B-cell restriction – an alternative piece to the puzzle

Gershoni, Jonathan M.

For this, the nature of the neutralizing epitope first needs to be mapped with precision. Then systematic removal of all other viral surfaces should leave only the desired epitope as an immunogen. Obviously, this is not a simple task, as most epitopes are discontinuous and highly conformational. 59 It should not be expected that by simply expressing the correct peptide sequences corresponding to the epitope, the native conformation of a functional epitope surface would be achieved. We have addressed this task of "epitope reconstitution" by implementing a novel combinatorial approach. 60 The RBS of SARS Coronavirus (SARS CoV) is contained in a sub-domain of the viral spike of about 200aa. The actual surface that contacts the viral receptor is less than 40 amino acid residues situated on two discontinuous antiparallel beta strands. 60, 61 Using combinatorial linkers to bridge the two strands of the bona fide RBS has enabled the affinity selection of functionally reconstituted neutralizing epitopes of the virus. 60 This same approach has since been found effective for the reconstitution of neutralizing epitopes of MERS Coronavirus and Dengue virus (not published). Focusing the immune response on exclusively neutralizing epitopes may be particularly important in Dengue prevention as it may obviate the development of antibody-dependent enhancement (ADE). 62, 63 Hence, the first level of B-cell restriction that should improve vaccines is to discard all irrelevant and distracting pathogen antigens and focus the B-cell response exclusively where it counts, towards neutralizing epitopes.