The dawn of mRNA vaccines: The COVID-19 case

In the paper

“All three major players in the mRNA vaccine field have previously optimized so-called lipid nanoparticles (LNPs), constructs that typically consist of an ionizable lipid and one or more helper lipids to improve LNP stability and promote endosomal escape upon cellular uptake [12,13]”

What the sources say

• Not checked yetcites [12] Sabnis S. Kumarasinghe E.S. Salerno T. Mihai C. Ketova T. Senn J.J. Lynn A. Bulychev A. McFadyen I. Chan J. A novel amino lipid series for mRNA delivery: improved endosomal escape and sustained pharmacology and safety in non-human primates Mol. Ther. 26 2018 1509 1519 29653760 PMC5986714 source
• Partly supported

  The Introduction describes typical LNP components, including an ionizable lipid and a helper lipid, and the Results report this paper’s screening of LNP formulations. The copy does not establish that all three major mRNA-vaccine players previously optimized LNPs, or that helper lipids improve stability and promote endosomal escape; the Discussion links improved endosomal escape to one ionizable lipid instead. No page numbers are available in our copy. (LLM, conf=0.87)

  cites [13] Hassett K.J. Benenato K.E. Jacquinet E. Lee A. Woods A. Yuzhakov O. Himansu S. Deterling J. Geilich B.M. Ketova T. Optimization of lipid nanoparticles forintramuscular administration of mRNA vaccines Mol. Ther. Nucleic Acids 15 2019 1 11 30785039 PMC6383180 sourceExperimental — accuracy not yet measured

In the paper

“For Moderna's LNP formulation, Hassett et al. reported that the SM-102 lipid was selected based on its improved tolerability profile in non-human primates, as evidenced by a reduced local reactogenicity (e.g., edema and erythema) and lowest induction of systemic cytokine responses (e.g., IL-6) [13]”

What the sources say

• Partly supported

  Split into 2 atoms — 0 confirmed, 2 partially supported, 0 disputed, 0 misattributed, 0 unverifiable. Expand the claim to see per-atom verdicts.

  cites [13] Hassett K.J. Benenato K.E. Jacquinet E. Lee A. Woods A. Yuzhakov O. Himansu S. Deterling J. Geilich B.M. Ketova T. Optimization of lipid nanoparticles forintramuscular administration of mRNA vaccines Mol. Ther. Nucleic Acids 15 2019 1 11 30785039 PMC6383180 sourceExperimental — accuracy not yet measured

In the paper

“Supported by evidence obtained in viral challenge experiments in non-human primates that both vaccines produced rapid viral control in the upper and lower airways”

What the sources say

• Partly supported

  The ‘BNT162b-elicted protection in macaques’ section reports rapid reduction of viral RNA in bronchoalveolar lavage fluid for both vaccines. Its nasal-swab results are less consistent with rapid upper-airway control by both: viral RNA was detected one day after challenge in five of six BNT162b2-immunized macaques, and the Fig. 4 legend reports no statistically significant nasal-swab difference for BNT162b2 versus its controls (P = 0.2622). (LLM, conf=0.86)

  cites [48] Vogel A.B. Kanevsky I. Che Y. Swanson K.A. Muik A. Vormehr M. Kranz L.M. Walzer K.C. Hein S. Güler A. Immunogenic BNT162b vaccines protect rhesus macaques from SARS-CoV-2 Nature 2021 33524990 sourceExperimental — accuracy not yet measured
• Partly supported

  The Results section reports rapid control of viral replication within two days in the upper and lower airways of nonhuman primates given mRNA-1273. The two groups in this paper received different doses of the same vaccine, not two distinct mRNA vaccines, so it does not support the claim about both vaccines. (LLM, conf=0.90)

  cites [52] Corbett K.S. Flynn B. Foulds K.E. Francica J.R. Boyoglu-Barnum S. Werner A.P. Flach B. O'Connell S. Bock K.W. Minai M. Evaluation of the mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates N. Engl. J. Med. 383 2020 1544 1555 32722908 PMC7449230 sourceExperimental — accuracy not yet measured

In the paper

“despite the lower mRNA-doses used, AEs were reported more frequently with BNT162b1 as compared to mRNA-1273”

What the sources say

• Partly supported

  The safety results (p. 3) report adverse-event rates for BNT162b1 recipients at 10, 30, and 100 µg. The paper compares those rates with placebo, not mRNA-1273; it therefore does not establish that BNT162b1 used lower doses or caused more frequent AEs than mRNA-1273. (LLM, conf=0.84)

  cites [82] Mulligan M.J. Lyke K.E. Kitchin N. Absalon J. Gurtman A. Lockhart S. Neuzil K. Raabe V. Bailey R. Swanson K.A. Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults Nature 586 2020 589 593 32785213 sourceExperimental — accuracy not yet measured
• ?Could not verify

  The Results (Vaccine Safety; page unavailable) report adverse-event frequencies for mRNA-1273 doses only. The Discussion mentions an interim report on a receptor-binding-domain mRNA vaccine but does not compare its doses or adverse-event frequency with mRNA-1273. Searches for BNT162b1 and the lower-dose comparison found no passage establishing the claimed comparison. (LLM, conf=0.76)

  cites [53] Jackson L.A. Anderson E.J. Rouphael N.G. Roberts P.C. Makhene M. Coler R.N. McCullough M.P. Chappell J.D. Denison M.R. Stevens L.J. An mRNA vaccine against SARS-CoV-2 - preliminary report N. Engl. J. Med. 383 2020 1920 1931 32663912 PMC7377258 sourceExperimental — accuracy not yet measured

In the paper

“Of the confirmed cases, most of the individuals had a documented history of allergic reactions and/or anaphylaxis.”

What the sources say

• Partly supported

  The main text (page not provided) reports that 21 of 66 cases (32%) had a documented prior episode of anaphylaxis. It does not give the number with a broader history of allergic reactions, so our copy does not establish that most cases had a history of allergic reactions and/or anaphylaxis. (LLM, conf=0.78)

  cites [86] Shimabukuro T.T. Cole M. Su J.R. Reports of anaphylaxis after receipt of mRNA COVID-19 vaccines in the US—December 14, 2020-January 18, 2021 JAMA 325 2021 1101 1102 33576785 PMC8890485 sourceExperimental — accuracy not yet measured

In the paper

“by incorporating naturally occurring modified nucleotides into the IVT mRNA, its innate immune activity could be drastically reduced [6,7]”

What the sources say

• Not checked yetcites [6] Andries O. Mc Cafferty S. De Smedt S.C. Weiss R. Sanders N.N. Kitada T. 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 217 2015 337 344 26342664 source
• Not checked yetcites [7] Durbin A.F. Wang C. Marcotrigiano J. Gehrke L. RNAs containing modified nucleotides fail to trigger RIG-I conformational changes for innate immune signaling Mbio 7 2016 PMC5030355 27651356 source

In the paper

“the identification of Toll-like receptors (TLRs) by Jules Hoffman and Bruce Beutler elucidated how the mammalian immune system could recognize highly conserved patterns associated with the presence of pathogens or damage [3]”

What the sources say

• Not checked yetcites [3] O’Neill L.A.J. Golenbock D. Bowie A.G. The history of toll-like receptors - redefining innate immunity Nat. Rev. Immunol. 13 2013 453 460 23681101 source

In the paper

“Additional efforts to remove double-stranded (ds)RNA contaminants even further ablated IVT RNA's immunostimulatory activity [8,9]”

What the sources say

• Not checked yetcites [8] Baiersdorfer M. Boros G. Muramatsu H. Mahiny A. Vlatkovic I. Sahin U. Kariko K. A facile method for the removal of dsRNA contaminant from in vitro-transcribed mRNA Mol. Ther. Nulceic Acids 15 2019 26 35 PMC6444222 30933724 source
• Not checked yetcites [9] Kariko K. Muramatsu H. Ludwig J. Weissman D. Generating the optimal mRNA for therapy: HPLC purification eliminates immune activation and improves translation of nucleoside-modified, protein-encoding mRNA Nucleic Acids Res. 39 2011 e142 PMC3241667 21890902 source

In the paper

“the many modifications observed in natural mRNA are in fact a way to avoid immune recognition, allowing the immune system to distinguish self from non-self RNA [5]”

What the sources say

• Not checked yetcites [5] Kariko K. Buckstein M. Ni H.P. Weissman D. Suppression of RNA recognition by toll-like receptors: the impact of nucleoside modification and the evolutionary origin of RNA Immunity 23 2005 165 175 16111635 source

In the paper

“Precedent work by Moderna and the NIH National Institute for Allergy and Infectious Diseases (NIAID) demonstrated that the membrane-bound MERS-CoV 2P S mRNA elicited more potent neutralizing antibody responses as compared to secreted MERS-CoV 2P S, or wild-type S mRNA”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [27] Corbett K.S. Edwards D.K. Leist S.R. Abiona O.M. Boyoglu-Barnum S. Gillespie R.A. Himansu S. Schäfer A. Ziwawo C.T. DiPiazza A.T. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness Nature 586 2020 567 571 32756549 PMC7581537

In the paper

“Codon optimization in the mRNA sequence to e.g., match host transfer (t)RNA abundances, or as a determinant of introducing secondary structures, can drastically impact the protein synthesis rate and ribosome dwell time (i.e. mRNA functional half-life) [33,34]”

What the sources say

• Not checked yetcites [33] Presnyak V. Alhusaini N. Chen Y.H. Martin S. Morris N. Kline N. Olson S. Weinberg D. Baker K.E. Graveley B.R. Codon optimality is a major determinant of mRNA stability Cell 160 2015 1111 1124 25768907 PMC4359748 source
• Not checked yetcites [34] Mao Y. Liu H. Liu Y. Tao S. Deciphering the rules by which dynamics of mRNA secondary structure affect translation efficiency in Saccharomyces cerevisiae Nucleic Acids Res. 42 2014 4813 4822 24561808 PMC4005662 source

In the paper

“A major advantage of the mRNA approach, is that the proteins are produced by the host cells as they would be in case of a natural infection with the virus. As a result, the produced proteins will undergo the same post-translational processing, including glycosylation, subunit cleavage and proper protein folding.”

In the paper

“the rapid development of the COVID-19 vaccines did not come out of the blue at all, the current COVID-19 pandemic merely provided momentum for mRNA vaccines to speed up their progress to approval”

In the paper

“most of the MERS-CoV and SARS-CoV-1 neutralizing antibodies were directed to the S protein, in particular to its receptor-binding domain (RBD) [18,19]”

What the sources say

• Not checked yetcites [18] Du L.Y. Yang Y. Zhou Y.S. Lu L. Li F. Jiang S.B. MERS-CoV spike protein: a key target for antivirals Expert. Opin. Ther. Tar. 21 2017 131 143 PMC5457961 27936982 source
• Not checked yetcites [19] Tang X.C. Agnihothram S.S. Jiao Y.J. Stanhope J. Graham R.L. Peterson E.C. Avnir Y. Tallarico A.S. Sheehan J. Zhu Q. Identification of human neutralizing antibodies against MERS-CoV and their role in virus adaptive evolution Proc. Natl. Acad. Sci. USA 111 2014 (pp. 6863–6863) PMC4024880 24778221 source

In the paper

“Moderna already reported on the good tolerability of an intramuscular/intradermal nucleoside-modified mRNA vaccine against two Influenza viruses (H10N8 and H7N9). Typical adverse events related to immune activation such as myalgia, fatigue and headache were reported which were mostly mild to moderate in severity and short-lived, not requiring medical interventions [16]”

What the sources say

• Not checked yetcites [16] Feldman R.A. Fuhr R. Smolenov I. Ribeiro A. Panther L. Watson M. Senn J.J. Smith M. Almarsson O. Pujar H.S. 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 2019 3326 3334 31079849 source

In the paper

“merely 42 days after sequence selection from the genetic sequence of the new coronavirus by the Chinese authorities, the first clinical-grade batch of Moderna's mRNA vaccine was ready [22]”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [22] Moderna Ships mRNA Vaccine Against Novel Coronavirus (mRNA-1273) for Phase 1 Study https://investors.modernatx.com/news-releases/news-release-details/moderna-ships-mrna-vaccine-against-novel-coronavirus-mrna-1273 2020

In the paper

“CureVac announced positive interim results from a phase 1 trial evaluating the safety and immunogenicity of a prophylactic mRNA Rabies LNP vaccine [17]”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [17] CureVac Announces Positive Results in Low Dose – 1 μg – Rabies Vaccine Clinical Phase 1 Study https://www.curevac.com/en/2020/01/07/curevac-announces-positive-results-in-low-dose-1-%C2%B5g-rabies-vaccine-clinical-phase-1-study/ 2020

In the paper

“The design of (non-coding) structural elements of the mRNA such as the CAP structure, poly(A) tail and untranslated regions (UTRs) all have a major impact on the mRNA stability and translation capacity [31,32]”

What the sources say

• Not checked yetcites [31] Orlandini von Niessen A.G. Poleganov M.A. Rechner C. Plaschke A. Kranz L.M. Fesser S. Diken M. Lower M. Vallazza B. Beissert T. Improving mRNA-based therapeutic gene delivery by expression-augmenting 3' UTRs identified by cellular library screening Mol. Ther. 27 2019 824 836 30638957 PMC6453560 source
• Not checked yetcites [32] Holtkamp S. Kreiter S. Selmi A. Simon P. Koslowski M. Huber C. Türeci O. Sahin U. Modification of antigen-encoding RNA increases stability, translational efficacy, and T-cell stimulatory capacity of dendritic cells Blood 108 2006 4009 4017 16940422 source

In the paper

“This carrier concept is very similar to the recently FDA-approved siRNA-based therapeutic Onpattro® (Alnylam® Pharmaceuticals) which was designed for hepatocyte targeting after intravenous administration [15]”

What the sources say

• Not checked yetcites [15] Akinc A. Maier M.A. Manoharan M. Fitzgerald K. Jayaraman M. Barros S. Ansell S. Du X.Y. Hope M.J. Madden T.D. The Onpattro story and the clinical translation of nanomedicines containing nucleic acid-based drugs Nat. Nanotechnol. 14 2019 1084 1087 31802031 source

In the paper

“Another factor that contributes to the rapid progression of the SARS-CoV-2 vaccines is the ability to build on earlier research on coronaviruses that induced severe acute respiratory syndrome (SARS, first reported in 2003) and Middle East respiratory syndrome (MERS, first outbreak in 2012).”

In the paper

“Taken together, as a platform technology, mRNA-LNP vaccines already reached a substantial degree of maturity.”

In the paper

“BNT162b2 and mRNA-1273 implement a combination of modified nucleotide 1mΨ replacement and removal of dsRNA fragments in the mRNA production process, which strongly reduces the innate immune signaling in response to mRNA through decreased activation of TLR signaling and cytosolic RNA sensors.”

What the sources say

• Not checked yetcites [37] Nelson J. Sorensen E.W. Mintri S. Rabideau A.E. Zheng W. Besin G. Khatwani N. Su S.V. Miracco E.J. Issa W.J. Impact of mRNA chemistry and manufacturing process on innate immune activation Sci. Adv. 6 2020 (eaaz6893) PMC7314518 32637598 source

In the paper

“Vaccine targeted cell types (see Mode of action), such as dendritic cells (DCs) and monocytes, highly express LDL receptors and other scavenger receptors [41]”

What the sources say

• Not checked yetcites [41] Liang F. Lindgren G. Lin A. Thompson E.A. Ols S. Röhss J. John S. Hassett K. Yuzhakov O. Bahl K. Efficient targeting and activation of antigen-presenting cells in vivo after modified mRNA vaccine administration in rhesus macaques Mol. Ther. 25 2017 2635 2647 28958578 PMC5768558 source

In the paper

“There are good reasons to believe that ApoE binding also plays a critical role in the uptake of the mRNA LNP vaccines after intramuscular injection.”

In the paper

“two vaccine doses of CVnCoV (12 μg mRNA dose) induced SARS-CoV-2 neutralizing antibody titers in all participants at levels that were comparable to those found in individuals who had recovered from natural infection [57]”

What the sources say

• Not checked yetcites [57] Kremsner P. Mann P. Bosch J. Fendel R. Gabor J.J. Kreidenweiss A. Kroidl A. Leroux-Roels I. Leroux-Roels G. Schindler C. Phase 1 assessment of the safety and immunogenicity of an mRNA-lipid nanoparticle vaccine candidate against SARS-CoV-2 in human volunteers medRxiv 2020 (Preprint) PMC8354521 34378087 source

In the paper

“owing to their relatively small size (~100 nm), neutral surface charge and diffusible PEG lipid coating, mRNA LNPs might also enter the lymphatics to directly target LN-resident APCs and B cells [11,58]”

What the sources say

• Not checked yetcites [11] Lutz J. Lazzaro S. Habbeddine M. Schmidt K.E. Baumhof P. Mui B.L. Tam Y.K. Madden T.D. Hope M.J. Heidenreich R. Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines npj Vaccines 2 2017 PMC5648897 29263884 source
• Not checked yetcites [58] Lindsay K.E. Bhosle S.M. Zurla C. Beyersdorf J. Rogers K.A. Vanover D. Xiao P. Araínga M. Shirreff L.M. Pitard B. Visualization of early events in mRNA vaccine delivery in non-human primates via PET–CT and near-infrared imaging Nat. Biomed. Eng. 3 2019 371 380 30936432 source

In the paper

“Several preclinical studies have indicated that an unmodified mRNA platform induces a more pronounced type-I IFN-polarized innate immune response [11,62]”

What the sources say

• Not checked yetcites [11] Lutz J. Lazzaro S. Habbeddine M. Schmidt K.E. Baumhof P. Mui B.L. Tam Y.K. Madden T.D. Hope M.J. Heidenreich R. Unmodified mRNA in LNPs constitutes a competitive technology for prophylactic vaccines npj Vaccines 2 2017 PMC5648897 29263884 source
• Not checked yetcites [62] Verbeke R. Lentacker I. Wayteck L. Breckpot K. Van Bockstal M. Descamps B. Vanhove C. De Smedt S.C. Dewitte H. Co-delivery of nucleoside-modified mRNA and TLR agonists for cancer immunotherapy: restoring the immunogenicity of immunosilent mRNA J. Control. Release 266 2017 287 300 28987878 source

In the paper

“Memory T cells, particularly those residing at the upper airways might limit disease severity and shorten the duration of disease by rapidly eliminating infected cells and coordinating the production of antibodies [67]”

What the sources say

• Not checked yetcites [67] Channappanavar R. Fett C. Zhao J. Meyerholz D.K. Perlman S. Virus-specific memory CD8 T cells provide substantial protection from lethal severe acute respiratory syndrome coronavirus infection J. Virol. 88 2014 11034 11044 25056892 PMC4178831 source

In the paper

“the usage of the SM-102 lipid in Moderna's mRNA-1273 vaccine was found to outperform Onpattro's MC3 LNPs for the intramuscular (i.m.) delivery of mRNA in rodents and non-human primates, given its improved tolerability and higher endosomal escape efficiency [12,13]”

What the sources say

• Not checked yetcites [12] Sabnis S. Kumarasinghe E.S. Salerno T. Mihai C. Ketova T. Senn J.J. Lynn A. Bulychev A. McFadyen I. Chan J. A novel amino lipid series for mRNA delivery: improved endosomal escape and sustained pharmacology and safety in non-human primates Mol. Ther. 26 2018 1509 1519 29653760 PMC5986714 source
• Not checked yetcites [13] Hassett K.J. Benenato K.E. Jacquinet E. Lee A. Woods A. Yuzhakov O. Himansu S. Deterling J. Geilich B.M. Ketova T. Optimization of lipid nanoparticles forintramuscular administration of mRNA vaccines Mol. Ther. Nucleic Acids 15 2019 1 11 30785039 PMC6383180 source

In the paper

“several research groups underlined that the type I IFN response can act as a driving force for mRNA vaccines to elicit cytotoxic T cell responses [1,60,61]”

What the sources say

• Not checked yetcites [1] Verbeke R. Lentacker I. De Smedt S.C. Dewitte H. Three decades of messenger RNA vaccine development Nano Today 28 2019 100766 source
• Not checked yetcites [60] Kranz L.M. Diken M. Haas H. Kreiter S. Loquai C. Reuter K.C. Meng M. Fritz D. Vascotto F. Hefesha H. Systemic RNA delivery to dendritic cells exploits antiviral defence for cancer immunotherapy Nature 534 2016 396 401 27281205 source
• Not checked yetcites [61] Broos K. Van der Jeught K. Puttemans J. Goyvaerts C. Heirman C. Dewitte H. Verbeke R. Lentacker I. Thielemans K. Breckpot K. Particle-mediated intravenous delivery of antigen mRNA results in strong antigen-specific T-cell responses despite the induction of type I interferon Mol. Ther. Nucleic Acids 5 2016 e326 PMC5022130 27327138 source

In the paper

“the transfection of human DCs with mRNA LNPs in an in vitro setting was also reported to be promoted in the presence of ApoE [42]”

What the sources say

• Not checked yetcites [42] Pardi N. Tuyishime S. Muramatsu H. Kariko K. Mui B.L. Tam Y.K. Madden T.D. Hope M.J. Weissman D. Expression kinetics of nucleoside-modified mRNA delivered in lipid nanoparticles to mice by various routes J. Control. Release 217 2015 345 351 26264835 PMC4624045 source

In the paper

“Upon intravenous administration, Akinc et al. found that the surface of neutrally-charged LNPs is strongly enriched with apolipoprotein E (ApoE), which leads to enhanced uptake by hepatocytes through low density lipoprotein (LDL) receptor-mediated endocytosis [40]”

What the sources say

• Not checked yetcites [40] Akinc A. Querbes W. De S. Qin J. Frank-Kamenetsky M. Jayaprakash K.N. Jayaraman M. Rajeev K.G. Cantley W.L. Dorkin J.R. Targeted delivery of RNAi therapeutics with endogenous and exogenous ligand-based mechanisms Mol. Ther. 18 2010 1357 1364 20461061 PMC2911264 source

In the paper

“T cells, on their own, will probably not be capable to prevent viral entry by providing sterilizing immunity against SARS-COV-2.”

In the paper

“Cationic lipids have been associated with the activation of several cellular pathways like pro-apoptotic and pro-inflammatory cascades [65]”

What the sources say

• Not checked yetcites [65] Lonez C. Vandenbranden M. Ruysschaert J.M. Cationic lipids activate intracellular signaling pathways Adv. Drug Deliv. Rev. 64 2012 1749 1758 22634161 source

In the paper

“the majority of the activated CD4+ T cells displayed a Th1 skewed profile (i.e. cells producing IFN-ɣ, TNF-α, and IL-2)”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [50] Sahin U. Muik A. Vogler I. Derhovanessian E. Kranz L.M. Vormehr M. Quandt J. Bidmon N. Ulges A. Baum A. BNT162b2 induces SARS-CoV-2-neutralising antibodies and T cells in humans medRxiv 2020 (Preprint)
• Not checked yetcites [53] Jackson L.A. Anderson E.J. Rouphael N.G. Roberts P.C. Makhene M. Coler R.N. McCullough M.P. Chappell J.D. Denison M.R. Stevens L.J. An mRNA vaccine against SARS-CoV-2 - preliminary report N. Engl. J. Med. 383 2020 1920 1931 32663912 PMC7377258 source

In the paper

“real-world data from Israel's immunization program with BNT162b2 demonstrate that two weeks after the second dose vaccine effectiveness was estimated at 97% in preventing symptomatic and severe COVID-19 disease”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [76] BioNTech Real-World Evidence Confirms High Effectiveness of Pfizer-BioNTech COVID-19 Vaccine https://investors.biontech.de/news-releases/news-release-details/real-world-evidence-confirms-high-effectiveness-pfizer-biontech 2021

In the paper

“the nucleoside-modified mRNA vaccines BNT162b2 (30 μg mRNA dose) and mRNA-1273 (100 μg mRNA dose) generally surpassed the titers from convalescent COVID-19 patient samples, even in the elderly trial group”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [49] Walsh E.E. Frenck R.W. Falsey A.R. Kitchin N. Absalon J. Gurtman A. Lockhart S. Neuzil K. Mulligan M.J. Bailey R. Safety and immunogenicity of two RNA-based COVID-19 vaccine candidates N. Engl. J. Med. 383 2020 2439 2450 33053279 PMC7583697
• Not checked yetcites [53] Jackson L.A. Anderson E.J. Rouphael N.G. Roberts P.C. Makhene M. Coler R.N. McCullough M.P. Chappell J.D. Denison M.R. Stevens L.J. An mRNA vaccine against SARS-CoV-2 - preliminary report N. Engl. J. Med. 383 2020 1920 1931 32663912 PMC7377258 source

In the paper

“In humans, both BNT162b2 and mRNA-1273 elicited S-specific CD4+ T cell responses directed against the S1 (including RBD) and S2 regions of the S glycoprotein”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [50] Sahin U. Muik A. Vogler I. Derhovanessian E. Kranz L.M. Vormehr M. Quandt J. Bidmon N. Ulges A. Baum A. BNT162b2 induces SARS-CoV-2-neutralising antibodies and T cells in humans medRxiv 2020 (Preprint)
• Not checked yetcites [53] Jackson L.A. Anderson E.J. Rouphael N.G. Roberts P.C. Makhene M. Coler R.N. McCullough M.P. Chappell J.D. Denison M.R. Stevens L.J. An mRNA vaccine against SARS-CoV-2 - preliminary report N. Engl. J. Med. 383 2020 1920 1931 32663912 PMC7377258 source

In the paper

“From the preclinical evidence of CVnCoV in mice, it can be appreciated that high numbers of S-specific CD8+ T cells were detected after two rounds of vaccination (up to 10% of total splenic CD8+ T cells) [56].”

What the sources say

• Not checked yetcites [56] Rauch S. Roth N. Schwendt K. Fotin-Mleczek M. Mueller S.O. Petsch B. mRNA based SARS-CoV-2 vaccine candidate CVnCoV induces high levels of virus neutralizing antibodies and mediates protection in rodents bioRxiv 2020 (Preprint) PMC8052455 33863911 source

In the paper

“in which their absolute numbers correlated with the levels of neutralizing antibodies [74].”

What the sources say

• Not checked yetcites [74] Lederer K. Castaño D. Gómez Atria D. Oguin T.H. 3rd Wang S. Manzoni T.B. Muramatsu H. Hogan M.J. Amanat F. Cherubin P. SARS-CoV-2 mRNA vaccines foster potent antigen-specific germinal center responses associated with neutralizing antibody generation Immunity 53 2020 1281 1295 33296685 PMC7680029 source

In the paper

“this capacity of CVnCoV to elicit robust CD8+ T cell responses could not yet be confirmed in humans”

What the sources say

• Not checked yetcites [57] Kremsner P. Mann P. Bosch J. Fendel R. Gabor J.J. Kreidenweiss A. Kroidl A. Leroux-Roels I. Leroux-Roels G. Schindler C. Phase 1 assessment of the safety and immunogenicity of an mRNA-lipid nanoparticle vaccine candidate against SARS-CoV-2 in human volunteers medRxiv 2020 (Preprint) PMC8354521 34378087 source

In the paper

“This specialized T cell phenotype is essential for the proper regulation of GCs [73].”

What the sources say

• Not checked yetcites [73] Crotty S. T follicular helper cell biology: a decade of discovery and diseases Immunity 50 2019 1132 1148 31117010 PMC6532429

In the paper

“which again highlights the benefit of delivering mRNA encoding the full-length S protein [50,53].”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [50] Sahin U. Muik A. Vogler I. Derhovanessian E. Kranz L.M. Vormehr M. Quandt J. Bidmon N. Ulges A. Baum A. BNT162b2 induces SARS-CoV-2-neutralising antibodies and T cells in humans medRxiv 2020 (Preprint)
• Not checked yetcites [53] Jackson L.A. Anderson E.J. Rouphael N.G. Roberts P.C. Makhene M. Coler R.N. McCullough M.P. Chappell J.D. Denison M.R. Stevens L.J. An mRNA vaccine against SARS-CoV-2 - preliminary report N. Engl. J. Med. 383 2020 1920 1931 32663912 PMC7377258 source

In the paper

“Pardi and colleagues recently demonstrated that a single immunization of mice with 1mΨ-modified mRNA LNP vaccines could elicit potent S-specific GC B cells and Tfh cells”

What the sources say

• Not checked yetcites [74] Lederer K. Castaño D. Gómez Atria D. Oguin T.H. 3rd Wang S. Manzoni T.B. Muramatsu H. Hogan M.J. Amanat F. Cherubin P. SARS-CoV-2 mRNA vaccines foster potent antigen-specific germinal center responses associated with neutralizing antibody generation Immunity 53 2020 1281 1295 33296685 PMC7680029 source

In the paper

“The neutralization activity of sera collected from both mRNA-1273 and BNT162b2 vaccinated individuals was largely preserved against the B.1.1.7 variant relative to prior variants.”

What the sources say

• Not checked yetcites [77] Muik A. Wallisch A.-K. Sänger B. Swanson K.A. Mühl J. Chen W. Cai H. Maurus D. Sarkar R. Türeci Ö. Neutralization of SARS-CoV-2 lineage B.1.1.7 pseudovirus by BNT162b2 vaccine–elicited human sera Science 371 6534 2021 1152 1153 33514629 PMC7971771 source
• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [78] Wu K. Werner A.P. Moliva J.I. Koch M. Choi A. Stewart-Jones G.B.E. Bennett H. Boyoglu-Barnum S. Shi W. Graham B.S. mRNA-1273 vaccine induces neutralizing antibodies against spike mutants from global SARS-CoV-2 variants bioRxiv 2021 (Preprint)
• Not checked yetcites [79] Liu Y. Liu J. Xia H. Zhang X. Fontes-Garfias C.R. Swanson K.A. Cai H. Sarkar R. Chen W. Cutler M. Neutralizing activity of BNT162b2-elicited serum N. Engl. J. Med. 2021 PMC7944950 33684280 source

In the paper

“The magnitude of CD4+ T cell responses correlated with the levels of S-binding IgG antibodies”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [50] Sahin U. Muik A. Vogler I. Derhovanessian E. Kranz L.M. Vormehr M. Quandt J. Bidmon N. Ulges A. Baum A. BNT162b2 induces SARS-CoV-2-neutralising antibodies and T cells in humans medRxiv 2020 (Preprint)
• Not checked yetcites [53] Jackson L.A. Anderson E.J. Rouphael N.G. Roberts P.C. Makhene M. Coler R.N. McCullough M.P. Chappell J.D. Denison M.R. Stevens L.J. An mRNA vaccine against SARS-CoV-2 - preliminary report N. Engl. J. Med. 383 2020 1920 1931 32663912 PMC7377258 source

In the paper

“several studies have shown that i.m. delivery of 1mΨ-modified mRNA vaccines results in the rapid and potent induction of follicular T helper cells (Tfh) [71,72].”

What the sources say

• Not checked yetcites [71] Lindgren G. Ols S. Liang F. Thompson E.A. Lin A. Hellgren F. Bahl K. John S. Yuzhakov O. Hassett K.J. Induction of robust B cell responses after influenza mRNA vaccination Is accompanied by circulating hemagglutinin-specific ICOS+ PD-1+ CXCR3+ T follicular helper cells Front. Immunol. 8 2017 PMC5693886 29181005 source
• Not checked yetcites [72] Pardi N. Hogan M.J. Naradikian M.S. Parkhouse K. Cain D.W. Jones L. Moody M.A. Verkerke H.P. Myles A. Willis E. Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses J. Exp. Med. 215 2018 1571 1588 29739835 PMC5987916 source

In the paper

“The interim analysis report on the ongoing phase 3 trial of BNT162b2 showed that a two dose vaccine regimen was very effective in preventing COVID-19 disease (up to 95% efficacy) [51].”

What the sources say

• Not checked yetcites [51] Polack F.P. Thomas S.J. Kitchin N. Absalon J. Gurtman A. Lockhart S. Perez J.L. Pérez Marc G. Moreira E.D. Zerbini C. Safety and efficacy of the BNT162b2 mRNA Covid-19 vaccine N. Engl. J. Med. 383 2020 2603 2615 33301246 PMC7745181

In the paper

“while the vaccine was 94% effective against asymptomatic SARS-CoV-2 infections [76].”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [76] BioNTech Real-World Evidence Confirms High Effectiveness of Pfizer-BioNTech COVID-19 Vaccine https://investors.biontech.de/news-releases/news-release-details/real-world-evidence-confirms-high-effectiveness-pfizer-biontech 2021

In the paper

“study results indicate that BNT162b2 outperforms mRNA-1273.”

• Also stated in: § Conclusions and perspectives · plain

  “the two seemingly similar (nucleoside-modified) mRNA vaccines elicited different S-specific CD8+ T cell responses.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [50] Sahin U. Muik A. Vogler I. Derhovanessian E. Kranz L.M. Vormehr M. Quandt J. Bidmon N. Ulges A. Baum A. BNT162b2 induces SARS-CoV-2-neutralising antibodies and T cells in humans medRxiv 2020 (Preprint)
• Not checked yetcites [53] Jackson L.A. Anderson E.J. Rouphael N.G. Roberts P.C. Makhene M. Coler R.N. McCullough M.P. Chappell J.D. Denison M.R. Stevens L.J. An mRNA vaccine against SARS-CoV-2 - preliminary report N. Engl. J. Med. 383 2020 1920 1931 32663912 PMC7377258 source

In the paper

“as compared to low or undetectable levels in the clinical evaluation of mRNA-1273 [53].”

What the sources say

• Not checked yetcites [53] Jackson L.A. Anderson E.J. Rouphael N.G. Roberts P.C. Makhene M. Coler R.N. McCullough M.P. Chappell J.D. Denison M.R. Stevens L.J. An mRNA vaccine against SARS-CoV-2 - preliminary report N. Engl. J. Med. 383 2020 1920 1931 32663912 PMC7377258 source

In the paper

“Most of the study participants vaccinated with BNT162b2 mounted significant S-specific CD8+ T cell responses (91.9%) [50]”

What the sources say

• Not checked yetcites [50] Sahin U. Muik A. Vogler I. Derhovanessian E. Kranz L.M. Vormehr M. Quandt J. Bidmon N. Ulges A. Baum A. BNT162b2 induces SARS-CoV-2-neutralising antibodies and T cells in humans medRxiv 2020 (Preprint)

In the paper

“underlining their supporting role in humoral immunity”

In the paper

“nor were any details on T cell activation reported in the first clinical data of the phase 1 trial of this mRNA vaccine [57].”

What the sources say

• Not checked yetcites [57] Kremsner P. Mann P. Bosch J. Fendel R. Gabor J.J. Kreidenweiss A. Kroidl A. Leroux-Roels I. Leroux-Roels G. Schindler C. Phase 1 assessment of the safety and immunogenicity of an mRNA-lipid nanoparticle vaccine candidate against SARS-CoV-2 in human volunteers medRxiv 2020 (Preprint) PMC8354521 34378087 source

In the paper

“fever was only reported after the second vaccination of Moderna's mRNA-1273 vaccine at the higher doses of 100 μg (fever in 40% of participants) and 250 μg (57% of participants, with 1/8 events graded as severe).”

What the sources say

• Not checked yetcites [53] Jackson L.A. Anderson E.J. Rouphael N.G. Roberts P.C. Makhene M. Coler R.N. McCullough M.P. Chappell J.D. Denison M.R. Stevens L.J. An mRNA vaccine against SARS-CoV-2 - preliminary report N. Engl. J. Med. 383 2020 1920 1931 32663912 PMC7377258 source

In the paper

“fever was already reported after the first vaccination for all dose groups (8% for the 10 and 30 μg doses, 50% for the 100 μg dose)”

What the sources say

• Not checked yetcites [82] Mulligan M.J. Lyke K.E. Kitchin N. Absalon J. Gurtman A. Lockhart S. Neuzil K. Raabe V. Bailey R. Swanson K.A. Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults Nature 586 2020 589 593 32785213 source

In the paper

“Even at this low dose, systemic AEs occurred more frequently in response to a prime dose compared to the modified mRNA vaccines.”

What the sources say

• Not checked yetcites [57] Kremsner P. Mann P. Bosch J. Fendel R. Gabor J.J. Kreidenweiss A. Kroidl A. Leroux-Roels I. Leroux-Roels G. Schindler C. Phase 1 assessment of the safety and immunogenicity of an mRNA-lipid nanoparticle vaccine candidate against SARS-CoV-2 in human volunteers medRxiv 2020 (Preprint) PMC8354521 34378087 source

In the paper

“No fever was reported for the 25 μg vaccine dose.”

What the sources say

• Not checked yetcites [53] Jackson L.A. Anderson E.J. Rouphael N.G. Roberts P.C. Makhene M. Coler R.N. McCullough M.P. Chappell J.D. Denison M.R. Stevens L.J. An mRNA vaccine against SARS-CoV-2 - preliminary report N. Engl. J. Med. 383 2020 1920 1931 32663912 PMC7377258 source

In the paper

“Based on the reactogenicity to the 100 μg dose, no boost vaccination was performed at this dosage.”

What the sources say

• Not checked yetcites [82] Mulligan M.J. Lyke K.E. Kitchin N. Absalon J. Gurtman A. Lockhart S. Neuzil K. Raabe V. Bailey R. Swanson K.A. Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults Nature 586 2020 589 593 32785213 source

In the paper

“with up to 75% showing moderate fever after a 30 μg boost vaccine [82].”

What the sources say

• Not checked yetcites [82] Mulligan M.J. Lyke K.E. Kitchin N. Absalon J. Gurtman A. Lockhart S. Neuzil K. Raabe V. Bailey R. Swanson K.A. Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults Nature 586 2020 589 593 32785213 source

In the paper

“merely 8% and 17% of participants aged 18–55 or 65–85, respectively, reported fever after a second 30 μg dose.”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [49] Walsh E.E. Frenck R.W. Falsey A.R. Kitchin N. Absalon J. Gurtman A. Lockhart S. Neuzil K. Mulligan M.J. Bailey R. Safety and immunogenicity of two RNA-based COVID-19 vaccine candidates N. Engl. J. Med. 383 2020 2439 2450 33053279 PMC7583697

In the paper

“This study demonstrated that the systemic AEs were milder for the BNT162b2 (full length S protein mRNA) vaccine as compared to the BNT162b1 (RBD trimer mRNA).”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [49] Walsh E.E. Frenck R.W. Falsey A.R. Kitchin N. Absalon J. Gurtman A. Lockhart S. Neuzil K. Mulligan M.J. Bailey R. Safety and immunogenicity of two RNA-based COVID-19 vaccine candidates N. Engl. J. Med. 383 2020 2439 2450 33053279 PMC7583697

In the paper

“none of the mRNA vaccines for which clinical results are available, report any major safety concerns.”

In the paper

“Moderna already reported that neutralizing antibodies continued to be detected in all the participants at 3 months post-vaccination [81].”

What the sources say

• Not checked yetcites [81] Widge A.T. Rouphael N.G. Jackson L.A. Anderson E.J. Roberts P.C. Makhene M. Chappell J.D. Denison M.R. Stevens L.J. Pruijssers A.J. Durability of responses after SARS-CoV-2 mRNA-1273 vaccination N. Engl. J. Med. 384 2021 80 82 33270381 PMC7727324 source

In the paper

“The mRNA vaccines that contain nucleoside-modified mRNA (BioNTech/Pfizer and Moderna) both report a clear dose-dependency in the occurrence of localized and systemic adverse events (AEs).”

What the sources say

• Not checked yetcites [53] Jackson L.A. Anderson E.J. Rouphael N.G. Roberts P.C. Makhene M. Coler R.N. McCullough M.P. Chappell J.D. Denison M.R. Stevens L.J. An mRNA vaccine against SARS-CoV-2 - preliminary report N. Engl. J. Med. 383 2020 1920 1931 32663912 PMC7377258 source

In the paper

“When LNPs package unmodified mRNA, this clearly affects the tolerability of the vaccine.”

In the paper

“Results of a phase 1/2 dose-escalation study (mRNA doses of 10–30-100 μg) revealed similar tolerability and safety.”

What the sources say

• Not checked yetcites [82] Mulligan M.J. Lyke K.E. Kitchin N. Absalon J. Gurtman A. Lockhart S. Neuzil K. Raabe V. Bailey R. Swanson K.A. Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults Nature 586 2020 589 593 32785213 source

In the paper

“but remained above levels that are expected to be protective”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [78] Wu K. Werner A.P. Moliva J.I. Koch M. Choi A. Stewart-Jones G.B.E. Bennett H. Boyoglu-Barnum S. Shi W. Graham B.S. mRNA-1273 vaccine induces neutralizing antibodies against spike mutants from global SARS-CoV-2 variants bioRxiv 2021 (Preprint)

In the paper

“Furthermore, AEs were more common after the boost vaccine compared to the prime dose.”

What the sources say

• Not checked yetcites [53] Jackson L.A. Anderson E.J. Rouphael N.G. Roberts P.C. Makhene M. Coler R.N. McCullough M.P. Chappell J.D. Denison M.R. Stevens L.J. An mRNA vaccine against SARS-CoV-2 - preliminary report N. Engl. J. Med. 383 2020 1920 1931 32663912 PMC7377258 source

In the paper

“in a study by Moderna a 6.4-fold reduction in neutralization titers was detected against a pseudovirus with a full set of B.1.351 mutations”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [78] Wu K. Werner A.P. Moliva J.I. Koch M. Choi A. Stewart-Jones G.B.E. Bennett H. Boyoglu-Barnum S. Shi W. Graham B.S. mRNA-1273 vaccine induces neutralizing antibodies against spike mutants from global SARS-CoV-2 variants bioRxiv 2021 (Preprint)

In the paper

“sera of all individuals were capable to obtain full neutralization [78].”

What the sources say

• ?Not matched

  Couldn’t be matched to a paper in Crossref, so it can’t be checked.

  cites [78] Wu K. Werner A.P. Moliva J.I. Koch M. Choi A. Stewart-Jones G.B.E. Bennett H. Boyoglu-Barnum S. Shi W. Graham B.S. mRNA-1273 vaccine induces neutralizing antibodies against spike mutants from global SARS-CoV-2 variants bioRxiv 2021 (Preprint)

In the paper

“only 1 out of the 82 participants who received the vaccine in a prime-boost schedule, developed a mild fever [84].”

What the sources say

• Not checked yetcites [84] Keech C. Albert A. Cho I. Robertson A. Reed P. Neal S. Plested J.S. Zhu M. Cloney-Clark S. Zhou H. Phase 1–2 Trial of a SARS-CoV-2 Recombinant Spike Protein Nanoparticle Vaccine N. Engl. J. Med. 383 2020 2320 2332 32877576 PMC7494251 source

In the paper

“It does, however, seem like mRNA vaccines more frequently elicit systemic AEs, particularly fever, compared to the other vaccine candidates.”

In the paper

“Rare events of anaphylaxis have been reported after vaccination with mRNA-1273 and BNT162b2, with an incidence currently estimated at approximately 1 in 100,000 [86].”

What the sources say

• Not checked yetcites [86] Shimabukuro T.T. Cole M. Su J.R. Reports of anaphylaxis after receipt of mRNA COVID-19 vaccines in the US—December 14, 2020-January 18, 2021 JAMA 325 2021 1101 1102 33576785 PMC8890485 source

In the paper

“not all of the differences in evoked immune responses to the different mRNA vaccine candidates, can be explained by the information provided by the manufacturers.”

In the paper

“this COVID-19 case seems to indicate that the nucleoside-modified mRNA approach allows higher maximal tolerable doses”

In the paper

“mRNA vaccines gained momentum due to the COVID-19 pandemic.”