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2 Dec 2020 16:45
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  •   Home > News > International

    How mRNA vaccines work, and how they might protect us from the flu and other diseases

    Pfizer and Moderna's COVID-19 vaccines are based on an as-yet unapproved technology. So beyond this pandemic, how might these and similar vaccines protect us against other diseases?

    First it was Pfizer, then Moderna: two drug company press releases, dropped days apart, announcing their COVID-19 vaccines that were more than 90 per cent effective against the disease.

    Even though there's plenty we don't yet know about the vaccines, such as long-term effects, experts are generally optimistic by these interim results.

    Aside from being potentially excellent news in the fight against COVID-19, these vaccines are based on relatively newish mRNA technology that's not approved in any vaccines — yet.

    And the fact that it seems to work so well, and — so far — without safety issues, means it could have benefits that reach much further than helping end the COVID-19 pandemic.

    How do mRNA vaccines work?

    Vaccines train our immune system to recognise pathogens, such as bacteria and viruses, and fight them off down the track.

    In other words, they give our body a practice run of the real thing, but without causing the full-blown disease.

    They do this by introducing our immune system to antigens — specific parts of a pathogen the body can then use to identify the invader in subsequent encounters.

    Traditional vaccines typically inject us with antigens as, for instance, bits of inactivated virus or purified molecules.

    But mRNA vaccines work differently. They don't contain antigens. Instead, they contain a blueprint for the antigen in the form of genetic material — that's the mRNA.

    In the case of Pfizer and Moderna's vaccines, both of which are two-dose vaccines, the mRNA provides the plans to build the spike protein that the SARS-CoV-2 virus uses to latch onto and infect our cells.

    When injected into muscle, the mRNA is taken into cells, which 'read' the mRNA and build antigens over the course of a few days, after which time the mRNA is broken down.

    The cells push the antigens outside their membrane and wave them around, a bit like a flag, alerting the immune system that something foreign has managed breach the body's defences.

    In response, a type of white blood cell called B cells make and pump out antibodies — Y-shaped molecules that form an immune 'memory' of that particular antigen. (Fun fact: the word 'antigen' comes from 'antibody generator'.)

    Antibodies can circulate in our blood stream for a long time, although we aren't sure how long SARS-CoV-2 antibodies last.

    Should an antibody encounter a virus bearing its matching antigen, it latches on, stopping the virus from worming its way into a cell, and signals to the immune system that an invader has been detected.

    Yet antibodies aren't the whole story. The other arm of what's known as our adaptive immune system hinges on T cells — a type of white blood cell.

    One T cell subset, known as memory T cells, helps B cells manufacture antibodies with more accurate antigen-recognition sites, which hones the immune response.

    A second subset of T cells, called cytotoxic or killer T cells, seeks and destroys cells in our body that have been infected by a pathogen.

    Some of these killer T cells retain a 'memory' of their foe and hang around in the body for a long time, ready to mobilise and strike again if needed.

    Interim results from Pfizer and Moderna suggest their mRNA vaccines certainly tick the antibody box, said Magdalena Plebanski, a professor of immunology at RMIT University.

    "But these mRNA vaccines, from what I've read in their press releases, do not seem to be as powerful at inducing cytotoxic T cells," she said.

    That said, T cell function is harder to measure than antibody levels — plus different laboratories have their own ways of doing it — so it's hard to compare vaccines that way.

    And less T cell action isn't necessarily bad news, Professor Plebanski added.

    mRNA vaccines' strength in generating antibodies means they may prevent pathogens from hijacking our cells in the first place, such as malaria, which invades and reproduces in red blood cells.

    Indeed, mRNA vaccines have been in early phase studies to protect against viral infections such as Zika and rabies, according to Sanjaya Senanayake, an infectious diseases specialist at the Australian National University.

    Could mRNA vaccines help control flu?

    mRNA vaccines could also potentially control seasonal influenza, which struck 310,000 Australians last year, Dr Senanayake said.

    Influenza strains that infect humans and spread around the world each year have two main types of spike protein on their surface: haemogglutinin and neuraminidase, or H and N respectively.

    Each influenza strain is named for its H and N subtypes. For instance, H1N1 was responsible for the 1918 pandemic and is still one of the main flu infections circulating today.

    But the same Hs and Ns aren't in circulation each flu season. They mutate and change year to year. So infectious disease experts make an educated guess about which H and N antigens the next flu vaccine should include.

    From deciding on H and N subtypes to final product, the seasonal flu vaccine process takes around six months.

    The beauty of mRNA vaccines is the speed at which they can be designed and made.

    Once you know the mRNA sequence for your antigen of interest, it's relatively quick and straightforward to synthesise that genetic material in the lab — and certainly much faster than producing the amount of antigen needed for flu jabs every year.

    And Moderna, at least, is already on it.

    In May 2019, the company reported Phase 1 clinical trial results for mRNA vaccines against two influenza strains with pandemic potential: H10N8 and H7N9, both of which were first found in humans in China in 2013.

    Terry Nolan, an epidemiologist at the Doherty Institute, was at the conference in Slovenia last year where Moderna presented its results.

    "They had much better antibody responses than any of the other conventional approaches to influenza vaccines," Professor Nolan said.

    And while it's true that Moderna has not yet produced a human vaccine all the way to FDA approval, "it already had human trials for influenza for these two candidates, which both looked spectacularly good".

    The seasonal flu vaccine is really a combination of four: two against influenza A strains, which can be transmitted between humans and animals, and two influenza B strains, which infect humans only.

    A mRNA vaccine could package them all up into one.

    "It would be theoretically possible to have those four components as different types of mRNA in a single vaccine," Professor Nolan said.

    "That would be much easier to make than the current egg-based or cell-based vaccines which are used for flu."

    Scientists have long been working towards developing a universal flu vaccine — that is, one that protects against all strains of the virus, no matter their H or N status.

    That would involve making mRNA that codes for a chunk of the virus that's identical across all strains, and does not mutate easily, Dr Senanayake said.

    "So I think if a mRNA vaccine is being looked at for flu, it's probably best to see if they can target those areas, then whatever technology you use, you're more likely to get a longer lasting flu vaccine, because it won't matter if the Hs and Ns change."

    Can mRNA vaccines help us be ready for the next pandemic?

    Alongside diseases like the flu that have been around for more than a century, our immune system must grapple with new and emerging infections.

    A 2007 World Health Organization report warned that infectious diseases are emerging at "the historically unprecedented rate of one per year".

    SARS, Zika, Ebola and avian and swine flu — not to mention COVID-19 — are just a few recent examples.

    For most vaccines against emerging diseases, the challenge is not vaccine effectiveness.

    Instead, it's about speed: developing and manufacturing a vaccine and getting it to the people who need it as quickly as possible.

    That's why once the infrastructure is in place, mRNA vaccines are potentially a good weapon to have on hand, said Larisa Labzin, an immunologist at the University of Queensland.

    "I think the biggest advantage of the mRNA vaccines is really against these emerging pathogens, the ones that we don't know much about," Dr Labzin said.

    "As long as we essentially have the mRNA sequence, we could theoretically deliver anything. That makes it very practical for making vaccines."

    A previous emerging infection — MERS — gave scientists a bit of a leg-up when it came to making mRNA vaccines for COVID-19.

    "A lot of people have been studying the spike protein of the MERS coronavirus, which is structurally similar (to the SARS-CoV-2 spike protein)," Dr Labzin said.

    "Then they could get the structure of the SARS-CoV-2 spike protein very, very quickly, and that meant they knew which kind of modifications to make to the (mRNA) sequence of the spike protein."

    Even though Pfizer and Moderna — and others — could make quick leaps forward based on existing work, none of it would be possible without basic research, she added.

    "Those small tweaks that we can make by studying the structure of RNA and how stable it is at different temperatures, and how we introduce this material into cells — they all make a huge difference.

    "All those things can be attributed to scientists working on what seemed like an obscure problem in a lab, but then has incredible benefits."

    © 2020 ABC Australian Broadcasting Corporation. All rights reserved

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