The dawn of mRNA vaccines: The COVID-19 case

In the paper

“not only viral RNA, but also endogenous mRNA associated with apoptotic cells as well as in vitro transcribed (IVT) mRNA could bind and activate TLR3, TLR7 and TLR8 [4,5]”

What the sources say

• Not checked yetcites [4] Kariko K. Ni H.P. Capodici J. Lamphier M. Weissman D. mRNA is an endogenous ligand for toll-like receptor 3 J. Biol. Chem. 279 2004 12542 12550 14729660 source
• 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

“In less than one year since the outbreak of the COVID-19 pandemic, two mRNA-based vaccines, BNT162b2 and mRNA-1273, were granted the first historic authorization for emergency use, while another mRNA vaccine, CVnCoV, progressed to phase 3 clinical testing.”

What the sources say

• ?Not matched

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

  cites [23] European Medicines Agency EMA Recommends First COVID-19 Vaccine for Authorisation in the EU https://www.ema.europa.eu/en/news/ema-recommends-first-covid-19-vaccine-authorisation-eu 2020
• ?Not matched

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

  cites [24] EMA Recommends COVID-19 Vaccine Moderna for Authorisation in the EU https://www.ema.europa.eu/en/news/ema-recommends-covid-19-vaccine-moderna-authorisation-eu 2021
• ?Not matched

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

  cites [25] FDA Briefing Document - BNT162b2 https://www.fda.gov/media/144245/download 2020

In the paper

“The COVID-19 mRNA vaccines represent a new class of vaccine products, which consist of synthetic mRNA strands encoding the SARS-CoV-2 Spike glycoprotein, packaged in lipid nanoparticles to deliver mRNA to cells.”

What the sources say

• Not checked yetcites [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 source
• ?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 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)

In the paper

“This review digs deeper into the scientific breakthroughs of the last decades that laid the foundations for the rapid rise of mRNA vaccines during the COVID-19 pandemic.”

In the paper

“research into the use of mRNA as a source of protein has been around for three decades [1]”

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

In the paper

“although it has been employed for various therapeutic targets, its use as a source of antigen in vaccination approaches is by far the most popular [2]”

What the sources say

• Not checked yetcites [2] Pardi N. Hogan M.J. Porter F.W. Weissman D. mRNA vaccines - a new era in vaccinology Nat. Rev. Drug Discov. 17 2018 261 279 29326426 PMC5906799 source

In the paper

“modified and purified IVT mRNA enables much higher protein expression and has a more favorable safety profile, as it drastically reduces the production of pro-inflammatory type I IFNs [6]”

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

In the paper

“In their final COVID-19 vaccines, both BioNTech and Moderna have made use of a highly-purified and N1-methyl-pseudouridine (1mΨ) modified mRNA. In contrast, CureVac has applied its “unmodified” mRNA vaccine technology”

What the sources say

• Not checked yetcites [10] Thess A. Grund S. Mui B.L. Hope M.J. Baumhof P. Fotin-Mleczek M. Schlake T. Sequence-engineered mRNA without chemical nucleoside modifications enables an effective protein therapy in large animals Mol. Ther. 23 2015 1456 1464 26050989 PMC4817881 source
• 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

In the paper

“1mΨ nucleotide-modifications were shown to provide additional base pair stability, giving rise to a high degree of secondary structure which significantly improves the mRNA translation [35]”

What the sources say

• Not checked yetcites [35] Mauger D.M. Cabral B.J. Presnyak V. Su S.V. Reid D.W. Goodman B. Link K. Khatwani N. Reynders J. Moore M.J. mRNA structure regulates protein expression through changes in functional half-life Proc. Natl. Acad. Sci. U. S. A. 116 2019 24075 31712433 PMC6883848 source

In the paper

“isolation of neutralizing antibodies from the serum of COVID-19 patients confirmed the strong immunogenicity of the S protein, but showed an equal immunogenicity of the RBD and the N-terminal domain (NTD)”

What the sources say

• Not checked yetcites [28] Liu L. Wang P. Nair M.S. Yu J. Rapp M. Wang Q. Luo Y. Chan J.F.W. Sahi V. Figueroa A. Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 spike Nature 584 2020 450 456 32698192 source

In the paper

“When the new SARS-CoV-2 virus was identified, detailed investigations into the structure and dynamics of the SARS-CoV-2 S protein revealed large homology to the SARS-CoV-1 S protein, which allowed the major players in vaccine development to immediately turn to the S protein as vaccine target [20,21]”

What the sources say

• ?Not matched

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

  cites [20] Cai Y.F. Zhang J. Xiao T.S. Peng H.Q. Sterling S.M. Walsh R.M. Rawson S. Rits-Volloch S. Chen B. Distinct conformational states of SARS-CoV-2 spike protein Science 369 2020 1586 1592 32694201 PMC7464562
• Not checked yetcites [21] Wrapp D. Wang N.S. Corbett K.S. Goldsmith J.A. Hsieh C.L. Abiona O. Graham B.S. McLellan J.S. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation Science 367 2020 1260 1263 32075877 PMC7164637 source

In the paper

“This protein mediates viral entry by first binding to its cellular receptor (i.e. angiotensin-converting enzyme 2, ACE2 for SARS-CoV-1 or dipeptidyl peptidase 4, DPP4/CD26 for MERS-CoV). Upon interaction, the S protein undergoes structural changes resulting in the fusion of viral and host cell membranes.”

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

In the paper

“All mRNA vaccines target the same SARS-CoV-2 antigen and incorporate mRNA encoding the full-length, transmembrane anchored S protein. The genetic sequence is slightly altered to stabilize the prefusion conformation of the glycoprotein using two proline (2P) substitutions (K986P and V987P mutations) (Fig. 2a) [21]”

What the sources say

• Not checked yetcites [21] Wrapp D. Wang N.S. Corbett K.S. Goldsmith J.A. Hsieh C.L. Abiona O. Graham B.S. McLellan J.S. Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation Science 367 2020 1260 1263 32075877 PMC7164637

In the paper

“This implies that vaccinating against the entire S protein, rather than only one of its structural components, is expected to result in an improved response which will be less affected when the virus undergoes genetic drift [28]”

What the sources say

• Not checked yetcites [28] Liu L. Wang P. Nair M.S. Yu J. Rapp M. Wang Q. Luo Y. Chan J.F.W. Sahi V. Figueroa A. Potent neutralizing antibodies against multiple epitopes on SARS-CoV-2 spike Nature 584 2020 450 456 32698192 source

In the paper

“The promising COVID-19 vaccines rapidly received Fast Track designation by the FDA and EMA, resulting in their approval by both regulatory agencies before the end of 2020 for emergency use [[23], [24], [25], [26]]”

What the sources say

• ?Not matched

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

  cites [23] European Medicines Agency EMA Recommends First COVID-19 Vaccine for Authorisation in the EU https://www.ema.europa.eu/en/news/ema-recommends-first-covid-19-vaccine-authorisation-eu 2020
• ?Not matched

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

  cites [24] EMA Recommends COVID-19 Vaccine Moderna for Authorisation in the EU https://www.ema.europa.eu/en/news/ema-recommends-covid-19-vaccine-moderna-authorisation-eu 2021
• ?Not matched

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

  cites [25] FDA Briefing Document - BNT162b2 https://www.fda.gov/media/144245/download 2020

In the paper

“During the mixing step, the pH of the formulation is kept low to protonate the ionizable lipid's amine function, enabling electrostatic complexation of the now positively charged lipids and the negatively charged mRNA. A dialysis or ultrafiltration is then performed to neutralize the pH, resulting in uncharged, solid-core LNPs that densely package the mRNA [14]”

What the sources say

• Not checked yetcites [14] Kulkarni J.A. Witzigmann D. Leung J. van der Meel R. Zaifman J. Darjuan M.M. Grisch-Chan H.M. Thöny B. Tam Y.Y.C. Cullis P.R. Fusion-dependent formation of lipid nanoparticles containing macromolecular payloads Nanoscale 11 2019 9023 9031 31021343 source

In the paper

“Moderna claimed that with such an approach, both local and systemic innate immune effects upon mRNA (vaccine) administration can be limited to a bare minimum in mice [37]”

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

“previous experience with the closely related SARS-CoV-1, showed that CD8+ and CD4+ memory T cells were detectable as late as 17 years post-infection, while neutralizing antibody titers had waned substantially by 1 year after infection [69,70]”

What the sources say

• Not checked yetcites [69] Sariol A. Perlman S. Lessons for COVID-19 immunity from other coronavirus infections Immunity 53 2020 248 263 32717182 PMC7359787 source
• Not checked yetcites [70] Le Bert N. Tan A.T. Kunasegaran K. Tham C.Y.L. Hafezi M. Chia A. Chng M.H.Y. Lin M. Tan N. Linster M. SARS-CoV-2-specific T cell immunity in cases of COVID-19 and SARS, and uninfected controls Nature 584 2020 457 462 32668444 source

In the paper

“the CVnCoV vaccine candidate contains an “unmodified” mRNA, which employs sequence engineering (e.g., reduction in uridine content), selected UTRs, and a stringent purification protocol to remove dsRNA fragments [11]”

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

In the paper

“the (local) induction of type IFNs and other inflammatory cytokines plays - in all likelihood - an important role in the reactogenicity of mRNA vaccines.”

In the paper

“In COVID-19 patients, a coordinated adaptive immunity of CD4+ T cells, CD8+ T cells, and antibody responses was correlated to milder disease, whereas an uncoordinated response frequently failed to control disease [68]”

What the sources say

• Not checked yetcites [68] Rydyznski Moderbacher C. Ramirez S.I. Dan J.M. Grifoni A. Hastie K.M. Weiskopf D. Belanger S. Abbott R.K. Kim C. Choi J. Antigen-specific adaptive immunity to SARS-CoV-2 in acute COVID-19 and associations with age and disease severity Cell 183 2020 996 1012 33010815 PMC7494270 source

In the paper

“Similar to the more classical vaccine approaches, the COVID-19 mRNA vaccines are injected in the muscle, where they trigger localized and transient inflammation that recruits different immune cells to the injection site (Fig. 3 ) [11,41]”

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 [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

“According to mechanistic studies on the fate of mRNA LNPs in rhesus monkeys, primarily monocytes and DC subsets translate the mRNA, likely involving ApoE dependent endocytosis [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

“the type I IFN activity of mRNA vaccines can prematurely stop mRNA-translation, thereby reducing antigen availability and diminishing the vaccine's efficacy to obtain adaptive immune responses [63,64]”

What the sources say

• Not checked yetcites [63] Pepini T. Pulichino A.M. Carsillo T. Carlson A.L. Sari-Sarraf F. Ramsauer K. Debasitis J.C. Maruggi G. Otten G.R. Geall A.J. Induction of an IFN-mediated antiviral response by a self-amplifying RNA vaccine: implications for vaccine design J. Immunol. 198 2017 4012 4024 28416600 PMC5421303 source
• Not checked yetcites [64] Van Hoecke L. Roose K. Ballegeer M. Zhong Z. Sanders N.N. De Koker S. Saelens X. Van Lint S. The opposing effect of type I IFN on the T cell response by non-modified mRNA-lipoplex vaccines is determined by the route of administration Mol. Ther. Nucleic Acids 22 2020 373 381 33230442 PMC7533292 source

In the paper

“The COVID-19 mRNA vaccines are primarily focused on triggering B cells to promote the induction of neutralizing antibodies, but there are also good reasons to believe that CD8+ T cell and CD4+ T cell responses may contribute to the protection against SARS-CoV-2 [66]”

What the sources say

• Not checked yetcites [66] Karlsson A.C. Humbert M. Buggert M. The known unknowns of T cell immunity to COVID-19 Sci. Immunol. 5 2020 (eabe8063) 33208380 source

In the paper

“Since the type I IFN activity can be better controlled with 1mΨ-modified mRNA, resulting in higher maximal tolerable doses of the 1mΨ-modified mRNA vaccines, they might achieve a more durable protein expression and thus prolonged antigen availability.”

In the paper

“In GCs, B cells undergo affinity maturation and isotype switching. After rounds of clonal expansion, this gives rise to high affinity B cells and their differentiation into plasma cells and memory B cells, which eventually determines the quality and durability of the antibody response.”

In the paper

“The vaccine efficacy of mRNA-1273 is in line with the outcome of BNT162b2, conferring 94.1% protection against symptomatic COVID-19 disease [54].”

What the sources say

• Not checked yetcites [54] Baden L.R. El Sahly H.M. Essink B. Kotloff K. Frey S. Novak R. Diemert D. Spector S.A. Rouphael N. Creech C.B. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine N. Engl. J. Med. 384 2021 403 416 33378609 PMC7787219 source

In the paper

“Both local and systemic AE occurred dose-dependently, were mostly mild to moderate and more common after boost vaccination.”

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

“no more than 37% of the participants reported any (localized or systemic) AE after the second dose, with fever only reported by max. 5% of the participants (depending on the dosing and prime-boost schedule) [83].”

What the sources say

• Not checked yetcites [83] Zhang Y. Zeng G. Pan H. Li C. Hu Y. Chu K. Han W. Chen Z. Tang R. Yin W. Safety, tolerability, and immunogenicity of an inactivated SARS-CoV-2 vaccine in healthy adults aged 18-59 years: a randomised, double-blind, placebo-controlled, phase 1/2 clinical trial Lancet Infect. Dis. 21 2 2021 181 192 33217362 PMC7832443 source

In the paper

“AEs occurred more frequent when NVX-CoV2373 was combined with the adjuvant, and slightly more AEs were reported after the boost dose.”

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

“fever was reported by 57% of the participants after the first dose, but the incidence of this AE did not further increase after the boost 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

“The mRNA dose selected for phase 2b/3 clinical testing of CureVac's CVnCoV vaccine candidate was 12 μg, substantially lower than what is used in the nucleoside-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

“Because of its improved safety profile, together with the benefit of BNT162b2 to induce immunity against epitopes in S1 and S2 regions of the S antigen, while BNT162b1 is only restricted to epitopes inside the RBD region, made that BNT162b2 was selected as lead candidate for further advancement.”

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

“Also local reactogenicity was less prominent for BNT162b2 and particularly in the older cohort, fewer severe systemic AEs were reported for this vaccine candidate.”

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

“events also peaked at day 2 after dosing and were resolved by day 7.”

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

“Typical other systemic AEs that occurred in more than half of the dosed participants were fatigue, chills, myalgia and headache, which were all increasingly reported for higher dosages, particularly after the boost vaccine [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

“Despite the high incidence of systemic AEs after a single dosage, no major toxicities were reported and all AEs resolved within 2 days after dosing.”

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

“Their exceptionally rapid development and production as well as high efficiency to prevent SARS-CoV-2 infection, demonstrate that mRNA-based therapeutics are ready for their place in the sun.”

In the paper

“Although this rapid pace was possible due to substantial pre-existing knowledge”

In the paper

“as they were demonstrated to be generally safe and very efficacious to prevent against symptomatic COVID-19 disease.”

In the paper

“The prime vaccine commonly caused fatigue and headache, but the incidence of these AEs could be significantly reduced by prophylactic paracetamol.”

What the sources say

• Not checked yetcites [85] Folegatti P.M. Ewer K.J. Aley P.K. Angus B. Becker S. Belij-Rammerstorfer S. Bellamy D. Bibi S. Bittaye M. Clutterbuck E.A. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial Lancet 396 2020 467 478 32702298 PMC7445431 source

In the paper

“it is clear that all of the described vaccines are generally safe, commonly trigger local reactogenicity and that all AEs resolved within 2 days after dosing.”

In the paper

“In the limited subset of 10 participants who received a prime-boost vaccine, fever was exclusively reported after the prime dose in 40% of the subjects, but once again resolved after 2 days.”

What the sources say

• Not checked yetcites [85] Folegatti P.M. Ewer K.J. Aley P.K. Angus B. Becker S. Belij-Rammerstorfer S. Bellamy D. Bibi S. Bittaye M. Clutterbuck E.A. Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial Lancet 396 2020 467 478 32702298 PMC7445431 source