Word of God:
Robert Kirkman - the creator of the Walking Dead franchise, writer of the comics and novels, and Executive Producer on both television shows - has given us as much of an explanation as we're likely to get:
The rule is: WHATEVER it is that causes the zombies, is something everyone already has. If you stub your toe, get an infection and die, you turn into a zombie, UNLESS your brain is damaged. If someone shoots you in the head and you die, you're dead. A zombie bite kills you because of infection, or blood loss, not because of the zombie "virus."
- Robert Kirkman, The Walking Dead, Issue #41, Letter Hacks
Just to get this on record once and for all - and it is complicated, I know - here's how zombification works. Whatever makes people come back as zombies after they die - it's inside them. It's inside everyone. No matter how anybody dies, as long as the brain is intact, they turn into a zombie.
So what the fuck does a bite do?
Well, bites, and direct to blood contact with zombie gunk, [...1] causes death. It's a strong infection that leads to fever that kills someone. Then the "virus" or whatever is already in them, turns them into a zombie.
- Robert Kirkman, The Walking Dead, Issue #146, Letter Hacks
Q: This is a real Comic Book Guy question – but do I gather that if someone swallows a tiny bit of zombie blood they won’t turn into one of the undead? There was a lot of it being sprayed around this episode [Season Three, Episode 6, Hounded].
A: Yeah, people to a certain extent think of zombie blood as being like the blood from Alien. You know, in the Alien movies it’s like, “Oh god, if it touches you, you explode!” or whatever. Whatever it is that turns these people into zombies is in them already. So the idea of getting zombie blood on your face, which happens all the time, and it turning you into a zombie is something that’s just not the case.
Now, that doesn’t make the zombie bite any less lethal. You know, breaking the skin, having that kind of contact with the toxicity that zombie mouths would have, would be something that causes an infection that definitely would lead to your death and then the thing that’s already in you would turn you into a zombie. So there is a science to this, to a certain extent.
Q: Although, to be clear, you are not technically a scientist.
A: No. No, no, no. But I know about everything that scientists know, I’m pretty certain! But anyway, zombie blood is not quite as deadly as a lot of people think. I wouldn’t drink it in high volumes, though.
- Robert Kirkman, interview with Entertainment Weekly
The mechanics of dying from a bite:
In the Season One finale, TS-19, Dr. Jenner at the CDC explains how and why a bitten person dies:
Jenner: It invades the brain like meningitis. The adrenal glands hemorrhage2, the brain goes into shutdown, then the major organs. Then death.
Putting the pieces together:
Combining Kirkman's explanations with Jenner's lines from the show, here's what we get:
Everyone is already infected with whatever turns corpses into zombies, but it doesn't seem to affect them.
When a zombie bites you, it infects you with mundane (i.e., non-zombifying) pathogens. Unless you're bitten on a limb and quickly amputate that limb, you will die from blood loss (like Amy), the mundane infections (like Jim), or both (like Tyreese3, perhaps).
It is hard to reconcile point #2 with the first Kirkman quote, but here's my best attempt: Once you're weakened to near-death from the blood loss or mundane infection, the zombie "virus" (or whatever it is) which has been laying dormant moves into your brain, causes the adrenal glands to hemorrhage, and the brain begins to fail. Vital organs start shutting down, and eventually, the brain is starved of oxygen and dies4.
After death, the brain is completely inactive or a while. Then the zombie "virus" (or whatever it is) reactivates the brain stem, and the dead body gets up and starts walking around, looking for people to bite. The rest of the brain remains dead.
Speculation on why bites are always fatal (barring a quick amputation of the bitten area):
At the end of season one of TWD, protagonist Rick Grimes discovers that everyone carries a virus which “reboots the brain” upon death, resulting in a ghastly transformation. But if it is merely death that turns you, why do all of the characters regard a zombie bite as a death sentence? Why is it one of the first questions they ask strangers, and why did Herschel need to lose a leg?
There is a way to square this with Kirkman’s quote5, and more interestingly, with science. Dead bodies can be dangerous in and of themselves, so humans have always taken precaution with them. In fact, in a case where we have to handle corpses, such as after a natural disaster, there are a number of steps responders have to take to avoid infection and disease. For example, a rotting body can still transfer gastrointestinal pathogens, tuberculosis, and hepatitis to the living. So, one can imagine that a biting mouth of a rotting corpse, continuously chomping down on humans, isn’t the most hygienic place.
- Scientific American: The Komodo Dead
Although it is a user-created resource, and therefore not canonical (which is why I relegated it to the "Speculation" section) the TWD Wiki has a very plausible explanation:
Everyone in The Walking Dead universe somehow contracted the pathogen that, for reasons and through means unknown, brings the dead back to "life." It is unknown how the disease is spread, though its apparently total infection rate worldwide suggests it is either water-borne, air-borne, or both. The exact taxonomy of the pathogen is unknown. The pathogen itself does not kill its hosts, but it seems to weaken their immune systems considerably, to the point where even minor illnesses are far more likely to be fatal than normal to humans.
As previously stated, the zombie pathogen itself is not lethal, and the zombie "infection" occurs due to pathogen weakening the host immune system. This makes bacteria found in zombies, especially in their mouths, that much more lethal than they normally would. Nevertheless, the pathogen has two separate but parallel modes of infection: latent and fluid contact/bites/scratches.
Zombie bites are not necessarily fatal because of the zombie pathogen. One possible explanation is that, through bites, the pathogen induces a rapid immune system response that accelerates the onset and severity of symptoms caused by bacteria in the zombie's mouth.
- TWD Wiki
The first half of the fourth season of The Walking Dead lends some credibility to this theory. These episodes tell the story of how the survivors in the crowded prison cope with an outbreak of some sort of disease; one of Rick's pigs dies from the illness, although it isn't clear whether the pig transmitted the disease to the survivors or vice versa.
Q: I’m not a doctor – I just play one on TV – but I’m assuming there’s some sort of nasty, swine flu-type virus abroad in the prison.
A: Well, it’s definitely some kind of nasty illness. Something that can make a guy go from "cough-cough-I’m-not-feeling-well-can-I-go-lay-down?" to essentially bleeding out in the shower after a few hours is something on the swine flu level – possibly a little bit more deadly.
- Robert Kirkman, Entertainment Weekly interview
Note: On Talking Dead, producer Greg Nicotero specifically said the disease was not Swine Flu. That isn't particularly important, of course - all we need to know is that the prison epidemic is a normal disease that would be easy to treat and not especially dangerous in the pre-apocalyptic world.
It’s important to know that this is really just some form of the Spanish Flu. It’s something that exists in our everyday world now.
- Robert Kirkman, Vulture interview
From the script of Season Four, Episode 2, Infected:
Rick: No bites. No wounds. I think he just died.
Dr. Subramanian: Horribly, too. Pleurisy aspiration.
Herschel: Choked to death on his own blood. Caused those trails down his face.
Rick: I've seen them before on a walker outside the fences. I saw them on Patrick, too.
Dr. Subramanian: They're from the internal lung pressure building up - like if you shake a soda can and pop the top. Only imagine your eyes, ears, nose, and throat are the top.
Rick: It's a sickness from the walkers?
Dr. Subramanian: No, these things happened before they were around. Could be pneumococcal. Most likely an aggressive flu strain.
Daryl: How could somebody die in a day just from a cold?
Rick: I had a sick pig, it died quick. Saw a sick boar in the woods.
Hershel: Pigs and birds. That's how these things spread in the past.
So the disease that killed so many people in the prison was something that we have in the real world, but it was far more deadly than it would be to us. Of those who were infected with the "flu" or whatever, we only know of two people - Lizzie and Glenn - who recovered; even those two only recovered after antiviral medication was delivered. At least 28 people6 - and one pig7 - died of the "flu", and at least two more people infected with the "flu" were killed before the "flu" itself could kill them.
Part of the increased mortality among the infected is related to the lack of medical supplies, but part of it may be that the zombie "virus" (or whatever it is) does weaken the immune system.
1I omitted this from the quote above because spoilers. The missing text is:
...like the Saviors attacked with...
2Incidentally, this might give us some insight into the zombie "virus" (or whatever it is):
In at least 50% of cases, bilateral adrenal hemorrhage is associated with an acute, stressful illness (eg, infection...) or event (eg, surgery or invasive procedure).
Infections associated with extensive, bilateral adrenal hemorrhage are diverse; they include sepsis, wound infections, pneumonia, pseudomembranous colitis, influenza, varicella, and malaria.
Waterhouse-Friderichsen syndrome (purpura fulminans) represents hemorrhagic necrosis of several organs, including adrenal hemorrhage, in the setting of overwhelming sepsis. The syndrome frequently is characterized by a distinctly hemorrhagic skin rash. Although Waterhouse-Friderichsen syndrome originally was recognized in association with meningococcal disease, which still accounts for 80% of cases, the syndrome also has been associated with other bacterial pathogens, including Streptococcus pneumoniae, group A beta-hemolytic streptococci, Neisseria gonorrhoeae, Escherichia coli, Klebsiella pneumoniae, Haemophilus influenzae (group B), Salmonella choleraesuis, Pasteurella multocida, Acinetobacter calcoaceticus, and Plesiomonas shigelloides.
3On the show - his death in the comic books was quite different.
4Ultimately, most people die because the brain is deprived of oxygen, and "causes of death" are basically explanations of why a particular person's brain wasn't getting any oxygen.
5The first quote in my "Word of God" section.
6At least 10 people from the prison community, and at least three unknown people from somewhere close to the prison. We don't know who they were or where they came from, but these guys showed up outside the prison fence, and clearly died of the same "flu":
There was also a large group of people who had died of the "flu" at the veterinary hospital in S4E4, Indifference; these two screen caps are from scenes in which roughly 15 such "flu-zombies" appear:
7R.I.P., Violet. You were just too beautiful for this world.