What does it really mean to be broad? Uncovering underlying biology behind broadly neutralizing antibodies

The importance of antibodies in preventing and controlling human disease cannot be underestimated. Many vaccines depend on neutralizing antibodies for protection. In addition, neutralizing antibodies are highly useful when administered therapeutically. The ongoing pandemic has brought to light that few therapeutic antibodies can stand the test of time as new viral variants emerge. The promise of broadly neutralizing antibodies, which recognize conserved epitopes shared across entire groups of related pathogens, is that they are evolution-proof and remain protective in the face of pathogen evolution. Yet, as evidenced by clinical data, there are few examples where such antibodies cannot be escaped. This led me to wonder, what properties truly define what it is to be broadly neutralizing? Irrespective of the pathogen, broadly neutralizing antibodies are almost always very rare. In any given study, one might screen thousands of antigen-specific B cells to find a single broadly neutralizing antibody. Therefore, this rarity may explain some crucial underlying biology. Perhaps, these neutralizing antibodies are only broad because they are rare. In other words, pathogens are under little selective pressure to escape antibodies that are infrequently made. This leads to my central hypothesis that most broadly neutralizing antibodies are broad because they are rare, not because they target conserved epitopes that cannot mutate without a fitness cost to the pathogen. Using SARS-CoV-2 as a model pathogen, I will test these concepts. In Aim 1, I will determine whether infrequency is a defining feature of broadly neutralizing antibodies. In Aim 2, I will determine whether some epitopes, are more difficult to evolve away from than others. The results of this work will provide a deeper understanding of the relationship between antibody epitopes and resistance to viral escape. The methods developed in this project have applications far beyond SARS-CoV-2. In addition, this approach may provide a more efficient way for researchers to screen large amounts of sequencing data to identify potentially broadly neutralizing antibodies.