Another question about H1N1 - this time, specifically about vaccination & immune systems

unstrung · September 23, 2009, 2:04am

So, I’ve been reading up today on the latest swine flu threat, and something keeps bugging me…

It has been noted how the 1918 swine flu outbreak was most problematic for folks with strong immune systems, due to the fact that (if I understand correctly) most deaths were caused by an overly strong reaction by peoples’ immune systems when trying to battle the virus. It has also been noted that this latest virus is behaving an awful lot like the 1918 strain.

The way that current flu vaccines work (again, if I understand correctly) is by exposing recipients to dead or weakened samples of the virus, in order to prompt the immune system to learn how to fight them.

Taking these two things and putting them together creates in my mind a concern that vaccination for this latest virus could, in fact, prompt a given recipient to have a similar immune system overreaction to what was seen back in 1918. If that were true, then it seems like it would follow that rolling out a large-scale vaccination program would be a bad idea.

Now, that’s probably not the case - it seems far more likely that I’m somehow missing the boat. Probably, my concern is really caused by:

a) Unstrung getting his facts wrong
b) Unstrung missing a simple explanation of why his logic ain’t up to par in this case

I’ve done some Google searching, and some digging in past SD threads that mention the virus, but I’m still not getting it (again, probably due to either a) or b)). So, my question is, can someone set me straight here? As mentioned, probably something simple that I’m missing, but if someone could clue me in, I’d appreciate it…

Leaffan · September 23, 2009, 3:03am

Huh?

Nothing in your message made any sense at all to me.

Of course vaccinations are still the preferred way to deal with these kinds of outbreaks. Your message is … circuitous and confusing.

Uncertain · September 23, 2009, 3:21am

It makes sense to me. The OP has heard that a major cause of death from the 1918 virus was too strong an immune response to it. He is wondering whether vaccination will, by increasing the strength of the immune response to the virus, make the virus more dangerous to the vaccinated person.

unstrung · September 23, 2009, 3:32am

Just to clarify… Yes - Uncertain summarizes my question exactly.

samclem · September 23, 2009, 4:02am

While I’m clueless about the correct answer to this, can you supply a cite for where I can read about this?

unstrung · September 23, 2009, 5:03am

Will do, although I am at a different computer than initially, and my internet connection here is, on a good day, craptacular.

The part about how vaccines work is the easiest to find - from the CDC’s Key Facts About Seasonal Flu Vaccine:

There are two types of vaccines:

* The "flu shot" — an inactivated vaccine (containing killed virus) that is given with a needle, usually in the arm. The flu shot is approved for use in people older than 6 months, including healthy people and people with chronic medical conditions.
* The nasal-spray flu vaccine — a vaccine made with live, weakened flu viruses that do not cause the flu (sometimes called LAIV for "live attenuated influenza vaccine" or FluMist®). LAIV (FluMist®) is approved for use in healthy* people 2-49 years of age who are not pregnant.

And from the CDC’s 2009 H1N1 Influenza Vaccine Q&A Page:

These lead me to believe that I had the story right on how the H1N1 vaccine works, at least. Bear with me for a bit - I’ll relocate the places where I found info on the 1918 pandemic as soon as possible…

dropzone · September 23, 2009, 5:07am

Cutting through the special features of H1N1, with my semi-elderly, attacked-from-all-quarters, immune system I’m more likely to fall to one of the more-normal ones. Fresh, young virii I either find immunologically unimpressive or kicked the ass of 50 years ago.

ETA: If a repeat of the 1918 version came through, I’d expect it to kill me, but I don’t see it in H1N1.

DSeid · September 23, 2009, 5:29am

The op refers to the speculation that some of the young adult mortality in the 1918 pandemic was due to something called a cytokine storm.

The male death rates in 1918 far exceed the female death rates among adults. One of the most unusual aspects of the Spanish flu was its ability to kill young adults. The reasons for this remain uncertain. In general the rate of death is highest for the very young and older persons. The 1918 pandemic followed a strikingly different pattern, with the highest mortality in young persons 25-30 years old. With the Spanish flu, mortality rates were high among healthy adults as well as the usual high-risk groups. The attack rate and mortality was highest among adults 20 to 50 years old. The severity of that virus has not been seen again in humans.

The reasons for this difference are still poorly understood. It is believed that a subset of victims experienced a primary viral pneumonia which caused a very rapid clinical decline and death. It is widely believed that cytokine storming [Immune-complexes-mediated pathogenesis] could be one of the mechanisms that resulted in damaging the lung tissue. Normally, when the lungs are under attack from a virus, T-cells, defenders from the immune system, are then sent to the site of the infection. The presence of T-cells initiate a second immune system attack by chemicals, known as cytokines, that cause inflammation. A cytokine is a small protein released by cells that has a specific effect on the interactions between cells, on communications between cells or on the behavior of cells. The cytokines includes the interleukins, lymphokines and cell signal molecules, such as the interferons, which trigger inflammation and respond to infections. When the lungs are infected with the flu virus, the T cells release chemical signals that cause them to stay longer in the lungs. The systemic symptoms of seasonal flu are caused by cytokine release, which is part of the human immune response.

A Cytokine storm [a systemic inflammatory response syndrome] – immune system “friendly fire” – is believed to be the underlying reason for the high death rate among young adults. It results when too many immune cells are in an endless loop of calling even more cytokines. During the flu infection the immune system has an “all hands on deck” attitude to the viral assault. More T cells are always arriving, and they in turn release more signal and stay longer, leading to a build up of T cells and chemical signals. The exaggerated immune response produces inflammatory molecules that lead to too many cells clogging up the airways and preventing efficient transfer of oxygen into the bloodstream. This Acute Respiratory Distress Syndrome [ARDS] is what makes the Cytokine storm so deadly in pandemic flu. It is suggested that the high death rate among healthy young adults was due to their strong immune systems producing a cytokine storm. The very young and very old would have had weaker immune systems, and thus weaker immune responses that would not result in a cytokine storm.

The op’s question is a good one and the answer is an interesting one in several parts.

First, the possibility that cytokine storm was responsible for the young adult mortality in 1918 is still speculative. There have been other explanations proposed as well.

There are two ways to look at the W-shaped curve. You can either ask, Why did the young adults die? Or you can ask, Why did the older adults NOT die? In other words, was there something that protected the older adults that the younger ones didn’t have?

One explanation (and I can’t find the original paper to give credit) is that somewhere around 1870-ish (that is, 45 or 50 years before 1918) some other influenza strain infected the population, and gave a little bit of cross-protection against the 1918 strain. People alive in 1870 were exposed to this (hypothetical) strain of virus, developed immunity, and fifty years later were protected against the 1918 strain.2 Of course, supporting this idea is the recent paper3 that received a fair bit of attention, showing that survivors of the 1918 pandemic still have specific immune responses to that virus, 90 years later — so certainly immunity could last fifty years.

(And those over 60 today are still moderately well protected from H1N1 based on exposure to a close enough virus over 50 years ago. That’s T-cell memory too.)

Still, the cytokine storm hypothesis is widely believed.

Second (see same link as above),

So vaccines used today raise antibody levels much more than they elevate the cytotoxic response. Although they do some.

Third, the cells that cause a cytokine storm in individuals who get it with influenza are not the T cells anyway. They are not cells that are primed by vaccination at all. They come from the inate response.

More on the way that system works here.

The immune system operates on two different time scales. There is an immediate response that is generic in character. Sound the alarm, there is a microbial intruder on the premises. Strike at it with generic weapons. That’s called the innate response. But then there is a second, later response. The immune system has figured out what kind of intruder it is. Send in the specialized units designed for just that person. That’s the adaptive response. Some of the adaptive response is via proteins made by immune cells that circulate in the blood. These antibodies are what vaccines are designed to elicit. Once you are familiar with different kinds of intruders you can react to them more quickly. The immune system learns how to react by seeing specific examples and training antibody making cells to respond quickly. The immune system also has its own Special Forces cells that go out to kill virally infected cells. These are a kind of T-cell, another one of the cells of the immune system. … When a flu virus infects a lung cell it sounds an immune system alarm. One of the first things that happens is a generic immune cell called a macrophage, like a cop on the lung beat, sounds an alarm by making a protein, MCP-1 (monocyte chemotactic protein-1). MCP-1 combines with CCR=2 (chemotactic chemokine receptor-2) which calls to the area another cell called a monocyte. CCR-2 also induces the monocyte to perform a more special function: produce two more proteins, Tumor Necrosis Factor-alpha (TNFalpha) and inducible nitric oxide synthase (iNOS). This may sound complicated, but I’m simplifying a great deal. It’s much more complicated than I’m letting on.

The monocytes have now changed into a cell called a dendritic cell (DC), or more precisely a special subset of dendritic cells called Tip-DCs (TNF-iNOS-producing DCs). There are many other kinds of immune cells in the mix: natural killer (NK) cells, neutrophils, other kinds of DCs, macrophages. Aldridge et al. found, however, that when a mouse is infected with the kind of virulent flu virus causing a runaway inflammatory response, the only kind of immune cell that ramps up compared to others is the Tip-DC. When a mouse was infected with a less virulent flu virus, there was no unusual increase in Tip-DC but with highly virulent strains, Tip-DC accumulated in the lungs. The Tip-DCs were also making a lot of TNFalpha and nitric oxide, damaging the lungs. The SWAT Team had arrived and was firing at will.

The point is that the inate response is not primed - it is generic. Vaccination does not make it stronger. If enough virus gets into the lungs in an individual with a strong inate response then a cytokine storm results. T cells, which do respond to previous infections and to vaccination (live nasal more than killed injectable however) do however get the viruses out of there faster - and help keep them from getting down onto the lungs in the first place.

So putting this all together - vaccinations produce a strong antibody response which helps reduce the risk of infection in the first place. If cytokine storms were indeed responsible for the excess young adult mortality in 1918, then it was triggered by cells that would have been unaffected by vaccination. The strengthening of the immune response to influenza due to the vaccine strengthens those parts of the system that prevent infection in the first place, prevent as many viruses from getting into the meat of the lungs if an infection does occur in the upper respiratory tract, and helps clear any viruses that do get into the lungs more effectively … all of which causes fewer of the buggers in the meat of the lungs for the fixed inate response to react to, thereby reducing the risk of the excess reaction that is the cytokine storm.

Yeah, more than you ever wanted to know. I know. Sorry.

aruvqan · September 23, 2009, 9:48am

No actually it was fascinating … and maybe should be turned into a report …

I am always fascinated about the issue, I have been a guinea pig for a testing lab for a while, and have gotten a number of flu shots that were experimental for various reasons so anything about influenza is interesting.

[last years was a sub-q variant instead of IM. I guess it was successful, no flu and i titred out ok]

samclem · September 23, 2009, 11:02am

Nope. As aruvqan said, fascinating and just what I wanted.

unstrung · September 23, 2009, 12:13pm

…and by “Bear with me for a bit”, I apparently meant “bear with me while I fall asleep at my computer and awaken several hours later, disoriented and drooling on my keyboard”. Luckily, in the meantime, DSeid came in and not only provided the reference info that I hadn’t, but also answered my question extremely well. Many thanks.

Hari_Seldon · September 23, 2009, 9:38pm

Count me in on that response too. Fascinating and informative.

DSeid · September 24, 2009, 12:01pm

Thank you. I am happy that you found it useful.

Ferret_Herder · September 24, 2009, 1:28pm

Just wanted to add to the chorus of “me too”-s. I got to the point where I was thinking about cytokine storms and gave up after that, so the concise, accessible explanation is appreciated.

ToeJam · September 24, 2009, 5:57pm

I had just learned recently about cytokine storms and so this was definitely a good explanation.
If there was some way to nominate this thing to maybe be pushed to become a “Ask Ceceil” Question I Think it should be done, as it’s topical and interesting…