Despite computational antigenicity prediction and empirical immunogenicity data from mouse immunization exhibited congruence, some variations were observed between in silico predicted accessible surface area (ASA) and in vitro antibody protection against bacterial adherence. CS5 epitope was calculated with a significant greater ASA (9.7%), but antibody protection against adherence of CS5/CS6 ETEC bacteria was the least efficient (41.6%), compared to antibody adherence inhibition against ETEC bacteria expressing the other six adhesins (an average of 52.8%). The CS5 epitope located close to the N-terminus likely allows it to be more surface accessible, and also more fluctuated as shown from dynamics simulation. In contrast, CS6 epitope showed a moderate ASA (4.6%); but antibody inhibition against adherence of CS6 ETEC bacteria was the most effective (75%). Similarly, the CFA/I epitope showed a significantly low ASA (0.93%), yet antibody protection against adherence of CFA/I ETEC H10407 (50.5%) was not noticeably lower than antibody inhibition against adherence of the other adhesins. The disagreement between a low CFA/I epitope ASA and a strong antibody protection against CFA/I bacteria adherence is explainable since other epitopes of the CfaB backbone also induce anti-CFA/I antibodies to additively protect against adherence of the CFA/I adhesin. The inconsistency of a high CS5 ASA and a below-an-average antibody protection against adherence of CS5 adhesin could suggest that the CS5 epitope is immunodominant but not necessarily strongly neutralizing; whereas differences between an average CS6 ASA and a greatest protection against adherence of CS6 ETEC bacteria may indicate that the CS6 epitope is strongly neutralizing. That also indicates future in vivo studies including colonization studies using a suitable animal model and even a controlled human challenge model, as well as immunization studies using other routes will be needed.