Reverse vaccinology 2.0: Human immunology instructs vaccine antigen design

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

Use of protective Abs in structure-based antigen design HIV. The incredible antigenic variability of HIV Env initially led to the belief that bNAbs would be nearly impossible to elicit, and that the only way to tackle HIV efficiently would be by generating T cell-mediated immunity. However, this viewpoint was dramatically impacted by landmark discoveries reported in 1994; namely, the generation of two new recombinant mAbs: mAb b12 from a combinatorial Fab phage display library (Burton et al., 1991) and the human mAb 2F5 isolated from an HIV-1-positive volunteer (Conley et al., 1994) , both of which were shown to be broadly neutralizing against panels of HIV strains. In particular, mAb b12 binds the conserved CD4 binding site (CD4bs) on the Env gp120 sub-unit and was shown to neutralize 50-75% of primary HIV isolates tested (Burton et al., 1994; Binley et al., 2004) . However, a clear limit of b12 was the somewhat low potency of this mAb, which required up to 25 µg/ml for neutralization of most HIV strains in the United States. Moreover, mAb b12 showed a very limited effect in controlling viremia in vivo, even when combined with 4E10, a distinct bNAb with similar potency (Poignard et al., 1999; Cardoso et al., 2005) ; in more recent analyses, b12 neutralized only 30-60% of diverse HIV strains (Walker et al., 2011) . These findings again led researchers to believe that Ab-based therapies and vaccines would be useless for HIV control, and the development of vaccines based on Env components lost some momentum.