I have a couple of theories.
The first of which would be another Flood outbreak (obviously), or another resurgence of a collective mind -a Gravemind. As previously mentioned, this particular outbreak has been dealt with, with the former Gravemind believed to be destroyed during the events of Halo 3. Now the Forerunners were known to have studied the Flood through various containment facilities and complex laboratories. There are also 5 more Halo Installations still spread out somewhere in the Milky Way Galaxy as well. The Gravemind that we all knew was created in a place that was sufficient in biological mass and calcium via Installations 05’s wildlife -which of course would lead to another compound intelligence elsewhere through the same means if internal, or external, instances allowed it.
However I doubt that the monitor’s from each of the Halo array’s would let this happen seeing as how that containment of the Flood threat are their sole function as advanced artificial intelligences. Not to mention their automated sentinel security forces and other restrictions wouldn’t allow this either. Now the case with 2401 Penitent Tangent and his own ineptitude and his “disregard of even the most basic protocols” (oh the irony) with his “own” Flood threat seem to countermand this.
Oh well.
Lets also not forget that these research stations and other installations would have to be found in order for them to be a true viable threat to the galaxy even if they experienced a break in quarantine within (they would still, technically, be contained since there is no means of escape however).
Now here is my other theory that is more involved with the plot of the storyline. So bare with me.
I remember reading in one of the latest Halo novels, Halo: Primordium(?), that the Gravemind, known at that time as The Primordial (if I recall correctly) was in fact a former Precursor fused together with several other creatures infected by the Flood. Now a particular conversation between It and The Didact towards the end of the book prompted me to come up with this theory-
The entity mentioned that the Flood was actually in existence in parallel to that of the Precursors, like a visual representation, or a physical manifestation if you will, for a specific purpose. A purpose that would play a definite role in the destruction of the Forerunners as a species and the ascension of humanity as the inheritors of the Mantle.
As Halopedian.com states in their Precursor article-
This species [Forerunner] was eventually judged to be unworthy of taking on the Mantle, and was slated for elimination. It was at this point that the early Forerunners became aware of this threat, engaged the Precursors, and succeeded in eliminating them, though a small but unspecified number managed to escape the Forerunner’s campaign of extermination. Prior to their destruction, however, the Precursors had created and shaped yet another potential holder of the Mantle, a collection of humanoid species referred to as humanity, hailing from the planet known as Erde-Tyrene.
The next paragraph
Before their ultimate downfall, a plan was created and put into play by the surviving Precursors, which would involve a reunifying of the Forerunners and humanity to their shared origin. This plan centered on the targeted species to be subject to the Flood, and whether or not the humans would be able to overcome this parasitic foe [A challenge, a trial for their inheritance], or ultimately succumb to it. While the humans would eventually prevail, their nearly concurrent defeat at the hands of the Forerunners would temporarily stifle this plan.
It makes sense up until this point. Then its all theory and speculation from here.
To summarize it:
The Precursors created the Flood in an effort to have humanity defeat it and to eventually usurp the Forerunner Empire as the current super-power of the Galaxy, thus being the inheritors of the Mantle, as the Precursors intended.
When ancient humanity engaged the Flood threat during their prolonged war, they supposedly developed a “cure” for this violent disease, yet it wasn’t fully administered in time when the Forerunners eventually declared war on humanity and defeated them in another war of their own. Humanity’s so called misuse of the “Forerunner-Mantle” eventually lead to their demise and “d-evolution” as a powerful and influential species, and as an Empire, in the galaxy. This precluded the Precursors final ultimatum against the Forerunners.
Humanity theoretically defeated the Flood when the Forerunners engaged them in war. The Primordial stated to The Didact that the Flood never really was “defeated”, but temporarily halted it’s plan in order for humanity to recover from the Forerunner threat, which they never did as we can see. However, the Forerunners did pay a price. When the Flood returned and another ensuing conflict erupted, the Forerunners were wiped out and virtually became extinct due to their initial carelessness -but humanity, through the Librarians extensive conservation process, became a formidable and enduring species once again over the next millennia.
In my opinion, which I could be very well wrong with, the Precursors are still in some extent in a state of existence, either physically or spiritually or perhaps metaphorically through the Flood (if that makes sense), who knows. Even though the Forerunners were defeated (I wouldn’t say wiped out since Halo 4 will feature them), that leaves humanity open for their original purpose -their inheritance. Yet they do not know what for nor even have a clue to what it is (which of course we obviously know what it is).
So where does that put the Flood threat right now? Most specifically during the post-war era of the Human-Covenant War?
The Didact knew the true purpose of the Flood and the Precursors intention for his kind. In reality, they were a disgrace to the Mantle. With Halo 4 depicting the advanced class of Warrior-Servants known as the Prometheans in which The Didact was one, along with his symbol being shown at the end of the E3 Live Action trailer, he might possibly return in another state (if he were killed during the activation of the Halo array), if not his own, to fully eradicate the human race and have the Forerunners previously return to their state of dominion over the Galaxy.
The way I see it, the history within the Halo Universe is repeating itself albeit in a different manner with the Flood quiet possible playing a different role in humanities ascension and the Forerunners ultimate destruction.
In my opinion.