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  • Alex Cloherty

Visualizing viruses for vaccines

Updated: Nov 7, 2022

Respiratory syncytial virus (RSV) has remained one of the last common childhood diseases for which we have no vaccine. Like SARS, RSV is a respiratory virus, meaning it infects our nose, throat, and lungs. Also like SARS, or influenza, RSV spreads readily during the winter months, which are just about upon us once more. This year, the winter of 2022, RSV cases are skyrocketing.

But, the status quo between us humans and RSV might be about to change.

You might have already read in the news that Pfizer announced very promising data from its Phase 3 clinical trial of an RSV vaccine. The goal of their current study was to see if their vaccine candidate can be given to pregnant people, in order to eventually protect their newborns from RSV disease - which can be fatal for infants. In a nutshell, they saw that the vaccine was highly effective in protecting infants from RSV-caused severe lower respiratory tract infections (i.e. infections in the lungs) particularly in the first 90 days of the newborns’ lives, but also up to the age of 6 months. This is great news, because RSV is most deadly to infants when they are under 6 months old. They also didn’t find any safety concerns for either the parents or the newborns.

This is definitely something to celebrate as a triumph of science, especially considering the difficult history of RSV vaccines. This new RSV vaccine was only possible due to the molecular and structural biology studies carried out by scientists in the lab over decades, and stemming from a breakthrough publication from 2013. So, what made the RSV vaccine so difficult to develop?

The trouble started in 1966.

In the late 1960s, just like today, there was also a clinical trial of an RSV vaccine. However, that one was terribly unsuccessful. That vaccine from the 1960s had the opposite effect versus what was intended: 80% of the infants that were vaccinated got very sick and needed to be hospitalised, which was a far greater percentage than those in the control group.

This type of vaccine was a 'whole virus' vaccine, in which the virus was inactivated with formalin (a solution of formaldehyde) before administration. Unfortunately scientists later figured out that it was the formalin inactivation causing the problem.

Just like SARS-CoV-2, RSV has spiky proteins on its surface which are responsible for grabbing onto and pulling the virus inside of its target cells: the cells of your respiratory system. In the case of SARS-CoV-2, that protein is literally called the Spike Protein. RSV on the other hand, has two of these spiky proteins: one is called the ‘attachment glycoprotein’, or just ‘G’ for short, and the other is called the ‘Fusion glycoprotein’, or by its nickname ‘F’. And it was the F protein that was causing a problem with the old RSV vaccine.

You see, the F protein has two different conformations. In the same way you can present your hand to somebody either as an open invitation for a handshake, or as an angry closed fist, the F protein can either be ready for engagement, or not. The F protein starts out in an open, ready-for-attack conformation called the “prefusion conformation”, in which it is ready to pull together the membranes of the virus and the target cell of the human it is about to infect. After that, the F protein rearranges itself into a “postfusion conformation”, a cone-shaped, closed-for-business conformation. But, it turns out that the successful infection of a human cell is not the only thing that can trigger the F protein to change from the “open-for-business” prefusion conformation to the “permanently closed” postfusion conformation.

Decades after the failed RSV vaccine trial in the ‘60s, scientists figured out that when RSV is treated with formalin, the viruses’ F proteins rearrange into the postfusion conformation, meaning that to our immune system, formalin-inactivated virus looks very different from a wild, live virus. Unlike the formalin-inactivated virus, a virus in the wild will have a lot of prefusion F protein on its surface.

Scientists now think that the old vaccine caused an over-reaction of the immune system, also known as “vaccine-enhanced disease”, exactly because the vaccine showed the infants’ immune systems the wrong conformation of the viruses’ F protein. In other words, the old vaccine made human immune systems make lots of antibodies, but only antibodies that could grab onto the postfusion conformation instead of the prefusion conformation of the F protein. That meant that if one of the vaccinated infants in the 1960s actually caught RSV, the antibodies recognized the live virus enough so that the infants’ immune systems started to make lots and lots of the same antibodies to try to protect the infant from the RSV… But the antibodies were not effectively grabbing onto the live virus. This leads to a confusing situation for the immune system, and can trick the immune system into an over-reaction that results in excessive inflammation that can ultimately damage the tissues in the respiratory system even more than the virus would have on its own.

What the scientific community learned from this case, is that it is very important to know exactly what a vaccine should look like to your immune system. And indeed, this new vaccine made use of the growing field of ‘structural biology’ to do exactly that.

Structural biology is the “study of how biological molecules are built”. This field of biology looks at tiny particles, like human or microbial “proteins, at a molecular level, unlocking secrets of structure, function, and interactions, and providing new avenues for medical research”. Basically, structural biologists use a variety of different high-powered microscopes and other imaging tools to take very, very high-resolution pictures of proteins and other biological molecules.

And that was exactly what we needed for the new RSV vaccine. Pfizer’s new vaccine is based on a sort of high-resolution image of RSV’s pre-fusion F protein, and structural biology studies that suggested a way to use structural biology to inform the development of safe and effective vaccines. That’s why Pfizer’s RSV vaccine candidate is called “RSVpreF”.

This story can surely be seen as a cautionary tale for vaccine development. It shows why it is so important to first test for vaccine safety in individuals who have a low risk of actually getting sick. The history of RSV vaccination is surely one of the reasons why Pfizer chose to vaccinate pregnant parents in their trials - i.e. younger adults unlikely to experience severe RSV disease - rather than the infants themselves. But, this story can also give us great hope: it shows how new technologies, like those used in structural biology, can be used to solve old problems, and overcome scientific challenges of the past to pave the way for a healthier future.

P.S. Pfizer made a short video about how new (structural biology) technology helped them with developing the RSV vaccine! You can check it out here.

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