Reverse vaccinology 2.0: Human immunology instructs vaccine antigen design

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

The HIV field changed completely around 2009/2010 with the identification of "second generation" bNAbs. First, using a neutralization screening of supernatants from thousands of MBCs from an HIV-infected donor, two more potent human mAbs (PG9 and PG16) targeting a broadly neutralizing epitope were described as able to neutralize 70-80% of the tested HIV strains with an IC 50 <50 µg/ml and 50-60% with an IC 50 <1 µg/ml (Walker et al., 2009) . Then, by using antigen-specific human B cell sorting and engineered "probe" Env antigens that better exposed conserved epitopes, powerful new bNAbs (e.g., mAbs of the group called VRC01) targeting the conserved CD4bs on the Env gp120 subunit were identified, and one of them was found able to neutralize up to 90% of HIV isolates at an IC 50 <50 µg/ml and ∼70% at an IC 50 <1 µg/ml, with an overall low geometric mean IC 50 of 0.3 µg/ml (Wu et al., 2010) . Subsequently, the ability to use single-cell technologies allowed for the identification of several hundred anti-HIV human mAbs, some of which were bNAbs with a median IC 50 as low as 0.02 µg/ml, >1,000-fold better than the recombinant b12 Ab isolated in 1994 (Scheid et al., 2011; Walker et al., 2011; Burton and Mascola, 2015) . Epitope mapping studies using the new Abs showed that in addition to the original CD4bs epitope, several other regions of HIV Env were able to induce bNAbs. The new Abs also showed remarkable therapeutic effects in vivo: in rhesus monkeys chronically infected with pathogenic simian-human immunodeficiency virus SHIV-SF162P3, they were able to rapidly reduce plasma viremia to undetectable levels and keep it at bay for months (Barouch et al., 2013) . Similarly, therapeutic benefits were observed by the suppression of viremia in SHIV-infected macaques (Shingai et al., 2013) . Excitingly, one such therapeutic bNAb, 3BNC117, which targets the CD4bs epitope on gp120, was tested in phase 1 clinical trials and was recently reported to reduce plasma viremia in chronically infected humans (Caskey et al., 2015) . Likewise, a phase 1 study using infusion of a VRC01 class Ab showed promising results, reducing plasma viremia and suppressing neutralization-sensitive strains in a subset of HIV-1-infected subjects (Lynch et al., 2015) .