The epitope of D29 was mapped using a random-peptide phage display library, an approach which has been widely used for the identification of both linear and conformational epitopes [26, [31] [32] [33] [34] . Two peptide phage clones, P3 (Cluster 1) and P9 (Cluster 2), displayed significant inhibition of D29 Fab-IgG binding to immobilized DENV2 by ELISA; P9 was also able to significantly block the binding of D29 Fab-IgG in a nonreducing Western blot analysis. This may be due to a better sequence match of P9 to its predicted cluster compared with P3 (Fig. 5) , hence, a higher affinity of the peptide to D29 Fab-IgG. To ascertain the authenticity of the predicted epitopes, the predicted residues were confirmed by site-directed mutagenesis of the P3 and P9 peptide sequence. The residues P56L, P58Q and P59N within the P3 epitope were found to be the principle residues involved in the interaction between prM and D29 Fab-IgG; they were also critical for the binding of m2H2, corroborating with results of competition assays. The binding for E protein was not really affected by mutation of aa residues within the P3 epitope; contrasting to the significant impact caused by mutation of 1-2 residues within the P9 epitope. The combined mutation of E129V, E131Q, E133E, and E134N completely abolished binding of D29 Fab-IgG to E protein, establishing the critical residues within the P9 epiotpe. Taken together, these results suggest that D29 Fab-IgG recognises two epitopes on DENV -a solvent-accessible epitope on prM as the principle binding epitope, and a cryptic epitope on E which mimics the prM epitope but is not available on a native, functionally-folded E protein. The P3 and P9 epitopes are highly conserved across the four DENV serotypes, as well as two other flaviviruses, Japanese encephalitis virus and West nile virus; but with increasing divergence in Yellow fever virus and Tick-borne encephalitis virus (Fig. S4) .