高出力X線ビームを用いて、抗体がワクチンを求める人々に希望を与えることを明らかにした Using high-powered X-ray beams, researchers see how antibodies can offer hope to those in search of a vaccine
2023-03-16 アルゴンヌ国立研究所(ANL)
Scientists have used Argonne’s APS to study a new antibody “cocktail” that can help counter the Lassa virus, responsible for thousands of deaths annually in Africa. (Image by Shutterstock/Kateryna Kon.)
アフリカで毎年数千人の死亡原因となっているLassaウイルスに対しては、これまでに承認されたワクチンや治療法はない。研究チームは、人工タンパク質である一連の生物分子を作成することで、17年間にわたりLassaウイルスの作用を調べ、感染を防止するための抗体を特定した。
抗体カクテルは、非人類霊長類でテストされたが、人間でのさらなる研究の承認待ちである。最終的な目標は、体が自然にこれらの抗体を産生するようにするワクチンを開発することである。
<関連情報>
- https://www.anl.gov/article/scientists-create-antibody-cocktail-to-fight-deadly-lassa-virus
- https://www.science.org/doi/10.1126/scitranslmed.abq0991
保護抗体のカクテルがラッサウイルスの緻密な糖鎖シールドを覆す A cocktail of protective antibodies subverts the dense glycan shield of Lassa virus
Haoyang Li ,Tierra Buck,Michelle Zandonatti ,Jieyun Yin,Alex Moon-Walker ,Jingru Fang,Anatoliy Koval,Megan L. Heinrich,Megan M. Rowland,Ruben Diaz Avalos,Sharon L. Schendel ,Diptiben Parekh,Dawid Zyla,Adrian Enriquez,Stephanie Harkins,Brian Sullivan,Victoria Smith,Onyeka Chukwudozie ,Reika Watanabe,James E. Robinson,Robert F. Garry,Luis M. Branco,Kathryn M. Hastie,Erica Ollmann Saphire
Science Translational Medicine Published:26 Oct 2022
DOI:https://doi.org/10.1126/scitranslmed.abq0991
Viral vulnerability
Lassa virus (LASV), the causative agent of Lassa fever, remains a major target for vaccine and therapeutic development. Here, Li et al. characterized how a cocktail of three antibodies targets the LASV glycoprotein complex. The authors found that the antibodies neutralize LASV via complementary mechanisms and either circumvented or exploited glycans on the glycoprotein complex for binding. The authors used this extensive characterization to generate a candidate LASV antigen that could be used for vaccine development or discovery of additional neutralizing antibodies.
Abstract
Developing potent therapeutics and effective vaccines are the ultimate goals in controlling infectious diseases. Lassa virus (LASV), the causative pathogen of Lassa fever (LF), infects hundreds of thousands annually, but effective antivirals or vaccines against LASV infection are still lacking. Furthermore, neutralizing antibodies against LASV are rare. Here, we describe biochemical analyses and high-resolution cryo-electron microscopy structures of a therapeutic cocktail of three broadly protective antibodies that target the LASV glycoprotein complex (GPC), previously identified from survivors of multiple LASV infections. Structural and mechanistic analyses reveal compatible neutralizing epitopes and complementary neutralization mechanisms that offer high potency, broad range, and resistance to escape. These antibodies either circumvent or exploit specific glycans comprising the extensive glycan shield of GPC. Further, they require mammalian glycosylation, native GPC cleavage, and proper GPC trimerization. These findings guided engineering of a next-generation GPC antigen suitable for future neutralizing antibody and vaccine discovery. Together, these results explain protective mechanisms of rare, broad, and potent antibodies and identify a strategy for the rational design of therapeutic modalities against LF and related infectious diseases.
