Activity Transcript

Susan J. Mayor, PhD: As the world enters the pandemic’s fourth year, the World Health Organization has announced that COVID-19 remains a public health emergency of international concern. But they also say that we’ve never been better positioned to bring the pandemic to its end. So, what will it take for us to move COVID-19 from pandemic to endemic?

Hello and welcome to season 1 – episode 2 -- of CME-TV: New Frontiers in Vaccinology. I’m your host, Susan Mayor. We’re here at the renowned Hannover School of Medicine where the world-leading pulmonologist Doctor Tobias Welte inspires medical students and leads a multicenter research group focused on respiratory infections. And if that weren’t enough, Dr Welte is also the President of the European Respiratory Society.

There is no one better than Dr Welte to help us understand, as medical professionals, what a shift from pandemic to endemic means for us and the communities we serve. Let’s go and see if we can find him, shall we?

Thank you for hosting us, Dr Welte. It’s great to be here in Hannover.

Tobias Welte, MD, PhD: Of course. My pleasure.

Dr Mayor: So, Dr Welte, the words epidemic, pandemic, and even endemic seem to be used almost interchangeably. But there are differences in their meanings. Can you help us understand how we should use these terms?

Dr Welte: Sure, let’s start with “epidemic.” An epidemic is the sudden outbreak of disease cases in a small population. Yellow fever, smallpox, measles, and polio are prime examples of viral epidemics. A pandemic occurs when an epidemic spreads over a wide geographical area affecting several countries. Or – as we recently saw -- the entire globe. Pandemics are often caused by the rapid spread of a new virus or viral strain that people have little to no immunity against. Endemic disease, on the other hand, is continuously present at a baseline level. A disease that isn’t eradicated is, by definition, endemic. This doesn’t necessarily mean that it’s circulating at low levels. Or that it’s harmless. But its spread and prevalence rates are more predictable. One of the best examples I can give of endemic disease is seasonal flu. It’s always present, has a predictable spread, and we know approximately when the season will begin and end. It’s the predictability of endemic disease that allows healthcare systems to prepare and prevent major loss of life. But occasionally, new variants can really throw things off.

Dr Mayor: The last 100 years have seen 4 influenza pandemics. The 1918 pandemic was caused by a viral strain thought to have originated in birds. And it was entirely new to humans when it made the jump. This H1N1 influenza A virus circled the world in 4 months, resulting in more than 50 million deaths. Eventually, transmissibility waned as population immunity rose. And the 1918 strain retreated. Down -- but not out -- the virus began to mutate and evolve into new viral strains. But how do those mutations occur? Let’s find out.

Can you remind us how influenza viruses evolve?

Dr Welte: There are basically 2 routes. Antigenic drift and antigenic shift. Drift is when mutations that occur during viral replication accumulate and change how antigens on the surface of the virus appear. If the changes offer a competitive advantage, they’re likely to persist. This helps the virus gradually evolve and evade immune systems. Antigenic shift is the swapping of genetic material with other strains of influenza infecting the same host. Sometimes this large exchange of genetic material creates an entirely new viral strain. And that’s exactly what happened in 1957 when a version of the 1918 H1N1 virus swapped genes with another bird flu giving us the H2N2 pandemic. It happened again in 1968, this time causing the H3N2 pandemic. The next influenza pandemic waited another 40 years to emerge in the spring of 2009. But it still had connections to the 1918 virus.

Dr Mayor: This is one stubborn virus!

Dr Welte: To say the least. And it was the 2009 strain that most closely resembled the one from 1918. Only this time it had elements originating from pigs, as well as humans and birds. Hence, its nickname -- the “swine flu.”

Dr Mayor: So...this version of H1N1 had hopped from people...to pigs and birds...?

Dr Welte: Yes. And then back to people again. So, by the time it began circulating in 2009, it had assorted genes from human, avian, and swine type influenza A viruses. It was an entirely new viral line, and its human hosts had virtually no immunity.

Dr Mayor: That’s remarkable. In less than 15 years, humanity has experienced 2 pandemics. And like the flu pandemic of 2009, COVID-19 spread quickly around the globe. Striking in waves. The virus causing COVID-19 -- SARS-CoV-2 – is also known for its multiple variants and subvariants. Omicron is currently the dominant strain. And the first outbreaks were caused by the subvariant BA.1. Then BA.5 became the dominant subvariant. And eventually it mutated into BQ.1 and BQ.1.1. And now, we have the subvariant XBB.1.5—nicknamed the Kraken. This is omicron’s most transmissible strain so far. More efficient and contagious than its predecessors.

And this is a Kraken. XBB.1.5 was nicknamed after this enormous mythical creature when scientists noticed how rapidly the subvariant was spreading. And the truth is, no one is certain how SARS-CoV-2 may evolve next. Or how many tentacles it may sprout. But it’s possible that the evolutionary path followed by the currently endemic flu virus may hold important clues. Either way, neither of these viruses are standing still. And we can’t either. So, as they continue to evolve, we must respond with safe and effective vaccines that tackle their changing characteristics. Let’s see if we can get some clarity on what the influenza virus and SARS-CoV-2 have in common. And what they don’t.

Dr Welte, can you help us understand how SARS-CoV-2 and influenza viruses compare?

Dr Welte: Well, one’s a mythical sea creature.

Dr Mayor: Right, with many tentacles.

Dr Welte: In all seriousness, both are single-stranded RNA viruses that require a host for replication. But their genomes differ in polarity and segmentation. Whereas SARS-CoV-2 has only one single strand of viral RNA, influenza’s genome is split into 8 segments of single-stranded RNA. Because it’s segmented, influenza can rearrange its genetic material to make different proteins that are harder for the immune system to recognize. While SARS-CoV-2 can’t rearrange its genetic material, a new RNA genome can be recombined – or stitched together – between 2 different viral strains when they infect the same host.

Both viruses use surface proteins to infect the host. But influenza is more variable than SARS-CoV-2 – one of the reasons why we see a different flu strain every year.

Dr Mayor: And it’s those surface proteins that are targeted by the vaccines. Correct?

Dr Welte: That’s correct. On the surface of the influenza virus are 2 proteins: hemagglutinin and neuraminidase. These are the H and N proteins. That’s where the references to an H1N1 or H3N2 strain come from. The flu virus uses the H and N proteins to bind to and infect host cells. SARS-CoV-2 uses S proteins – or spike proteins. Current seasonal flu vaccines are formulated to protect against 4 strains of influenza known to cause epidemics: H1N1, H3N2, and 2 influenza B viruses – the Victoria and Yamagata lineages.

With influenza, egg-based, cell-based, and live attenuated vaccines all target the H and N surface proteins. The recombinant flu vaccine only targets the H surface protein. The problem with influenza is that the dominant strain changes every year. The H and N proteins undergo frequent mutation, changing their appearance enough that the immune system can’t recognize them from one year to the next. That’s the antigenic drift that we talked about earlier. And because of this, the immunity that we develop to a previous strain will have only a muted effect on the new strain. This is one of the main reasons why flu vaccines have to be updated every for year. And it’s also the main reason for seasonal flu epidemics.

Dr Mayor: The World Health Organization predicts which flu strains will be most prevalent in the coming year. There are 18 different H and 11 different N subtypes, which means that one hundred and ninety eight combinations are possible.

And of course, the World Health Organization considers a variety of data when selecting which strains to recommend for vaccine production. They monitor which strains are causing infections, how efficiently those strains are spreading, where they’re spreading, their antigenic properties, and how well previous vaccines worked against those viruses. Once recommendations have been made, it takes manufacturers about six months to update the vaccine. And, unfortunately, it’s possible for the virus to mutate again during this time.

You know what, let’s check in with Dr Welte. I wonder how often that happens. And the impact it has on vaccine efficacy.

So, we were wondering. Because of the gap between the recommendation on which strains to include and administration when flu vaccines are updated each year, how effective are they?

Dr Welte: It depends on the match between the strains selected for vaccine inclusion and those that are found circulating that year. When projections are off, the mismatch has led to vaccine effectiveness as low as 10%. For example, estimates coming out of the US between 2004 and 2020 have ranged from 10% to 60%. In Europe, vaccine efficacy for 2021 thru 2022 was 33% against any influenza. Against H1N1 specifically, vaccine efficacy was 75%. The goal is to eventually develop a vaccine against all or most of the antigenic variants.

Dr Mayor: Does SARS-CoV-2 pose the same mutational challenges as influenza?

Dr Welte: In a way, but again, influenza is much more variable than SARS-CoV-2. During the first 2 years of the COVID pandemic, new variants of concern evolved independently. Delta didn’t come from the Beta variant. And Beta didn’t come from the Alpha variant. But since Omicron has assumed dominance, it has been the main lineage from which new subvariants have emerged. And the subvariants do seem to be inching more toward immune evasion.

Dr Mayor: Are current COVID vaccines still effective against the subvariants?

Dr Welte: Yes. So far the COVID vaccines and boosters have been effective in preventing severe illness and death. They also reduce, but do not eliminate, the risk of infection and transmission.

Dr Mayor: And why is that?

Dr Welte: They’re not able to prevent every virus particle from replicating. That means if you encounter the virus after vaccination, you may still get sick. But severe disease is prevented in most who become ill. And from a medical standpoint, this is enough because you want to avoid hospitalizations and deaths. But it's not so easy to be understood by patients who presume if they are vaccinated, that they will not get ill from this virus.

Dr Mayor: Is it the same with influenza vaccines?

Dr Welte: Yes, flu vaccines also lessen the severity and duration of illness in most people with infection. But they don’t necessarily prevent every infection. Influenza replicates fast and mutates a lot. How well flu vaccines work varies from season to season.

Dr Mayor: The breakthroughs behind the COVID vaccines unfolded over decades – starting more than 60 years ago with the discovery of messenger RNA. The first mRNA vaccines to combat COVID-19 were developed, tested, and given emergency use authorization in less than a year. This was achieved by applying years of pre-existing research and using established production systems. Given their global success during the COVID-19 pandemic, mRNA vaccines have gained much attention as a new vaccine platform.

With an mRNA vaccine, recipients don’t receive the pathogen, either as a whole or in pieces. Instead, this type of vaccine uses a genetic code instructing the body’s cells to make a small, noninfectious piece of the coronavirus’ spike protein that trains the immune system to respond. This is different from influenza vaccines that contain inactivated virus, a particle designed to look like a flu virus, or a live attenuated virus.

From our experience with COVID-19, can you explain how the agility of the mRNA platform impacts vaccine development?

Dr Welte: mRNA is a small molecule, and with this platform, you can quickly swap out the mRNA encoding different antigens. You can also include multiple antigens. But the question is whether mRNA technology can produce other viral glycoproteins. If so, the development time for flu vaccines could be shortened, and we could wait until closer to the flu season to determine which strains to include. Or if an unpredicted strain turned out to be the dominant one, we could quickly adjust the vaccine and use it immediately to protect more people.

Dr Mayor: How effective have mRNA vaccines been against COVID-19?

Dr Welte: In clinical studies, mRNA-based vaccines showed over 90% effectiveness against the clinical illness caused by COVID-19. Side effects were minimal. The most common were short-term localized pain, fatigue, and headache. Serious adverse events were rare. And similar in incidence to placebo.

Dr Mayor: Will yearly boosters be needed for COVID-19?

Dr Welte: We know the at-risk patients are the elderly, the multimorbid, frail, and immunosuppressed. These populations are likely to need yearly boosters. For younger, healthy patients, I'm not sure. But if everything stays as it is now, I expect the recommendation will be a yearly booster for a well-defined population. Similar to the flu.

Dr Mayor: When will COVID-19 become endemic?

Dr Welte: There’s no scientific consensus on the threshold for declaring endemicity. The COVID-19 pandemic is at an inflection point — meaning that high levels of immunity to SARS-CoV-2 are beginning to limit its impact and reach. If COVID-19 becomes endemic, it will be present at a certain level in a population at certain times of the year or year-round. Another indicator of endemicity is how many people are developing severe disease. Hospitalizations and deaths are substantially reduced in an endemic stage, but they still occur. The seasonal flu causes between 290,000 to 650,000 deaths annually, according to the World Health Organization.

Dr Mayor: What are current and future strategies to move COVID-19 from pandemic to endemic?

Dr Welte: Equitable vaccine distribution and ease of access to treatment are essential. COVID-19 vaccines became available in large quantities, but only in high-income countries. It's not enough to be successful with vaccination in one part of the world. The key is to increase vaccination rates and increase population immunity at the global level. If immunity is high in Europe but low in Africa, variants will occur because, in the regions with low population immunity, the virus will evolve. To move from pandemic to endemic, we must maintain a global health perspective.

Dr Mayor: On behalf of Dr Welte 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 3 – Influenza vaccines: What does the mRNA platform have to offer?

This transcript has not been copyedited.