In the wake of Covid-19 has come a push for pandemic prevention measures. One of which is a universal influenza vaccine. While it may not seem like it, seasonal influenza takes the lives of up to 650 000 people a year. On top of that lies the looming threat of an influenza pandemic, which occurred 3 times during the 20th century. In theory, a universal influenza vaccine would immunize people to both the seasonal strains and possible pandemics. But how exactly would it work? In order to answer this question, a quick rundown on influenza and vaccines in neccicary.
There are 4 types of influenza: A, B, C and D. Type D influenza effects cattle and swine, while type C influenza only mildly affects humans. The main 2 types that affect humans are type A and type B influenza . Unlike type B influenza, type A influenza can affect both humans and animals and tends to be much more deadly.
Type A and B viruses can also be classified further. Type A viruses are classified into subtypes based on the type of protein found on their surface, called glycoproteins. A-type of viruses contain 2 different glycoproteins on their surface: hemagglutinin (HA) and neuraminidase (NA). There are 18 different HA subtypes and 11 different NA subtypes. Each type A surface will be populated by many different HAs and NAs, however only one HA and NA subtype. These subtypes are named H1 through H18 and N1 through N11. So, when you see that the seasonal flu is an H1N1 virus, you know that it contains the H1 subtype and the N1 subtype on its surface. The combination of these glycoproteins theoretically projects 198 possibilities of subtypes (18 multiplied by 11). To date, only 138 have been detected in nature. These types of subtypes can be further classified into clades and sub-clades, based on the changing genetic sequencing of the HA protein.
While type B influenza also has HA and NA glycoproteins, they are classified by lineage. These 2 lineages, B/Yamagata and B/Victoria, can also be further classified into clades and subclades. However, type B viruses change much slower in terms of their genetic properties.
One of the ways we immunize ourselves against influenza is through the HAs. Hemagglutinin is an antigen, meaning our body can recognize it and trigger an immune response by producing antibodies. These antibodies will then bind to the virus and trigger a cascade of effects to neutralize it. But if it was just this easy, why do we have seasonal flu vaccines? Why can we not just create an H1N1 vaccine? Well, this is explained by something called antigenic drift. These are small changes (or mutations) in the genes of influenza viruses that occure during genetic replication. These mutations can lead to changes in the surface proteins of the virus. These genetic changes are do not always mean a new vaccine. If the new virus is antigenically similar, meaning it has simmilar enough surface proteins, to another circulating influenza virus to produce an immune response against that circulating virus, there is no need for a new vaccine. However, for the majority of seasonal flus (and more importantly in the case of a pandemic outbreak), we do not have antigenically simmilar antibodies.
What’s the Solution?
The answer fundamental flaw in the vaccine is not found within another method, but rather in HA inself. There are two parts in an HA: the head and the stalk. Existing flu vaccines contain weakened or inactivated influenza viruses with a mix of HAs. This concoction usually contains One influenza A(H1N1), one influenza A(H3N2), and one or two influenza B viruses that are circulating that year. These vaccines primarily aim to trigger antibody responses against HA’s top part, or head. However, changes in genetic material and antigenetic properties are also expressed in a part of the head. So as new clades and subcladdes are formed, that part of the head changes and new vaccines are required. But what about the stalk? The stalk’s antigenetic properties do not change much through genetic change, making it the perfect target for a universal vaccine.
A Universal Vaccine?
Though targeting the stalk seems an easy enough thing to do, it comes with its own set of problems. Our immune memory cells, the cells that remember pathogens for future antibody production, have built up over a lifetime of flu infections. They react so strongly to the HA’s head that this response overrides production of antibodies against the stalk. So, if we use a complete HA in the vaccine, we will not create enough antibodies targeting the stalk. On its own, the stalk is too unstable, so a vaccine that only uses the stalk is out of the question. However, scientists have found a solution: chimeric HAs. To bypass the issues, scientists have linked the stalk to an entirely new head that is unrecognizable by our immune system. This way, our bodies do not default to head antibody production, allowing a strong new immune response to stalk to dominate.
Where are we now?
The latest news comes from a small clinical test run a multi-institutional universal flu vaccines consortium funded by the U.S. National Institute of Allergy and Infectious. They have found that candidates have had high levels of “induced remarkably high antistalk antibody [concentration].” Though this trials only tested immune response, and not effectivity, it is a solid marker of progress. Florian Krammer, who co-leads this consortium, estimates that it will likely take at least 2 years to develop chimeric HAs representing enough other strains from influenza groups A and B to be combined into a universal vaccine. Then, that mix would have to be tested in. a large scale, multi-year study.
The prospect of new medical advancments has always been something that has excited me. Its almost crazy to think that in a decade we might have a global population immune to type A and B influenza viruses. As much as it is crazy it is also hopeful. The future is bleak for many of our youth, and advancements like these for me generate fascination for the the world that we will see in 30 years time.
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