Modeling And Manipulating Antibody Response Against Influenza And Coronavirus Spike Proteins And Exploring Their Role In Directing Spike Evolution

The antibody repertoire possesses near limitless diversity, enabling the adaptive immune system to accommodate essentially any antigen. However, this diversity explores the antigenic space unequally, allowing some pathogens like the influenza virus to impose complex immunodominance hierarchies that distract antibody responses away from key sites of virus vulnerability. We developed a computational model of affinity maturation to map the patterns of immunodominance that evolve upon immunization with natural and engineered displays of hemagglutinin (HA) - the influenza spike, which mediates entry to the host cell and is the main vaccine antigen. Based on this knowledge, we designed immunization protocols that subvert immune distraction and focus serum antibody responses upon a functionally conserved, but immunologically recessive, target of human broadly neutralizing antibodies. These antibodies would confer universal immunity to influenza. We tested in silico predictions by vaccinating transgenic mice in which antibody diversity was humanized to mirror clinically relevant humoral output. We further used 3d coarse-grained computational models to estimate the antibody pressure on the seasonal flu H1N1 and sarbecovirus subgenus spikes. Analyzing publically available sequences, we found that antibody pressure, through the geometrical organization of spikes on viral surface, shaped their mutability. Studying the mutability patterns of SARS-CoV-2 and the 2009 H1N1 pandemic spikes, we found that they are not predominantly shaped by antibody pressure. However, for SARS-CoV-2, we find that over time, it acquired, at low frequency, several mutations at antibody-accessible positions, which could indicate possible escape. Hence, we offer a geometry-based approach to estimate and assess whether a pandemic virus is changing its mutational pattern to that indicative of a circulating virus.