From Pseudouridine to the COVID-19 Vaccines

In 2005, Katalin Karikó and Drew Weissman reported that building RNA with a naturally occurring variant of one of its four chemical letters — pseudouridine — quieted the immune alarm that laboratory-made messenger RNA (mRNA) sets off. Three years later they wrote that mRNA in its plain form was “unfeasible for clinical use because of its labile and immunogenic nature.” The Nobel committee’s 2023 press release dates the turning point: “These seminal results were published in 2005, fifteen years before the COVID-19 pandemic.” By December 2020 a close chemical cousin of that letter was in both mRNA COVID-19 vaccines, alongside three other inventions made by other groups. This page follows the path from the discovery to the vial: the four pieces in each dose, the 2020 timeline, how the mRNA is manufactured, exactly what the FDA labels list, and what happens in the body after the injection.

This is one of five record pages under the Karikó–Weissman hub. It works from the documents themselves — the published papers, the FDA labels and authorization records, the trial registry, and the European Medicines Agency’s (EMA) public assessment report — quotes them where the exact words matter, and labels every study by the kind of evidence it is: test tube and cells, animals, or people. Products are named where the documents name them. Side effects and harms are not weighed on this page; they are on the hub’s safety record.

Table of Contents

  1. Four Inventions in One Dose
  2. From Pseudouridine to N1-Methylpseudouridine
  3. The Envelope: Lipid Nanoparticles
  4. The Target: A Spike Locked in Shape
  5. 2020, Month by Month
  6. How the mRNA Is Made
  7. What Is in the Vial
  8. After the Injection
  9. Dr. Ardis’s Questions About the Vaccine
  10. The Safety Record
  11. Key Research Papers
  12. Connections
  13. Featured Videos

1. Four Inventions in One Dose

The mRNA vaccines are often described as one invention. The scientific record describes at least four, published by different groups between 2005 and 2017. Each answered a separate problem, and every dose carries all four.

  1. The quiet letter (2005 and 2008, refined in 2015). The problem: the body’s first-line immune sensors treated laboratory-made mRNA as a sign of infection. Karikó and Weissman showed in 2005 (cell and test-tube study) that RNA sets off the sensors called Toll-like receptors 3, 7 and 8, and that building it with naturally modified letters — pseudouridine among them — “ablates activity.” In 2008 (cell and mouse study), mRNA made with pseudouridine produced more protein than ordinary mRNA, and only the unmodified version raised the alarm signal interferon-alpha in mice. In 2015 a further-modified letter, N1-methylpseudouridine, outperformed pseudouridine (cell-line and mouse study) — the version both vaccines carry (section 2).
  2. Clean mRNA (2011). The problem: even modified mRNA still caused a residual alarm. Karikó and Weissman’s 2011 paper (cell study) traced it to contaminants, “including double-stranded RNA,” made by the copying reaction, and found that removing them by high-performance liquid chromatography (HPLC) gave mRNA that “does not induce IFNs and inflammatory cytokines” and was translated “at 10- to 1000-fold greater levels in primary cells.” The commercial process uses its own purification steps (section 6); the EMA report names double-stranded RNA as “the sole product-related impurity addressed” and records batch results showing its level to be “low, acceptable and consistent.”
  3. The lipid envelope (2015). The problem: bare mRNA is broken down by enzymes called ribonucleases and cannot get into cells on its own. Lipid nanoparticles — microscopic droplets built from four fat-like molecules — had already proved efficient carriers for short interfering RNAs, small gene-silencing molecules; in 2015 Weissman’s group packed modified mRNA into them and injected it into mice by six different routes (mouse study). In the EMA report’s words, the particles “protect the RNA from degradation by RNAses and enable transfection of host cells after intramuscular (IM) delivery” (section 3).
  4. The locked spike (2017). The problem: the coronavirus spike protein changes shape as it fuses with a cell, and an unlocked spike drifts out of the shape that makes the best vaccine target. In 2017, scientists at the NIH’s Vaccine Research Center and university colleagues described “a generalizable strategy for retaining coronavirus S proteins in the antigenically optimal prefusion conformation” for the MERS coronavirus (structure and mouse study): two substitutions of the amino acid proline, known as “2P” (section 4).

The diagram lines the four pieces up side by side, with the problem each one solved.

Four pieces in every dose of the mRNA COVID-19 vaccines, each published separately and each solving one problem: a quiet modified RNA letter (2005, 2008, 2015) that stopped laboratory-made mRNA tripping the immune alarm; clean mRNA (2011) with double-stranded by-products removed; a lipid envelope (2015) that protects the mRNA and carries it into cells; and a spike protein locked in its pre-fusion shape by two prolines, called 2P (2017). Lines join all four into one dose, in emergency use from December 2020; today’s labels list 30 mcg of mRNA per dose of COMIRNATY and 50 mcg per dose of SPIKEVAX. FOUR PIECES IN EVERY DOSE four problems, four answers, published years apart · all four were needed before one dose existed QUIET LETTER 2005 · 2008 · 2015 Pseudouridine, later N1-methylpseudouridine, in place of plain U PROBLEM SOLVED Lab-made mRNA tripped the immune alarm CLEAN mRNA 2011 Purification strips out double-stranded RNA by-products PROBLEM SOLVED Leftover by-products still tripped alarms LIPID ENVELOPE 2015 Four fat-like molecules wrap the mRNA in a tiny particle PROBLEM SOLVED Bare mRNA is broken down before it can get into cells LOCKED SPIKE 2017 Two prolines hold the spike in its pre-fusion shape: “2P” PROBLEM SOLVED An unlocked spike drifts out of its best target shape ONE DOSE emergency use from December 2020 COMIRNATY 30 mcg · SPIKEVAX 50 mcg of mRNA per dose on the 2026–2027 Formula labels Years mark first publication. Evidence levels (cells, mice, people) are given in the text.

Read the picture from the top down: four separate answers to four separate problems, published in 2005, 2008, 2011, 2015 and 2017, and all present in the vaccines that went into emergency use in December 2020. On today’s labels, a dose carries 30 mcg of mRNA in COMIRNATY and 50 mcg in SPIKEVAX.

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2. From Pseudouridine to N1-Methylpseudouridine

RNA is written in four chemical letters: A, C, G and U, the last standing for uridine. Cells do not leave their own RNA plain; they decorate it with many small chemical modifications after it is made. One of the most common is pseudouridine, written Ψ — uridine’s base attached to the sugar backbone through a carbon atom instead of a nitrogen, a change that still lets it pair with A. N1-methylpseudouridine, written m1Ψ, is pseudouridine carrying one extra methyl group: a single carbon atom with its hydrogens.

2005: a mark of “self.” The 2005 Immunity paper (cell and test-tube study) found that RNA “signals through human TLR3, TLR7, and TLR8, but incorporation of modified nucleosides m5C, m6A, m5U, s2U, or pseudouridine ablates activity.” Immune sentinel cells called dendritic cells were “potently activated by bacterial and mitochondrial RNA, but not by mammalian total RNA, which is abundant in modified nucleosides.” The authors drew a conclusion about how the body tells friend from foe: the innate immune system “may therefore detect RNA lacking nucleoside modification as a means of selectively responding to bacteria or necrotic tissue.” In plain words, the modifications act like a house style that the body reads as its own. The Toll-like receptor family and the dendritic cell were the subjects of the 2011 Nobel Prize to Beutler, Hoffmann and Steinman.

2008: more protein, less alarm. The 2008 Molecular Therapy paper (cell and mouse study) turned the observation into a tool. mRNAs containing pseudouridine had “a higher translational capacity than unmodified mRNAs” in mammalian cells and in mice injected into a vein, and “Even at higher doses, only the unmodified mRNA was immunogenic, inducing high serum levels of interferon-alpha (IFN-alpha).” The authors called such mRNA “a promising tool for both gene replacement and vaccination.” The Nobel committee named the 2005 and 2008 papers among the key publications behind the 2023 prize (The 2023 Nobel Prize); every joint paper in the series is listed on their research, paper by paper.

2015: the methylated version. Andries and colleagues (cell-line and mouse study), crediting what they called “the Kariko paradigm,” compared the two letters directly. mRNA built with N1-methylpseudouridine “outperformed” pseudouridine mRNA, giving “up to ~44-fold (when comparing double modified mRNAs) or ~13-fold (when comparing single modified mRNAs) higher reporter gene expression upon transfection into cell lines or mice, respectively,” with “reduced intracellular innate immunogenicity and improved cellular viability.” They suggested the gain may come “at least partially” from the mRNA’s greater ability “to evade activation of endosomal Toll-like receptor 3.” The same year, Weissman’s group was already using “HPLC purified, 1-methylpseudouridine-containing mRNA” in its lipid-nanoparticle experiments (Pardi 2015, mouse study).

Which letter the vaccines carry. For COMIRNATY, the EMA report is explicit: “The RNA does not contain any uridines; instead of uridine the modified N1-methylpseudouridine is used in RNA synthesis.” For mRNA-1273, the mRNA in SPIKEVAX, the NIH–Moderna preclinical paper (Corbett 2020, mouse study) describes “complete replacement of uridine by N1m-pseudouridine.” The Nobel committee’s scientific background to the 2023 prize puts both in one sentence, with the reasons: “Both the Pfizer/BioNTech’s and Moderna’s mRNA vaccines had complete substitutions of uridine with N1-methylpseudouridine (m1Ψ) to avoid unwanted inflammatory responses, to ramp up protein translation, and to enable higher mRNA amounts to be used in each vaccine dose.” The FDA labels use the general term “nucleoside-modified messenger RNA.”

What the strand spells. Nance and Meier’s 2021 review of the modified letter (review) lays out the COMIRNATY strand as “a 4284 nucleotide linear sequence of RNA consisting of five main elements”:

“Each of the elements above were highly intentional choices that in many cases reflect decades of fundamental research in the RNA biology field,” the review’s authors wrote. How a ribosome reads such a strand, three letters at a time, is the code that Nirenberg, Khorana and Holley worked out in the 1960s.

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3. The Envelope: Lipid Nanoparticles

Messenger RNA cannot do its job from outside a cell, and on its own it does not last long enough to get in. Both vaccines solve this with a lipid nanoparticle — a droplet far smaller than a cell, built from four fat-like molecules that wrap the mRNA. A 2021 review by Hou, Zaks, Langer and Dong (review) explains what each kind does; the EMA report sorts them into “functional lipids” and “structural lipids.”

The EMA report notes that DSPC and cholesterol “are used in several already approved finished products,” and that ALC-0315 and ALC-0159 “are novel excipients, not previously used in an approved finished product.”

A second job. “Vaccines often require coadministration of adjuvants, which are agents that prime the immune system to respond to an antigen of interest,” Nance and Meier write (review). With the mRNA itself made quiet, “In the case of tozinameran and mRNA-1273, this role appears to be fulfilled by the lipid nanoparticle, which can be tailored to predictably activate the immune response via mechanisms that do not halt protein production.” (Tozinameran is the generic name of the mRNA in COMIRNATY.)

Testing the pairing. In 2015, Weissman’s group (Pardi 2015, mouse study) packed purified, modified mRNA coding for a glowing test protein, firefly luciferase, into lipid nanoparticles and injected it into mice by six routes, and “high levels of protein translation could be measured using in vivo imaging.” The authors concluded that lipid nanoparticles “are appropriate carriers for mRNA in vivo.” What that study saw at the injection site is in section 8.

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4. The Target: A Spike Locked in Shape

Coronaviruses are studded with spike (S) proteins, the “corona” of the name. The spike “mediates receptor recognition and membrane fusion and is the primary target of the humoral immune response during infection,” Pallesen and colleagues wrote of the MERS coronavirus in 2017. Put simply, it is the key the virus uses to open a cell, and antibodies that jam the key block infection. The spike changes shape as it works: it holds a “pre-fusion” form until it engages a cell, then refolds into a different, post-fusion form as the virus and cell membranes merge.

The 2017 design. The 2017 paper (structure and mouse study), by scientists at the Scripps Research Institute, Dartmouth’s Geisel School of Medicine, the NIH’s Vaccine Research Center and Vanderbilt, used the spike’s structure to design “a generalizable strategy for retaining coronavirus S proteins in the antigenically optimal prefusion conformation,” and showed that the engineered MERS spike could “elicit high neutralizing antibody titers against MERS-CoV.” Three years later the Vaccine Research Center team described the trick in one sentence: “we identified 2 proline substitutions (2P) at the apex of the central helix and heptad repeat 1 that effectively stabilized” the spikes of MERS, the 2003 SARS virus and the common-cold coronavirus HKU1 “in the prefusion conformation,” and the stabilized MERS spike “was more immunogenic at lower doses than wild-type S protein” (Corbett 2020). Proline is the most rigid of the amino acids; two of them at the hinge work like a doorstop.

Ready when the new virus arrived. The NIH–Moderna team wrote that the 2P principle “has been applied to design mRNA-1273, an mRNA vaccine that encodes a SARS-CoV-2 spike protein that is stabilized in the prefusion conformation,” and showed (mouse study) that it “protects against SARS-CoV-2 infection in the lungs and noses of mice without evidence of immunopathology.” The paper’s title names the strategy: “SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness” — years of work on related viruses, done in advance. The BioNTech–Pfizer vaccine uses the same lock: the EMA report describes “two proline” changes in its spike sequence that hold it in “an antigenically optimal pre-fusion” shape, the design it labels “P2 S.” The SPIKEVAX label describes its mRNA as encoding “the pre-fusion stabilized spike glycoprotein.”

A choice between two designs. BioNTech and Pfizer first tested two candidates side by side (Walsh 2020, randomized, placebo-controlled phase 1 trial in the United States): BNT162b1, which encoded only a fragment of the spike, “a secreted trimerized SARS-CoV-2 receptor-binding domain,” and BNT162b2, which encoded “a membrane-anchored SARS-CoV-2 full-length spike, stabilized in the prefusion conformation.” The trial’s data, the authors wrote, “support the selection of BNT162b2” for the pivotal trial. BNT162b2 became the mRNA authorized in December 2020; later formulas encode the spikes of newer variants (section 7).

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5. 2020, Month by Month

The dates below come from the documents: the papers’ publication records, the trial registry (ClinicalTrials.gov), the FDA’s authorization and approval records, and the EMA report. Each trial is labelled by its design.

After 2020

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6. How the mRNA Is Made

Vaccine mRNA is not grown inside cells. It is copied in a vessel from a DNA template, by an enzyme, out of purified building blocks. The fullest public account is the EMA’s assessment report for COMIRNATY (EMA/707383/2020, 140 pages), a regulator’s summary of the manufacturer’s dossier. It describes the active substance as “Single-stranded, 5’-capped messenger RNA produced using a cell-free in vitro transcription from the corresponding DNA templates.” The steps, in plain words:

  1. Write the recipe in DNA, and let bacteria copy it. DNA is far easier to build than RNA, so the spike instructions are first assembled as DNA and placed in a plasmid — a small ring of DNA that bacteria copy as they multiply — next to a start signal for the copying enzyme (Nance & Meier). The EMA report: “The BNT162b2 active substance is manufactured by in vitro transcription using a linear DNA template, produced via plasmid DNA from transformed Escherichia coli cells.” Once the bacteria have grown, “the cells are harvested and chemically lysed to recover the plasmid DNA,” and the ring-shaped plasmid DNA is purified.
  2. Open the ring. The circular plasmid is cut open into a straight, “linear” template. Between the two processes used during development, the report records, the DNA template “changed from a PCR template to linearised plasmid DNA” (PCR being a test-tube method of copying DNA), along with an “increased process scale.” “The linear DNA template is not part of the final product but defines the sequence of the mRNA product.”
  3. Copy DNA into RNA, without cells. In the transcription step the template is mixed with an RNA-copying enzyme and the four RNA building blocks, with N1-methylpseudouridine supplied in place of uridine. The enzyme named in the published accounts is T7 RNA polymerase (Nance & Meier; for mRNA-1273, Corbett 2020), an enzyme first found in T7, a virus that infects bacteria. Nance and Meier describe it as able to “produce RNAs longer than 20 000 nucleotides without making an error” and as tolerant of modified building blocks; each template is read over and over, so one DNA molecule yields many RNA copies.
  4. Destroy the template. Once copying is done, the DNA is no longer wanted. The report refers to “the DNase digestion step” — a DNase being an enzyme that cuts DNA into small pieces. What is left is measured: “Residual DNA template is a process-related impurity derived from the linearised DNA template added to the in-vitro transcription reaction,” and “The levels are controlled by a specification limit which is considered suitably low.” Independent laboratories’ reports of DNA fragments in vials, and the regulators’ responses, are set out on the hub’s list of questions still argued in good faith.
  5. Digest leftover protein. The scaled-up process replaced an earlier magnetic-bead purification with “proteinase K digestion and UFDF steps.” Proteinase K is an enzyme that breaks proteins apart; a digestion step of this kind breaks down leftover protein, such as the enzymes used in the reaction, so that it can be filtered away.
  6. Filter and wash. UFDF stands for ultrafiltration/diafiltration: the solution is pushed through membranes whose pores hold back the large mRNA while small leftovers pass through, and the liquid around the mRNA is exchanged for a clean buffer. The report sums up the sequence: “The RNA is synthesised from linear DNA via an in vitro transcription (IVT) step. The IVT step is followed by a number of purification and filtration steps. Lastly, the RNA undergoes a final filtration before being dispensed and stored frozen.”
  7. Wrap it in lipids. In a separate stage the mRNA meets the lipids. The report lists the main steps: “active substance thawing and dilution, LNP formation and stabilisation, buffer exchange, concentration and filtration, concentration adjustment and addition of cryoprotectant, sterile filtration, aseptic filling, visual inspection, labelling, freezing and storage,” with ethanol and a citrate buffer used as processing aids.

Tests before release. The report lists the tests in the specification for the mRNA, among them the identity of the encoded RNA sequence, RNA integrity, the 5′ cap, the poly(A) tail, residual DNA template, double-stranded RNA, bacterial endotoxin and bioburden, the count of microbes.

Materials of animal origin. The report makes two statements. Of the materials used to make the DNA template: “All materials used are animal origin free and sourced from approved suppliers.” Of the process as a whole: “Reagents used in active substance manufacturing and in the establishment of the MCB and WCB are the only materials of animal origin used in the manufacture of BNT162b2” — the MCB and WCB being the master and working cell banks, the stored stocks of the bacteria that grow the plasmid. The report says the applicant identified contamination by transmissible spongiform encephalopathy (TSE) agents — prions, the cause of diseases such as BSE, “mad cow” disease — as “the main theoretical risk associated with these ingredients and it is deemed of minimal risk.” The public report does not list those reagents by name.

Words that do not appear. The EMA report contains neither “venom” nor “phosphodiesterase,” nor “snake.” The process steps it names include a DNase digestion and a proteinase K digestion; the published papers name T7 RNA polymerase as the copying enzyme. The EMA report covers COMIRNATY; for mRNA-1273, the NIH–Moderna preclinical paper describes the same basic method, “an optimized T7 RNA polymerase-mediated transcription reaction” (Corbett 2020).

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7. What Is in the Vial

Section 11 of each FDA label, “Description,” lists what a dose contains. These are the current labels on DailyMed, for the 2026–2027 Formula (COMIRNATY published 7 September 2026, SPIKEVAX 31 August 2026), quoted word for word.

COMIRNATY — the single-dose prefilled syringe for people 65 and older and people 12 through 64 with at least one underlying condition that puts them at high risk:

“Each 0.3 mL dose of COMIRNATY (2026-2027 Formula) is formulated to contain 30 mcg nucleoside-modified messenger RNA (modRNA) encoding the viral spike glycoprotein (S) of SARS-CoV-2 JN.1-descendent variant XFG. Each 0.3 mL dose of COMIRNATY also includes the following ingredients: lipids (0.43 mg ((4-hydroxybutyl)azanediyl)bis(hexane-6,1-diyl)bis(2-hexyldecanoate), 0.05 mg 2-(polyethylene glycol 2000)-N,N-ditetradecylacetamide, 0.09 mg 1,2-distearoyl-sn-glycero-3-phosphocholine, and 0.19 mg cholesterol), 0.06 mg tromethamine, 0.4 mg tromethamine hydrochloride, and 31 mg sucrose.”

The label also lists a single-dose vial for children 5 through 11 with at least one high-risk condition, holding 10 mcg of modRNA, smaller amounts of the same four lipids and the same buffer and sugar, and it closes the section: “COMIRNATY does not contain preservatives.”

SPIKEVAX — the 0.5 mL dose:

“Each 0.5 mL dose of SPIKEVAX (2026-2027 Formula) contains 50 mcg nucleoside-modified messenger RNA (mRNA) encoding the pre-fusion stabilized spike glycoprotein (S) of the SARS-CoV-2 JN.1-descendent variant XFG. Each dose also contains the following ingredients: a total lipid content of 1.01 mg (SM-102, polyethylene glycol [PEG] 2000 dimyristoyl glycerol [DMG], cholesterol, and 1,2-distearoyl-sn-glycero-3-phosphocholine [DSPC]), 0.25 mg tromethamine, 1.2 mg tromethamine hydrochloride, 0.021 mg acetic acid, 0.10 mg sodium acetate trihydrate, and 43.5 mg sucrose.”

A 0.25 mL dose with 25 mcg of mRNA and about half of each other ingredient is also listed, and the section ends: “SPIKEVAX does not contain a preservative.” For comparison, the 2020 trials gave 30 micrograms per dose of BNT162b2 and 100 micrograms per dose of mRNA-1273 (section 5).

Ingredient by ingredient

Three words that are not there. Neither label contains the words “venom,” “snake” or “phosphodiesterase,” and neither does the EMA’s 140-page assessment report, including its account of manufacture (section 6). A label lists what is in the finished dose rather than every reagent used along the way, which is why the manufacturing account is quoted above as well. In the 20 joint Karikó–Weissman papers from 2008 onward that are openly available in full, the word “venom” appears three times, in the discussion sections of one 2008 paper and one 2011 paper, each passage citing a 1965 chemistry study; those sentences are quoted in full on Snake Venom Phosphodiesterase in the Karikó–Weissman Papers.

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8. After the Injection

Both labels describe the vaccine as an “injectable suspension for intramuscular use” — a shot into a muscle. From there, the documents describe a short chain of events.

  1. The particles are taken into cells. “After intramuscular injection, lipid nanoparticle–mRNA (LNP–mRNA) vaccines are internalized by somatic cells (for example, muscle cells) and tissue-resident or recruited antigen-presenting cells (APCs),” the immune cells that show pieces of foreign proteins to the rest of the immune system (Hou 2021, review). Inside the cell, the ionizable lipid’s charge switch is thought to let the mRNA escape into the cytoplasm — the cell’s working space, outside the nucleus that holds its DNA (section 3).
  2. Ribosomes read the mRNA. The cell’s protein-making machines read the vaccine mRNA as they read any messenger RNA, and build the spike protein. The EMA report: “The mRNA is translated into the SARS-CoV-2 S protein in the host cell cytosol. The S protein is then expressed on the cell surface where it induces an adaptive immune response.” The FDA labels’ own summary: the lipid particles “enable delivery of the mRNA into host cells to allow expression of the SARS-CoV-2 S antigen. The vaccine elicits an immune response to the S antigen, which protects against COVID-19.” The animation How Your Body Reads DNA shows a ribosome at work.
  3. The immune system trains in the lymph nodes. The review adds that the vaccine particles can also reach the draining lymph nodes, “where various immune cells reside, including naive T and B cells.” There, in structures called germinal centres, antibody-making B cells are tested against the spike and the best-fitting are selected and multiplied. Röltgen and colleagues examined human lymph nodes after vaccination and after infection (human tissue study): “In contrast to disrupted germinal centers (GCs) in lymph nodes during infection, mRNA vaccination stimulates robust GCs containing vaccine mRNA and spike antigen up to 8 weeks postvaccination in some cases.” See How Vaccines Train Your Immune System and The Lymphatic System.
  4. The mRNA is broken down. RNA is degraded by enzymes called ribonucleases — the reason the lipid envelope is there at all, in the EMA’s words to “protect the RNA from degradation by RNAses.” The strand’s cap, tail and modified letter slow that process rather than stop it: Nance and Meier describe N1-methylpseudouridine as able to “increase mRNA functional half-life,” meaning the time a strand keeps working before it is degraded. How long it lasts has been measured rather than assumed. In mice (Pardi 2015, mouse study), mRNA injected into muscle was read at the injection site for up to 10 days, and to a lesser extent some of an intramuscular dose travelled through the body and was read in the liver for 1 to 4 days. In people, the lymph-node study above found vaccine mRNA “up to 8 weeks postvaccination in some cases.”

The lipids’ fate. The EMA report records animal and test-tube studies of the two new lipids. Both are broken down by hydrolysis, the splitting of chemical bonds with water, and “this hydrolytic metabolism is observed across the species evaluated” (test-tube samples from mice, rats, monkeys and humans, and living rats). In rats given the lipids into a vein, ALC-0315 left the liver slowly, at a pace the report estimates would clear it “in approximately 6-weeks”; ALC-0159 left faster (rat study).

Questions about vaccine mRNA and a person’s own DNA are taken up on the hub’s safety record, with the evidence; this page does not re-argue them.

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9. Dr. Ardis’s Questions About the Vaccine

Dr. Bryan Ardis, a chiropractor and podcaster, has raised three questions about the mRNA vaccines that touch this page. Each is set out in his own words on its own page; here they are signposted as he states them.

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10. The Safety Record

This page describes how the vaccines were built and what the documents list; it does not weigh their benefits against their harms. That record — the documented side effects, the claims that large studies examined, and the questions still argued in good faith — is kept in one place so that it can be read whole: the hub’s safety record.

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Key Research Papers

  1. Karikó K, Buckstein M, Ni H, Weissman D (2005). Suppression of RNA recognition by Toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA. Immunity. — PubMed PMID: 16111635
  2. Karikó K, Muramatsu H, Welsh FA, et al. (2008). Incorporation of pseudouridine into mRNA yields superior nonimmunogenic vector with increased translational capacity and biological stability. Mol Ther. — PubMed PMID: 18797453
  3. Karikó K, Muramatsu H, Ludwig J, Weissman D (2011). Generating the optimal mRNA for therapy: HPLC purification eliminates immune activation and improves translation of nucleoside-modified, protein-encoding mRNA. Nucleic Acids Res. — PubMed PMID: 21890902
  4. Pardi N, Tuyishime S, Muramatsu H, et al. (2015). Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes. J Control Release. — PubMed PMID: 26264835
  5. Andries O, Mc Cafferty S, De Smedt SC, et al. (2015). N(1)-methylpseudouridine-incorporated mRNA outperforms pseudouridine-incorporated mRNA by providing enhanced protein expression and reduced immunogenicity in mammalian cell lines and mice. J Control Release. — PubMed PMID: 26342664
  6. Pallesen J, Wang N, Corbett KS, et al. (2017). Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen. Proc Natl Acad Sci U S A. — PubMed PMID: 28807998
  7. Jackson LA, Anderson EJ, Rouphael NG, et al. (2020). An mRNA Vaccine against SARS-CoV-2 - Preliminary Report. N Engl J Med. — PubMed PMID: 32663912
  8. Corbett KS, Edwards DK, Leist SR, et al. (2020). SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature. — PubMed PMID: 32756549
  9. Walsh EE, Frenck RW Jr, Falsey AR, et al. (2020). Safety and Immunogenicity of Two RNA-Based Covid-19 Vaccine Candidates. N Engl J Med. — PubMed PMID: 33053279
  10. Polack FP, Thomas SJ, Kitchin N, et al. (2020). Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine. N Engl J Med. — PubMed PMID: 33301246
  11. Baden LR, El Sahly HM, Essink B, et al. (2021). Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine. N Engl J Med. — PubMed PMID: 33378609
  12. Nance KD, Meier JL (2021). Modifications in an Emergency: The Role of N1-Methylpseudouridine in COVID-19 Vaccines. ACS Cent Sci. — PubMed PMID: 34075344
  13. Hou X, Zaks T, Langer R, Dong Y (2021). Lipid nanoparticles for mRNA delivery. Nat Rev Mater. — PubMed PMID: 34394960
  14. Röltgen K, Nielsen SCA, Silva O, et al. (2022). Immune imprinting, breadth of variant recognition, and germinal center response in human SARS-CoV-2 infection and vaccination. Cell. — PubMed PMID: 35148837

PubMed Topic Searches

  1. PubMed: N1-methylpseudouridine in mRNA vaccines
  2. PubMed: Lipid nanoparticles for mRNA delivery
  3. PubMed: Prefusion-stabilized (2P) coronavirus spike

External Authoritative Resources

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Connections

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