Innovations in structure-based antigen design and immune monitoring for next generation vaccines

Abstract

Please cite this article as: Ward AB, Wilson IA, Innovations in structure-based antigen design and immune monitoring for next generation vaccines, J o u r n a l P r e -p r o o f Highligthts Immunofocusing as a strategy for structure-based vaccine design. Structure-based vaccine design for RSV F, influenza HA, HIV-1 Env. Structure-based vaccine design translated into the clinic. AbstractThe recent explosion of atomic-level structures of glycoproteins that comprise the surface antigens of human enveloped viruses, such as RSV, influenza, hepatitis C and HIV, provide tremendous opportunities for rational, structure-based vaccine design. Several concepts in structure-based vaccine design have been put into practice and are are well along preclinical and clinical implementation. Testing of these designed immunogens will provide key insights into the ability to induce the desired immune responses, namely neutralizing antibodies. Many of these immunogens in human clinical trials represent only the first wave of designs and will likely require continued tweaking and elaboration to achieve the ultimate result of ever increasingly breadth and potency. Considerable effort is now being invested in germline targeting, epitope focusing, and improved immune presentation such as multivalent nanoparticle incorporation. This review highlights some of the recent advances in these areas as we prepare for the next generation of immunogens for subsequent rounds of iterative vaccine development.

Cross-neutralization of a SARS-CoV-2 antibody to a functionally conserved site is mediated by avidity

“…Due to the inaccessibility of the COVA1-16 epitope on the S protein, it is possible that an RBD-based rather than Sbased immunogen can elicit larger numbers of COVA1-16-like antibodies. Crossneutralizing antibodies have also provided important insights into therapeutic and vaccine design, as for influenza virus [44] and HIV [45].…”

“…Due to the inaccessibility of the COVA1–16 epitope on the S protein, it is possible that an RBD-based rather than S-based immunogen can elicit larger numbers of COVA1–16-like antibodies. Cross-neutralizing antibodies have also provided important insights into therapeutic and vaccine design, as for influenza virus [ 44 ] and HIV [ 45 ]. As SARS-CoV-2 continues to circulate in the human population and other zoonotic coronaviruses constitute future pandemic threats [ 46 ], it is certainly worth considering the development of more universal coronavirus vaccines and therapeutics that can cross-neutralize antigenically drifted SARS-CoV-2 viruses, as well as zoonotic SARS-like coronaviruses.…”

High-resolution mapping of the neutralizing and binding specificities of polyclonal rabbit serum elicited by HIV Env trimer immunization

“…While both rational, structure-based vaccine design (Alam et al, 2017; Correia et al, 2014; Dubrovskaya et al, 2019; Haynes et al, 2012; Kong et al, 2019; Kwong and Mascola, 2018; Saunders et al, 2017; Xu et al, 2018) and broadly neutralizing antibody germline-targeting (Briney et al, 2016; Dosenovic et al, 2015; Escolano et al, 2019, 2016; Jardine et al, 2013, 2016; Medina-Ramírez et al, 2017; Steichen et al, 2019, 2016; Tian et al, 2016) approaches have begun to show exciting promise for HIV, continued progress will require iterative rounds of evaluating vaccine responses and redesigning immunogens and vaccine regimens (Ward and Wilson, 2020). Determining the extent of immunofocusing to targeted epitopes, while also tracking – and subsequently eliminating – off-target responses to less conserved regions will be critical to these efforts.…”

Neutralizing Antibodies Targeting HIV-1 gp41

“…Notably, the development of new technologies that allow the identification and isolation of bnAbs from donors whose serum has been identified to have potent and broadly neutralizing activity have revolutionized the field [ 16 ]. This led to the discovery of a plethora of antibodies targeting many exposed regions of the prefusion Env trimer and in turn accelerated the structural characterization and optimization of Env-based immunogens [ 17 , 18 ]. Key structures of bnAbs target V1/V2 [ 19 , 20 , 21 ], glycan-V3 [ 22 , 23 , 24 ], the CD4-binding site [ 25 , 26 , 27 , 28 , 29 ], the fusion peptide [ 11 , 30 ], the gp120/gp41 interface [ 31 , 32 ], the silent face of gp120 [ 33 ], the N-terminal region of the gp41 membrane-proximal external region (MPER) [ 34 ] as well as C-terminal MPER [ 35 , 36 , 37 , 38 , 39 , 40 , 41 ].…”