In 1928, Alexander Fleming, a Scottish pathologist working at St Mary’s Hospital in London left for a Suffolk holiday, omitting to tidy his lab before departing. On returning, he made a curious observation. Some of his petri dishes growing Staphylococcus aureus – a type of bacteria that causes wound infections – had been contaminated by a Penicillium mould. As the mould grew, the Staphylococcus died.
Fleming was lucky. The phenomenon is notoriously hard to re-create. Nevertheless, he had intuition. Unlike 19th century scientists with similar observations, Fleming interpreted his results correctly. The mould, he realised, made something that killed the Staphylococcus. It wasn’t just depriving the bacteria of nutrients. Fleming named his substance ‘penicillin’ and did a few experiments to show which bacteria were killed by crude extracts. But he had no idea what penicillin was chemically, nor how to purify it. His boss discouraged further work, so Fleming wrote up his results in a second-tier journal and departed the topic.
A decade later, World War Two spurred research in wound infections, including by Howard Florey’s Oxford group. Florey’s colleague, Ernst Chain, a Jewish refugee from Berlin, stumbled on Fleming’s paper. Between them they re-found Fleming’s substance and extended his work. Norman Heatley, another colleague, discovered how to purify penicillin and rigged a Heath-Robinson apparatus that produced enough to dose mice infected with sepsis-inducing Streptococcus bacteria. Treated mice survived; control mice died.
They gave their drug to a dying cancer patient. It didn’t poison her. That counted as toxicity testing. Next, to a policeman, Albert Alexander, dying of sepsis. Alexander began to improve but the penicillin ran out, despite desperate efforts to recover the drug from his urine and to recycle it into his veins. Alexander died but the potential was clear. Another Alexander – Fleming – resurfaced. Unlike Florey he had political friends and a nose for the media.
Penicillin, never patented, passed to U.S. pharma with the skills and money to scale production. From a rotting melon, they isolated a Penicillium mould that made 1,000 times more antibiotic than Florey’s strain. They mutated it with X-rays, further increasing yield. Next, they learnt to grow the mould in huge fermenters, fed with a maize extract, ‘corn steep liquor‘. This led to a consistent product, penicillin G. By 1943, penicillin G was with the Allied military. At first much was used for gonorrhoea, where cases needed little drug and could immediately return to the battlefront. Wound infections responded too, but needed more drug and took longer.
Florey, Chain and Fleming won the 1945 Nobel Prize for Medicine. Heatley was a shameful omission. Without Heatley’s ramshackle production line, penicillin wouldn’t have got off the ground. Fleming – who’d contributed a lucky observation and a shrewd guess – was a lucky awardee, but relished the limelight and is remembered in the popular mind as the ‘discoverer of penicillin’.
Which brings us to the 2023 laureates, Katalin Karikó and Drew Weissman, for work on mRNA vaccines. The principle of an mRNA vaccine – well familiar to readers of this website – was first outlined in 1987 by Dr. Robert Malone, then of the SALK Institute. mRNA encoding a pathogen component – in Covid’s case, the spike protein – is given to the vaccinee, who manufactures the corresponding protein. In theory, this elicits both an antibody and a cellular immune response against the protein, much like when someone develops natural immunity. If the vaccinee is later infected, he or she is primed to make an immune response against the pathogen. This differs from a traditional vaccine, where you are given an attenuated or dead pathogen or part of the pathogen. With an mRNA vaccine you make the pathogen component yourself, as if you had been infected but without the risk of the live virus. mRNA, it should be added, is a long string-like molecule composed of four types of ‘bases’: adenine, cytidine, guanidine and uridine. It carries instructions from DNA, which stores the cell’s information, to the ribosomes, which manufacture proteins.
Malone’s experiments, and those of later investigators, stalled owing to two problems. First, naked mRNA causes a strong inflammatory response if injected as part of a lipid nanoparticle. Secondly, it is swiftly degraded. The answers were to modify the mRNA, converting uridine bases to pseudouridine, and to encapsulate this modified mRNA within lipid nanoparticles. These modifications protect the mRNA and facilitate cellular uptake.
Karikó and Weissman’s Prize is specifically for the uridine-to-pseudouridine conversion, which is used – with a further modification to 1-N-methyl pseudouridine – in both the Pfizer and Moderna vaccines. A similar vaccine from CureVac used unmodified mRNA in lipid nanoparticles at lower doses, and was less effective, albeit with fewer side effects. CureVac consequently lost out in the race. This might underscore the importance of Karikó and Weissman’s conversion. Or it might merely reflect the lower dosage for CureVac’s product. Or it might be because CureVac’s initial testing (and funding) slightly lagged Pfizer-BioNTech and Moderna, so that the circulating virus evolved further away from the original Wuhan variant upon which all these vaccines were predicated.
In any event, the immune protection afforded by the winners’ vaccines hasn’t proved lasting. Only last week I dined with a chap on his sixth mRNA shot and his third Covid infection. I doubt he’s the record.
Dr. Malone – whose claim on mRNA vaccines is hugely better than Fleming’s for penicillin – gets nothing. Nor does Pieter Cullis, who laid the groundwork on lipid nanoparticles for drug delivery used in all three of the mRNA Covid vaccine candidates.
It’s easy to see why Malone is excluded. He has turned vehemently against his brainchild and become persona non grata. Some deny his discovery role, but his name is on early patents. Even Nature, no friend of his views, begin its account of mRNA vaccines with him.
Malone’s concerns about mRNA vaccines are numerous, but include the well-demonstrated fact that, in some vaccinees, spike protein production persists for at least six months. This may trigger immunosuppression, as the body begins to treat the protein as a ‘normal’ component. Moreover, the lipid nanoparticles distribute widely in the body – as was known from pre-pandemic animal experiments – causing spike protein production in tissues that no respiratory coronavirus would ordinarily reach. Furthermore, peer-reviewed data indicate that the mRNA vaccines induce much more spike protein, and induce its production for longer, than does viral infection. Since the spike protein has some inherent toxicity, including for heart tissue, this may be deeply undesirable.
The prolonged spike protein production is precisely due to Karikó and Weissman’s modification. This stops the mRNA being broken down in the normal way. Also among Dr. Malone’s further concerns is the fact that the body ordinarily converts a few uridine residues to pseudouridine (without the 1-N-methyl) in a precisely controlled manner. This naturally-modified mRNA may link to innate immunity, which forms the body’s first barrier against infection. The consequence of delivering an mRNA with all its uridines converted is unknown.
I doubt Dr. Malone wishes to share with Karikó and Weissman’s Prize, though it remains more than plausible that other mRNA vaccines, based on his insights, will find a useful future niche. Much work, for example, continues on anti-cancer mRNA vaccines. I’m guessing that Dr. Cullis would like to be on the podium. He has shared other recent awards with Drs. Karikó and Weissman and his local (Vancouver) newspaper laments his being “overlooked“. It has a point: he’s been treated like Heatley and his discoveries have found wide and uncontentious application for the delivery of otherwise toxic or swiftly-metabolised drugs.
But it’s clear that the Nobel Committee has very deliberately chosen a narrow award, perhaps precisely because it cannot honour Dr Malone. Olle Kampe, the Committee’s vice-chair gives a hint, telling the press that he hopes the award will help to combat anti-vaccination sentiment, adding: “We know that it is a very safe and effective vaccine.”
He’d better be right. If the troubling litany of side-effects does reflect protracted spike protein production owing to Karikó and Weissman’s modification, they’ll have awarded the prize for the Covid vaccines’ Achilles Heel, not for the more-widely applicable discoveries of Drs. Malone and Cullis. That’d be in the realms of the unfortunate 1949 prize to Egas Moniz who, from the 1930s, devised and promoted lobotomy as a treatment for psychiatric disease.
In a self-exculpatory article for this latter faux pas, the Prize Committee notes: “It should be recognised that more rigorous, prospective long-term studies… are essential to assess the long-term outcomes.”
By 1945 the benefits of penicillin were beyond dispute. It took until the early 1960s to debunk lobotomy. In 2023 the long-term performance of mRNA Covid vaccines in general, and Karikó and Weissman’s modification in particular, remains open to debate.
The Nobel Committee, turning its prize into propaganda, has forgotten its post-Moniz wisdom.
Dr. David Livermore is a retired Professor of Medical Microbiology at the University of East Anglia.