What Are the Most Powerful Immunogen Design Vaccine Strategies? Reverse Vaccinology 2.0 Shows Great Promise

Abstract

Functional antibodies, i.e., those with antipathogen activity in in vitro assays, are generally the best correlate of vaccine protection. Mimics of natural infection, including live attenuated and killed pathogens, which induce such antibodies in vivo, have generated highly successful vaccines. However, pathogens that induce functional antibodies at lower levels or more sporadically have been more refractory to vaccine design. Such pathogens are being tackled by more systematic approaches involving identifying functional antibodies, templating immunogens from the antibodies, and then evaluating the immunogens iteratively. I believe this is a powerful new approach to vaccine design as discussed below.

Figure 1.

Reverse vaccinology 2.0. Typically memory B cells or plasmablasts from seropositive individuals with high serum functional titers are used as a source of human monoclonal antibodies (mAbs) that are isolated by direct functional screening or antigen selection approaches. The mAbs are investigated for in vivo protective activity in appropriate animal models (e.g., mice and ferrets have been much used for influenza virus, cotton rats for RSV, and monkeys for HIV). Protective mAbs are studied in interaction with their pathogen target (e.g., Env molecules for many viruses and the structural data used to help guide immunogen design). Immunogens are then evaluated in animal models. Typically iterative improvements are expected in the immunogen design before moving forward to vaccine candidates to be tested in humans. (Image adapted from data in Burton 2002 and Rappuoli et al. 2016.)

Figure 2.

The HIV envelope trimer. The trimer is, in many ways, a prototype “evasion-strong” molecule. Much of the protein surface of individual protomers is buried in the interior of the molecule. Glycans are shown in deep blue and individual Env protomers (gp120 and gp41) in orange, teal, and purple. The self-glycan coating is very dense, making antibody access to the protein surface highly restricted. The CD4-binding site is shown in the middle of the molecule. In addition, variable parts of the molecule (not highlighted) are more accessible than more conserved regions that are targeted by bnAbs. The bnAbs have proved invaluable in identifying targets for immunogen design and serves as templates for such design. (Figure courtesy of Sergey Menis, Christina Corbaci, and James Voss.)

Figure 3.

Sequential immunization as a strategy to induce broadly neutralizing antibodies to HIV. For “evasion-strong” pathogens such as HIV, it may be necessary to guide affinity maturation in a manner not hereto necessary to thwart evasion mechanisms. This may require the use of multiple different immunogens in a vaccination protocol rather than repeated immunizations with the same immunogen as performed classically. For HIV, examples of possible strategies are shown. Strategy #1 might involve sequential immunization with trimer Env (Fig. 2) molecules from different clades, for example, perhaps presented in cocktails (Wang et al. 2015). Strategy #2 would involve immunization with trimers chosen on the basis of viral evolution in an individual who developed bnAbs (Haynes 2015). Strategy #3 involves the rational design of germline targeting and boosting immunogens that could be based on trimers but also other Env-related molecules followed by a final immunization with native or native-like trimer(s) (Escolano et al. 2016; Steichen et al. 2016).