Cell Host Microbe. 2019 Jan 09; 25(1):59-72.

PubMed ID: 30629920

HIV-1 neutralizing antibody signatures and application to epitope-targeted vaccine design

Bricault CA, Yusim K, Seaman MS, Yoon H, Theiler J, Giorgi EE, Wagh K, Theiler M, Hraber P, Macke JP, Kreider EF, Learn GH, Hahn BH, Scheid JF, Kovacs JM, Shields JL, Lavine CL, Ghantous F, Rist M, Bayne MG, Neubauer GH, McMahan K, Peng H, Cheneau C, Jones JJ, Zeng J, Ochsenbauer C, Nkolola JP, Stephenson KE, Chen B, Gnanakaran S, Bonsignori M, Williams LD, Haynes BF, Doria-Rose N, Mascola JR, Montefiori DC, Barouch DH, Korber B

Eliciting HIV-1-specific broadly neutralizing antibodies (bNAbs) remains a challenge for vaccine development, and the potential of passively delivered bNAbs for prophylaxis and therapeutics is being explored. We used neutralization data from four large virus panels to comprehensively map viral signatures associated with bNAb sensitivity, including amino acids, hypervariable region characteristics, and clade effects across four different classes of bNAbs. The bNAb signatures defined for the variable loop 2 (V2) epitope region of HIV-1 Env were then employed to inform immunogen design in a proof-of-concept exploration of signature-based epitope targeted (SET) vaccines. V2 bNAb signature-guided mutations were introduced into Env 459C to create a trivalent vaccine, and immunization of guinea pigs with V2-SET vaccines resulted in increased breadth of NAb responses compared with Env 459C alone. These data demonstrate that bNAb signatures can be utilized to engineer HIV-1 Env vaccine immunogens capable of eliciting antibody responses with greater neutralization breadth.