A general flu vaccine! (?)

The influenza virus is a tough critter to combat. It changes shape too often for effective vaccines to train the immune system to recognize all the possible shapes. That's why we need a new vaccine each year, targeted to the strain that the authorities guess will be predominant.

The problem is that the immune system recognizes the overall shape of the virus in order to attack it. A key molecule that immune systems 'see' is the protein hemagglutinin (HA), which is located on the virus surface (the blue and red mushrooms in the figure). The name comes from the fact that this kind of molecule can cause blood cells to coagulate when exposed to it, the details of which are unrelated to this post.


The HA molecule binds to a sugar-related molecule on host cells' surfaces, and the virus then pops into the cell where it can proliferate. There are many variants, or strains, of HA, numbered H1 to H16 etc., and a vaccine must be targeted to the specific characteristics of the strain that you want to be protected against. The strain variation targeted by traditional flu vaccines is in the blue or 'head' part of the HA molecule as seen in this figure.

A general flue vaccine would not have to be targeted to any given HA variant. It would in principle lead your immune system to recognize all strains, but that's not how flu vaccines have worked so far. However, a new tactic may be about to bear fruit. Part of the HA molecule is apparently not as visible to the immune system (shown as the red stems under the blue head in the figure), but it doesn't vary nearly as much as the head of the molecule--apparently, if it changes, the virus's protein coat won't form properly. This conservation of structure makes this a vulnerable region in the virus. The new strategy would target the stem, perhaps along with a seasonal supplement for a specific HA strain when/if needed. The hope is that this will generate broad long lasting, or even lifetime, immunity after a single vaccination in early childhood. Here is a release from Gary Nabel at NIH who is one of the investigators, explaining the approach, although we cannot yet find a detailed description of how the vaccine allows the immune system to 'see' the HA stem.

This is an evolutionary approach to vaccination because it targets the part of HA that is conserved, presumably by strong natural selection. You attack the pathogen at a place it cannot easily vary, so it can't quickly evolve a defense. Exactly why the HA stem section cannot vary very much is probably known, but not by us--perhaps it has to do with the proper assembly of the virus's protein packaging--all the coat proteins must fit tightly together, etc. There would thus be no stem-variant viruses that could take the place of those destroyed by the vaccine-boosted immune system.

Why natural immunity does not also generate antibodies that recognize the stem is an interesting question. Virologists may know the answer.....but we don't.

Getting the bugs out of medical research

Infectious disease born again?
Of many interesting stories for us to blog about this week -- so many that they'll be spilling over into next week -- here's one that seems to represent a more sensible approach to disease than the relentless focus on genetics that we so commonly see. It's about a new effort by pharmaceutical companies to invest in vaccine development. The AP story says

Malaria. Tuberculosis. Alzheimer's disease. AIDS. Pandemic flu. Genital herpes. Urinary tract infections. Grass allergies. Traveler's diarrhea. You name it, the pharmaceutical industry is working on a vaccine to prevent it.

Another story of what seems to be money well-spent appears on the BBC website. Researchers have developed a new-fangled lab-on-a-chip that will allow easier, faster and cheaper diagnosis of dozens of diseases.

The device relies on an array of antibody molecules that are designed to latch on to the protein-based molecular markers of disease in blood.

The antibodies are chemically connected to molecules that emit light of a specific colour when illuminated - but only when they have bound to the disease markers.

Some of the vaccines in the pipeline won't pan out, but some surely will, and we can imagine the lab-on-a-chip device being useful in many settings, including medically underserved areas, so we find these stories rather heartening. The money being invested is private, not taxpayer money, but not long ago a lot of pharmaceutical money was being bet on personalized genomics, and so on, which our regular readers will recognize as efforts we wouldn't have put our money on. So, it's good to see that following the money takes us in a different direction these days -- industry sees a lot more promise in preventing and treating infectious disease than in fixing genes. Indeed, a lot more disease seems to be infectious than the age of genetics led us to believe.

The Fall of deCode Genetics
It's interesting to juxtapose these two stories with this story from the Wednesday New York Times that reports on the demise of a company established to "exploit the promise of the human genome", that is, to profit from what it could learn about genetic disease from the genealogies of Iceland. Predicated on the idea that common genetic variants would be found to explain most complex disease, deCode Genetics set out to find those variants in Iceland and then develop drugs to target them. But, it turns out that complex disease is too complex for that. Again, regular readers won't be surprised if we find it hard to suppress a little "told you so".

Now, here we want to be careful about the concepts -- and it's related to central issues in The Mermaid's Tale. Life is lived, day to day, on the molecular level. Infection is essentially attack from without, and the immune system tries to recognize molecular signatures of the invading soldiers, to latch onto them and destroy them. Vaccines traditionally help the immune system do that, by exposing it to harmless mimics of the real thing (dead viruses, so to speak).

There are countless infectious diseases, affecting most body systems, and more and more complex 'chronic' diseases that were thought to be 'environmental' or 'genetic' in the traditional senses, seem to be turning out to have infectious or inflammatory components. Thus, enhanced abilities to make vaccines could have farther-reaching implications than has been thought.

The immune system is 'genetic' of course, and its functions are fairly close to genes in many ways. But there may be other and perhaps even surprising ways this subject can bring us back to genetics. We'll deal with them in a post in the near future....