Broad ultra-potent neutralization of SARS-CoV-2 variants by monoclonal antibodies specific to the tip of RBD.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants of concern (VOCs) continue to wreak havoc across the globe. Higher transmissibility and immunologic resistance of VOCs bring unprecedented challenges to epidemic extinguishment. Here we describe a monoclonal antibody, 2G1, that neutralizes all current VOCs and has surprising tolerance to mutations adjacent to or within its interaction epitope. Cryo-electron microscopy structure showed that 2G1 bound to the tip of receptor binding domain (RBD) of spike protein with small contact interface but strong hydrophobic effect, which resulted in nanomolar to sub-nanomolar affinities to spike proteins. The epitope of 2G1 on RBD partially overlaps with angiotensin converting enzyme 2 (ACE2) interface, which enables 2G1 to block interaction between RBD and ACE2. The narrow binding epitope but high affinity bestow outstanding therapeutic efficacy upon 2G1 that neutralized VOCs with sub-nanomolar half maximal inhibitory concentration in vitro. In SARS-CoV-2, Beta or Delta variant-challenged transgenic mice and rhesus macaque models, 2G1 protected animals from clinical illness and eliminated viral burden, without serious impact to animal safety. Mutagenesis experiments suggest that 2G1 is potentially capable of dealing with emerging SARS-CoV-2 variants in the future. This report characterized the therapeutic antibodies specific to the tip of spike against SARS-CoV-2 variants and highlights the potential clinical applications as well as for developing vaccine and cocktail therapy.

Synthesis and immunogenicity of the Mycobacterium tuberculosis arabinomannan-CRM197 conjugate.

Lipoarabinomannan (LAM) is a major structural surface component of Mycobacterium tuberculosis. This study describes the synthesis of the well-defined lipoarabinomannan (LAM) specific dodecasaccharide-protein conjugate and immunological studies. Arabinomannan (AM) dodecasaccharide has been efficiently synthesized and covalently conjugated to carrier proteins, including cross reactive mutant (CRM197) diphtheria toxoid and bovine serum albumin (BSA) for novel neoglycoconjugates, creating a potent T-dependent conjugate vaccine. Preliminary mice immunization studies on the neoglycoconjugate revealed that it could give rise to a strong IgG antibody titer in mice at 4.0 µg dose with an aluminum phosphate adjuvant. AM-CRM197 shows potential as an excellent candidate for a new carbohydrate-based vaccine that would be capable of eliciting a protective immune response against tuberculosis.