# Bactericidal human monoclonal antibody 1B1 shows specificity for meningococcal factor H binding protein variant 2 and displaces human factor H

## TL;DR

A human antibody called 1B1 specifically targets a less-studied variant of a protein on meningococcal bacteria, helping to kill the bacteria and potentially improving vaccine design.

## Contribution

The first detailed structural and functional analysis of an antibody with specificity for fHbp variant 2.

## Key findings

- The crystal structure of the 1B1-fHbp variant 2 complex was determined at 2.4 Å resolution.
- Key hotspots in the antibody-protein interface were identified through mutagenesis and binding studies.
- 1B1 displaces human factor H from fHbp variant 2, contributing to its bactericidal activity.

## Abstract

Thousands of disease cases and hundreds of deaths occur globally each year due to invasive meningococcal disease. Neisseria meningitidis serogroup B (MenB) is the leading cause of such disease in developed countries. Two vaccines, 4CMenB and MenB‐fHbp, that protect against MenB are available and include one or two forms respectively of factor H binding protein (fHbp), a key protective antigen. Studies of circulating meningococci have identified over 1380 different fHbp amino acid sequences, which form three immunologically distinct clusters, termed variants 1, 2, and 3. Neither of the current vaccines contains a variant 2 antigen, which is less well characterized than fHbp variants 1 and 3. We characterized the interaction of fHbp variant 2 with humAb 1B1 using biochemical methods and live meningococcal assays. Further, we determined the crystal structure of the complex at 2.4 Å resolution, clearly revealing the epitope and providing the first detailed report of an antibody with distinct specificity for fHbp variant 2. Extensive mutagenesis and binding studies elucidated key hotspots in the interface. This combination of structural and functional studies provides a molecular explanation for the bactericidal potency and specificity of humAb 1B1 for fHbp variant 2. Our studies, focused on fHbp variant 2, expand the understanding of this previously under characterized group of the vast family of variants of fHbp, a virulence factor present on all meningococci. Moreover, the definition of a protective conformational epitope on fHbp variant 2 may support the design and development of novel variant 2‐containing MenB vaccines affording greater breadth of protection.

We performed a structural and functional characterization of human monoclonal antibody 1B1. x‐ray crystallographic studies revealed the molecular basis of the distinct specificity of 1B1 for factor H binding protein (fHbp) variant 2. Understanding the epitope/paratope interface shows how 1B1 displaces human factor H from fHbp variant 2, which contributes to the high potency of antibody 1B1 in the killing of serogroup B meningococcus (MenB).