Mapping Polyclonal Antibody Responses in Non-human Primates Vaccinated with HIV Env Trimer Subunit Vaccines

• Published in: Cell reports (Cambridge) Vol. 30; no. 11; pp. 3755 - 3765.e7
• Main Authors: Nogal, Bartek, Bianchi, Matteo, Cottrell, Christopher A., Kirchdoerfer, Robert N., Sewall, Leigh M., Turner, Hannah L., Zhao, Fangzhu, Sok, Devin, Burton, Dennis R., Hangartner, Lars, Ward, Andrew B.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.03.2020; Elsevier
• Subjects: Animals; Antibodies, Neutralizing - immunology; Antibody Formation - immunology; Cross Reactions - immunology; Cryoelectron Microscopy; env Gene Products, Human Immunodeficiency Virus - immunology; Epitopes - chemistry; Epitopes - immunology; HEK293 Cells; HIV Antibodies - chemistry; HIV Antibodies - immunology; Humans; Immunity, Humoral; Macaca mulatta; Models, Molecular; Protein Multimerization; Vaccination; Vaccines, Subunit - immunology
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2020.02.061

Rational immunogen design aims to focus antibody responses to vulnerable sites on primary antigens. Given the size of these antigens, there is, however, potential for eliciting unwanted, off-target responses. Here, we use our electron microscopy polyclonal epitope mapping approach to describe the antibody specificities elicited by immunization of non-human primates with soluble HIV envelope trimers and subsequent repeated viral challenge. An increased diversity of epitopes recognized and the approach angle by which these antibodies bind constitute a hallmark of the humoral response in most protected animals. We also show that fusion peptide-specific antibodies are likely responsible for some neutralization breadth. Moreover, cryoelectron microscopy (cryo-EM) analysis of a fully protected animal reveals a high degree of clonality within a subset of putatively neutralizing antibodies, enabling a detailed molecular description of the antibody paratope. Our results provide important insights into the immune response against a vaccine candidate that entered into clinical trials in 2019. [Display omitted] •Electron microscopy polyclonal epitope mapping of immunized and challenged macaques•Diversity of epitopes and specific angles of approach are hallmarks of protection•Neutralization breadth is due in part to fusion peptide-specific antibodies•Cryo-EM analysis of a protected animal details a putatively neutralizing paratope Nogal et al. use electron microscopy polyclonal epitope mapping of BG505 Env-immunized and matched SHIVBG505-challenged non-human primates to identify hallmarks of protection. Additionally, cryo-EM polyclonal analysis of a fully protected animal reveals a high degree of clonality, allowing detailed characterization of a putative neutralizing paratope.