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Michael Linde

I agree that the lack of understanding as to why these vaccines fail is cause for major concern. In my opinion, the main roadblock in determining the critical surrogate for a protective immune response is the fact that we don’t fully understand how the immune system works. It reminds me of a conversation I had a few years ago; I was working with a high profile researcher on a basic chapter on HIV biology/immunology and I asked him if we should include something on regulatory T cells. He responded, “I don’t know what they do in HIV,” rhetorically asking, “Can you tell me what they do?” We can’t even define what constitutes a regulatory T cells, let alone discern what they do. Add in factors like gamma/delta T cells, mechanisms of cross-presentation, and even the basics of antigen presentation (lymph nodes only?) and you begin to understand that vaccine research is hampered by a basic lack of knowledge about immune system.

This is not a criticism: immunology is a very complicated field because it deals both with stoichiometric interactions as well as three-dimensional space. Finding one or a few in vitro/ex vivo parameters that are going to always (or at least usually) predict protective immunity may not even be possible. But you’ve got to use what you’ve got, and I agree that functional assays that best recapitulate in vivo function—such as chromium release assays—may be better than elispots or intracellular cytokine staining.

I take some solace in the thought that medicine is littered with success stories based on biological principals that are not even remotely understood. That’s one of the reasons why it is important to press on with the vaccine trials in spite of our general lack of immunologic knowledge. It’s too bad that these trials are so amazingly expensive, because we are probably in store for many more surprising failures like the MERCK vaccine. But who knows, maybe we’ll get lucky.

Richard Jefferys

Couldn't agree more! I think people often fail to appreciate just how daunting the immunology is. But it's also fascinating, and the upsides to unraveling the mysteries of the human immune system potentially huge. I guess the short version of these recent posts is: given that so much of of this is uncharted territory, it would be helpful if people could at least calibrate their navigation equipment.

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