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Flu Shots Can be Shot in the Dark – Scientists are Looking to Shed Light on a New Approach

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Why the Flu Shot Fails So Often

Some virus species are more likely to mutate and evolve quickly than others. Among the champions of rapid changes is the flu virus (influenza).

This means that every season's flu strain is different from the previous year's strain. It is also the main way for the flu to escape our immune system, as the new strain is likely to be different enough not to be neutralized by antibodies designed for last year's version of the virus.

Source: David Hager

Vaccine designers and manufacturers face the same issue. They know what last year's flu genetic and immunologic profile was, but they can only guess what the current year's profile will be. Since vaccines are a preventive measure, they need to create in advance a treatment for a virus that is still unidentified.

They also have to cover the different species of influenza, often adding as many as there are flu strains in one vaccine, 2 for influenza A and 2 for influenza B.

So far, vaccine makers have played this game with mixed results. A correct guess can result in a very effective seasonal vaccine. An incorrect one can bring down the vaccine's efficiency dramatically. This leads to both poor health outcomes, but also poor utilization of the flu vaccine, as people are often not convinced it will be efficient enough to be worth the trouble.

How the Flu Shot Works

Flu viruses contain a code describing two particular surface proteins at the surface of the virus particle, for example, H5N1. The H is for hemagglutinin (HA), a protein that binds to a receptor on human cells. The N is neuraminidase, a second protein that enables a newly made virus to escape the host cell.

So the “H” component is responsible for targeting human cells, and the “N” component is key in infecting new cells once the virus is replicated. Between the 2, hemagglutinin is 5-10x more abundant than neuraminidase. So natural immunity and vaccines both tend to focus on this hemagglutinin.

Source: David Hager

Hemagglutinin is shaped a little like a lollipop, and the quickly changing head is what is usually targeted by vaccines. In contrast, the “stalk” part is a lot less changing. Multiple experiments by researchers have proven that the stalk cannot change much without the protein losing its function.

By making the immune system (both natural and vaccine-enhanced) focus on the head, the virus can make sure every new seasonal strain has a good chance to escape the immune system's memory. With that in mind, researchers at Duke University, USA, have looked for a strategy to force the immune system to focus on the stalk part of hemagglutinin instead.

Changing The Flu Shot Target

In a scientific publication called “Vaccination with antigenically complex hemagglutinin mixtures confers broad protection from influenza disease“, published in Science Translational Medicine, the Duke research explains how they use mutation against the flu virus.

Using modern gene editing techniques, they created 80,000 variations of the portion at the head of hemagglutinin. This creates a very diverse mix of virus strains, where a specific configuration of the protein's head would rarely be met twice by an immune cell.

So, due to the extremely high level of variations of the head part, the immune system went on ignoring it and focused on the more consistent stalk part of the protein instead.

In animal models (mice), this resulted in 100 percent of the mice avoiding illness or death from what should have been a lethal dose of flu viruses.

This made the vaccine containing this massive mix of 80,000 different hemagglutinin heads much more efficient than traditional flu vaccines.

Does This New Flu Shot Work?

The surprising result was that in many cases, the vaccine designed to target the stalk was also improving antibody responses to the head region of the protein as well.

This is important because targeting the head helps limit the initial step of the infection.

Antibodies against the stalk work differently,” Heaton said. “Their mechanism of protection is not necessarily to block the first step of infection.

So then our idea was, ‘What if we can come up with a vaccine that gives us both? What if we can get good head antibodies and at the same time also get stalk antibodies in case the vaccine selection was wrong, or if there's a pandemic?’”

“Essentially, the paper says, Yes, we can accomplish that,” – Dr. Nicholas Heaton, associate professor of molecular genetics and microbiology at Duke University.

The next step will be to understand how many hemagglutinin variants are actually needed. The 80,000 variants were more of a proof-of-concept, but a final product usable on humans could be simpler.

And of course, tests on human cells and people to assess for safety and efficiency in real patients will be needed before any commercialization of this idea occurs.

Flu Vaccine Companies

While Novartis used to be a major flu vaccine producer, it sold its flu vaccine assets to CSL Sequirus, a company part of the larger CSL limited, now the largest flu shot manufacturer in the world but also mostly active in plasma collection.

This leaves the leadership of flu vaccine production and innovation among publicly listed companies to a few other pharmaceutical giants. This is a very large market, with no less than 156 million shots planned for 2024 in the US alone and around 760 million globally, a number that surged after the Covid pandemic.

Source: WHO

1. Sanofi

finviz dynamic chart for  SNY

Sanofi is a leader in the vaccine market, with a strong presence in the yearly flu vaccine. It notably has a long history of involvement in flu vaccine research, back to as far as 1947.

Source: Sanofi

It is also a leader in overall immunology, notably thanks to Duxipent, an anti-allergic therapy.

Sanofi's R&D efforts in the sector rely on both traditional vaccine technologies and mRNA vaccines. By 2025, it expects to present at least 5 “best-in-class” new vaccine candidates in phase 3 of clinical trials.

As a result, the company expects its vaccine sales to grow to as much as $10B+ by 2030, mostly from a continuous lead in influenza, and growth in RSV, Pneumococcal, and new mRNA markets.

It is also working on innovative immunology technology platforms, like antibody-drug conjugate, SYNTHORIN, and leveraging the body's Natural Killer (NK) cells, as well as combining these with AI and genomic research.

Sanofi is expanding in areas where vaccines tend to underperform, like infants with an immature immune system. And it is also looking to expand vaccines' potential, notably by targeting acne.

Sanofi being a leader in immunology in general, and vaccines in particular, including flu vaccines, makes it a good candidate to be among the companies to commercialize the ultra-high variation of hemagglutinin head sequence. And it could experience solid growth from its R&D strategy to focus on immunology and inflammation (dermatitis, psoriasis, asthma, multiple sclerosis, auto-immune diseases, etc).

Source: Sanofi

2. GSK

finviz dynamic chart for  GSK

GSK is another heavyweight in vaccine production, notably with an advanced 5-in-1 meningococcal vaccine (for meningitis) that brought $1.6B in revenues in 2023, even though it has been accepted for review in the USA only in April 2024.

GSK has a strong focus on respiratory therapies and vaccines, making £11B in 2022, or 38% of the group’s sales.

Source: GSK

Another remarkable data point is that GSK has the largest patent volumes related to influenza vaccine vectors.

The company is also working on expanding its vaccine offer. Its RSV vaccine targeting 50-59-year-old adults was approved in January 2024 and is the first to be available for this population. More innovative vaccines are in development, including for:

  • Influenza
  • Singles
  • Meningococcal diseases
  • Pneumococcal diseases
  • Hepatitis B
  • Herpex simplex virus

GSK expects the vaccine category to keep growing at a “High-single-digit % CAGR”.

GSK's focus on infectious diseases, through vaccines and new antibiotics, answers a pressing need in the context of rising antibiotic resistance and new epidemics. It is also the provider of adjuvants or manufacturing services to other companies' vaccines, which puts it in a prime position to benefit from improvements in classical vaccines and manufacture them at scale.

If seasonal flu vaccine performance were to rise thanks to ultra-high variation of hemagglutinin head sequence design, GSK would likely benefit from it.

Partially through higher sales of adjuvants and manufacturing services. And partially through its own version of this technology, as a strong presence in the vaccine and respiratory markets is central to GSK's overall corporate and R&D strategies.

Jonathan is a former biochemist researcher who worked in genetic analysis and clinical trials. He is now a stock analyst and finance writer with a focus on innovation, market cycles and geopolitics in his publication 'The Eurasian Century".