Patel Sara V, Leeman Brooke M, Botros Patricia J, Folta Joanna, Shahid Dhiman, Rocque Anya I, Joyal Andrew S, Vecchio Joseph A, Passell Eliza, Tien Dessie, Reynolds Zahra, Su Karry, Vyas Tammy D, Vyas Jatin M, Abar Emory, Barry Mamadou, Alexandrescu Andrew, Wallace Zachary, DaCosta Jeffrey M, Choudhary Manish C, Tamura Trevor, Edelstein Gregory, Li Yijia, Deo Rinki, Sparks Jeffrey A, Boucau Julie, Glover Owen, Barczak Amy, Lemieux Jacob, Siedner Mark J, Li Jonathan Z, Fofana Ismael Ben
Biology Department, Boston College, 140 Commonwealth Avenue, Chestnut Hill, MA.
Massachusetts General Hospital, Harvard Medical School, Cambridge, MA, USA.
Res Sq. 2024 Dec 5:rs.3.rs-5487774. doi: 10.21203/rs.3.rs-5487774/v1.
As of May 2023, the public health emergency of COVID-19 was lifted across the globe. However, SARS-CoV-2 infections continue to be recorded worldwide. This situation has been attributed to the ability of the virus to evade host immune responses including neutralizing antibody-derived Immunity. The vast majority of antibody escape mutations have been associated with the S1 subunit of the spike protein, especially the Receptor Binding Domain (RBD) but also the N-terminal Domain (NTD). The other region of the spike, the S2 subunit, is the most conserved region amongst coronaviruses. We hypothesized that S2-specific antibody responses are suboptimal in vaccinated and SARS-CoV-2 infected patients resulting in an ineffective neutralization of distant coronaviruses. Here, we analyzed S2-specific antibody responses SARS-CoV-2-infected individuals, including a mixed cohort of those with and without immunosuppression and prior vaccination. We found that S2-specific antibody responses are generally lower than S1-specific antibody responses. Furthermore, we observed in immunocompetent individuals that S1 and S2-specific antibody responses are both positively correlated with Wuhan, Omicron, SARS-CoV and W1V1-CoV pseudovirus neutralization. Among the immunocompromised patients, S1-specific antibody responses were rarely correlated with pseudovirus neutralization in contrast to S2-specific antibody responses which frequently correlated with pseudovirus neutralization. These data highlight the potential of the S2-subunit as an ideal target for induction of cross-neutralizing antibody immunity against divergent coronaviruses.
截至2023年5月，全球范围内的新冠疫情公共卫生紧急状态已解除。然而，全球范围内仍不断有SARS-CoV-2感染病例被记录。这种情况归因于该病毒逃避宿主免疫反应的能力，包括逃避由中和抗体产生的免疫。绝大多数抗体逃逸突变与刺突蛋白的S1亚基有关，尤其是受体结合域（RBD），但也与N端结构域（NTD）有关。刺突蛋白的另一个区域，即S2亚基，是冠状病毒中最保守的区域。我们推测，在接种疫苗和感染SARS-CoV-2的患者中，针对S2的抗体反应欠佳，导致对远距离冠状病毒的中和作用无效。在此，我们分析了SARS-CoV-2感染个体中针对S2的抗体反应，包括有和没有免疫抑制以及既往接种疫苗的混合队列。我们发现，针对S2的抗体反应通常低于针对S1的抗体反应。此外，我们在免疫功能正常的个体中观察到，针对S1和S2的抗体反应均与针对武汉株、奥密克戎株、SARS-CoV和W1V1-CoV假病毒的中和作用呈正相关。在免疫功能低下的患者中，与经常与假病毒中和作用相关的针对S2的抗体反应相反，针对S1的抗体反应很少与假病毒中和作用相关。这些数据凸显了S2亚基作为诱导针对不同冠状病毒的交叉中和抗体免疫的理想靶点的潜力。
