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

Abstract

The recent explosion of atomic-level structures of glycoproteins that comprise the surface antigens of human enveloped viruses, such as RSV, influenza, 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 goal of enhanced 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.

Figure 1

Overview of the different aspects of structure-based antigen design. Because many of the targets being pursued are envelope glycoproteins that mediate viral entry into the cell, they are metastable by nature and adopt different conformations to carry out their function. (a) In the case of RSV F, many mutations have now been introduced to stabilize the prefusion conformation, which is the preferred antigenic state that can be targeted by potent neutralizing antibodies. (b) For influenza HA, the prefusion conformation is relatively stable, except at the low pH for membrane fusion, but many potential epitopes are less desirable or result in strain-dependent neutralizing antibody responses that are easily escaped. One strategy to focus on the more conserved HA stalk region is to eliminate the more variable HA head altogether, or make chimeric HA with a conserved stalk attached to variable heads for which there is no pre-existing immunity. (c) Many HIV Env bnAbs are restricted in their gene usage and place further constraint on vaccine design. One approach to overcome this hurdle is known as germline targeting in which an epitope is presented on a small scaffold and mutations introduced to bind very specifically, and with high affinity, to a particular germline B cell precursor. (d) While there has been much success in structure-based antigen design, protein subunit antigens are not necessarily very immunogenic on their own. Thus, many efforts are ongoing to understand how the immune system responds to protein subunit vaccines and development of new modalities for delivery and formulation, such as multivalent nanoparticles and slow release of antigen, as with alum depots.