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| Jenner vaccinating a child |
As I said last week, one of the biggest vaccine fiascos was the vaccine against respiratory syncytial virus (RSV) that was introduced in the 1960s. RSV is essentially a universal infection of children; it usually causes fairly mild respiratory disease, but because it’s so common the small fraction of cases that are more severe, end up being a leading cause of hospitalization for children. The vaccine was supposed to prevent that. As it happened, the vaccine itself didn’t cause any problems on its own; but children vaccinated with this RSV vaccine, who then later on were infected with RSV, actually had worse disease than those children who were uninfected. (Two children died.)
This enhanced respiratory disease (ERD) was really puzzling at the time, because the vaccine actually did induce a good, strong antibody response. But the antibody turned out to be non-protective. Just having an antibody response is not enough; the overall immune response needs to be involved and protective.
(I think we’re seeing some parallels to this concept now with T cell responses, where we are discovering that just having CD8 T cells doesn’t necessarily offer protection against things like HIV and hepatitis C virus, whereas the quality of the CD8 cells — now being measured as the range of cytokines they can produce — seems to be correlated with protection.)
The RSV vaccine turned out to trigger a TH2 type immune response. TH1/TH2 type responses are now a fundamental concept in immunology, but that hypothesis is a relatively new. Tim Mossman proposed it in 19861 and there was a significant lag before it was widely accepted. I think one of the findings that helped make TH1/TH2 accepted was the finding that the RSV vaccine triggered a strong TH2 immune response,2 compared to the actual virus infection which mainly causes TH1-type immunity. This — to me, anyway — abruptly made the paradigm look less like a laboratory curiosity only seen in mice, and more like a real, clinically important phenomenon.
So the TH2 immune response seemed to more or less explain why the RSV vaccine caused disease. TH1 immune responses are generally protective against viruses, while TH2 immune responses are apparently more geared toward parasitic worms; TH2 responses tend to induce eosinophils and allergic-type responses, and that’s consistent with the clinical disease seen in the vaccinated children who got ERD.
But why did the vaccine induce a TH2 response? This is, of course, a huge question, especially if you’re trying to develop a new antiviral vaccine. One suggestion was the the vaccine screwed up the viral antigens too much. The vaccine used a formalin-inactivated virus, and the proposal was that the formalin alters the virus antigens and that directly caused the abnormal response3 If so, then this is a potential problem for any formalin-inactivated vaccine.
A new paper4 reaches a different conclusion. They say that formalin isn’t the main problem; rather, it’s the lack of adjuvant stimulation. Specifically, they say, you need to stimulate innate immunity via toll-like receptors (TLRs). Unless you do this, B cells don’t become completely activated, and though B cells produce antibodies the B cells don’t progress toward affinity maturation. That is, the normal process where antibodies are selected and shuffled to produce ultra-strong binders to their target antigens never gets underway. As a result, the vaccine induces low-affinity antibodies, and these low affinity antibodies are not protective.
It’s not clear — according to this model — whether the TH2 bias is actually the problem. Immune responses become biased to TH2 when there’s little innate immune stimulation, so the low affinity antibody and the TH2 response go hand in hand. Steve Varga (who has a nice commentary5 on this paper) has shown that some of the TH2 effects that were believed to be important in the pathogenesis of the ERD are not necessarily critical after all. Still, Varga and Delgado et al do seem to still feel that the TH2 shift is part of the disease.
The really exciting part of this finding is that it might actually be easy to fix. We now know a lot about TLR stimulation, and it should be possible to include TLR ligands along with the RSV vaccine:
These findings … open the possibility that inactivated RSV vaccines may be rendered safe and effective by inclusion of TLR agonists in their formulation. 4
Will this induce strong, protective immunity? Hopefully we’ll find out soon.
- Mosmann TR, Cherwinski H, Bond MW, Giedlin MA, Coffman RL. Two types of murine helper T cell clone. I. Definition according to profiles of lymphokine activities and secreted proteins. J Immunol 1986; 136: 2348-2357[↩]
- Priming immunization determines T helper cytokine mRNA expression patterns in lungs of mice challenged with respiratory syncytial virus. Graham BS, Henderson GS, Tang YW, Lu X, Neuzil KM, Colley DG. J Immunol. 1993 Aug 15;151(4):2032-40.[↩]
- A potential molecular mechanism for hypersensitivity caused by formalin-inactivated vaccines. Moghaddam A, Olszewska W, Wang B, Tregoning JS, Helson R, Sattentau QJ, Openshaw PJ. Nat Med. 2006 Aug;12(8):905-7.[↩]
- Maria Florencia Delgado, Silvina Coviello, A Clara Monsalvo, Guillermina A Melendi, Johanna Zea Hernandez, Juan P Batalle, Leandro Diaz, Alfonsina Trento, Herng-Yu Chang, Wayne Mitzner, Jeffrey Ravetch, José A Melero, Pablo M Irusta, Fernando P Polack (2008). Lack of antibody affinity maturation due to poor Toll-like receptor stimulation leads to enhanced respiratory syncytial virus disease Nature Medicine, 15 (1), 34-41 DOI: 10.1038/nm.1894[↩][↩]
- Steven M Varga (2009). Fixing a failed vaccine Nature Medicine, 15 (1), 21-22 DOI: 10.1038/nm0109-21[↩]
Do you still get a big antibody response when your body goes down the Th1 response path? I thought going down the Th1 path basically meant that you wouldn’t produce a lot of antibodies. (Don’t the beta cells need the Th2 helper T-cells to interact with them and give them the signal to start cranking out antibodies? Can Th1 cells do that, too?)
Are antibodies important in your immune response to viruses? I thought they were. (Don’t they measure antibody levels in blood to see whether some old vaccine is still protecting people against infection?) Or do you still produce antibodies when you go down the Th1 path, but just different classes?
You still get an antibody response in TH1 responses, though it tends to be different classes (isotypes) of antibody.
It’s hard to make general statements in virology, but antibodies are often important in immunity to viruses. Antibodies are very commonly critical in protection against viruses — that is, in preventing a second infection (or a first infection if you’re vaccinated) — which is one reason so many killed virus vaccines are so effective. In some cases, antibodies are also important in clearing ongoing virus infections.
Thanks! That makes sense. Is the TH1 response the one that generally works for stuff that invades the cells, and TH2 for stuff that stays outside the cells? That’s how it looked from what I read, but I clearly didn’t get the whole detail of the TH1/TH2 distinction before….
I think this is very interesting. Is the magnitude of stimulation of APC (DC, MAC, B cell) related to what type of immunity (Th1/2) is elicited? So that the presence of foreign peptide (even something abstract like moth cytochrome) can result in increasing order or PAMP (whether it is TLR, RIG or other cytosolic, or P2X/Y) stimulation in 1. tolerance, 2. Th2, 3. Th1 immune responses?
A crude rule of thumb (in other words, the rule I teach to the undergrads) is that with strong innate immune stimulation you get TH1 responses, without innate stimulation you get TH2. The concept is that parasitic worms tend to be pretty good at hiding, which means they don’t induce strong innate immune stimulation; so immune responses with only weak innate stimulation (throughout evolutionary history, anyway) are more likely to be from parasitic worms, and TH2 responses are more appropriate. Of course that’s only an approximation, but you can see how it fits with the RSV story here.
Th2 responses can be elicited to OVA in the presence of alum adjuvant, which is a strong immune stimulator. At least the initial sensitization response is CD8+ T cell and IFN-y dependent (so I guess a Th1 response, if the paradigm of Th1/Th2 is trustworthy), but after the challenge (with OVA+alum), the immune response after a sensitization (with OVA protein alone) is Th2.
Maybe this is similar to the vaccination case, where the initial response with RSV was enough to elicit an immune response but subsequent (“suboptimal”) exposures to the virus antigens resulted in a Th2 response.
But then I wonder how the localization of vaccination and the location of subsequent exposure to the virus play a role.
Th2 responses can be elicited to OVA in the presence of alum adjuvant, which is a strong immune stimulator.
I’d call alum a moderate immune stimulator, not a particularly strong one. also (and maybe relevant to the RSV paper comment on TLR stimulation) alum doesn’t work through TLRs per se (see here, for example).