Activity Transcript

Susan J. Mayor, PhD: Why not start this episode with a riddle? What do gossip on the internet, wildfires, and flu have in common? Ready for the answer? They can spread rapidly and are difficult to control.

In today's age, influenza isn't always thought of as a serious disease -- headaches, runny nose, cough, and muscle pain are symptoms most people feel can be slept off. Yet seasonal influenza kills up to 650,000 people every year. Around the world, and here in the heart of London, hospital admission rates this year for flu matched the highest rates seen in the years just before COVID.

Hello and welcome to season 1 -- episode 3 -- of "CME-TV: New Frontiers in Vaccinology." I'm your host, Susan Mayor.

Influenza vaccines are important, especially to protect young children, older people, pregnant women, those with chronic disease, and people who have vulnerable immune systems. But influenza vaccines have strengths and limitations that are important for us to understand. And to be able to explain to patients.

Which is why I've brought you here. I'd like you to meet a good friend of mine. This gentleman knows everything there is to know about influenza and vaccines. For 27 years, Dr George Kassianos has been the UK National Immunisation Lead for the Royal College of General Practitioners. He is a board member of the Scientific Working Group on Influenza. President of the British Global and Travel Health Association. And was appointed in 2020 by Her Majesty the Queen as Commander of the Order of the British Empire for his services to General Practice and Travel Medicine.

He is also extremely humble, which is why I must tell you all of this before we join him.

Are you ready? Let's go.

Dr Kassianos, meet… the Medscape world. World… meet Dr Kassianos.

George Kassianos, CBE, MD(Hons), FRCGP: Hello, world. So nice to be with you.

Dr Mayor: Shall we jump in?

Dr Kassianos: We shall.

Dr Mayor: Alright. Are current flu vaccines effective in preventing influenza?

Dr Kassianos: We expect vaccination to prevent both influenza infection and its complications.

Our current flu vaccines are good at both. But they're not perfect. And they vary in effectiveness across seasons and strains.

Let me show you these data.

In a meta-analysis of global data from 2004 to 2015 -- so, over 11 flu seasons -- vaccine effectiveness was highest against A/H1N1 and B viruses and lowest against A/H3N2. And in people older than 60, effectiveness against A/H3N2 was very low -- only 24%. It was 35% for working-age adults. And 43% for the pediatric population.

Dr Mayor: Do you see this trend continuing today?

Dr Kassianos: Maybe. A/H3N2 is often the dominant strain in the UK, but vaccines are less effective against it than other common strains.

More recently -- at the end of the 2019-2020 flu season -- vaccine effectiveness averaged 43% against all confirmed influenza. A/H3N2 dominated the season, and vaccine effectiveness was 31% against it. This was for all ages, that is, any vaccine used in the UK.

When we looked at age groups, effectiveness against A/H3N2 dropped to 23% for adults 65 and older. And to around 31% for the pediatric population.

Similar story in 2021-2022, and again with A/H3N2 as the dominant strain. In adults -- this time age 50 years and older -- the provisional overall adjusted influenza vaccine effectiveness was 26% against all confirmed cases using inactivated quadrivalent vaccines, 76% against A/H1N1, and 28% against A/H3N2.

The adjusted influenza vaccine effectiveness for the intranasal live attenuated influenza vaccine was much higher, 72%.

Dr Mayor: Does it matter when you get vaccinated?

Dr Kassianos: In Europe, influenza seasons can last until late May. And it's expected that vaccination will provide protection for the season's duration. But vaccine-induced immunity has been shown to wane over the course of a flu season. The European I-MOVE study analyzed data from flu seasons between 2010 through 2014-2015 and found that vaccine effectiveness against A/H3N2 declined to 0 after 111 days -- so roughly after 3 to 4 months.

More recently, in the US -- from the 2015 through 2018-2019 flu seasons -- vaccine effectiveness against influenza-associated hospitalizations declined for adults by about 9% every month. And, more specifically, by 10% to 11% every month for those 65 years and older. That might seem small, but people are not starting from 100% protection. Several other studies conducted around the world have found vaccine waning to be more pronounced among older adults.

Dr Mayor: In relation to the data we've discussed so far, what may cause protection to be lower against certain influenza strains or in specific populations?

Dr Kassianos: According to the UK's Joint Committee on Vaccinations & Immunisations, the JCVI, 3 main reasons exist that explain lower vaccine effectiveness, particularly in older adults, and more specifically for A/H3N2. Antigenic drift. Immunosenescence. And egg adaptation.

Now, let me say, we are seeing improvement in vaccine effectiveness and duration of protection with newer vaccine technologies, but challenges do remain.

Let's start with antigenic drift.

The World Health Organization predicts which flu strains will be most prevalent in the coming year. And makes annual recommendations for vaccine production. Vaccine effectiveness depends on how well the strains included in the vaccine match the strains in circulation.

Antigenic drift is when gradual genetic mutations are introduced during viral replication that change how the virus appears. And despite being vaccinated, a person's immune system may or may not recognize a viral strain that's been partly changed by mutation.

Typically, the World Health Organization changes 1 or 2 of the influenza strains recommended for the vaccine each year to keep up, among others, with antigenic drift variants.

But vaccine production is a lengthy process. It takes about 6 months to update and deliver the vaccine to us. And unfortunately, it's possible during this time for the circulating virus to mutate again. Back in the 2017-2018 season, it drifted so much that vaccine effectiveness for A/H3N2 was in the minus figures.

That's antigenic drift. The second is immunosenescence.

This is a weakening of the immune system that occurs when we age. As we get older, we do not respond so well to vaccines, nor do we respond so well to infection. While older adults are at high risk of complications from flu, our primary method of protection -- which is vaccination -- becomes less effective as we age.

Dr Mayor: What's being done to overcome immunosenescence and improve vaccine efficacy?

Dr Kassianos: One strategy is to use a high-antigen dose vaccine, resulting in higher inhibition titres and a more immunogenic vaccine.

Most symptomatic influenza infections are self-limited, but acute febrile illness can range in severity from mild to debilitating. And can be exacerbated by secondary complications like superimposed pneumococcal or staphylococcal infections.

Influenza can also exacerbate existing chronic diseases. And it can lead to pneumonia, Reye's syndrome, myocarditis, pericarditis, encephalopathy. Even death.

High-antigen dose vaccines have been shown to increase effectiveness in preventing influenza-like illness, pneumonia, and hospitalization in older people. And to decrease influenza-related mortality compared with standard-dose vaccines.

Another option to combat immunosenescence is to add an adjuvant.

Dr Mayor: I see. So, antigenic drift, immunosenescence, and the third was…

Dr Kassianos: Egg adaptation. Influenza vaccines from inactivated egg-grown viruses have been available for over 50 years. The infrastructure is solid. And most influenza vaccines are produced in fertilized eggs.

But scalability is limited, and there is a reliance on fertilized egg supply. It is also possible for egg-grown human influenza viruses to acquire mutations in hemagglutinin. While this helps the virus to grow inside the egg, it becomes less like the flu we used to produce the vaccine, but also less like the flu viruses circulating among the human population.

Hemagglutinin is the major target of the protective immune response against influenza viruses. And even subtle differences in hemagglutinin between the egg-grown and circulating viruses can lower vaccine effectiveness.

Dr Mayor: Is egg adaptation more common for one viral strain vs another?

Dr Kassianos: It occurs in both influenza A and B viruses, but is more common for A/H3N2 viruses. And is partly responsible for the reduced efficacy of this vaccine component.

Dr Mayor: Recently, vaccines made from cell culture-grown viruses and recombinant vaccines have been licensed. And these newer ways to manufacture vaccines may overcome the current limitations of egg-based manufacturing.

Cell-based vaccines use inactivated viruses grown in cultured mammalian cells instead of in eggs. And recombinant vaccines are created synthetically using baculovirus, a virus that infects invertebrates.

Now we have cell lines available on request and ways of avoiding reliance on fertilized eggs. Let's find out how it's possible.

I find it fascinating the different ways vaccines are produced. Can you tell us how cell culture and recombinant flu vaccines are made?

Dr Kassianos: Sure. I find it fascinating, too. The first cell-based quadrivalent flu vaccine was introduced during the UK's 2019-2020 flu season. The vaccine is made from flu viruses grown in a cell line started in 1958 with canine kidney cells. The cells have been immortalized, and the cell line is always available to produce vaccines.

Growing the virus in cells may enable a closer antigenic match to circulating strains of influenza virus by avoiding egg-adapted mutations. It's also easier to scale up cell-based vaccines because they don't rely on egg supplies.

The recombinant influenza vaccine is created synthetically using DNA-encoding hemagglutinin antigen and a baculovirus. The baculovirus helps deliver the genetic instructions for making the antigen into a host cell. In this case, the host cells are insect cells.

Dr Mayor: Remarkable. So, essentially, cultures of insect cells are infected with the baculovirus and turned into tiny hemagglutinin factories.

Dr Kassianos: Yes, well said.

Then the antigen is grown in bulk, harvested, purified, and packaged as recombinant flu vaccine. Although the process may sound complicated, it offers the same benefits of speed, flexibility, and scalability as cell-based flu vaccines. Plus, it eliminates reliance on influenza virus replication for vaccine production. Because there is no need to grow the virus, antigen match may be more accurate. This vaccine also provides a higher amount of antigen than usual flu vaccines. But it does not contain neuraminidase, only hemagglutinin.

Dr Mayor: I see. And, of course, along with benefits come limitations. So, what would you say are the limitations of these technologies?

Dr Kassianos: So, our experience with them is evolving. And there is a higher cost in comparison to egg-based vaccines. Neither technology could currently replace the entirety of egg-based manufacturing, at a low cost, without a significant investment in new production facilities. The infrastructure to manufacture enough doses for an entire flu season without egg-based manufacturing is not yet possible.

Dr Mayor: Vaccines are arguably one of the most important inventions in human history. From eradicating smallpox to ending pandemics, vaccines now help protect against more than 20 diseases. But the fight isn't over. Viruses continue to evolve. And most of them evolve rapidly.

We're seeing a paradigm shift in flu vaccine development, from using whole viral particles and protein subunits to using viral genetic material. mRNA vaccines used to protect against SARS-CoV-2 are considered a global success. And now, this platform is entering the influenza vaccine challenge, potentially delivering a new generation of high-efficacy vaccines. Let's pop back over to Dr Kassianos and see what he thinks about applying mRNA technology to influenza vaccine development.

Can you describe how mRNA vaccines work?

Dr Kassianos: Well, rather than using the virus itself, either as a whole or in parts, mRNA vaccines use the genetic code of a virus. That genetic code instructs the body to make a small, noninfectious piece of the virus that trains the immune system to respond.

Dr Mayor: Can the mRNA platform overcome some of the limitations we've seen with other flu vaccines?

Dr Kassianos: Based on the success we've seen with COVID vaccines, mRNA technology shows some distinct advantages. But, at the moment, we can only speculate about its capabilities in flu prevention. What will determine the platform's success is how well mRNA vaccines can match circulating strains; the speed with which they can be formulated and produced; and their ability to improve vaccine effectiveness, particularly in vulnerable older adults and immunosuppressed patients.

That said, at the height of the COVID pandemic and throughout, mRNA vaccines could be adapted to new SARS-CoV-2 variants, more or less as quickly as they arose. Because of the agility of mRNA technology, manufacturers could create vaccines with new genetic sequences in about 3 months or so. The same would be expected for influenza, which may allow the vaccine to be developed closer to flu season. And to be a better match against circulating viruses. Strain match may also be more accurate because there is no need to grow the virus.

Dr Mayor: And is it true that any protein can be expressed from mRNA without adjusting the production process.

Dr Kassianos: Yes. So, if we had a huge drift with influenza virus A/H3N2, like we did back in 2017-2018, producing a vaccine for the drifted strain could be possible during the same flu season.

Dr Mayor: Is a multivalent influenza vaccine achievable using the mRNA platform?

Dr Kassianos: Perhaps. We hope we will be able to include multiple antigens. So, it should be achievable.

Dr Mayor: And most important is the protection provided, together with safety. Do we know anything about the efficacy and safety of mRNA influenza vaccines?

Dr Kassianos: Two quadrivalent mRNA influenza vaccines are in phase 3 clinical trials. Both trials target the 4 flu strains that the World Health Organization identified as most likely to circulate during the 2022-2023 flu season. And both trials have study completion dates of August 2023.

Dr Mayor: Very soon, then. I have one last question. For decades, the medical community has accepted that the dominant flu strain will change every year. And that a highly variable -- and sometimes low -- vaccine effectiveness is unavoidable. As a clinician, what would you like to see come from future vaccine technologies?

Dr Kassianos: Susan, I've been waiting a lifetime for someone to ask me this question.

I'd like to see greater vaccine effectiveness against the influenza A/H1N1 and B viruses, and particularly against A/H3N2. Also, greater vaccine effectiveness among the over 50s, particularly those over 65, and those with chronic disease, particularly the immunosuppressed patients. Faster production of flu vaccines. An expiry date of the vaccine that goes beyond the perceived end of flu season, as we have travelers to the tropics and subtropics where influenza is active throughout the year.

I can keep going.

Dr Mayor: Yes, please do. And feel free to take a breath first.

Dr Kassianos: Well, I'd like to see lower incidence of adverse events than those we have experienced with the existing vaccines. And if not, at least similar. Lower incidence of injection site adverse effects than we have seen with COVID vaccines. Creation of antibodies against both hemagglutinin and neuraminidase. Creation of antibodies that persist throughout the flu season and beyond. And, of course, a vaccine that induces mucosal immunity in the upper respiratory tract, where influenza viruses invade our bodies.

Dr Mayor: Okay then. Do you hear that universe?

On behalf of Dr Kassianos and myself, we have enjoyed spending this time with you.

Please continue on to answer the questions that follow and complete the evaluation for your CME credit.

And be sure to check back soon for Episode 4 where we'll explore how RSV impacts older adults.

This transcript has not been copyedited.

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