Jenner vaccination bookVaccination is one of the (if not the most) important medical advances in history. The problem today is that most of the easy diseases already have vaccines available, and now we’re trying to develop vaccines against the hard ones. Fortunately, I think we’re entering a new golden age of vaccine development, as we begin to understand why immunization works at the molecular level, to the point where we may soon be able to deliberately tweak them for optimal efficacy.

Back in the dark ages, when I was first working with vaccines,1 adjuvants were a witches’ brew of newts’ eyes and frogspawn, and the ones that worked, just sort of … worked. No one really knew why. But around the time I backed away from vaccines, (partly because of this empirical adjuvant stuff) new theoretical frameworks were being developed that began to explain how and why adjuvants work, and now — some 20 years later — we are at the point where theory is moving solidly toward practice.

I’ve commented several times on the issue of immunodominance. T cell responses to antigens aren’t smoothly distributed over all the possible targets in the antigen; instead, a handful of targets get the lion’s share of the T cell response. Sometimes this is a good thing (for example, it’s a way of getting a screaming hot response to a target, instead of having a bunch of wimpy little responses); sometimes it’s bad (if it’s a moving target, as with rapidly-mutating viruses such as HIV, then your screaming hot response may be to a target that no longer exists, whereas having a bunch of targets at least nearly guarantees that you’ve got something to shoot at.)

In spite of its importance, though, the underlying mechanisms that drive immunodominance aren’t well understood. For example, one possible explanation is that the T cell that ends up becoming dominant, started out as the most abundant clone originally. A paper last year2 (I talked about it here) supported that possibility, but a more recent study3 that I talked about earlier this week suggested that while clonal abundance is one factor, there must be other, equally important, influences on the response.

That fits with another paper that came out in May,4 looking at the effects of different adjuvants on the immune response. Of course this has been done many times in a quantitative way — which adjuvant gives the biggest response? — but Malherbe et al. asked the question qualitatively: What exactly happens to the T cell response? That is: We know that different adjuvants can cause higher or lower responses to an antigen; but are the different responses made up of the same CTL5, or do different adjuvants crank up different sets? Can we drive a T cell response that is qualitatively, as well as quantitatively, better?

Smallpox vaccine vialI, for one, (and I think most of the field) would have said “No”; no matter what your adjuvant is, the response would be qualitatively the same. Why would one particular CTL precursor clone be stimulated better or worse by a particular adjuvant? That’s the answer that would be predicted from the first study, that suggested that immunodominance is determined mainly by the precursor frequency: You can’t really affect the precursor frequency (that’s set during thymic development), so no matter what you do with your antigen you should get the same relative response (even though the total response may be higher or lower, it would contain the same proportion of T cell clones).

In fact, that’s not what happens. Malherbe et al. compared five different adjuvants, mixed with the same antigen. The adjuvants are known to act through different mechanisms. (That is, while they all act by stimulating innate immune recognition molecules, they stimulate different innate receptors — different TLR molecules, or [as we now know6 ] pattern recognition receptors that are different from TLRs altogether.) Then they assessed the subsequent immune response by comparing the immunodominance hierarchies that came out of the immunization. The different adjuvants drove expansion of different T cell clones, so that the response was qualitatively different.

In particular, adjuvants drove expansion of higher-affinity clones:

…adjuvants regulate clonal composition by using a mechanism that alters initial TCR-based selection thresholds and that relies most heavily on blocking the propagation of antigen-specific clonotypes expressing low-affinity TCR. … Thus, adjuvant formulation can modify the TCR-based selection threshold that regulates Th cell clonal composition in response to protein vaccination.

How adjuvants do this remains unknown. It wasn’t related to the antigen dose (which has previously been shown to affect the TcR affinity). Possibilities include differential dendritic cell maturation, altering local antigen contentration (the “depot” effect that has been the classic explanation for alum’s mechanism of action — though that explanation is at least partly rendered obsolete by the recent paper7 from Richard Flavell’s group), and direct stimulation of T cell clones — but who knows.

Assuming this holds up for different antigens (they’ve only looked at one, so far) the key thing, in clinical terms, is that it’s possible to alter immunodominance without changing the antigen. We need to understand how this works, because it may be a much simpler way of improving immune responses than altering the antigen itself.

  1. It looks as if I may be doing so again; our proposal for a Vaccine Center here has been funded, at least for a few years; although I’m only a small part of the group[]
  2. Naive CD4(+) T Cell Frequency Varies for Different Epitopes and Predicts Repertoire Diversity and Response Magnitude. Moon JJ, Chu HH, Pepper M, McSorley SJ, Jameson SC, Kedl RM, Jenkins MK. Immunity. 2007 Aug;27(2):203-13.[]
  3. Obar, J., Khanna, K., LeFrancois, L. (2008). Endogenous Naive CD8+ T Cell Precursor Frequency Regulates Primary and Memory Responses to Infection. Immunity, 28(6), 859-869. DOI: 10.1016/j.immuni.2008.04.010[]
  4. Malherbe, L., Mark, L., Fazilleau, N., McHeyzer-Williams, L., McHeyzer-Williams, M. (2008). Vaccine Adjuvants Alter TCR-Based Selection Thresholds. Immunity, 28(5), 698-709. DOI: 10.1016/j.immuni.2008.03.014

    Commentary at:
    Immunity 28:602-604 (16 May 2008) doi:10.1016/j.immuni.2008.04.008
    Preview: Taking a Toll Road to Better Vaccines
    Sharon Celeste Morley and Paul M. Allen[]

  5. CTL: Cytotoxic T lymphocytes[]
  6. Eisenbarth, S.C., Colegio, O.R., O’Connor, W., Sutterwala, F.S., Flavell, R.A. (2008). Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature DOI: 10.1038/nature06939[]
  7. Eisenbarth, S.C., Colegio, O.R., O’Connor, W., Sutterwala, F.S., Flavell, R.A. (2008). Crucial role for the Nalp3 inflammasome in the immunostimulatory properties of aluminium adjuvants. Nature. DOI: 10.1038/nature06939[]