The flu comes back year after year, and every season we get vaccinated (well, some of us anyway). Why do we need to keep getting a new shot for the flu while for others, like measles, we got way back in childhood and are done with it for the rest of our lives?
Our immune response to influenza involves production of antibodies, large proteins that specifically bind to the virus and help clear it out or neutralize it. It seems like the key to influenza immunity is neutralizing antibodies, antibodies that bind to the virion and prevent it from attaching to the host cell. You can imagine this large protein just being physically in the way, preventing the virus from binding the host receptor. The immune response that develops from natural exposure or vaccination generates neutralizing antibodies to HA, a viral envelope protein that is necessary for attachment to the host. I’ve mentioned HA in a previous post about influenza. The problem is that last season’s neutralizing antibodies dont bind to this season’s virus. Although it may be nearly identical to the virus from a past season, the new strain’s HA is slightly different, and those differences are enough to evade existing neutralizing antibodies.
Now a new approach to vaccination has shown that it may be possible to develop a vaccine that illicits broadly neutralizing antibodies, that is, antibodies that will protect against influenza strains with slightly different HAs. They used a prime/boost approach, in which a DNA vaccine was used to induce an initial response against HA, and then boosted with a regular seasonal flu vaccine. The only difference between this and what is currently done is the addition of the DNA vaccine. However the response seems quite different. Neutralizing antibodies were generated that can neutralize a variety of different influenza viruses. It seems the vaccine induced antibodies to a different part of HA. Antibodies are so specific, the dont recognize the whole HA, but rather discrete parts of it. The part recognized by these antibodies, called the stem, is highly conserved, meaning it doesnt change season to season.
This raises many interesting questions and possibilities. Could we soon have a universal vaccine that will protect us for life or at least for many years? Why did the change in vaccine regimen induce antibodies to a different part of HA? Why does the current vaccine or natural exposure fail to develop antibidies to the conserved portion of HA? Will the conserved portion of HA eventually change too, if sufficient selective pressure is applied through mass vaccination?
I think that the virus will find a way to survive. Changing the target region on the virion from the globular head to the stem would result in the development of a non conserved stem, somehow, and the virus would continue to infect. Though the idea of a universal vaccine is amazing, I don’t think it’ll come with just targeting the stem of virons. There definitely seems to be the possibility of a longer lasting vaccine at least initially. And as Professor Esteban mentioned, because the HA virus is not limited to humans, there is also the possibility of greater drift within animal mixing pots that can pass the virus to humans, meaning that the region specific vaccine would have less effect over time.
I haven’t read everyone else’s responses so I’m sorry if I end up repeating what you’ve already said…
I think the idea of a universal flu shot may sound intriguing at first, but the results could be potentially detrimental in the long-run. People would obviously think that this’ll be the solution to most, if not all, future strains of the flu virus, and it certainly seems like we’ll have access to this vaccine in the near future. But I don’t think that administering this vaccination would be such a great idea in the long-run. The vaccination would do a great deal of good for a little while, but after mass vaccination has been administered and the vaccine has run its course, the conserved portion of the HA will inevitably change and lead to the formation of a wholly new strain of the flu virus that we will be completely unready for. The outcome would be somewhat similar to the situation of the rabbits in Australia. Like the rabbits, the flu virus will eventually develop greater resistance to the vaccination. It could, however, be argued that the virus will become less virulent due to its inability to reproduce within hosts. But this is unlikely because we all know that the flu virus infects not only humans but other species as well.
I find this new vaccine to be quite interesting. The new approach to target the stem instead of the globular head demonstrates innovation that should constantly be experimented with in the scientific community of viruses. However, I ultimately believe that this vaccine’s success will be short-lived because as others have said the virus will simply evolve to resist the vaccine. In addition, viral mutations may occur that will also help the virus resist the vaccine, and, as discussed in class, viral mutations have a greater impact on viral phenotype because viruses have a smaller number of genes to begin with.
In response to Rachel’s comment, this vaccine probably wouldnt require an annual booster, but a single booster shot probably a few months after the first shot.
Several commenters have indicated the possibility of eradication with an effective universal vaccine. While high vaccine compliance and broad effectiveness has the potential to dramatically reduce the incidence of this disease, there are some major barriers to eradication. The problem is that influenza can infect many different species (pigs, birds, seals, whales, walruses…). Pigs can be infected with human strains, and humans with pig strains. Pigs can be infected with bird strains and in rare cases, humans can be infected with bird strains. So flu will always be jumping into humans one way or another from other animals. Unless we vaccinate all the animals, this will continue to happen with novel strains that shifted or drifted as a result of infections in other species. Smallpox, the only eradicated disease so far, was limited to humans.
I think that in order to have an effectively combat the influenza virus it is critical that most people actually get vaccinated. As you mentioned previously, not many people get annual flu shots, even though if more people did, new viral strains would have less opportunity to infect and adapt. Since this new vaccination still requires annual booster shots it will be interesting to see if the benefits of the new DNA component of the vaccine alone are enough to encourage a more widespread urge to get the shot.
Before i say anything, let me clarify that this new vaccine sounds like an incredible breakthrough to me. The possibility of having a vaccine which aids in the production of antibodies which specifically target a constant, rather than a variable, part of the viral HA in order to neutralize a wide array of influenza strains does seem very advantageous to me. But for the sake of playing devils advocate (despite the risk of sounding like a horrible person), i would like to ask if it is possible that mild influenza viruses serve an important purpose? It seems that fully developed countries (specifically the United States) have become increasingly concerned with cleanliness. But this attention to hindering the spread of viruses and bacteria has its drawbacks, doesnt it? With hand sanitizers in every public room, antibacterial soap in every bathroom, as well as overuse of antibiotics, arent viruses more rapidly evolving and becoming more resourceful while at the same time our bodies are being exposed to less and less mild viruses which keep our immune system active and productive? so wouldnt a vaccine such as this one, which would eliminate the immune systems need to combat commonplace viruses that cause symptoms that are (for the most part) manageable with simple over the counter products, further render us susceptible to infections in the long run?
It is certainly apparent in this paper that scientists believe that the new form of the influenza virus will be able to protect us from the virus for an extended period of time. I find it difficult to imagine that this new vaccine will be the last alteration we make to the influenza vaccine, since as it is, the slight change in the HA of the virus results in having to administer a new virus each season. I believe that even though it may take some time, the virus will evolve and find ways past the new vaccine. It might take more than one year, but I don’t think this new vaccine will protect us from influenza forever.
While a universal vaccination would certainly be a dream come true, but I think that trying to implement this new technology before it has been perfected (ie: before it is certain to wipe out ALL flu strains) would do more harm than good. Even if it was able to prevent a large portion of cases of the flu, similar to the way that overuse of antibiotics or even hand sanitizer may eliminate many immediate threats of illness, it will ultimately forcing virus (and bacteria) to evolve into super-resistant strains that we cannot yet combat. Before this is put on a wide-scale, it should not be implemented just to see how it would turn out, though that might, as Justin said, be interesting. We can’t cause a bigger problem by trying to solve the one at hand.
I think the new DNA vaccine for the influenza virus will protect us for a certain number of years, but not forever. Viruses, especially the influenza virus, can mutate so rapidly that who knows how much it will change in a decade or so. Though the stem, recognized by antibodies, is highly conserved there is still the possibility that it will change in response to the pressure it faces from a mass vaccination. New strains will consist of changes in the stem instead of the globular head. If we are able to create a vaccine that recognizes the changes in the stem of HA influenza virus, perhaps it will bring us closer to developing a universal flu vaccine.
I also agree with Muderi; the vaccine must be given quickly in order to not allow it time to mutate and create new strains of influenza virus.
I think Muderi’s comment is very interesting- it seems that there is a possibility of creating a vaccine to eradicate the flu completely, but if scientists want a vaccine to do so, it will have to be administered very rapidly so that the virus cannot easily evolve during the administration process, thus rendering the vaccine ineffective.
However, I am still skeptical that this would provide a permanent solution, since we have seen frequently that viruses evolve mechanisms to evade the immune system’s most crucial responses. Thus, it seems likely that the portion of the virus targeted by this vaccine could become one that does mutate, and eventually a new vaccine would be necessary.
@Michael: As far as I know, all viruses could potentially evolve and evade vaccines, as the selective pressure is still there no matter the virus, so natural selection will allow beneficially mutated viruses to propagate when the original is targeted. However, influenza’s unique DNA configuration allows for more modification at much higher rates than most viruses, hence the greater difficulty of elimination.
I agree with Muderi, as faster dissemination of the vaccine will work to outpace influenza’s high mutability. If Mandy’s point is true, then perhaps an attempt at influenza eradication should include DNA vaccination against multiple serotypes of the virus, perhaps including these several variations within the same booster.
I think there is a possibility for the virus to be completely erradicated by this vaccine, but I think this possibility is time dependent. If the vaccine is administered more rapidly, the virus will have less time to effectively evolve and there will be greater chance for the strains with similar HA stems to become extinct. A less rapid adminstration could result in evolutionary changes that foster differing methods of entering host cells, independent of HA integral proteins. Basically, the virus will have the propensity to evolve past the general vaccine; it is just a matter of time to develope these evolutionary traits.
I think it is possible that this new vaccination method could permanently end influenza. If HA is allowed so little divergence that the changes required to evade the antibodies would also render HA useless as a receptor, than no amount of selective pressure will allow influenza to evolve past the vaccine. Its survival hinges on whether or not the stem can be radically changed without being rendered useless.
There is, of course, the possiblity that influenza could evolve another means of entering cells besides HA. It is certainly possible that influenza, as a result of selective pressure, will develop a new protein that is not covered by the vaccine.
The paper talked about how HAs in the prime and the boost must match. Apparently, boost HA from H3N2 in combination with prime HA from H1N1 didn’t result in broad neutralization. I see now that H1N1 and H3N2 are different serotypes, so while DNA priming helps immunize against different strains of the same serotype, it will not be effective with different syrotypes. I was wondering if this new vaccine works with all types of antibodies?
I don’t think we will ever truly develop a universal influenza vaccine. Like people have said, this vaccine would most likely cause influenza to evolve and and change the region the vaccine was targeting. Is influenza the only virus that does this; have the ability to evolve and evade vaccines? I know the smallpox vaccine completely eradicated that virus, so I find it unlikely that smallpox evolves. So, the common cold may be the only virus without a cure.
Although i don’t believe this would be a universal vaccine that would protect us for life, it is certainly appears that it will have longer lasting affects than what is present now. However, the stronger and more effective vaccine would force the virus to evolve and eventually change the stem region of the HA so that it will be able to go on undetected. The new DNA vaccine could have altered the tip structure of the antibodies so that they could recognize the stem of the HA instead of the globular head.
Judson, that is certainly a possibility. I checked the paper to see if the HA expressed from the DNA vaccine is secreted or ends up in the cell membrane. They actually dont say, unfortunately. But Im going to assume its secreted, which means there would be lots of free floating HA around, which could make the stem much more accessible. The stem is normally the part closest to the viral membrane and may be less accessible to antibodies.
One thought I had is that the different immunoresponse of the DNA vaccine could be driven by the greater accessibility of the HA stem when it’s expressed in as a fragment rather than as part of the entire virus. If so then it could be possible to custom-design DNA vaccines that (purposefully) express multiple different fragments of the virus. That is, if there are multiple targets it should result in better and more general immunoresponse to the vaccinated disease and related strains.
Also, you said “globular head…” Huh-huh, huh-huh, huh-huh.
Sam’s point assumes that such a shared component exists. Unrelated viruses are so different from each other that there doesnt seem to exist anything that is actually shared by all of them or even shared by more closely related ones. Of course in a previous post, I described a structure that was common to 3 very different viruses that infect hosts in different cellular domains (archaea, bacteria, and eukarya), but that structure is likely still far too dissimilar to be recognized as the same thing by antibodies. No one has tried though.
I think it will be interesting to see if, once this vaccine is widely spread – and that’s assuming that it will work as intended as a ‘universal vaccine’ against influenza virus – if we will eventually begin seeing mutations of influenza in which the stem’s form is changed. It would be an interesting study of mutations and evolution to see if the presence of this vaccine would promote the alteration of a part of the virus that doesn’t currently change. As you said in the last sentence of the post, there would be a large amount of selective pressure put on the viruses, so a strain that managed to change its stem sufficiently would have a large advantage.
Moving towards a more general vaccine is moving towards better immunity. Ideally we would discover a shared identifying component not just among influenza virions, but among virions of all different viruses. I guess the limiting factor here is that if the biochemical marker gets to general, our antibodies might start attacking things that we need. As long as the identifying property is strictly viral it’s a great option for an antibody target. This being said, using this tactic for lifetime immunity seems like a pipe dream. No matter how important the viral component that our antibodies recognize is, eventually a virus will evolve to not need it.
Certainly the virus could continue to spread and evolve among unvaccinated people, and there is generally low numbers of people that get the flu shot. Perhaps a universal vaccine would get better compliance. We certainly cant stop it from evolving although we can try to slow it down. A vaccine like this might put pressure on the virus to evolve in different ways than we have seen before, ie, changing the stem region of HA instead of the globular head.
Its unlikely though that the reason different antibodies were generated in this vaccine was due to evolution of HA. In the DNA vaccine, no virus is actually administered. Its just a piece of DNA with the HA gene, which does not replicate and therefore experiences no selective pressure.
The reason the vaccine is universal is that the immune response that develops following vaccination targets a part of the virus that does not seem to change. What has been observed in the past is that only part of the HA changes easily, a region called the globular head. Normally, we develop a response that targets the globular head, and since it changes quickly, new strains of the virus are not recognized. The response illicited by this vaccine targets the stem region of HA which has not been observed to change in different strains, so since its the same in different strains the immune system sees it as the same pathogen.
The role of the DNA vaccine here is to prime the immune response. For many vaccinations, you need several shots over a period of time to get full immunity. The fist shot is called priming, the subsequent shots are called boosters. Usually, the priming and booster shots are the same thing, so its just multiple shots of the same stuff. In this case though the priming shot is a piece of DNA encoding HA, which enters your cells which then make HA. Something about priming that way results in making antibodies to the stem instead of the globular head, although its not clear why that is.
I agree with Dip’s first statement. As a virus spreads, it evolves from person to person. As it spreads from region to region it also develops.
However, if a vaccine is to be universal…how would that work? even if there is a universal vaccine to stop the spread of the virus for a certain amount of people for a number of years, there would still be a number of people in the population who could not be vaccinated. As well, vaccines don’t always work, and if a person has the virus and is spreading it to others who were or were not vaccinated, there is still a chance for the virus to evolve.
Different antibodies were induced to a different part of HA because the viral strains evolve, altering the location of the HA.
It is clear to me why we may need a new Influenza virus vaccination annually. It is because strains of influenza rapidly evolve from infection to infection so that by the end of one cycle there is a relatively new strain that our bodies as hosts do not recognise. As you have explained in this and the previous post, the change is in the structure of HA.
However, I do not understand the concept of a universal flu vaccine that you explained. Is it that the vaccine in question has the potential to mutate randomly and accurately change as do influenza strains? Is that how the vaccine provides immunity… by considering the many possible changes in structure of HA?
Also, I do not understand the exact effect or role of the DNA vaccine used in the creation of the universal flu vaccine.