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The mRNA Vaccine Story

By Updated 23 min read
The mRNA Vaccine Story

When the first COVID-19 vaccines were approved in December 2020, less than a year after the virus’s genome was published, the speed looked almost miraculous. It rested on sixty years of slower work: the discovery of messenger RNA in 1961, decades of failed attempts to turn it into a medicine, a chemical tweak that stopped it provoking the immune system, and tiny fat bubbles that could carry it into cells. This essay follows that story, from a laboratory question about how genes make proteins, through the 2023 Nobel Prize for Katalin Karikó and Drew Weissman, to what the evidence shows about the vaccines’ benefits and risks, and to the cancer and gene-editing treatments now in late-stage trials.

Key findings

  • Messenger RNA was identified in 1961 as the short-lived molecule that carries instructions from genes to the cell’s protein factories[1, 2].
  • In 2005 Katalin Karikó and Drew Weissman showed that swapping in modified versions of uridine stopped synthetic mRNA from triggering inflammation, work recognised by the 2023 Nobel Prize in Physiology or Medicine[3, 4].
  • In phase 3 trials the Pfizer–BioNTech and Moderna vaccines were 95% and 94.1% effective against symptomatic COVID-19; the UK regulator approved the first on 2 December 2020[5, 6, 7].
  • One modelling study estimated that COVID-19 vaccines of all types averted 14.4 million deaths in their first year; myocarditis, mostly in young males after a second dose, is the best-documented serious side effect[8, 9].
  • In August 2026 Merck and Moderna reported that a personalised mRNA cancer therapy met its main endpoint in a 1,137-patient phase 3 melanoma trial; the companies have not yet released the figures, which are due at ESMO in October[10, 11].

A messenger between genes and proteins

By the late 1950s biologists knew that genes were made of DNA and that proteins were assembled on particles called ribosomes in the body of the cell, outside the nucleus. What carried the instructions between them was unclear. In 1961 Sydney Brenner, François Jacob and Matthew Meselson published evidence, from bacteria infected with a virus, for “an unstable intermediate carrying information from genes to ribosomes”[1]. It was a small, short-lived fraction of the cell’s RNA, and it was soon named messenger RNA, or mRNA[2].

The idea behind an mRNA medicine follows directly. If a cell will make whatever protein an mRNA molecule describes, then injecting the right mRNA could turn the body’s own cells into factories for a vaccine antigen or a missing enzyme. Making the molecule was the first hurdle. In 1984 Paul Krieg and Douglas Melton showed that large amounts of mRNA could be made in a test tube using an enzyme from a bacterial virus, and the related T7 RNA polymerase system became the standard way to produce any mRNA sequence on demand[2].

Getting mRNA into cells was the second. RNA is fragile and negatively charged, and cells do not readily take it up. Researchers tried wrapping it in liposomes, tiny bubbles of fat; as early as 1978 they had used liposomes to carry purified globin mRNA into mouse lymphocytes and human epithelial cells[2]. At Syntex Research Philip Felgner made a positively charged lipid that bound nucleic acids tightly, and in 1989 Robert Malone, Felgner and Inder Verma at the Salk Institute used it to deliver mRNA into cultured cells, reporting that mRNA with a protective cap and suitable flanking sequences made at least 1,000 times more protein than mRNA without them[2, 12]. In 1990 Jon Wolff, Felgner and colleagues showed that mRNA injected straight into mouse muscle produced protein, and in 1993 a French team showed that mRNA in liposomes could prime immune cells against influenza in mice[13, 14].

Those results did not lead quickly to medicines. According to the Nobel Committee’s scientific background, most vaccine researchers in the 1990s regarded DNA as the more promising approach because it is more stable, and doubted that mRNA could ever be robust enough for use in patients[2]. A small community kept working on it anyway.

To see why anyone persisted, it helps to compare the alternatives. Most antiviral vaccines in use before 2020 were made from weakened or inactivated whole viruses. Live attenuated vaccines, such as those against measles, mumps and rubella or yellow fever, give strong and long-lasting immunity; inactivated ones, such as the hepatitis A vaccine, need repeated boosting. Molecular biology then made it possible to produce single viral proteins. The first such subunit vaccine, against hepatitis B, was approved in 1986, followed by the first HPV vaccine in 2006; both protect against cancers caused by viruses. A third route uses a harmless carrier virus engineered to carry the gene for an antigen, and the first licensed viral vector vaccine, against Ebola, was approved in 2019[2]. All of these need large cell-culture plants to grow viruses or proteins, which is one reason researchers were drawn to delivering the genetic instructions instead and letting the body make the protein itself[2].

DNA and mRNA offered the same promise of speed: change the sequence and the vaccine encodes a different antigen, with nothing new to grow. Because the antigen is made inside the body’s own cells and displayed on their surface, both can also train cytotoxic T cells, the immune cells that kill infected or cancerous cells, which matters for cancer vaccines in particular. But DNA vaccines that worked well in small animals did poorly in people. The Nobel Committee suggests a likely reason: injected DNA must cross two barriers, the cell membrane and then the membrane of the nucleus where it is copied into mRNA, whereas mRNA only has to reach the cytoplasm, where proteins are made. mRNA also cannot integrate into the genome. Its handicap was a reputation for being too unstable to be useful[2].

Some groups tried to get more protein from each dose with alphavirus replicons, RNA derived from a family of viruses that copies itself once inside a cell, so that each cell makes many antigen-encoding transcripts. In animals these gave strong immune responses even when injected as naked RNA. Even so, the Nobel Committee notes, more than two decades passed before the first mRNA vaccine against an infection was tested in a human trial[2].

Karikó and Weissman’s modification

One of them was Katalin Karikó. Trained at the Biological Research Centre in Szeged, where she completed her PhD in 1982, she moved to the United States and eventually to the University of Pennsylvania, where she spent years trying to make mRNA produce therapeutic proteins efficiently[2]. In the late 1990s she began working with Drew Weissman, an immunologist who had trained in Anthony Fauci’s laboratory at the National Institutes of Health and joined Penn in 1997. Weissman wanted to use mRNA to load dendritic cells, the immune system’s sentinels, with antigens from HIV[2].

Karikó’s route to Philadelphia ran through postdoctoral work at the Hungarian Academy of Sciences and research posts at Temple University and the Uniformed Services University of the Health Sciences in Bethesda; in 1997 she set up her own group in Penn’s Department of Neurosurgery. She worked through the parts of test-tube mRNA one at a time to find what made it produce protein well. Among other results, she showed that mRNA encoding luciferase, a light-producing reporter protein, could be delivered to the rat brain in a lipid carrier, and that a longer poly(A) tail, the run of adenosines at the end of the molecule that is added in cells by polyadenylation, increased the amount of protein made[2]. NobelPrize.org’s own profile describes a career in which she “was met with mistrust and eventually forced to leave academia”[15].

They kept running into the same problem. Synthetic mRNA made in the test tube set off an inflammatory response in dendritic cells; mRNA taken from mammalian cells did not[2, 3]. Cells detect foreign RNA through sensors including the Toll-like receptors, and Karikó and Weissman suspected the difference lay in the chemistry. RNA in human cells carries many small chemical modifications to its four bases; RNA made in a test tube carries none[3].

The clues came in stages. At first the activation looked like a bonus, since activated dendritic cells are better at priming T cells, and the pair showed that dendritic cells loaded with mRNA for the HIV protein Gag stimulated T-cell responses in the laboratory; only later did the cost of this innate immune activation become clear[2]. In 2004 they reported that test-tube mRNA contains contaminating double-stranded RNA, a hallmark of viral replication, which activates the sensor TLR3. In another study, with Brian Czerniecki and colleagues, they tested chains made of a single repeated base on dendritic cells and found that only the uridine chain provoked a response, a hint that the bases themselves mattered. Caetano Reis e Sousa’s group reported a similar finding for another sensor, TLR7, the same year[2].

Their 2005 paper in the journal Immunity tested the idea. They made mRNA in which one of the four bases had been replaced by a modified form, such as pseudouridine, and found that several such substitutions abolished the inflammatory response. Only changes to uridine stopped the activation of dendritic cells altogether[2, 3]. Follow-up work in 2008 and 2010 showed a second benefit: pseudouridine-containing mRNA was translated into far more protein, partly because it avoided an antiviral enzyme, PKR, that shuts down protein synthesis[16, 17]. Later researchers found that a related base, N1-methylpseudouridine, worked better still, and it is now the most common modified base in mRNA vaccines[2, 18].

The result also explained an old observation. More than forty years earlier, Isaacs and colleagues had found that chemically deaminated RNA provoked a stronger interferon response than ordinary RNA; deamination raises the proportion of uridines. More than a hundred chemical modifications of RNA are now known, and pseudouridine, discovered in 1951, is one of the most abundant, although the function of most modifications is still poorly understood[2]. A further refinement followed in 2011. Karikó, Weissman and colleagues showed that removing double-stranded RNA and other contaminants from nucleoside-modified mRNA by high-performance liquid chromatography eliminated its remaining induction of interferons and inflammatory signals and raised protein production 10- to 1,000-fold in primary cells; unmodified mRNA, even when purified, still provoked strong cytokine release[19]. A cheaper cellulose-based purification step was later reported with colleagues at BioNTech[2].

Three companies built on mRNA had been founded by 2010: CureVac in 2000, BioNTech in 2008, initially aiming at personalised cancer vaccines, and Moderna in 2010[2]. CureVac optimised mRNA without modified bases; when the pandemic came, BioNTech and Moderna chose mRNA with modified bases, building on Karikó and Weissman’s discoveries[2]. In 2023 Karikó and Weissman received the Nobel Prize in Physiology or Medicine “for their discoveries concerning nucleoside base modifications that enabled the development of effective mRNA vaccines against COVID-19”[4].

Each company took its own route. Moderna’s original plan was to use mRNA to reprogram adult cells into stem cells and to deliver therapeutic proteins, for example to repair damaged tissue. CureVac’s founding team, among them Ingmar Hoerr, Günter Jung, Steve Pascolo and Hans-Georg Rammensee, raised protein output by optimising the untranslated regions at either end of the mRNA and its choice of codons rather than by modifying bases. In 2000 they reported that RNA, naked or in liposomes, induced antibody and killer T-cell responses in mice, and about eight years later they tested in people a vaccine made from melanoma patients’ own tumour RNA, which proved safe and increased anti-tumour immune responses in some patients. In 2017 a CureVac vaccine against rabies became the first mRNA vaccine against an infectious disease to enter clinical trials[2]. The same year brought promising animal results for modified-base mRNA vaccines against Zika virus, including protection against transmission to the fetus in pregnant animals, and Moderna began human trials of mRNA vaccines against Zika and against two avian influenza strains with pandemic potential, H10N8 and H7N9[2].

Fat bubbles that carry the message

Modified mRNA still had to reach the inside of cells without being destroyed. The solution came largely from work on another kind of RNA medicine. In the laboratory of Pieter Cullis at the University of British Columbia, researchers developed ionisable lipids that are positively charged when the particles are made in acid, so they pack tightly around the negatively charged RNA, but become neutral at the body’s normal pH, which makes them much less toxic[2, 20]. Combined with a helper lipid, cholesterol and a coating of polyethylene glycol, these form the four-part lipid nanoparticles used in today’s mRNA products[2].

The earlier cationic lipids had caused unwanted side effects in animals, which is why the ionisable design mattered[2]. The particles are formed by rapid mixing: a T-shaped connector brings the lipids and the nucleic acid together and produces dense particles of the four components, and more efficient ionisable lipids were later found in large screening programmes at several biotechnology companies[2]. The first medicine to reach patients in such a particle was not an mRNA at all. Patisiran, sold as Onpattro by Alnylam Pharmaceuticals, is a small interfering RNA that silences the gene for transthyretin in the liver, and it is carried in a lipid nanoparticle built around the ionisable lipid DLin-MC3-DMA, with a helper lipid, cholesterol and a PEG lipid. It was approved in 2018 for nerve damage caused by hereditary transthyretin amyloidosis, and its developers, Cullis among them, wrote that the approval paved the way for many nucleic acid medicines delivered by nanoparticles[21].

What is in an mRNA vaccine. The active ingredient is a strand of mRNA, made in a test tube, that encodes a single viral protein, in the COVID-19 vaccines the coronavirus spike. Every uridine is replaced by N1-methylpseudouridine to keep the immune system from reacting to the RNA itself. The mRNA is packed inside lipid nanoparticles. After injection, cells near the site take up the particles, read the mRNA and make the protein for a short time; the mRNA is then broken down. It does not enter the cell nucleus and cannot become part of the cell’s DNA[2].

The last ingredient was the right antigen. At the Vaccine Research Center of the US National Institutes of Health, a team led by Barney Graham, working with the structural biologist Jason McLellan, had found that adding two proline amino acids at a key point locked coronavirus spike proteins into the shape they hold before fusing with a cell, which improved how well the protein was made and how strongly it stimulated immunity[22]. They showed this for the MERS coronavirus in 2017[23]. Moderna and the Vaccine Research Center had begun collaborating on an mRNA vaccine against MERS using this design[2]. When a new coronavirus appeared, the template was ready.

The proline trick had a history of its own. Earlier work had shown that placing prolines in part of the influenza haemagglutinin, a protein that changes shape when the virus fuses with a cell, interfered with fusion. Because viruses of different families have evolved similar fusion machinery, well-placed prolines were later used to stabilise the spike proteins of HIV-1, respiratory syncytial virus and coronaviruses. The stabilised SARS-CoV-2 spike was used not only in the Pfizer–BioNTech and Moderna vaccines but also in Janssen’s viral-vector vaccine and Novavax’s protein vaccine[2].

Sixty-six days to the clinic

On 10 January 2020 the virologist Edward Holmes, on behalf of a consortium led by Zhang Yongzhen of Fudan University in Shanghai, posted the first genome sequence of the new coronavirus on the Virological website[24]. Within weeks McLellan’s group had used the sequence to determine the structure of the spike protein in its prefusion form, and the Vaccine Research Center and Moderna had designed mRNA-1273 to encode the stabilised spike[22, 25]. On 16 March 2020 the first volunteer received it in a phase 1 trial at Kaiser Permanente Washington Health Research Institute in Seattle, which planned to enrol 45 healthy adults[26]. BioNTech, led by Uğur Şahin and Özlem Türeci, developed its vaccine with Pfizer[2].

The phase 3 trials reported at the end of 2020. In the Pfizer–BioNTech trial, 43,548 people aged 16 or over were randomised; there were 8 cases of COVID-19 in the vaccine group and 162 in the placebo group, an efficacy of 95%[5]. In Moderna’s trial of 30,420 volunteers at 99 US sites there were 11 cases in the vaccine group and 185 in the placebo group, an efficacy of 94.1%; all 30 severe cases were in the placebo group[6]. Both vaccines replaced every uridine in the mRNA with N1-methylpseudouridine[2]. The Nobel Committee attributes much of the speed to trials designed to run in parallel rather than in sequence, backed by large public and private funding, “while still completing all the necessary steps”[2].

Not every mRNA vaccine did as well. CureVac’s candidate, CVnCoV, used mRNA without modified bases at a dose of 12 micrograms. In a phase 2b/3 trial of 39,680 adults in ten countries in Europe and Latin America it was 48.2% effective against symptomatic COVID-19 caused by any strain, and 70.7% against moderate-to-severe disease[27]. Comparisons are complicated because more antibody-resistant variants were circulating by then, but analyses across trials found that CVnCoV produced lower neutralising antibody levels than the Pfizer–BioNTech and Moderna vaccines, and the Nobel Committee concludes that modified bases, by allowing higher doses, were critical to protection[2]. A modelling study using data from seven vaccines had found neutralising antibody levels to be highly predictive of protection: the level estimated to give 50% protection against symptomatic infection was about 20% of the average after natural infection, and the level for 50% protection against severe disease was far lower, about 3%[28].

On 2 December 2020 the UK’s Medicines and Healthcare products Regulatory Agency approved the Pfizer–BioNTech vaccine, the first COVID-19 vaccine approved for use in the UK, after a “rolling review” of data that had begun in October[7]. The US Food and Drug Administration issued an emergency use authorisation on 11 December 2020 and granted full approval, under the name Comirnaty, on 23 August 2021[29].

TrialVaccineParticipants randomisedCOVID-19 cases (vaccine vs placebo)Efficacy
Polack et al., 2020BNT162b2 (Pfizer–BioNTech), two doses 21 days apart43,5488 vs 16295%
Baden et al., 2021mRNA-1273 (Moderna), two doses 28 days apart30,42011 vs 18594.1%
Results of the two pivotal phase 3 trials of mRNA COVID-19 vaccines against symptomatic disease, as reported in the New England Journal of Medicine. Sources: [5, 6].

Benefits and risks

The Nobel Assembly noted in 2023 that more than 13 billion doses of COVID-19 vaccines of all types had been given worldwide[4]. Estimating what they achieved requires modelling. A widely cited study in The Lancet Infectious Diseases estimated that vaccination prevented 14.4 million deaths from COVID-19 in 185 countries and territories in its first year, from December 2020, based on officially reported deaths, or 19.8 million using estimates of excess deaths[8]. The figures cover all vaccine types, not mRNA vaccines alone, and depend on the model’s assumptions[8].

The best-documented serious side effect is myocarditis, inflammation of the heart muscle. A US study of reports to the national Vaccine Adverse Event Reporting System found 1,626 confirmed cases among about 354 million doses of mRNA vaccines given up to August 2021. Rates were highest after the second dose in adolescent and young men, reaching 105.9 cases per million doses in males aged 16 and 17 after the Pfizer–BioNTech vaccine. Most patients were admitted to hospital, and 87% of those with information had their symptoms resolve by discharge[9]. The authors concluded that the risk “should be considered in the context of the benefits of COVID-19 vaccination”[9]. The Nobel Committee describes serious adverse effects of the two licensed mRNA vaccines as “exceptionally rare”[2].

Milder reactions were common and expected. For vaccines given to millions of healthy people, the Nobel Committee notes, a short-lived reaction at the injection site may be acceptable, whereas systemic symptoms such as fever, muscle aches and headache are undesirable, so the balance between reactogenicity and protection has to be judged for each product, mainly through the dose[2].

Policy has since diverged. On 5 August 2025 the US Department of Health and Human Services announced that its Biomedical Advanced Research and Development Authority would wind down mRNA vaccine development, affecting 22 projects worth nearly $500 million. Health Secretary Robert F. Kennedy Jr. said the data showed that these vaccines “fail to protect effectively against upper respiratory infections like COVID and flu”, and the department said it would shift funding to other platforms, while stating that other uses of mRNA technology within the department were not affected[30]. Earlier, the FDA had approved Moderna’s mRNA vaccine against respiratory syncytial virus, mRESVIA, for adults aged 60 and over on 31 May 2024[31].

Beyond infectious disease

BioNTech was founded to make cancer vaccines, and the cancer work is now reaching late-stage trials. The idea is to sequence a patient’s tumour, identify mutations that produce abnormal proteins, and make an mRNA encoding up to a few dozen of them so that the immune system learns to attack cells carrying them. In a phase 2b trial in 157 patients with high-risk melanoma removed by surgery, Moderna and Merck’s mRNA-4157 (now called intismeran autogene) given with the immunotherapy pembrolizumab reduced the risk of recurrence or death compared with pembrolizumab alone, with a hazard ratio of 0.561 (two-sided p=0.053, just above the conventional 0.05 threshold), and 18-month recurrence-free survival was 79% against 62%[32]. The companies report that five-year follow-up, presented in 2026, gave a hazard ratio of 0.51[10].

On 19 August 2026 Merck and Moderna announced that the phase 3 trial, INTerpath-001, which randomised 1,137 patients, had met its primary endpoint of recurrence-free survival and a key secondary endpoint of distant metastasis-free survival at a pre-specified interim analysis[10]. The announcement is company-reported and gives no figures; the data are due to be presented as the first late-breaking abstract in a Presidential Symposium at the European Society for Medical Oncology congress in Madrid, which runs from 23 to 27 October 2026[11]. In pancreatic cancer, a phase 1 study of BioNTech and Genentech’s personalised vaccine autogene cevumeran in 16 patients found strong vaccine-induced T-cell responses in 8, and those responders had longer recurrence-free survival at 18 months’ follow-up[33].

Not all of the newer approaches rely on modified bases. BioNTech’s personalised cancer vaccines, including those tested in melanoma and in the pancreatic cancer study, use unmodified bases with changes to the poly(A) tail that increase stability and protein production. Researchers are also developing circular RNA, which has no free ends for enzymes to attack, and self-copying replicons; the Nobel Committee expects such alternatives to spread, along with the number of trials in infection and cancer[2].

The same delivery technology carries gene-editing tools. In 2021 a phase 1 study of NTLA-2001, a lipid nanoparticle carrying mRNA for the CRISPR enzyme Cas9 and a guide RNA, reduced levels of the disease-causing protein in hereditary transthyretin amyloidosis by an average of 87% in three patients given the higher dose, after a single infusion[34]. In 2025 a US team reported treating an infant with a severe inherited metabolic disorder, carbamoyl-phosphate synthetase 1 deficiency, using a base editing therapy designed for the child’s specific mutation and delivered in lipid nanoparticles. After regulatory approval the infant received two infusions, at about seven and eight months of age, and in the following seven weeks was able to eat more protein and halve the dose of a medication, with no serious adverse events[35].

What the story shows

The mRNA vaccines were fast because the slow work had already been done. The discovery of messenger RNA in 1961, cheap test-tube synthesis in the 1980s, lipid delivery from the 1990s onwards, Karikó and Weissman’s modified bases in 2005, and the stabilised spike of 2017 were each developed for other reasons. The pandemic brought them together with unusual funding and urgency.

Several questions remain open. Antibody responses to the COVID-19 vaccines were relatively short-lived, and boosters were needed to maintain protection, especially against the Omicron variant[2]; and public funding in the United States has turned away from the platform for respiratory vaccines. The next tests are in other diseases. The full INTerpath-001 results at ESMO in October 2026 will show how large the benefit of a personalised mRNA cancer therapy is, and gene-editing trials will show whether lipid nanoparticles can deliver one-off cures safely.

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