A pan-serotype human monoclonal antibody protects against pneumococcal infection by targeting multiple choline...

Area of Science:

• Microbiology
• Immunology
• Infectious Diseases

Background:

• Streptococcus pneumoniae causes significant global health issues, especially in vulnerable populations.
• Current vaccines have limitations, failing to cover all serotypes and contributing to antibiotic resistance.
• There is a need for novel therapeutics targeting conserved pneumococcal components.

Purpose of the Study:

• To identify and characterize broadly protective human monoclonal antibodies (mAbs) against Streptococcus pneumoniae.
• To evaluate the therapeutic potential of a novel mAb targeting conserved pneumococcal surface proteins.

Main Methods:

• Isolation and characterization of human mAbs from patients with prior pneumococcal infection.
• Binding assays to identify target pneumococcal surface proteins (PcpA, PspA) and conserved domains.
• In vivo efficacy studies in lethal pneumococcal challenge and coinfection models.
• Mechanistic studies including opsonophagocytic killing and bacterial dissemination assays.
• Cryo-electron microscopy to determine the structural basis of antibody binding.

Main Results:

• A first-in-class mAb, 5995-40, was identified, targeting conserved choline-binding domains of pneumococcal surface proteins like PcpA and PspA.
• mAb 5995-40 demonstrated complete protection in lethal pneumococcal challenge models.
• The mAb improved survival in coinfection models involving influenza A, influenza B, and RSV.
• Mechanistic studies revealed enhanced opsonophagocytic killing, reduced bacterial spread, and blocked translocation.
• Cryo-electron microscopy elucidated the binding site on a repeating motif within the choline-binding domain.

Conclusions:

• mAb 5995-40 represents a promising first-in-class therapeutic candidate for broad-spectrum pneumococcal protection.
• Targeting conserved surface protein domains offers a strategy to overcome limitations of current polysaccharide-based vaccines.
• This mAb has potential applications in preventing and treating pneumococcal infections and coinfections.