Evolution of SARS-CoV-2 neutralizing human antibody response and the impact of escape variants

During the coronavirus diseases 2019 (COVID-19) pandemic, different prophylactic and therapeutic tools have been approved to prevent and treat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. Their administration initially mitigated the impact of the pandemic, but the continuous evolution of SARS-CoV-2 generated highly mutated variants able to evade natural and vaccine-induced immunity and limiting the clinical application of monoclonal antibodies (mAbs). To understand how the human antibody response evolved in the past years to control highly mutated variants, in this PhD project we longitudinally investigated at single cell level the antibody response of infected and vaccinated individuals to SARS-CoV-2 and its variants. Thanks to this analysis we also identified broadly neutralizing mAbs that were used to investigate the ability of the virus to evolve under selective pressure and to understand the suitability of these antibodies as medical tools. Our results showed that multiple immunizations or infections with the ancestral SARS-CoV-2 Wuhan virus are not sufficient to improve the breadth of the antibody response to the variants. Conversely, exposure to heterologous and distantly related SARS-CoV-2 variants led to the maturation and reactivation of the B cell compartments increasing the overall breadth of the antibody response. In addition, mAb pressure on SARS-CoV-2 has shown that the virus can rapidly evolve to escape antibodies when used alone. However, the combination of two mAbs increased the time of evasion up to almost 4-fold compared to the use of the single mAbs. Overall, this project shed light on the human antibody response induced after SARS-CoV-2 infection and vaccination, highlighting the need of heterologous boosts to increase the breadth of coverage against variants. Furthermore, our work showed that the use of mAb cocktails dramatically increased the resistance to SARS-CoV-2 evasion suggesting that the use of two antibodies could be an important strategy to increase variant resistance to these therapeutic tools.