EDIT: I updated this post to make it a bit clearer to a broader audience (8/15/11)
When I finished up my Spanish Influenza series back in March, I did not expect to come back to it. However, earlier this week I stumbled upon a blurb in Nature magazine that discussed a new area of influenza vaccine research. I downloaded the paper, realized that it dealt with the hemaglutinin protein, which I’ve shown you pictures of, as well as the yearly flu vaccine that most people receive, and decided that this paper would be an interesting topic for all!
When I finished up my Spanish Influenza series back in March, I did not expect to come back to it. However, earlier this week I stumbled upon a blurb in Nature magazine that discussed a new area of influenza vaccine research. I downloaded the paper, realized that it dealt with the hemaglutinin protein, which I’ve shown you pictures of, as well as the yearly flu vaccine that most people receive, and decided that this paper would be an interesting topic for all!
Let’s start with antibodies.
In response to viral or bacterial exposure (either through infection or inoculation), our immune systems produce antibodies. In short, antibodies are proteins that can bind the invading virus both very specifically and very tightly and this binding leads to blocking of infection. There are two key things to antibodies: specific/tight binding to virus and blocking the viral infection.
Think of antibodies as policemen. Once the city (body) knows a fugitive (virus) is within their boundaries, they gather lots of information on what he looks like (makes antibodies) and send the police (antibodies) after him. Once they find him, the police are all over him (antibodies bind the virus), which blocks the fugitive’s ability to perform anymore harm.
In order for our bodies to produce antibodies, our bodies must first encounter these invaders. We aren’t born with the antibodies against chicken pox. However, once we are infected, we churn out antibodies to overcome the infection. After infection, our bodies “remember” chicken pox in the form of these antibodies. Should we ever encounter it again, we have the antibodies waiting to vanquish an infection before it has the chance to make us sick.
This is the theory behind vaccinations: inoculate with a weakened (attenuated) form of the virus or something that looks a whole lot like the virus and allow our bodies to form the antibodies. Should we ever encounter the real deal in our lifetimes, our body has the antibodies waiting!
We are vaccinated against many things when we are children and most of them only occasionally need boosters. Sooo – why do we need a new flu vaccine each year?
Ah. Influenza is a tricky little virus!
Figure 28.2 shows you the size of the virus relative to the size of an antibody. The virus is pretty big in comparison, huh? Clearly that little bitty antibody isn’t binding the entire virus.
Think about the size difference between a human hand and a car. Pretend the hand is the antibody and the car is the virus. What can the hand, standing outside the car, grab on to? Examples: the side mirror, a tire, the hubcap. The hand can touch anything that is outside the car. The hand would be unable to touch the seats or the steering wheel inside.
So, what do influenza antibodies grab on to? Primarily, they bind the hemaglutinin protein that is a major coat protein to the virus (see Spanish Influenza series for more info). Antibodies won't be able to grab anything inside the virus so they must aim for something on the outside. Hemaglutinin is typically what they target.
Antibodies, which are similar in size to the hemaglutinin protein, are only binding to one specific part of the entire hemaglutinin protein. This is called the epitope. Nature doesn’t dictate exactly where the epitope needs to be so our bodies can make antibodies that bind to any part of the protein. However, remember that antibodies have two goals: 1. bind the virus and 2. block infection. While many antibodies will be able to bind the hemaglutinin protein, not all of those will be able to effectively block infection. Not all antibodies are made alike.
The structure and amino acid sequence of hemaglutinin proteins change slightly every year because the virus is evolving. Each year, scientists create a vaccine against the most prominent strains of the virus, and each year the influenza changes a bit to get around our antibodies. It’s a constant cat-and-mouse game.
Instead of guessing each year what kind of influenza will be around and relying on our bodies to make the correct antibodies, what if we had a different approach? What if we designed a super antibody that could recognize hemaglutinin despite its yearly change and effectively block infection of all viruses? What if, instead of vaccines, we just gave people this super antibody? Would this work?? How would we go about finding such an antibody?
Instead of guessing each year what kind of influenza will be around and relying on our bodies to make the correct antibodies, what if we had a different approach? What if we designed a super antibody that could recognize hemaglutinin despite its yearly change and effectively block infection of all viruses? What if, instead of vaccines, we just gave people this super antibody? Would this work?? How would we go about finding such an antibody?
A study published last week in Science talked about how scientists are looking for an antibody that will do just that. Called broadly neutralizing antibodies, these antibodies would be able to bind to all hemaglutinins and effectively block infection of the virus. Such antibodies are rare finds, difficult to design de novo (from scratch) and previous attempts have lead to antibodies that aren’t very powerful at stopping infection. However, Corti et al. discuss one particular antibody they were able to find that:
- Tightly and specifically bound all hemaglutinin proteins currently known
- Neutralized infection of known influenza viruses
This is actually pretty cool!
This one antibody was made by a donor's immune system and the scientists were able to purify it away from everything else in his cells to study how it worked. This antibody is a needle in a haystack!
This one antibody was made by a donor's immune system and the scientists were able to purify it away from everything else in his cells to study how it worked. This antibody is a needle in a haystack!
Interested where this antibody was binding hemaglutinin (where its epitope is), the authors investigated and found it bound in the stalk region of the protein (Figure 28.3). This area of the protein tends to be very similar among all hemaglutinins and doesn’t change much in the yearly influenza evolution.
What is even more fascinating is that they found the antibody to be protective when administered before influenza infection (prophylactic) or after, even with lethal forms of the influenza virus.
The authors show quite clearly that the antibody is binding hemaglutinin protein specifically/tightly and they are able to show convincing results that this antibody can block viral infection when inside an animal. From the viewpoint of the general population, this is good news and mostly what is interesting. From the viewpoint of me, a biochemist, I want to know how. How does an antibody binding a protein lead to blocking an entire viral infection?
While they authors are not sure, they speculate at the end of their paper. All three possibilities rest in the idea that the antibody is binding an area of the protein that is needed for successful viral infection. For example, the antibody is holding an area of the protein in particular position and will not allow the protein to change from that position. Or, perhaps the antibody is covering an area of the protein that needs to be cut. If the scissors (protease) can’t get near the spot it needs to cut because a big old antibody is in the way, then it won’t happen. Finally, maybe that area of the protein needs to bind something else but the big antibody is already there. Based on what scientists know about hemaglutinin’s role in viral infection, all of these possibilities are valid. However, which one is actually responsible remains a mystery!
Inoculation: placement of something that will elicit a response, such as growth or reproduction. In the case of vaccination, it places something in the body that will lead to an immune response and production of antibodies.
Varicella: scientific name for the chicken pox virus
Epitope: area of a protein that an antibody binds to
Prophylaxis: medical procedure performed with the intent to prevent disease
Protease: a protein whose specific job is cut other proteins apart
REFERENCES
Science paper in its full scientific glory: Corti et al. “A Neutralizing Antibody Selected from Plasma Cells That Binds to Group 1 and Group 2 Influenza A Hemaglutinins.” Science (2011) 333, pgs 850 – 856.
An easier version for non-scientists to read: Wang and Palese. “Catching a Moving Target.” Science (2011) 333, pgs 834 – 835.
Lodish, et al. “Molecular Cell Biology.” (2004) WHFreeman Publishing, 5th Edition.
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