Humoral immune response to circulating SARS-CoV-2 variants elicited by inactivated and RBD-subunit vaccines

Area of Science:

• Virology
• Immunology
• Vaccinology

Background:

• SARS-CoV-2 variants possess mutations in receptor-binding domain (RBD) and N-terminal domain (NTD), potentially causing immune escape.
• Understanding the humoral immune response to these variants is crucial for vaccine development and efficacy.

Purpose of the Study:

• To investigate the neutralizing antibody (NAb) response against SARS-CoV-2 variants elicited by different vaccines (CoronaVac, ZF2001) and natural infection.
• To assess the impact of specific mutations (e.g., E484K, K417N) and deletions (242-244Δ) on antibody neutralization.

Main Methods:

• High-throughput single-cell VDJ sequencing to identify potent NAbs from vaccinees and convalescents.
• Pseudovirus and authentic virus neutralization assays to evaluate plasma and antibody responses against SARS-CoV-2 variants (e.g., 501Y.V2).
• Analysis of antibody binding and neutralization efficiency concerning specific mutations and deletions in RBD and NTD.

Main Results:

• Nearly half of identified anti-RBD NAbs showed reduced neutralization against the K417N/E484K/N501Y combination, with E484K being the primary driver.
• The 242-244 deletion in NTD significantly reduced neutralization by anti-NTD NAbs, impacting the NTD antigenic supersite.
• Plasma from convalescents and CoronaVac recipients showed similar neutralization reductions against 501Y.V2, while RBD-subunit vaccinees (ZF2001) exhibited higher tolerance.
• An extended dosing interval for ZF2001 improved neutralizing activity and variant tolerance compared to standard administration.

Conclusions:

• RBD-subunit vaccines, particularly with a third-dose boost, demonstrate potential for effective combating SARS-CoV-2 variants, especially those with mutations affecting the NTD supersite.
• The diversity and mutation tolerance of NAbs elicited by RBD-subunit vaccines are superior to those from inactivated vaccines or natural infection.
• Optimizing vaccine schedules, such as extending the interval between doses, can enhance neutralizing capacity against emerging SARS-CoV-2 variants.