Reverse vaccinology 2.0: Human immunology instructs vaccine antigen design

Rappuoli, Rino; Bottomley, Matthew J.; D’Oro, Ugo; Finco, Oretta; De Gregorio, Ennio

An alternative route toward the same goal was reported by Impagliazzo et al. (2015) , who used ingenious structure-based design methods combined with a library approach to generate minimally sized trimeric stem-only HA immunogens (termed mini-HAs), which were soluble and conformationally stable and satisfied the prerequisite to structurally and antigenically mimic the highly conserved stem region of full-length HA, as revealed by their capacity to bind anti-HA stem bNAbs. Impagliazzo et al. described a lead candidate, mini-HA #4900, that raised broad and protective immune responses, completely protecting mice in lethal heterologous and heterosubtypic challenge models. Furthermore, in an NHP model, when compared with TIV, this immunogen elicited higher Ab titers against homologous as well as a variety of heterologous and heterosubtypic strains that bound HA in the stem-neutralizing epitope and triggered potent Ab-dependent cellular cytotoxicity activity and were able to neutralize an H5N1 heterosubtypic strain. However, the capacity of lead mini-HA candidates to reduce fever in NHPs after sublethal challenge with a heterologous H1N1 strain was only comparable to that of TIV, whereas no reduction of tracheal viral load could be observed in mini-HA-immunized animals, leaving some doubts about the superiority of this novel vaccine in this animal model and, thus, about its potential as a universal flu vaccine for humans. Nevertheless, these small HA-stem constructs can be considered good starting points for a vaccine candidate raising a broadly protective immune response against group 1 flu viruses, which may be extendable to group 2. Finally, it should be noted that both the structurally designed mini-HAs and the H1-SS-np described in the previous paragraph were reported to elicit broadly reactive Abs against the HA stem when administered in the presence of Ribi and Matrix M, respectively. Again, these studies appear to suggest that a strong adjuvant may be required to obtain an appropriate response to conserved subdominant epitopes in the HA stem region, most likely acting by enhancing T follicular helper cells in the germinal center and therefore driving selection of scarce B cells specific for these epitopes. Collectively, such studies are fine demonstrations of how structure-based antigen designs can be used to obtain an improved immune response specifically directed toward a target epitope identified by human immunology studies and validated by structural biology studies. Clinical studies in humans will be required to fully demonstrate the power of these synergistic approaches.