I have a love/hate relationship with Nature Reviews: Immunology. It comes out once per month, and is usually packed with easy to read articles about fascinating (to me) topics, and each is filled with tons of great references so I can dig into the issue more. On the one hand, I get really excited about all the great things to read and new ways to expand my knowledge. On the other hand – that’s a lot of reading. My Instapaper queue is about 80% Nature Reviews (15% other papers, and 5% random crap).
This month is no different, but I decided to have the goal of blogging about the ones that I read as motivation to actually make that reading happen. First up: Vaccines!
Abbie has apparently conscripted me into the vaccine wars, which is fine, except that I feel woefully inadequate in the face of her and Orac. So I was naturally excited to see this paper in this month’s issue:
This review is particularly well written, but of course it’s behind a paywall. I’ll do the best I can to summarize.
Every vaccine is immunological in nature, that’s kinda the point. So, when trying to improve them, it makes sense to think about the mechanisms at work in the immune system. The point is to train the immune system to do all the things it would durring a normal infection, but without actually making you sick. In the early days of vaccines, they used naturally occurring, live, infectious viruses. These produced a pretty potent immune response, but had some obvious downsides.
Vaccinology has changed greatly since these times. The most recently licensed vaccines are typically recombinant products and are well defined at the molecular level. Vaccine-associated mortalities are now extremely rare events. Unfortunately, for recombinant vaccines, the efficacy profile has also changed. Modern vaccines require two to three initial injections followed by occasional booster injections to maintain protective antibody levels. Indeed, limited immunogenicity and the sometimes great difficulties in inducing antibodies of the appropriate specificity (as, for example, in the case of vaccines against HIV) are major limitations of modern vaccine development[...]
To increase immunogenicity without compromising safety and tolerability is the holy grail of the vaccine industry.
The trouble is, increasing safety often means reducing efficacy, and increasing immunogenicity (how strongly it activates the immune system) often increases side effects. As I’ve said before, many of the symptoms associated with flu and cold are actually the result of your immune system in active mode, but no one wants to have to suffer through an illness for a chance of preventing suffering through an illness. So we have to be a bit more strategic, and use what we know about the immune system to target the right systems.
The first component they mention is the size of the delivery vehicle. Many vaccines are just a mix of proteins and adjuvants (molecules that activate the innate immune system), but the newest vaccines use special structures that are designed to be more efficiently recognized. Their size varies widely, however, and this can effect everything from up-take by antigen presenting cells, to movement through the lymphatic vessels, to how B-cells react to it.
The authors also mention mimicking the geometry of viruses, which typically have only a few types of recognizable molecules on the surface, but have a lot of them ordered in a predictable way. Immune cells like it when they see a lot of antigen ordered close together, and tend to get activated more strongly when this happens. Using nanoparticles allows researchers to precisely organize what molecules are displayed and in what configuration, which could help find the best possible way to activate the immune system.
We’ve also got to properly modulate dosage.
Too little antigen exposure, as is the case during HPV infections, fails to result in a protective T cell response. By contrast, overwhelming infections, such as those caused by high doses of lymphocytic choriomeningitis virus (LCMV) in mice or sometimes by hepatitis B or C viruses in humans, lead to T cell exhaustion, abrogating immunity. Whereas high doses of LCMV induce T cell exhaustion, low doses of the same virus induce potent and long-lived T cell responses in mice.
We’re only just starting to understand why T-cells behave this way. T-cell exhaustion has been recognized for a long time, but the mechanisms and possible solutions are only just beginning to come to light. It’s hard to make molecules in the body persist for the right durration, but it’s possible to modulate the vaccine schedule (when you get more injections), though the authors note that getting a vaccine every day for a week is not realistic for a prophylactic vaccine, even though it might be the most effective.
Finally, they mention adjuvants. This is the part that’s most interesting to me, since it involves the innate immune system. Nothing (well, very little) can happen without the innate immune system, and all of the instructions for the ensuing response are decided very early, according to the cytokines that the macrophages, DC’s and other cells spew out in response to infection. I would argue that this is where we have the greatest gap in our knowledge, even though we’ve been using adjuvants for over 100 years. The only adjuvant approved for use in the US is alum, which is just aluminum salt. This causes a sort of general inflammation that can activate and recruit the adaptive immune cells like T-cells and B-cells (and I didn’t know this, but alum can serve as an “antigen depot,” which is kinda like a slow-release pill for the immune system).
Modern adjuvants under development target the innate immune system more directly, through selective targeting of TLR’s (my favorite) and other pattern-recognition receptors. But we still know almost nothing about how stimulation of these receptors, in what order, and for how long, will cause T-cells and B-cells to have the right functions. Until now, we’ve mostly just tried to copy what naturally occurring bugs do. But if we want to truly control the outcome, we need to understand a lot more about how this stuff works. The earliest events in an immune response shape the course of that immune response, directing everything from where T-cells and B-cells migrate, to what sorts of antibodies to produce, to how much memory to generate. My (possibly/probably biased) opinion is that this is the field that has the most potential to revolutionize how we vaccinate.
I’ll let the authors conclude:
The key properties of viruses that are responsible for eliciting potent immune responses may be used as a framework for rational vaccine design. These important immunogenic properties of viruses include their size, geometry, an ability to induce innate immunity with appropriate conditioning of the adaptive immune responses and an ability to replicate, leading to characteristic antigen kinetics and distribution. New-generation vaccines aim to harness these properties[...]
In summary, vaccine carrier systems that mimic the size, geometry, replication kinetics and PAMPs [pathogen associated molecular patterns - KB] of viruses may be one possible way to optimally harness viral properties without the risks associated with infection.
Bachmann MF, & Jennings GT (2010). Vaccine delivery: a matter of size, geometry, kinetics and molecular patterns. Nature reviews. Immunology, 10 (11), 787-96 PMID: 20948547