Trying to design better vaccines

Part 2

Now, how do we deal with continually mutating germs?

Let’s look at how our immune system produces antibodies to antigens (foreign substances).

We have about a million million (1 followed by 12 zeroes) antibody-producing cells in our body at any one time. Those cells produce about 10 million million (1 followed by 13 zeroes) antibody molecules per second. Those antibodies are not all the same (except the ones produced by the same cell); they usually have varied binding properties. The large number of different binding properties is Nature’s way of increasing the likelihood that there would be antibody that would be able to bind to whatever foreign substance gets into our body. There are exceptions, of course. For example, we do not normally produce antibodies to food (although some people are allergic to certain foods). 

The antibodies that bind the tightest to the antigen are selected for and more of them are produced. In fact, the antibody-producing cells themselves mutate and those which produce antibodies that bind more tightly to the antigen are selected for. After several cycles of such selection, the antibodies that predominate in the end are the ones with the highest affinity for the antigen (this process is referred to as “affinity maturation”).

Now, every exposed part of an antigen can elicit an antibody response. (The parts of an antigen to which antibodies bind are called epitopes.) Naturally, since tight binding is desired, the antibodies are mainly attracted to the parts of the antigen that are the most reactive — the so-called “immunodominant epitopes.” Of course, the viruses and other pathogens which are continually changing, tend to do most of their mutations in the immunodominant epitopes. In so doing, the antibodies that we had produced earlier, which were mainly directed against the immunodominant epitopes, can no longer provide adequate protection. So, we get sick again (and need to be vaccinated again). Clever little creatures, they are!

How could we design vaccines that would work against continually mutating germs? Now, those germs do not mutate every part of their antigens, since those molecules are not just there to confound our immune system, but are most probably crucial for the germs’ survival, so that the essential parts are kept the same. We could design vaccines that mimic those antigens, but with the immunodominant epitopes reduced in reactivity [1].  That might shift the antibody response to the parts that do not change. An example would be to reduce the reactivity (in other words, the antigenicity, that is, the ability to elicit an antibody response) of the head region of the hemagglutinin of flu virus (the part that the virus uses to bind to its target cell and which the virus continually mutates), so that the antibody response would be elicited more to the stem region (the part that the virus needs to invade cells and which is essentially invariant).

Better yet, we could design a vaccine that would focus the antibody response on a part of the antigen that is critical to its function [2]. For example, if the antigen is an enzyme, we could target its catalytic site. If the molecule is used for binding, we could target its binding site. If a part undergoes a change in structure for the molecule to function properly, antibodies binding to that part could prevent the structural transformation. 

Lately, I have been using this second method to design possibly useful vaccines against a variety of germs. For example, I am designing molecules that I expect will elicit an antibody response that is mainly directed against the part of the hemagglutinin molecule which needs to be cleaved by an enzyme in order for the flu virus to be able to invade cells. I am also designing vaccines that may be useful against dengue, this time targeting that part of the virus’ envelope protein to which a neutralizing antibody has been shown to bind. Etc. Etc. Etc.

Hopefully, what I’m doing will someday bear fruit.

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Cited references:

[1] Padlan EA. A novel method for designing vaccines against constantly mutating pathogens. Phil J Sci 2008; 137(1):39-51.

[2] Padlan EA. A method for designing molecules for use in directing the antibody response to a chosen region of a protein antigen. Phil Sci Letts 2008; 3(2):36-47.

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Eduardo A. Padlan was a research physicist at the US National Institutes of Health until his retirement in 2000. He is currently serving as an adjunct professor in the Marine Science Institute, University of the Philippines Diliman, and is a corresponding member of the NAST.  He may be contacted at eduardo.padlan@gmail.com.