Reverse vaccinology 2.0: Human immunology instructs vaccine antigen design

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

Yet another important area where human immunology is informing the design of novel immunogens is in the search for broadly protective vaccine antigens to protect against influenza (flu), a persistent global public health threat (Lambert and Fauci, 2010) . Traditional flu vaccines made using HA and neuraminidase antigens purified from egggrown influenza virus are efficacious when the vaccine antigens are genotypically matched against the circulating strains and subtypes. However, the frequent occurrence of genetic variation via antigenic drift and reassortment implies that such flu vaccines need to be revised annually to elicit protective responses. Indeed, the bulk of the immune response triggered either by the vaccine or by natural infection is against the head of HA, which is highly diverse between distinct strains, and therefore, only minimal cross-protection from one strain to another is typically achieved. Consequently, flu vaccine efficiency can be highly variable depending on how much the HA of the circulating flu strains matches the HA in the vaccine strains. Moreover, all presently available seasonal flu vaccines are probably unable to prevent infection with a new emerging strain of highly pathogenic flu virus to which the human population has not been previously exposed, such as the H5N1 or H7N9 strains. Because the latter circulates among avian populations, there is the risk that zoonosis to humans may trigger a deadly pandemic infection. Therefore, an important goal is the development of a potent and universally protective flu vaccine to generate high titers of bNAbs against influenza virus. Such a vaccine should ideally induce an immune response against one or more conserved epitopes in the viral proteins to prevent infection or disease from all or nearly all possible circulating strains of the flu virus. The HA stem region is indeed highly conserved among different strains and subtypes of influenza virus, but this region is poorly immunogenic when in the full-length HA protein contained in conventional vaccines. Therefore, conventional flu vaccines are not able to elicit a powerful anti-stem HA Ab response.