Elicitation of potent neutralizing antibodies in obese mice by ISA 51-adjuvanted SARS-CoV-2 spike RBD-Fc vaccine.

Vaccination is considered to be the most effective countermeasure to prevent and combat the global health threats of COVID-19. People with obesity are at a greater risk of hospitalization, life-threatening illness, and adverse outcomes after having COVID-19. Therefore, a safe and effective COVID-19 vaccine for obese individuals is urgently needed. In the study, the vaccine composed of the ISA 51 adjuvant and the SARS-CoV-2 spike (S) receptor-binding domain (RBD) in conjugation with the human IgG1 Fc fragment (named as ISA 51-adjuvanted RBD-Fc vaccine) was developed and inoculated in the regular chow diet (RCD) lean mice and the high-fat diet (HFD)-induced obese mice. The S protein-specific IgG titers were largely induced in an increasing manner along with three doses of ISA 51-adjuvanted RBD-Fc vaccine without causing any harmful side effect. In the HFD mice, the S protein-specific IgG titers can be quickly observed 2 weeks post the first inoculation. The antisera elicited by the ISA 51-adjuvanted RBD-Fc vaccine in the RCD and HFD mice exhibited potent SARS-CoV-2 neutralizing activities in the plaque reduction neutralization test (PRNT) assays and showed similar specificity for recognizing the key residues in the RBD which were involved in interacting with angiotensin-converting enzyme 2 (ACE2) receptor. The immune efficacy of the ISA 51-adjuvanted RBD-Fc vaccine in the HFD mice can be sustainably maintained with the PRNT50 values of 1.80-1.91×10-3 for at least 8 weeks post the third inoculation. Collectively, the RBD-Fc-based immunogen and the ISA 51-adjuvanted formulation can be developed as an effective COVID-19 vaccine for obese individuals. KEY POINTS: • The ISA 51-adjuvanted RBD-Fc vaccine can induce potent SARS-CoV-2 neutralizing antibodies in the obese mouse • The antibodies elicited by the ISA 51-adjuvanted RBD-Fc vaccine can bind to the key RBD residues involved in interacting with ACE2 • The immune efficacy of the ISA 51-adjuvanted RBD-Fc vaccine can be sustainably maintained for at least 8 weeks post the third inoculation.

Neutralization or enhancement of SARS-CoV-2 infection by a monoclonal antibody targeting a specific epitope in the spike receptor-binding domain.

Neutralizing antibodies (NAbs) are believed to be promising prophylactic and therapeutic treatment against the coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Here, we reported two mouse monoclonal antibodies 7 Eb-4G and 1Ba-3H that specifically recognized the receptor-binding domain (RBD) of SARS-CoV-2 spike (S) protein without exhibiting cross-reactivity with the S proteins of SARS-CoV and MERS-CoV. The binding epitopes of 7 Eb-4G and 1Ba-3H were respectively located in the regions of residues 457-476 and 477-496 in the S protein. Only 1Ba-3H exhibited the neutralizing activity for preventing the pseudotyped lentivirus from binding to the angiotensin-converting enzyme 2 (ACE2)-transfected HEK293T cells. The competitive ELISA further showed that 1Ba-3H interfered with the binding between RBD and ACE2. Epitope mapping experiments demonstrated that a single alanine replacement at residues 480, 482, 484, 485, and 488-491 in the RBD abrogated 1Ba-3H binding. 1Ba-3H exhibited the neutralizing activity against the wild-type, Alpha, Delta, and Epsilon variants of SARS-CoV-2, but lost the neutralizing activity against Gamma variant in the plaque reduction assay. On the contrary, 1Ba-3H enhanced the cellular infection of Gamma variant in a dose-dependent manner. Our findings suggest that the antibody-dependent enhancement of infection mediated by the RBD-specific antibody for different SARS-CoV-2 variants must be considered while developing the NAb.