mRNA vaccines for infectious diseases: principles, delivery and clinical translation

In the paper

“Each pathogen poses a unique set of challenges, including high lethality, rapid mutations, immune evasion, new strains and variants252–258.”

What the sources say

• Partly supported

  The Introduction reports more than three million COVID-19 deaths, and the sections on spike mutations and variants describe mutations, emerging variants, and reduced antibody neutralization. The paper does not characterize SARS-CoV-2 as having high lethality, and its Abstract describes an initial 11-month period of relative evolutionary stasis rather than unqualified rapid mutation. It addresses SARS-CoV-2, not the challenges posed by each pathogen. (LLM, conf=0.84)

  cites [252] Harvey, W. T. et al. SARS-CoV-2 variants, spike mutations and immune escape. Nat. Rev. Microbiol. 19, 409–424 (2021). sourceExperimental — accuracy not yet measured
• Partly supported

  The Introduction describes influenza’s immune-escape variants, novel strains, and mutation-driven antigenic drift, including strain differences observable within a season. It does not establish high lethality, and it qualifies the timing of new strains and rapid antigenic evolution rather than presenting them as uniformly rapid. The paper addresses influenza, not the challenges posed by each pathogen. (LLM, conf=0.86)

  cites [253] Boni, M. F. Vaccination and antigenic drift in influenza. Vaccine 26, C8–C14 (2008). sourceExperimental — accuracy not yet measured
• ?Could not verify

  The Abstract and Summary and Conclusions describe challenges in storing and transporting an Ebola vaccine, not challenges posed by pathogen biology. Searches for lethality, mutation, immune evasion, and new strains or variants found no passage in our copy addressing those claims. (LLM, conf=0.76)

  cites [254] Jusu, M. O. et al. Rapid establishment of a cold chain capacity of −60 °C or colder for the STRIVE Ebola vaccine trial during the Ebola outbreak in Sierra Leone. J. Infect. Dis. 217, S48–S55 (2018). sourceExperimental — accuracy not yet measured
• Not checked yetcites [255] Panchaud, A., Stojanov, M., Ammerdorffer, A., Vouga, M. & Baud, D. Emerging role of Zika virus in adverse fetal and neonatal outcomes. Clin. Microbiol. Rev. 29, 659–694 (2016). source
• Supported

  The paper’s Abstract reports an extremely high HIV-1 mutation rate in vivo. Its Discussion links viral mutation rates to genetic diversity and the ability to evade immune responses. In this grouped citation, the paper supports the rapid-mutation challenge; it need not establish every challenge listed for every pathogen. (LLM, conf=0.90)

  cites [256] Cuevas, J. M., Geller, R., Garijo, R., López-Aldeguer, J. & Sanjuán, R. Extremely high mutation rate of HIV-1 in vivo. PLoS Biol. 13, e1002251 (2015). source
• Partly supported

  The Abstract (page unavailable) says the HIV-1 Env glycan shield masks the protein from immune recognition, supporting immune evasion. The Discussion (page unavailable) suggests that glycan stabilization may enable hypermutation and escape from immune pressure, but does not establish rapid mutation. The paper does not substantiate high lethality or the emergence of new strains and variants as challenges posed by each pathogen. (LLM, conf=0.86)

  cites [257] Berndsen, Z. T. et al. Visualization of the HIV-1 Env glycan shield across scales. Proc. Natl Acad. Sci. USA 117, 28014–28025 (2020). sourceExperimental — accuracy not yet measured
• Partly supported

  The introduction (p. 1) describes high mortality from several infectious diseases, and the review’s discussion of resistance (p. 7) identifies pathogen resistance as a treatment challenge. These passages support parts of the sentence, but our copy does not establish rapid mutations, immune evasion, or new strains and variants as challenges posed by each pathogen. (LLM, conf=0.86)

  cites [258] Kirtane, A. R. et al. Nanotechnology approaches for global infectious diseases. Nat. Nanotechnol. 16, 369–384 (2021). sourceExperimental — accuracy not yet measured

In the paper

“In comparison with serum from patients recovering from COVID-19, vaccinated macaque serum contained 15-fold higher titres of neutralizing antibodies, 348-fold more potent inhibitory activity for spike binding to the angiotensin-converting enzyme 2 and 12-fold higher virus-neutralizing activity128.”

What the sources say

• Partly supported

  The Results (Antibody Responses after mRNA-1273 Vaccination) support all three comparisons with human convalescent-phase serum, but they come from different dose groups: the 15-fold neutralizing titer and 348-fold ACE2-binding inhibition were measured in the 100-μg group, while the 12-fold live-virus neutralization figure was measured in the 10-μg group. The sentence omits that distinction and makes the figures appear to describe the same vaccinated serum. (LLM, conf=0.86)

  cites [128] Corbett, K. S. et al. Evaluation of the mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates. N. Engl. J. Med. 383, 1544–1555 (2020). sourceExperimental — accuracy not yet measured

In the paper

“In 2020, the COVID-19 pandemic catalysed the most rapid vaccine development in history, with mRNA vaccines at the forefront of those efforts.”

In the paper

“Unlike some viral vaccines, mRNA does not integrate into the genome, obviating concerns about insertional mutagenesis5.”

What the sources say

• Not checked yetcites [5] Pardi, N., Hogan, M. J., Porter, F. W. & Weissman, D. mRNA vaccines — a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261–279 (2018). source

In the paper

“Moreover, a single mRNA vaccine can encode multiple antigens, strengthening the immune response against resilient pathogens7”

What the sources say

• Not checked yetcites [7] Freyn, A. W. et al. A multi-targeting, nucleoside-modified mRNA influenza virus vaccine provides broad protection in mice. Mol. Ther. 28, 1569–1584 (2020). source

In the paper

“Successful vaccination campaigns eradicated life-threatening diseases such as smallpox and nearly eradicated polio1”

What the sources say

• Not checked yetcites [1] Pollard, A. J. & Bijker, E. M. A guide to vaccinology: from basic principles to new developments. Nat. Rev. Immunol. 21, 83–100 (2021). source

In the paper

“Furthermore, they require regular modification to address rapidly mutating pathogens, such as the influenza virus.”

In the paper

“For example, research on MERS-CoV and SARS-CoV suggested that the antigen should be the spike protein and that its amino acid sequence should be slightly modified to lock the protein in its prefusion conformation, maximizing its immunogenicity127.”

What the sources say

• Not checked yetcites [127] Corbett, K. S. et al. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature 586, 567–571 (2020). This study reports the development process of mRNA-1273. source

In the paper

“For instance, the biopharmaceutical company CureVac AG discovered that human mRNA codons rarely have A or U at the third position and patented a strategy that replaces A or U at the third position in the open reading frame with G or C21.”

What the sources say

• Not checked yetcites [21] von der Mülbe, F., Hoerr, I. & Pascolo, S. Pharmaceutical composition containing a stabilised mRNA optimised for translation in its coding regions. US 2015/0104476 A1 (2015).

In the paper

“The Moderna and Pfizer–BioNTech vaccines, in contrast, were approved 11 months after initiation, 8 months of which were spent in clinical trials.”

In the paper

“As in mammals, the first or second nucleotide from the 5′ end is methylated on the 2′ hydroxyl of the ribose (2′-O-methylation), which prevents recognition by cytosolic sensors of viral RNA10, and hence prevents unintended immune responses.”

What the sources say

• Not checked yetcites [10] Wadhwa, A., Aljabbari, A., Lokras, A., Foged, C. & Thakur, A. Opportunities and challenges in the delivery of mRNA-based vaccines. Pharmaceutics 12, 102 (2020). source

In the paper

“However, because UTR performance can vary by cell type, alternative UTR sequences may be used that have been optimized for the desired application and intended cell target16–18.”

What the sources say

• Not checked yetcites [16] Sample, P. J. et al. Human 5′ UTR design and variant effect prediction from a massively parallel translation assay. Nat. Biotechnol. 37, 803–809 (2019). This study designs novel UTR sequences and predicts ribosome loading using deep learning. source
• Not checked yetcites [17] Orlandini von Niessen, A. G. et al. Improving mRNA-based therapeutic gene delivery by expression-augmenting 3′ UTRs identified by cellular library screening. Mol. Ther. 27, 824–836 (2019). source
• Not checked yetcites [18] Zeng, C. et al. Leveraging mRNA sequences and nanoparticles to deliver SARS-CoV-2 antigens in vivo. Adv. Mater. 32, 2004452 (2020). source

In the paper

“During the SARS-CoV-2 pandemic, mRNA-based vaccines were shown to be highly effective against SARS-CoV-2 and were developed and administered at unprecedented speed to millions of people globally to combat COVID-19 (Box 1).”

In the paper

“A colossal investment was also required for each vaccine candidate, with Pfizer–BioNTech and Moderna receiving $1.95 billion and $2.48 billion, respectively, from the US government through its Operation Warp Speed initiative (see Related links).”

In the paper

“These vaccines, initially developed by Pfizer–BioNTech and Moderna, have validated the platform and stimulated substantial interest in the application of mRNA for both prophylactic and therapeutic indications.”

In the paper

“These studies enabled Moderna to generate the mRNA-1273 sequence in 2 days and start phase I trials in 66 days127.”

What the sources say

• Not checked yetcites [127] Corbett, K. S. et al. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature 586, 567–571 (2020). This study reports the development process of mRNA-1273. source

In the paper

“Further, the 5′ cap protects the mRNA sterically from degradation by exonucleases, and it works synergistically with the poly(A) tail at the 3′ end, poly(A) binding proteins and translation initiation factor proteins to circularize mRNA and recruit ribosomes for initiating translation10,11.”

What the sources say

• Not checked yetcites [10] Wadhwa, A., Aljabbari, A., Lokras, A., Foged, C. & Thakur, A. Opportunities and challenges in the delivery of mRNA-based vaccines. Pharmaceutics 12, 102 (2020). source
• Not checked yetcites [11] Linares-Fernández, S., Lacroix, C., Exposito, J. Y. & Verrier, B. Tailoring mRNA vaccine to balance innate/adaptive immune response. Trends Mol. Med. 26, 311–323 (2020). source

In the paper

“During the SARS-CoV-2 pandemic, mRNA-based vaccines were shown to be highly effective against SARS-CoV-2 and were developed and administered at unprecedented speed to millions of people globally to combat COVID-19 (Box 1).”

In the paper

“For example, MERS-CoV and SARS-CoV vaccines required about 2 years of development before entering phase I trials259 and have yet to be approved.”

What the sources say

• Not checked yetcites [259] Kim, Y. C., Dema, B. & Reyes-Sandoval, A. COVID-19 vaccines: breaking record times to first-in-human trials. NPJ Vaccines 5, 34 (2020). source

In the paper

“As of 18 June 2021, 185 COVID-19 vaccine candidates were in preclinical development and an additional 102 had entered clinical trials (see Related links).”

In the paper

“Poly(A) tails of >100 bp are optimal for therapeutic mRNAs; however, the DNA sequences that encode these long poly(A) stretches can destabilize the DNA plasmids used for transcription.”

In the paper

“Together, these innovations have overcome significant manufacturing bottlenecks and facilitated the development of a simple, cost-effective and scalable one-step mRNA synthesis process.”

In the paper

“The poly(A) tail is encoded in the DNA template, which eliminates reaction steps and reduces overall production time and material loss29.”

What the sources say

• Not checked yetcites [29] Pardi, N., Hogan, M. J. & Weissman, D. Recent advances in mRNA vaccine technology. Curr. Opin. Immunol. 65, 14–20 (2020). source

In the paper

“90% efficacy in real-world conditions in USA132”

What the sources say

• Not checked yetcites [132] Thompson, M. G. et al. Interim estimates of vaccine effectiveness of BNT162b2 and mRNA-1273 COVID-19 vaccines in preventing SARS-CoV-2 infection among health care personnel, first responders, and other essential and frontline workers — eight U.S. locations, December 2020–March 2021. Morb. Mortal. Wkly Rep. 70, 495–500 (2021). source

In the paper

“The attached spike protein is then cut open by the cell’s transmembrane serine protease 2, which induces a conformational change that exposes the spike protein’s fusion peptide and facilitates fusion with the cell or endosomal membrane118.”

What the sources say

• Not checked yetcites [118] Shang, J. et al. Cell entry mechanisms of SARS-CoV-2. Proc. Natl Acad. Sci. USA 117, 11727–11734 (2020). This study describes the cell-entry mechanism of SARS-CoV-2. source

In the paper

“Moreover, inside the body, it is engulfed by cells of the innate immune system and degraded by nucleases.”

In the paper

“anti-spike IgG, anti-RBD IgG and serum-neutralization titres comparable to convalescent serum133”

What the sources say

• Not checked yetcites [133] Kremsner, P. et al. Phase 1 assessment of the safety and immunogenicity of an mRNA- lipid nanoparticle vaccine candidate against SARS-CoV-2 in human volunteers. medRxiv https://www.medrxiv.org/content/10.1101/2020.11.09.20228551v1 (2020). source

In the paper

“In preclinical studies in rhesus macaques, two 100 μg doses of BNT162b2 delivered 21 days apart elicited neutralizing antibody titres 10.2–18.0 times higher than convalescent patient serum as well as strong CD4+ and CD8+ T cell responses122.”

What the sources say

• Not checked yetcites [122] Vogel, A. B. et al. BNT162b vaccines protect rhesus macaques from SARS-CoV-2. Nature 592, 283–289 (2021). source

In the paper

“same formulation as mRNA-1273”

In the paper

“Both candidates were well tolerated and efficacious, but only the BNT162b2 vaccine advanced to phase II/III trials owing to its milder systemic and local adverse reactions124.”

What the sources say

• Not checked yetcites [124] Walsh, E. E. et al. Safety and immunogenicity of two RNA-based covid-19 vaccine candidates. N. Engl. J. Med. 383, 2439–2450 (2020). source

In the paper

“The vaccine uses the ionizable lipid SM-102 to formulate LNPs that encapsulate an N1-methylpseudouridine-modified mRNA. The sequence encodes the SARS-CoV-2 spike protein with two proline substitutions that confer the prefusion conformation127.”

What the sources say

• Not checked yetcites [127] Corbett, K. S. et al. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature 586, 567–571 (2020). This study reports the development process of mRNA-1273. source

In the paper

“In a mass vaccination campaign involving 3,159,136 participants in Israel, two doses of BNT162b2 were 94% effective at preventing symptomatic COVID-19, 87% effective at preventing hospitalizations and 92% effective at preventing the onset of severe COVID-19 (ref.126).”

What the sources say

• Not checked yetcites [126] Dagan, N. et al. BNT162b2 mRNA Covid-19 vaccine in a nationwide mass vaccination setting. N. Engl. J. Med. 384, 1412–1423 (2021). source

In the paper

“Another study used LNPs to deliver a 50 ng dose of nucleoside-modified mRNA encoding three conserved influenza proteins: neuraminidase, nucleoprotein and matrix-2 ion channel protein (Fig. 4) in addition to the haemagglutinin stalk7. Incredibly, this minuscule mRNA dose generated broadly protective antibodies and protected mice from an extraordinarily large viral challenge (500× LD50).”

What the sources say

• Not checked yetcites [7] Freyn, A. W. et al. A multi-targeting, nucleoside-modified mRNA influenza virus vaccine provides broad protection in mice. Mol. Ther. 28, 1569–1584 (2020). source

In the paper

“In preclinical studies, CV2CoV showed 1.8-fold higher protein expression than CVnCoV in vitro, and elicited high titres of cross-neutralizing antibodies against the B.1.1.7, B.1.1.298 and B.1.351 variants in rats134.”

What the sources say

• Not checked yetcites [134] Roth, N. et al. CV2CoV, an enhanced mRNA-based SARS-CoV-2 vaccine candidate, supports higher protein expression and improved immunogenicity in rats. bioRxiv, https://www.biorxiv.org/content/10.1101/2021.05.13.443734v1.full (2021).

In the paper

“In transgenic mice expressing human angiotensin-converting enzyme 2, doses of 2 µg and 10 µg produced strong T cell responses, high IgG titres and protected mice from SARS-CoV-2 infection137.”

What the sources say

• Not checked yetcites [137] de Alwis, R. et al. A single dose of self-transcribing and replicating RNA-based SARS-CoV-2 vaccine produces protective adaptive immunity in mice. Mol. Ther. 29, 1970–1983 (2021). source

In the paper

“Adverse effects were limited to pain at the injection site, redness, muscle pain, joint pain, headache, fatigue and chills/common-cold-like symptoms, indicating that the vaccine is safe and well tolerated150.”

What the sources say

• Not checked yetcites [150] Feldman, R. A. et al. mRNA vaccines against H10N8 and H7N9 influenza viruses of pandemic potential are immunogenic and well tolerated in healthy adults in phase 1 randomized clinical trials. Vaccine 37, 3326–3334 (2019). source

In the paper

“In the first demonstration of an effective mRNA vaccine against influenza in 2012, three intradermal injections of 80 µg RNActive-mRNA encoding haemagglutinin from the PR8 H1N1 strain induced homologous and heterologous immunity against H1N1 and H5N1 strains, respectively, and protected the mice against a lethal viral dose (10× LD50)141.”

What the sources say

• Not checked yetcites [141] Petsch, B. et al. Protective efficacy of in vitro synthesized, specific mRNA vaccines against influenza A virus infection. Nat. Biotechnol. 30, 1210–1216 (2012). source

In the paper

“CVnCoV uses LNPs formulated using an ionizable lipid from Acuitas Therapeutics (potentially ALC-0315) and an unmodified mRNA sequence encoding a full-length spike protein with the two proline substitutions133.”

What the sources say

• Not checked yetcites [133] Kremsner, P. et al. Phase 1 assessment of the safety and immunogenicity of an mRNA- lipid nanoparticle vaccine candidate against SARS-CoV-2 in human volunteers. medRxiv https://www.medrxiv.org/content/10.1101/2020.11.09.20228551v1 (2020). source

In the paper

“In phase I clinical trials, primer and booster injections of a 12 μg dose of CVnCoV administered 28 days apart generated neutralizing antibodies similar to those in plasma from patients who were convalescing from COVID-19 and was well tolerated133.”

What the sources say

• Not checked yetcites [133] Kremsner, P. et al. Phase 1 assessment of the safety and immunogenicity of an mRNA- lipid nanoparticle vaccine candidate against SARS-CoV-2 in human volunteers. medRxiv https://www.medrxiv.org/content/10.1101/2020.11.09.20228551v1 (2020). source

In the paper

“Although the ARCT-021 dose is higher than the LNP-nCoVsaRNA dose, no booster is required, ensuring that recipients are fully vaccinated after a single injection.”

In the paper

“The broadly protective antibodies conferred homologous immunity against Cal09 H1N1, heterologous immunity against PR8 H1N1 and heterosubtypic immunity against H5N1 in mice and protected them against a lethal viral challenge149.”

What the sources say

• Not checked yetcites [149] Pardi, N. et al. Nucleoside-modified mRNA immunization elicits influenza virus hemagglutinin stalk-specific antibodies. Nat. Commun. 9, 3361 (2018). source

In the paper

“Of note, the neutralizing antibody titres generated by the mRNA vaccine were 50–100 times higher than those induced by purified inactivated virus and DNA vaccines in mice, and 50 times higher than a 1 mg DNA vaccine in macaques153.”

What the sources say

• Not checked yetcites [153] Pardi, N. et al. Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination. Nature 543, 248–251 (2017). source

In the paper

“In two separate phase I trials in 2016, Moderna evaluated two influenza candidates. These vaccines were dosed via two intramuscular injections of LNPs encapsulating nucleoside-modified mRNA expressing full-length haemagglutinin from H10N8 and H7N9 (Table 1).”

What the sources say

• Not checked yetcites [147] Bahl, K. et al. Preclinical and clinical demonstration of immunogenicity by mrna vaccines against H10N8 and H7N9 influenza viruses. Mol. Ther. 25, 1316–1327 (2017). source

In the paper

“CureVac’s candidate vaccine CVnCoV is stable for 3 months at 5 °C and 24 h at room temperature (see Related links).”

What the sources say

• Not checked yetcites Related links

In the paper

“Several preclinical studies have delivered mRNA vaccines encoding HIV proteins using multiple delivery vehicles, including cationic nanoemulsions109,161, DOTAP/DOPE liposomes162, polymers84,163,164 and ionizable LNPs165,166, but they have had varied success.”

What the sources say

• Not checked yetcites [109] Brito, L. A. et al. A cationic nanoemulsion for the delivery of next-generation RNA vaccines. Mol. Ther. 22, 2118–2129 (2014). source
• Not checked yetcites [161] Bogers, W. M. et al. Potent immune responses in rhesus macaques induced by nonviral delivery of a self-amplifying RNA vaccine expressing HIV type 1 envelope with a cationic nanoemulsion. J. Infect. Dis. 211, 947–955 (2015). source
• Not checked yetcites [162] Pollard, C. et al. Type I IFN counteracts the induction of antigen-specific immune responses by lipid-based delivery of mRNA vaccines. Mol. Ther. 21, 251–259 (2013). source
• Not checked yetcites [84] Li, M. et al. Enhanced intranasal delivery of mRNA vaccine by overcoming the nasal epithelial barrier via intra- and paracellular pathways. J. Control. Rel. 228, 9–19 (2016). source
• Not checked yetcites [163] Moyo, N. et al. Efficient induction of T cells against conserved HIV-1 regions by mosaic vaccines delivered as self-amplifying mRNA. Mol. Ther. Methods Clin. Dev. 12, 32–46 (2019). source
• Not checked yetcites [164] Zhao, M., Li, M., Zhang, Z., Gong, T. & Sun, X. Induction of HIV-1 gag specific immune responses by cationic micelles mediated delivery of gag mRNA. Drug Deliv. 23, 2596–2607 (2016). source
• Not checked yetcites [165] Blakney, A. K., McKay, P. F., Yus, B. I., Aldon, Y. & Shattock, R. J. Inside out: optimization of lipid nanoparticle formulations for exterior complexation and in vivo delivery of saRNA. Gene Ther. 26, 363–372 (2019). source
• Not checked yetcites [166] Pardi, N. et al. Characterization of HIV-1 nucleoside-modified mRNA vaccines in rabbits and rhesus macaques. Mol. Ther. Nucleic Acids 15, 36–47 (2019). source

In the paper

“Using a similar approach, Moderna successfully delivered mRNA encoding the mAb CHKV-24, 4 h after chikungunya virus inoculation and protected mice from chikungunya virus-induced arthritis158.”

What the sources say

• Not checked yetcites [158] Kose, N. et al. A lipid-encapsulated mRNA encoding a potently neutralizing human monoclonal antibody protects against Chikungunya infection. Sci. Immunol. 4, 6647 (2019). source

In the paper

“Notably, the broadly neutralizing mAbs, VRC01, have recently gained attention thanks to their ability to neutralize 98% of HIV strains167 and prevent transmission of antibody-sensitive strains with 75.4% efficacy168.”

What the sources say

• Not checked yetcites [167] Singh, A. Eliciting B cell immunity against infectious diseases using nanovaccines. Nat. Nanotechnol. 16, 16–24 (2021). source
• Not checked yetcites [168] Corey, L. et al. Two randomized trials of neutralizing antibodies to prevent HIV-1 acquisition. N. Engl. J. Med. 384, 1003–1014 (2021). source

In the paper

“These encouraging preclinical results prompted a phase I trial, and interim results suggest that the vaccine — mRNA-1893 (Table 1) — induces 94–100% seroconversion in 10 μg and 30 μg dose groups and is well tolerated (see Related links).”

What the sources say

• Not checked yetcites Related links

In the paper

“Two 10 µg doses of the LNP-encapsulated modified mRNA delivered 21 days apart protected mice from a Zika challenge and diminished the production of dengue-enhancing antibodies156.”

What the sources say

• Not checked yetcites [156] Richner, J. M. et al. Modified mRNA vaccines protect against Zika virus infection. Cell 168, 1114–1125.e10 (2017). source

In the paper

“Interestingly, although the delivery route did not affect the immune response, the delivery device did, with only the intradermal injector producing a short-lived humoral response188.”

What the sources say

• Not checked yetcites [188] Alberer, M. et al. Safety and immunogenicity of a mRNA rabies vaccine in healthy adults: an open-label, non-randomised, prospective, first-in-human phase 1 clinical trial. Lancet 390, 1511–1520 (2017). source

In the paper

“In 1968, for example, a formalin-inactivated RSV vaccine candidate caused vaccine-associated enhanced disease (VAED) in children. This response triggered excessive eosinophil and neutrophil infiltration in the lungs, resulting in severe bronchiolitis or pneumonia in 80% of the vaccinated children and two fatalities172.”

What the sources say

• Not checked yetcites [172] Kim, H. W. et al. Respiratory syncytial virus disease in infants despite prior administration of antigenic inactivated vaccine. Am. J. Epidemiol. 89, 422–434 (1969). source

In the paper

“In phase I clinical trials, mRNA-1777 elicited a robust humoral response with RSV neutralizing antibodies, a CD4+ T cell response to RSV F peptides and no serious adverse events181.”

What the sources say

• Not checked yetcites [181] Aliprantis, A. O. et al. A phase 1, randomized, placebo-controlled study to evaluate the safety and immunogenicity of an mRNA-based RSV prefusion F protein vaccine in healthy younger and older adults. Hum. Vaccines Immunother. 17, 1248–1261 (2021). source

In the paper

“In 2019, the FDA approved a recombinant vesicular stomatitis virus (VSV)-based Ebola vaccine (rVSV-EBOV).”

What the sources say

• Not checked yetcites Related links

In the paper

“In non-human primates, two 100 µg doses spaced 28 days apart were well tolerated and provoked 20-fold higher antibody titres than a commercially licensed rabies vaccine189.”

What the sources say

• Not checked yetcites [189] Lutz, J. et al. Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines. NPJ Vaccines 2, 29 (2017). source

In the paper

“Phase I results suggest that two 1 µg doses yield high neutralizing titres, strong adaptive immune responses, and were well tolerated190.”

What the sources say

• Not checked yetcites [190] Aldrich, C. et al. Proof-of-concept of a low-dose unmodified mRNA-based rabies vaccine formulated with lipid nanoparticles in human volunteers: a phase 1 trial. Vaccine 39, 1310–1318 (2021). source

In the paper

“The vaccine elicited glycoprotein-specific IgG antibodies and robust expression of IFNγ and IL-2 by CD8+ and CD4+ T cells, and two dosing regimens (two 4 μg doses or one 40 μg dose) protected mice from a lethal challenge184.”

What the sources say

• Not checked yetcites [184] Chahal, J. S. et al. Dendrimer-RNA nanoparticles generate protective immunity against lethal Ebola, H1N1 influenza, and Toxoplasma gondii challenges with a single dose. Proc. Natl Acad. Sci. USA 113, E5250 (2016). source

In the paper

“Two 15 µg primer–booster doses improved helper T cell development and elicited anti-Plasmodium IgG antibodies and memory T cell responses192.”

What the sources say

• Not checked yetcites [192] Baeza Garcia, A. et al. Neutralization of the Plasmodium-encoded MIF ortholog confers protective immunity against malaria infection. Nat. Commun. 9, 2714 (2018). source

In the paper

“Another study vaccinated guinea pigs with two 20 μg doses of a LNP-encapsulated, nucleoside-modified mRNA encoding the EBOV glycoprotein, inducing high antibody titres and protecting the animals from a lethal viral challenge185.”

What the sources say

• Not checked yetcites [185] Meyer, M. et al. Modified mRNA-based vaccines elicit robust immune responses and protect guinea pigs from Ebola virus disease. J. Infect. Dis. 217, 451–455 (2018). source

In the paper

“In a preclinical study, two 80 µg vaccine doses delivered 21 days apart induced high neutralizing antibody titres and elicited antigen-specific CD4+ and CD8+ T cell responses in mice and pigs187.”

What the sources say

• Not checked yetcites [187] Schnee, M. et al. An mRNA vaccine encoding rabies virus glycoprotein induces protection against lethal infection in mice and correlates of protection in adult and newborn pigs. PLoS Negl. Trop. Dis. 10, e0004746 (2016). source

In the paper

“In clinical trials, two doses of mRNA-1273 also elicited durable antibody responses over a period of 6 months. Although antibody titres declined slightly over the duration of the study, high neutralizing ability was retained across all age groups205.”

What the sources say

• Not checked yetcites [205] Doria-Rose, N. et al. Antibody persistence through 6 months after the second dose of mRNA-1273 vaccine for covid-19. N. Engl. J. Med. 384, 2259–2261 (2021). source

In the paper

“One study in mice showed that LNPs encapsulating nucleoside-modified mRNA circulated for longer and induced stronger TFH cell and germinal centre B cell responses than LNPs carrying unmodified mRNA200.”

What the sources say

• Not checked yetcites [200] Pardi, N. et al. Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. J. Exp. Med. 215, 1571–1588 (2018). source

In the paper

“Novel strategies against these viruses involve delivering mRNA vaccines that target conserved regions such as the haemagglutinin stalk on influenza149, or encodeing broadly neutralizing antibodies such as VRC01 that bind to conserved regions of the CD4 binding site on the HIV gp120 protein206.”

What the sources say

• Not checked yetcites [149] Pardi, N. et al. Nucleoside-modified mRNA immunization elicits influenza virus hemagglutinin stalk-specific antibodies. Nat. Commun. 9, 3361 (2018). source
• Not checked yetcites [206] Li, Y. et al. Mechanism of neutralization by the broadly neutralizing HIV-1 monoclonal antibody VRC01. J. Virol. 85, 8954–8967 (2011). source

In the paper

“These results are promising; however, the duration of antibody response is a complex phenomenon that will vary from antigen to antigen and will require longer-term data for a comprehensive understanding.”

In the paper

“At the time of this writing, Moderna is evaluating the original mRNA-1273 vaccine and updated versions of the vaccine as a third dose booster — mRNA-1273.351, which encodes the spike protein from the B.1.351 variant, and mRNA-1273.211, a multivariant vaccine that is a 1:1 mix of mRNA-1273 and mRNA-1273.351 (ref.8).”

What the sources say

• Not checked yetcites [8] Wu, K. et al. Variant SARS-CoV-2 mRNA vaccines confer broad neutralization as primary or booster series in mice. bioRxiv https://www.biorxiv.org/content/10.1101/2021.04.13.439482v1 (2021). source

In the paper

“Three 50 μg doses were able to reduce parasitaemia in Aotus monkeys after a P. falciparum challenge193.”

What the sources say

• Not checked yetcites [193] Raj, D. K. et al. Anti-PfGARP activates programmed cell death of parasites and reduces severe malaria. Nature 582, 104–108 (2020). source

In the paper

“PfGARP is expressed on the surface of infected erythrocytes and is recognized by antibodies from children who are relatively resistant to P. falciparum193.”

What the sources say

• Not checked yetcites [193] Raj, D. K. et al. Anti-PfGARP activates programmed cell death of parasites and reduces severe malaria. Nature 582, 104–108 (2020). source

In the paper

“Anti-PEG antibodies have been reported in 40% of the population, which might heighten the risk of allergic reactions in certain individuals and impede vaccine efficacy218.”

What the sources say

• Not checked yetcites [218] Kozma, G. T., Shimizu, T., Ishida, T. & Szebeni, J. Anti-PEG antibodies: properties, formation, testing and role in adverse immune reactions to PEGylated nano-biopharmaceuticals. Adv. Drug Deliv. Rev. 154–155, 163–175 (2020). source

In the paper

“Rare in utero transmission of SARS-CoV-2 has also been reported222,223; its implications on maternal, fetal and neonatal health are under active investigation.”

What the sources say

• Not checked yetcites [222] Barrero-Castillero, A. et al. COVID-19: neonatal-perinatal perspectives. J. Perinatol. 41, 940–951 (2021). source
• Not checked yetcites [223] Fenizia, C. et al. Analysis of SARS-CoV-2 vertical transmission during pregnancy. Nat. Commun. 11, 5128 (2020). source

In the paper

“Cytomegalovirus infection, for example, causes complications in up to 1% of pregnancies and can lead to congenital disabilities and neurological impairment in infants220.”

What the sources say

• Not checked yetcites [220] Bialas, K. M., Swamy, G. K. & Permar, S. R. Perinatal cytomegalovirus and varicella zoster virus infections: epidemiology, prevention, and treatment. Clin. Perinatol. 42, 61–75 (2015). source

In the paper

“Zika virus can infect cortical neurons and glial cells in the fetus, resulting in cell death, neuroinflammation and severe congenital malformations221.”

What the sources say

• Not checked yetcites [221] Yockey, L. J., Lucas, C. & Iwasaki, A. Contributions of maternal and fetal antiviral immunity in congenital disease. Science 368, 608–612 (2020). source

In the paper

“Overall, mRNA vaccines have promising safety profiles, with only mild or moderate adverse events occurring in clinical trials.”

In the paper

“Cytomegalovirus infection, for example, causes complications in up to 1% of pregnancies and can lead to congenital disabilities and neurological impairment in infants220.”

What the sources say

• Not checked yetcites [220] Bialas, K. M., Swamy, G. K. & Permar, S. R. Perinatal cytomegalovirus and varicella zoster virus infections: epidemiology, prevention, and treatment. Clin. Perinatol. 42, 61–75 (2015). source

In the paper

“Maternal IgG antibodies readily cross the placenta by binding to the neonatal crystallizable fragment (Fc) receptor, enter the fetal circulation and protect the fetus from pathogens224.”

What the sources say

• Not checked yetcites [224] Roopenian, D. C. & Akilesh, S. FcRn: the neonatal Fc receptor comes of age. Nat. Rev. Immunol. 7, 715–725 (2007). source

In the paper

“In a preclinical study, CureVac’s RNActive delivery platform activated TLR7 and generated durable immune responses against a lethal influenza dose in 18-month-old mice105.”

What the sources say

• Not checked yetcites [105] Kallen, K. J. et al. A novel, disruptive vaccination technology: self-adjuvanted RNActive® vaccines. Hum. Vaccines Immunother. 9, 2263–2276 (2013). source

In the paper

“Preliminary data suggest that mRNA-1273 and BNT162b2 elicited similar adverse events in pregnant and non-pregnant people, and the vaccines did not increase the incidence of neonatal death or congenital anomalies231.”

What the sources say

• Not checked yetcites [231] Shimabukuro, T. T. et al. Preliminary findings of mRNA Covid-19 vaccine safety in pregnant persons. N. Engl. J. Med. 384, 2273–2282 (2021). source

In the paper

“By 2050, the proportion of the global population over 60 years old is expected to almost double from 12% to 22% (see Related links).”

What the sources say

• Not checked yetcites Related links

In the paper

“70–90% of influenza-related mortalities occur in people older than 65 years232”

What the sources say

• Not checked yetcites [232] Crooke, S. N., Ovsyannikova, I. G., Poland, G. A. & Kennedy, R. B. Immunosenescence and human vaccine immune responses. Immun. Ageing 16, 25 (2019). source

In the paper

“The Moderna vaccine candidate mRNA-1273 was also highly effective, and showed 86.4% efficacy in volunteers ≥65 years old, in comparison with 95.6% efficacy in 18–65-year-old volunteers131.”

What the sources say

• Not checked yetcites [131] Baden, L. R. et al. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384, 403–416 (2020). source

In the paper

“Reduced Toll-like receptor expression stalls cytokine and chemokine secretion by monocytes and macrophages and limits crosstalk with the adaptive immune system234.”

What the sources say

• Not checked yetcites [234] Van Den Biggelaar, A. H. J. et al. Impaired innate immunity predicts frailty in old age. The Leiden 85-plus study. Exp. Gerontol. 39, 1407–1414 (2004). source

In the paper

“COVID-19 is reported to be 62 times more fatal in patients older than 65 than it is in younger patients233.”

What the sources say

• Not checked yetcites [233] Yanez, N. D., Weiss, N. S., Romand, J. A. & Treggiari, M. M. COVID-19 mortality risk for older men and women. BMC Public Health 20, 1742 (2020). source

In the paper

“Although vertically transferred maternal antibodies can prevent neonatal infection, they can also impede the efficacy of vaccines that are administered to infants later in life.”

In the paper

“Enhanced efficacy will lower the acceptance rates required for herd immunity, and improved safety will stem media reports of adverse events and, thus, decrease fear of vaccination.”

In the paper

“public mistrust fuelled by misinformation and anti-vaccination movements threatens the maintenance of herd immunity and puts our most vulnerable populations at risk.”

In the paper

“MF59 amplifies the immunogenicity of influenza vaccines and has been approved for use in elderly adults110.”

What the sources say

• Not checked yetcites [110] Tsai, T. F. Fluad®-MF59®-adjuvanted influenza vaccine in older adults. Infect. Chemother. 45, 159–174 (2013). source

In the paper

“Access to vaccines is the greatest challenge in achieving widespread protection against infectious diseases, especially in low-income countries.”

In the paper

“The first two mRNA vaccines, which were developed at revolutionary speed to fight SARS-CoV-2, have exceeded expectations and offer hope that the COVID-19 pandemic will end.”

In the paper

“it is undeniable that vaccines have eradicated several infectious diseases in portions of the world and saved countless lives.”

In the paper

“Decades of progress in mRNA design and nucleic acid delivery technology, together with the discovery of novel antigen targets have made mRNA vaccines an extraordinary tool for combating emerging pandemics and existing infectious diseases.”

In the paper

“Enhanced efficacy will lower the acceptance rates required for herd immunity, and improved safety will stem media reports of adverse events and, thus, decrease fear of vaccination.”

In the paper

“measles, which was eradicated from the USA in 2000, infected more than 1,200 people in 2019 owing to poor vaccine compliance in multiple communities (see Related links).”

What the sources say

• Not checked yetcites Related links