Methods exist to experimentally test whether a viral variant can lead to escape from antibody mixtures, but they are relatively low-throughput and laborious, as each variant needs to be tested individually—a tall order in situations when viral adaptation is rapid, and many different variants arise in the population. Crucially, these methods also rely on prior knowledge of the mutations to produce, which leaves us constantly ‘one step behind’ the virus we are trying to fight.