Author: Amino, Rogerio ; Flynn, Barbara J ; Thiberge, Jean-Michel ; Aliprandini, Eduardo ; Nacer, Adéla ; Zavala, Fidel ; Flores-Garcia, Yevel ; Aguirre-Botero, Manuela C ; Wang, Lawrence T ; da Silva Pereira, Lais ; Le Duff, Yann ; Mathis-Torres, Shamika ; Formaglio, Pauline ; Seder, Robert A ; Bowyer, Paul W ; Hurley, Mathew ; Idris, Azza H ; Schön, Arne ; Francica, Joseph R

Human monoclonal antibodies (hmAbs) targeting the Plasmodium falciparum circumsporozoite protein (PfCSP) on the sporozoite surface are a promising tool for preventing malaria infection. However, their mechanisms of protection remain unclear. Here, using 13 distinctive PfCSP hmAbs, we provide a comprehensive view of how PfCSP hmAbs neutralize sporozoites in host tissues. Sporozoites are most vulnerable to hmAb-mediated neutralization in the skin. However, rare but potent hmAbs additionally neutralize sporozoites in the blood and liver. Efficient protection in tissues mainly associates with high-affinity and high-cytotoxicity hmAbs inducing rapid parasite loss-of-fitness in the absence of complement and host cells in vitro. A 3D-substrate assay greatly enhances hmAb cytotoxicity and mimics the skin-dependent protection, indicating that the physical stress imposed on motile sporozoites by the skin is crucial for unfolding the protective potential of hmAbs. This functional 3D cytotoxicity assay can thus be useful for downselecting potent anti-PfCSP hmAbs and vaccines.

01 Apr 2023·Science China Life Sciences

A human antibody potently neutralizes RSV by targeting the conserved hydrophobic region of prefusion F

Article

Author: He, Yonghui ; Su, Caixia ; Wen, Jing ; Yuan, Hong ; Si, Chuanya ; Ling, Zhiyang ; Sun, Xiaoyu ; Sun, Bing ; Ma, Liyan ; Wang, Bin ; Lu, Xiao ; Yi, Chunyan ; Huang, Yuying ; Zhao, Gan ; Cong, Yao ; Liu, Caixuan ; Zhang, Yaguang ; Yang, Zhuo

Respiratory syncytial virus (RSV) continues to pose serious threats to pediatric populations due to the lack of a vaccine and effective antiviral drugs. RSV fusion (F) glycoprotein mediates viral-host membrane fusion and is a key target for neutralizing antibodies. We generated 23 full-human monoclonal antibodies (hmAbs) against prefusion F protein (pre-F) from a healthy adult with natural RSV infection by single B cell cloning technique. A highly potent RSV-neutralizing hmAb, named as 25-20, is selected, which targets a new site Ø-specific epitope. Site-directed mutagenesis and structural modelling analysis demonstrated that 25-20 mainly targets a highly conserved hydrophobic region located at the a4 helix and a1 helix of pre-F, indicating a site of vulnerability for drug and vaccine design. It is worth noting that 25-20 uses an unreported inferred germline (iGL) that binds very poorly to pre-F, thus high levels of somatic mutations are needed to gain high binding affinity with pre-F. Our observation helps to understand the evolution of RSV antibody during natural infection. Furthermore, by in silico prediction and experimental verification, we optimized 25-20 with KD values as low as picomolar range. Therefore, the optimized 25-20 represents an excellent candidate for passive protection against RSV infection.

01 Feb 2023·Immunity

A human antibody epitope map of Pfs230D1 derived from analysis of individuals vaccinated with a malaria transmission-blocking vaccine

Article

Author: Healy, Sara A ; Salinas, Nichole D ; Narum, David L ; Long, Carole A ; Coelho, Camila H ; Tang, Wai Kwan ; Tolia, Niraj H ; Miura, Kazutoyo ; Sagara, Issaka ; Nguemwo Tentokam, Bergeline C ; Duffy, Patrick E

Pfs230 domain 1 (Pfs230D1) is an advanced malaria transmission-blocking vaccine antigen demonstrating high functional activity in clinical trials. However, the structural and functional correlates of transmission-blocking activity are not defined. Here, we characterized a panel of human monoclonal antibodies (hmAbs) elicited in vaccinees immunized with Pfs230D1. These hmAbs exhibited diverse transmission-reducing activity, yet all bound to Pfs230D1 with nanomolar affinity. We compiled epitope-binning data for seventeen hmAbs and structures of nine hmAbs complexes to construct a high-resolution epitope map and revealed that potent transmission-reducing hmAbs bound to one face of Pfs230D1, while non-potent hmAbs bound to the opposing side. The structure of Pfs230D1D2 revealed that non-potent transmission-reducing epitopes were occluded by the second domain. The hmAb epitope map delineated binary hmAb combinations that synergized for extremely high-potency, transmission-reducing activity. This work provides a high-resolution guide for structure-based design of enhanced immunogens and informs diagnostics that measure the transmission-reducing response.

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