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Pandora’s box in Mr. Roger’s Neighborhood: Immunogenicity and Tolerance

Seattle is an absolutely beautiful city. I just spent a few days there with my crew, and we had the opportunity to walk back and forth between a vaccine meeting (Keystone/Gates) and an autoimmunity meeting (Benaroya’s 25th). The meetings were great, and full of luminous presences (Bluestone, Ahmed, Fauci, Marrick) but what struck me more than anything else were the commonalities. Not only were the two conferences in the same beautiful neighborhood, with stunning views of Elliot bay between tall buildings perched on Seattle’s hills, but the themes discussed at these disparate conferences (one on immunogenicity, and one on tolerance) were strikingly similar.

For example, did you know that the very same innate immune systems pathways that are required for stimulating autoimmunity, are required for effective vaccination? It’s not so surprising when you think about it – what works for stimulating immune responses for pathogens is probably also important for stimulating immune response against self. So – yes – CPG, LPS, all types of TLR ligands and innate immune system stimulators and the very same pathways (involving TRAF and TRIF and what have you), are important for triggering autoimmunity. And as we learned from the same pathways triggered by vaccine adjuvants-and the most effective adjuvants trigger innate immune pathways the most effectively. Right in the same neighborhood, complete with striking views of the bay, vaccinologists are busy trying to figure out how to get innate immune responses to be activated, and the autoimmunity folks were trying to figure out how to shut them off.

What made these commonalties even more striking was a talk that we heard recently at our own small meeting, by Christine Shaw of Novartis, in which she discussed the impact of immunization using whole killed RSV contaminated with host cell proteins in the existing model of RSV – basically, impure vaccine led to lung pathology, while highly purified vaccine failed to induce the post-vaccination lung pathology in the cotton rat that has been the standard model in the field. When dissecting this observation, she found that the pathological response was directed against the host cell proteins that are present in the viral cultures. Thus vaccination with adjuvant + self proteins led to significant ‘autoimmune’ pathology. Hmmm. Something to make you wonder. . .

At the vaccine meeting, Pippa Marrack said that alum is a very potent immune stimulator, stimulating antigen presenting cells to “effectively present any and all antigens that are in the vicinity”. It is well known that bystander antigens can get drawn into the immune response – when innate immune response is triggered in the same immediate neighborhood. This is called epitope spreading, in both vaccination and immunity, and it raises an important question – one that perhaps is much like opening Pandora’s box – what about antigens that happen to be in the neighborhood that are not, necessarily, the target of the vaccine? What other antigens might be drawn into the immune response to vaccines, and how do we modulate  auto immunity? Do self antigens get drawn into the vaccine response? It’s a marvel. Maybe what we need to know about vaccines, is how they manage to drive immune response to antigen and not to self, when administered IM with alum, and how we might marshall this selectivity (dampened immune response to self) to cure autoimmune disease.

This of course leads to the most obvious and most dangerous question – which I would like to suggest may be virtually opening “Pandora’s box”.* Is the effect of vaccination limited to the target antigen? Or, is it possible that vaccination induces immune response against host cell proteins that are in the same neighborhood? This raises an even bigger question that must be answered  – both in the context of autoimmunity and vaccination: How does the host control inflammation in the ‘neighborhood’ of immune response, and thereby decrease the potential for inflammation to lead to autoimmunity? The potential for ‘bystander’ immunogenicity also raises the obvious question for vaccines that are made in mammalian cell cultures. How pure are they, and what host cell proteins do they include in minute quantities, and what might be the impact of inclusion of these host cell proteins in the immune response to vaccination? Probably no different than injecting alum directly into muscle, inducing immune response to flu antigen as well as to any other host cell proteins that are in the mix . . . but how is the immune response to host proteins controlled?

Perhaps that is a question that we, vaccinologists, might ask our autoimmune disease colleagues. And perhaps we, autoimmune disease researchers, should pay close attention to immune control of anti-self response after vaccination. . .  after all, it is the marvelous nature of immune response, and how the body controls it, that both vaccinologists and autoimmune disease researchers seek to understand.

Of course, you could say that asking these questions leads inevitably to a discussion of ‘adverse immune responses to vaccines’ and the ‘connection to autoimmune disease’. As was true for Pandora’s box, I think we need to get to the bottom of the box (letting loose all kinds of ugly speculation that vaccination induces autoimmunity) before we reach improved understanding of vaccination and its interaction with tolerance. I believe that understanding tolerance and immune responses will lead to the development of safer vaccines – shouldn’t we be thinking about this, and looking at the potential for T cell responses to self in vaccination? And what might be the long term impact of this anti-self activation, if it does indeed occur?

Do we need to stop vaccination? Well, no, since there have been numerous studies looking at the association between autoimmune disease and vaccination, and no causal link has been shown. But yes, we do need to think about what we’re doing with vaccination.  We need to marvel. We need to learn.

Keeping our minds open, and asking questions, is how we learn important new things. Speaking of neighborhoods, here’s what Mr. Rogers* to say about that: Did you know/ Did you know/ Did you know that it’s alright to wonder/ Did you know that it’s alright to wonder/ There are all kinds of wonderful things/ Did you know/ Did you know/ Did you know that it’s alright to marvel/ Did you know that it’s alright to marvel/ There are all kinds of marvelous things/ You can ask a lot of questions/ About the world, and your place in it/ You can ask about people’s feelings/ You can learn the sky’s the limit/ Did you know/ Did you know/ Did you know that when you wonder, you’re learning/ Did you know that when you marvel, you’re learning/ About all kinds of wonderful/ All kinds of marvelous/ Marvelously wonderful things.

Pandora’s box: Pandora’s box is an artifact  in Greek mythology. The “box” was actually a large jar (πιθος pithos) given to Pandora (Πανδώρα) (“all-gifted”), which contained all the evils of the world. When Pandora opened the jar, the entire contents of the jar were released, but for one – hope. Definition from

Mr. Roger’s neighborhood: Mister Rogers’ Neighborhood, also known as Mister Rogers, is an American children’s television series that was created and hosted by Fred Rogers. Definition from