Jenner vaccinating a child
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.

ABCs of RSVSo 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.


  1. 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[]
  2. 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.[]
  3. 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.[]
  4. 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[][]
  5. Steven M Varga (2009). Fixing a failed vaccine Nature Medicine, 15 (1), 21-22 DOI: 10.1038/nm0109-21[]