Non-neutralizing SARS CoV-2 directed polyclonal antibodies demonstrate cross-reactivity with the HA glycans of influenza virus

Kumar, Praveen; Perween, Reshma; Shrivastava, Tripti; Singh, Vanshika; Ahmed Parray, Hilal; Singh, Swarandeep; Chiranjivi, Adarsh; Thiruvengadam, Ramachandran; Singh, Savita; Yadav, Naveen; Jakhar, Kamini; Sonar, Sudipta; Mani, Shailendra; Bhattacharyya, Sankar; Sharma, Chandresh; Vishwakarma, Preeti; Khatri, Ritika; Kumar Panchal, Anil; Das, Supratik; Ahmed, Shubbir; Samal, Sweety; Kshetrapal, Pallavi; Bhatnagar, Shinjini; Luthra, Kalpana; Kumar, Rajesh

The spike protein of the SARS-CoV-2 virus is the foremost target for the designing of vaccines and therapeutic antibodies and also acts as a crucial antigen in the assessment of COVID-19 immune responses. The enveloped viruses; such as SARS-CoV-2, Human Immunodeficiency Virus-1 (HIV-1) and influenza, often hijack host-cell glycosylation pathways and influence pathobiology and immune selection. These glycan motifs can lead to either immune evasion or viral neutralization by the production of cross-reactive antibodies that can lead to antibody-dependent enhancement (ADE) of infection. Potential cross-protection from influenza vaccine has also been reported in COVID-19 infected individuals in several epidemiological studies recently; however, the scientific basis for these observations remains elusive. Herein, we show that the anti-SARS-CoV2 antibody cross-reacts with the Hemagglutinin (HA) protein. This phenomenon is common to both the sera from convalescent SARS-CoV-2 donors and spike immunized mice, although these antibodies were unable to cross-neutralize, suggesting the presence of a non-neutralizing antibody response. Epitope mapping suggests that the cross-reactive antibodies are targeted towards glycan epitopes of the SARS-CoV-2 spike and HA. Overall, our findings address the cross-reactive responses, although non-neutralizing, elicited against RNA viruses and warrant further studies to investigate whether such non-neutralizing antibody responses can contribute to effector functions such as antibody-dependent cellular cytotoxicity (ADCC) or ADE.