Reverse vaccinology 2.0: Human immunology instructs vaccine antigen design

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

Another great advance in our knowledge of the human immune response to pathogens that can aid the design of new efficacious vaccines comes from the possibility of obtaining a detailed overview of the Ab repertoire generated by infection. Such an analysis applied to HIVinfected individuals has revealed that rare, naturally occurring anti-Env bNAbs are characterized by a large number of somatic mutations arising from multiple rounds of selection in response to emerging escape mutants of the HIV Env glycoprotein (Mouquet et al., 2010) . Surprisingly, it was then found that germline Ab precursors of these HIV bNAbs have only very low affinity for most of the native heterologous Env variants; these observations suggested that immunogens based on natural Env are inefficient in expanding the right germline B cell clones and are unable to elicit cross-neutralizing Abs (Xiao et al., 2009; Liao et al., 2013; Doria-Rose et al., 2014) . Therefore, an alternative step-wise vaccination strategy has been recently proposed based on priming with an engineered antigen designed to target the germline precursors of HIV bNAbs followed by a sequential boost with a series of intermediate antigens, which would progressively match the conformation of the natural Env protein. Although a complete demonstration of the validity of the germline-targeting vaccine approach has not been achieved yet, promising supporting data have been published in recent months.