Investigation of the cross-reactive humoral responses to SARS-CoV-2 in human and mice

Abstract

The new severe acute respiratory coronavirus 2 (SARS-CoV-2), which has caused the pandemic of a life-threatening disease (COVID-19), has overwhelmed the whole world with its high transmissibility and wide range of severity. Although the use of several antiviral drugs such as paxlovid and molnupiravir has been approved by the FDA, COVID-19 vaccines still play an important role to minimize the risk of infection or even death through induction of the immune responses, especially neutralizing antibodies. However, it has been found that the recently identified SARS-CoV-2 variants of concern (VOCs) like Omicron earn new mutations on the spike protein and lead to immune evasion from the current vaccines. Though a booster dose of mRNA vaccine is still effective against the antigenically distinct variant, it is not known how well it may protect from new VOCs and/or other coronaviruses. Thus, understanding the cross-reactive immunity between different coronaviruses is a crucial step to design an effective pan-coronavirus vaccine.

Understanding the cross-reactive immunity between different coronaviruses is needed before we can design a pan-coronavirus vaccine. Another coronavirus, SARS-CoV-1, which caused a global outbreak in 2003, shares 80% genomic nucleotide sequence identity with the SARS-CoV-2. We thus investigated the immunological question of cross-reactivity by comparing the serological responses between the patients infected by SARS-CoV-1 and SARS-CoV-2. Similar question was addressed from mice after immunization or infection. Our results showed that induction of cross-binding antibody to the spikes of these two viruses is common, while the presence of cross-neutralization against both strains is rare. Moreover, we also found that sequential heterologous Sarbecovirus immunization induced cross-reactive binding antibodies for both viruses but delayed the emergence of neutralizing antibody responses against the booster strain.

We also established a high-throughput sequencing platform to characterize signatures of the B cell repertoire to SARS-CoV-2 infection. We identified 38 significantly expanded clonal lineages which are specific to the SARS-CoV-2. Several monoclonal antibodies were identified and showed to have cross-neutralizing capacity against different SARS-CoV-2 VOCs. Additionally, we compared the serological responses to the N-terminal domains of SARS-CoV-1 and SARS-CoV-2 from the plasma samples of COVID-19 patients. A mice model was also used to evaluate the antigenicity of the NTDs. Our results suggested that though NTD is not suitable to be an immunogen, it provides a supplementary strategy for serology testing.

Taken together, our results show that cross-binding antibodies between SARS-CoV-1 and SARS-CoV-2 cannot contribute the cross-neutralizing function. Moreover, the cross-reactive immunity induced by the primed strain may delay the neutralizing antibody against the booster strain during heterologous immunization. These results address several fundamental questions about the cross-reactive immunity to coronaviruses and have implications for vaccine development.