As much as anything, the game of football is a "guessing game" between the OC and the DC. Regardless of his base scheme, the DC will sub in certain personnel packages based on the situation (i.e., down, distance, score, clock, scouting report, etc.). And that is why you often see some "strange" calls by the offense (e.g., run on 3rd and long; pass on 3rd and short, etc.). The only way a defense can minimize the use of such packages is to be overwhelmingly dominant with their base package players.
FWIW, IMHO, the best all around defense in terms of "adjusting without substitution" is the 4-2-5. The key here is having the 2 "outside safeties " that can both cover receivers and tackle runners.
Peace