War spurs medical innovation. Ambulances to swiftly deliver the casualties of Napoleon’s armies to field surgeons were the brainchild of Jean-Dominique Larrey. Florence Nightingale established professional nursing in the Crimea. The Kaiser’s War brought the Thomas Splint, reducing mortality and amputation following limb fracture; 1939-45 spurred Florey and Chain’s development of penicillin and McIndoe’s reconstructive plastic surgery. All are now integral to civilian healthcare.
mRNA vaccines are offspring of George Bush’s ‘War on Terror’.
The idea of mRNA vaccines goes back to Robert Malone’s discoveries of the late 1980s, but he was unable to pursue them and the patents passed to Merck, who spent the end of the old century expensively failing to develop a product. The idea might have remained in abeyance had it not been for 9/11 and the curious episode, immediately afterwards, when letters laced with anthrax spores were posted – allegedly by a disaffected U.S. Army scientist – to Senators and media outlets, killing five people and infecting 17 more.
A world already shaken by planes-turned-to-missiles awoke to bioterrorism. With modern molecular biology it isn’t hard for a disaffected PhD student to insert genes for virulence or antibiotic resistance into a pathogen; it’s a lot easier than building a nuclear bomb in your backyard. The bigger barriers are obtaining the pathogen in the first place and finding an effective distribution system. As then-Director of the Antibiotic Resistance Laboratory at the Public Health Laboratory Service (UKHSA’s major predecessor) I wrote advice on which antibiotic to consider if some ‘bad actor’ modified anthrax or plague. My counterparts at Porton Down were more deeply involved.
Concerns extended to viruses. In 2018 a pharmaceutical company – seeking new smallpox vaccines – re-created the extinct horsepox virus using DNA chemistry alone. Given the right conditions, the reborn virus infected tissue culture, replicating itself. The potential to recreate smallpox became all too apparent. Many of us believe that the COVID-19 pandemic began with the escape of a virus manipulated by collaborating U.S. and Chinese scientists.
The U.S. response has been to lavishly fund its Biomedical Advanced Research and Development Authority (BARDA), Defence Advanced Research Projects Agency (DARPA) and Defence Threat Reduction Agency (DTRA). Please don’t ask me how these interact and divide responsibilities; I never did understand. But they passed money to anyone with plausible product. By 2011, I’d moved to UEA and was consulting on antibiotic development for biotechs. We’d always review whether their prospective drug might cover some bioterrorism agent. If so, there was a chance of biodefence money.
DARPA alighted upon mRNA vaccines. Their beauty was that, if you sorted delivery, mRNA instability and toxicity, then you could adapt them for any pathogen. Think of the mRNA vaccine as a missile (lipid nanoparticle and mRNA modification to give stability) and payload (specific mRNA encoding the antigen). Once you have the missile you can fill it with an armour-piercing payload, or a high explosive, or shrapnel, gas or nuclear. Likewise with mRNA, different strands of mRNA cause the vaccinee to make different proteins, which elicits (in theory) the desired immune response. Bingo.
mRNA technology allows swift adaptation in a world of diverse threats. Making a conventional vaccine requires you to grow the virus and then kill it or develop an attenuated variant that induces immunity but not the disease. In the latter case, you must ensure that your attenuated virus can’t revert to virulence, as has happened with some polio vaccines. Alternatively, you can purify a viral component and use that as the antigen, perhaps conjugated to a carrier to increase immunogenicity. That is laborious compared with just swapping an mRNA payload. What’s more, mRNA vaccines, giving prolonged antigen synthesis, might better resemble natural infection than a single shot of an inert protein conjugate.
DARPA funded mRNA vaccine research at pharmaceutical majors. But none pursued it. According to a DARPA spokesman: “They were reticent about taking on any risk with a new regulatory pathway for vaccines, even though the data looked good.” The technology passed to Moderna and BioNTech, start-ups without marketed products.
It was their vaccines – hurriedly given Emergency Use Authorisation under classical vaccine rules, not the anticipated ‘new regulatory pathway’ – that became the backbone of the West’s Covid response. Some see a grand military-industrial conspiracy. Others, like me, think it was just a consequence of: (i) competing DNA vector vaccines – AZ and J&J – being less effective in early trials and becoming associated with blood clots; (ii) killed virus and protein component vaccines coming much later; and (iii) competing non-mRNA vaccines not being updated (however spuriously) as the pandemic continued.
The big three vaccine companies – GSK, Merck and Sanofi – were not big players in the Covid vaccine business. GSK and Sanofi collaborated but abandoned their initial product after disappointing Phase I/II results; much later they developed a protein vaccine but, by then, the bottom was falling out of the market. Merck sold a major equity interest in Moderna on December 2nd 2020, one day after the latter reported “94% efficacy” for its vaccine in Phase III. The shares, at $143, were up seven-fold on the purchase price, but it was early to sell, with profits expected to flow. In August 2021 they hit $480. You might think that Merck wanted ‘Out, and fast’.
The vaccine majors retain an interest in mRNA: Merck is co-developing a skin cancer vaccine with Moderna and has an mRNA flu vaccine for pigs. But their big commitments lie with conventional vaccines. The folks who are betting big on mRNA are our Governments. The U.K., Canada and Australia have each put around £1 billion of taxpayers’ money into mRNA vaccine plants, to be developed by Moderna.
Is this wise?
There are differing opinions of the recent mRNA Covid vaccines. The official view, heard less and less, is that they saved 20 million lives. At the other extreme, some believe that they failed completely and are the major driver of ongoing excess deaths. Others, like me, believe that they did some good in 2021 but then were recklessly overused in low-risk groups and as untrialled multi-booster regimens, causing harm without further benefit. All these viewpoints remain defensible.
What’s not defensible is any assertion that mRNA vaccines stopped viral circulation, gave long-term protection or are as safe as, say, traditional inactivated-virus flu vaccines. The failure to protect is evident to everyone from personal experience, and the vast excess of VAERS and Yellow Card reports for Covid vaccines evidences the safety issue. This is far from the clear-cut success of many conventional vaccines, for example against smallpox, polio, diphtheria, measles, tetanus and Haemophilus b meningitis.
There is an urgent need to understand where the problems lie. In the missile or the payload? Is the spike protein inherently toxic, leading to cardiac damage? Are induced bloodstream antibodies in the wrong place to abort infection in the upper airways? Have coronaviruses evolved so that you can’t achieve lasting immunity however you try? Those would be payload problems, irrelevant to a different target. Or is the whole strategy flawed because lipid nanoparticles cause prolonged antigen production in tissues that the target viruses would never reach? Does harm arise from replacing uridine with pseudouridine in the mRNA, giving a persistent product? Such problems might require a total rethink of the missile.
Which brings us back to Moderna’s share price, down from $104 to $85.60 over the past fortnight owing to disappointing results on a developmental mRNA respiratory syncytial virus (RSV) vaccine. RSV causes some mortality at the extremes of life and bounced back strongly after the end of the Covid lockdowns. Most (97%) RSV infant deaths occur in low-income countries. In adults, Moderna’s mRNA vaccine gave 84% protection against symptomatic infection to 3.3 months but only 63% to 8.6 months. Conjugate RSV vaccines already marketed by GSK and Pfizer performed better, with the former’s product still giving 77% protection to 14 months. Comparison is complicated owing to differences in trial design and end-points, but it’s hard to dispute the market’s conclusion that the mRNA product has an uphill battle.
Unless and until manufactures can show that, with the right payload, mRNA vaccines are as safe and effective as traditional vaccines against the same pathogen, governments really should be more careful about ‘investing’ our money. God knows, they’ve blown enough of it already, these past four years.
Dr. David Livermore is a retired Professor of Medical Microbiology at the University of East Anglia.
Stop Press: Lord Sugar seems unimpressed by the mRNA vaccines.
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