COVID-19 mRNA vaccines

Qingrui Huang; Jiawei Zeng; Jinghua Yan

doi:10.1016/j.jgg.2021.02.006

Volume 48 Issue 2

Feb. 2021

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Article Navigation > Journal of Genetics and Genomics > 2021 > 48(2): 107-114

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COVID-19 mRNA vaccines

doi: 10.1016/j.jgg.2021.02.006

a
CAS Key Laboratory of Microbial Physiological and Metabolic Engineering, Institute of Microbiology, Chinese Academy of Sciences, Beijing 100101, China
b
University of Chinese Academy of Sciences, Beijing 101408, China

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Corresponding author: E-mail address: yanjh@im.ac.cn (Jinghua Yan)
Received Date: 2021-01-05
Accepted Date: 2021-02-01
Rev Recd Date: 2021-01-31

Available Online: 2021-03-15

Publish Date: 2021-02-20

Abstract

Abstract

The ongoing COVID-19 pandemic and its unprecedented global societal and economic disruptive impact highlight the urgent need for safe and effective vaccines. Taking substantial advantages of versatility and rapid development, two mRNA vaccines against COVID-19 have completed late-stage clinical assessment at an unprecedented speed and reported positive results. In this review, we outline keynotes in mRNA vaccine development, discuss recently published data on COVID-19 mRNA vaccine candidates, focusing on those in clinical trials and analyze future potential challenges.

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References

[1]	Alberer, M., Gnad-Vogt, U., Hong, H.S., Mehr, K.T., Backert, L., Finak, G., Gottardo, R., Bica, M.A., Garofano, A., Koch, S.D., et al., 2017. 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.
[2]	Amanat, F., Stadlbauer, D., Strohmeier, S., Nguyen, T.H.O., Chromikova, V., McMahon, M., Jiang, K., Arunkumar, G.A., Jurczyszak, D., Polanco, J., et al., 2020. A serological assay to detect SARS-CoV-2 seroconversion in humans. Nat. Med. 26, 1033−1036.
[3]	Anderson, E.J., Rouphael, N.G., Widge, A.T., Jackson, L.A., Roberts, P.C., Makhene, M., Chappell, J.D., Denison, M.R., Stevens, L.J., Pruijssers, A.J., et al., 2020. Safety and immunogenicity of SARS-CoV-2 mRNA-1273 vaccine in older adults. N. Engl. J. Med. 383, 2427−2438.
[4]	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., et al., 2021. Efficacy and safety of the mRNA-1273 SARS-CoV-2 vaccine. N. Engl. J. Med. 384, 403−416.
[5]	Baum, A., Fulton, B.O., Wloga, E., Copin, R., Pascal, K.E., Russo, V., Giordano, S., Lanza, K., Negron, N., Ni, M., Wei, Y., et al., 2020. Antibody cocktail to SARS-CoV-2 spike protein prevents rapid mutational escape seen with individual antibodies. Science 369, 1014−1018.
[6]	Cai, Y., Zhang, J., Xiao, T., Peng, H., Sterling, S.M., Walsh, R.M., Jr., Rawson, S., Rits-Volloch, S., Chen, B., 2020. Distinct conformational states of SARS-CoV-2 spike protein. Science 369, 1586−1592.
[7]	Cao, Y., Su, B., Guo, X., Sun, W., Deng, Y., Bao, L., Zhu, Q., Zhang, X., Zheng, Y., Geng, C., et al., 2020. Potent neutralizing antibodies against SARS-CoV-2identified by high-throughput single-cell sequencing of convalescent patients' B cells. Cell 182, 73−84.
[8]	Chandrashekar, A., Liu, J., Martinot, A.J., McMahan, K., Mercado, N.B., Peter, L., Tostanoski, L.H., Yu, J., Maliga, Z., Nekorchuk, M., et al., 2020. SARS-CoV-2 infection protects against rechallenge in rhesus macaques. Science 369, 812−817.
[9]	Chen, W.H., Tao, X., Agrawal, A.S., Algaissi, A., Peng, B.H., Pollet, J., Strych, U., Bottazzi, M.E., Hotez, P.J., Lustigman, S., et al., 2020. Yeast-expressed SARS-CoV recombinant receptor-binding domain (RBD219-N1) formulated with aluminum hydroxide induces protective immunity and reduces immune enhancement. Vaccine 38, 7533−7541.
[10]	Corbett, K.S., Edwards, D.K., Leist, S.R., Abiona, O.M., Boyoglu-Barnum, S., Gillespie, R.A., Himansu, S., Schafer, A., Ziwawo, C.T., DiPiazza, A.T., et al., 2020a. SARS-CoV-2 mRNA vaccine design enabled by prototype pathogen preparedness. Nature 586, 567−571.
[11]	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., et al., 2020b. Evaluation of the mRNA-1273 vaccine against SARS-CoV-2 in nonhuman primates. N. Engl. J. Med. 383, 1544−1555.
[12]	Dai, L., Gao, G.F., 2021. Viral targets for vaccines against COVID-19. Nat. Rev. Immunol. 21, 73−82.
[13]	Dai, L., Zheng, T., Xu, K., Han, Y., Xu, L., Huang, E., An, Y., Cheng, Y., Li, S., Liu, M., et al., 2020. A universal design of betacoronavirus vaccines against COVID-19, MERS, and SARS. Cell 182, 722−733.
[14]	de Jong, W., Aerts, J., Allard, S., Brander, C., Buyze, J., Florence, E., van Gorp, E., Vanham, G., Leal, L., Mothe, B., et al., 2019. iHIVARNA phase IIa, a randomized, placebo-controlled, double-blinded trial to evaluate the safety and immunogenicity of iHIVARNA-01 in chronically HIV-infected patients under stable combined antiretroviral therapy. Trials 20, 361.
[15]	Du, S., Cao, Y., Zhu, Q., Yu, P., Qi, F., Wang, G., Du, X., Bao, L., Deng, W., Zhu, H., et al., 2020. Structurally resolved SARS-CoV-2 antibody shows high efficacy in severely infected hamsters and provides a potent cocktail pairing strategy. Cell 183, 1013−1023.
[16]	Feldman, R.A., Fuhr, R., Smolenov, I., Mick Ribeiro, A., Panther, L., Watson, M., Senn, J.J., Smith, M., Almarsson Ӧ., Pujar, H.S., et al., 2019. 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.
[17]	Gay, C.L., DeBenedette, M.A., Tcherepanova, I.Y., Gamble, A., Lewis, W.E., Cope, A.B., Kuruc, J.D., McGee, K.S., Kearney, M.F., Coffin, J.M., et al., 2018. Immunogenicity of AGS-004 dendritic cell therapy in patients treated during acute HIV infection. AIDS Res. Hum. Retroviruses 34, 111−122.
[18]	Haynes, B.F., Corey, L., Fernandes, P., Gilbert, P.B., Hotez, P.J., Rao, S., Santos, M.R., Schuitemaker, H., Watson, M., Arvin, A., 2020. Prospects for a safe COVID-19 vaccine. Sci. Transl. Med. 12, eabe0948.
[19]	Hoffmann, M., Kleine-Weber, H., Schroeder, S., Kruger, N., Herrler, T., Erichsen, S., Schiergens, T.S., Herrler, G., Wu, N.H., Nitsche, A., et al., 2020. SARS-CoV-2 cell entry depends on ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitor. Cell 181, 271−280.e278.
[20]	Hsieh, C.L., Goldsmith, J.A., Schaub, J.M., DiVenere, A.M., Kuo, H.C., Javanmardi, K., Le, K.C., Wrapp, D., Lee, A.G., Liu, Y., et al., 2020. Structure-based design of prefusion-stabilized SARS-CoV-2 spikes. Science 369, 1501−1505.
[21]	Hu, B., Guo, H., Zhou, P., Shi, Z.L., 2020. Characteristics of SARS-CoV-2 and COVID-19. Nat. Rev. Microbiol. 19, 141−154.
[22]	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., et al., 2020. An mRNA vaccine against SARS-CoV-2 - preliminary report. N. Engl. J. Med. 383, 1920−1931.
[23]	Juno, J.A., Tan, H.X., Lee, W.S., Reynaldi, A., Kelly, H.G., Wragg, K., Esterbauer, R., Kent, H.E., Batten, C.J., Mordant, F.L., et al., 2020. Humoral and circulating follicular helper T cell responses in recovered patients with COVID-19. Nat. Med. 26, 1428−1434.
[24]	Kaczmarek, J.C., Kowalski, P.S., Anderson, D.G., 2017. Advances in the delivery of RNA therapeutics: From concept to clinical reality. Genome Med. 9, 60.
[25]	Kowalski, P.S., Rudra, A., Miao, L., Anderson, D.G., 2019. Delivering the messenger: Advances in technologies for therapeutic mRNA delivery. Mol. Ther. 27, 710−728.
[26]	Kremsner, P., Mann, P., Bosch, J., Fendel, R., Gabor, J.J., Kreidenweiss, A., Kroidl, A., Leroux-Roels, I., Leroux-Roels, G., Schindler, C., et al., 2020. Phase 1 assessment of the safety and immunogenicity of an mRNA-lipid nanoparticle vaccine candidate against SARS-CoV-2 in human volunteers. medRxiv .
[27]	Laczko, D., Hogan, M.J., Toulmin, S.A., Hicks, P., Lederer, K., Gaudette, B.T., Castano, D., Amanat, F., Muramatsu, H., Oguin, T.H., et al., 2020. A single immunization with nucleoside-modified mRNA vaccines elicits strong cellular and humoral immune responses against SARS-CoV-2 in mice. Immunity 53, 724−732.
[28]	Linares-Fernandez, S., Lacroix, C., Exposito, J.Y., Verrier, B., 2020. Tailoring mRNA vaccine to balance innate/adaptive immune response. Trends Mol. Med. 26, 311−323.
[29]	Liu, C., Yang, Y., Gao, Y., Shen, C., Ju, B., Liu, C., Tang, X., Wei, J., Ma, X., Liu, W., et al., 2020a. Viral architecture of SARS-CoV-2 with post-fusion spike revealed by Cryo-EM. bioRxiv .
[30]	Liu, Y., Wang, K., Massoud, T.F., Paulmurugan, R., 2020b. SARS-CoV-2 vaccine development: An overview and perspectives. ACS Pharmacol. Transl. Sci. 3, 844−858.
[31]	Lu, J., Lu, G., Tan, S., Xia, J., Xiong, H., Yu, X., Qi, Q., Yu, X., Li, L., Yu, H., et al., 2020. A COVID-19 mRNA vaccine encoding SARS-CoV-2 virus-like particles induces a strong antiviral-like immune response in mice. Cell Res. 30, 936−939.
[32]	Lv, Z., Deng, Y.Q., Ye, Q., Cao, L., Sun, C.Y., Fan, C., Huang, W., Sun, S., Sun, Y., Zhu, L., et al., 2020. Structural basis for neutralization of SARS-CoV-2 and SARS-CoV by a potent therapeutic antibody. Science 369, 1505−1509.
[33]	Maruggi, G., Zhang, C., Li, J., Ulmer, J.B., Yu, D., 2019. mRNA as a transformative technology for vaccine development to control infectious diseases. Mol. Thera. 27, 757−772.
[34]	McKay, P.F., Hu, K., Blakney, A.K., Samnuan, K., Brown, J.C., Penn, R., Zhou, J., Bouton, C.R., Rogers, P., Polra, K., et al., 2020. Self-amplifying RNA SARS-CoV-2 lipid nanoparticle vaccine candidate induces high neutralizing antibody titers in mice. Nat. Commun. 11, 3523.
[35]	Mercado, N.B., Zahn, R., Wegmann, F., Loos, C., Chandrashekar, A., Yu, J., Liu, J., Peter, L., McMahan, K., Tostanoski, L.H., et al., 2020. Single-shot Ad26 vaccine protects against SARS-CoV-2 in rhesus macaques. Nature 586, 583−588.
[36]	Monteil, V., Kwon, H., Prado, P., Hagelkruys, A., Wimmer, R.A., Stahl, M., Leopoldi, A., Garreta, E., Hurtado Del Pozo, C., Prosper, F., et al., 2020. Inhibition of SARS-CoV-2 infections in engineered human tissues using clinical-grade soluble human ACE2. Cell 181, 905−913.
[37]	Mulligan, M.J., Lyke, K.E., Kitchin, N., Absalon, J., Gurtman, A., Lockhart, S., Neuzil, K., Raabe, V., Bailey, R., Swanson, K.A., et al., 2020. Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults. Nature 586, 589−593.
[38]	Pallesen, J., Wang, N., Corbett, K.S., Wrapp, D., Kirchdoerfer, R.N., Turner, H.L., Cottrell, C.A., Becker, M.M., Wang, L., Shi, W., Kong, et al., 2017. Immunogenicity and structures of a rationally designed prefusion MERS-CoV spike antigen. Proc. Natl. Acad. Sci. U.S.A 114, E7348−E7357.
[39]	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., et al., 2018a. Nucleoside-modified mRNA vaccines induce potent T follicular helper and germinal center B cell responses. J. Exp. Med. 215, 1571−1588.
[40]	Pardi, N., Hogan, M.J., Pelc, R.S., Muramatsu, H., Andersen, H., DeMaso, C.R., Dowd, K.A., Sutherland, L.L., Scearce, R.M., Parks, R., et al., 2017. Zika virus protection by a single low-dose nucleoside-modified mRNA vaccination. Nature 543, 248−251.
[41]	Pardi, N., Hogan, M.J., Porter, F.W., Weissman, D., 2018b. mRNA vaccines - a new era in vaccinology. Nat. Rev. Drug Discov. 17, 261−279.
[42]	Polack, F.P., Thomas, S.J., Kitchin, N., Absalon, J., Gurtman, A., Lockhart, S., Perez, J.L., Perez Marc, G., Moreira, E.D., Zerbini, C., et al., 2020. Safety and efficacy of the BNT162b2 mRNA COVID-19 vaccine. N. Engl. J. Med. 383, 2603−2615.
[43]	Poland, G.A., Ovsyannikova, I.G., Crooke, S.N., Kennedy, R.B., 2020. SARS-CoV-2 vaccine development: Current status. Mayo Clin. Proc. 95, 2172−2188.
[44]	Pollard, C., De Koker, S., Saelens, X., Vanham, G.,Grooten, J., 2013. Challenges and advances towards the rational design of mRNA vaccines. Trends Mo.l Med. 19, 705−713.
[45]	Richner, J.M., Himansu, S., Dowd, K.A., Butler, S.L., Salazar, V., Fox, J.M., Julander, J.G., Tang, W.W., Shresta, S., Pierson, T.C., et al., 2017. Modified mRNA vaccines protect against Zika virus infection. Cell 168, 1114−1125.
[46]	Sahin, U., Kariko, K.,Tureci, O., 2014. mRNA-based therapeutics--developing a new class of drugs. Nat. Rev. Drug Discov. 13, 759−780.
[47]	Sahin, U., Muik, A., Derhovanessian, E., Vogler, I., Kranz, L.M., Vormehr, M., Baum, A., Pascal, K., Quandt, J., Maurus, D., et al., 2020. COVID-19 vaccine BNT162b1 elicits human antibody and TH1 T cell responses. Nature 586, 594−599.
[48]	Santos, I.A., Grosche, V.R., Bergamini, F.R.G., Sabino-Silva, R.,Jardim, A.C.G., 2020. Antivirals against coronaviruses: Candidate drugs for SARS-CoV-2 treatment?. Front. Microbiol. 11, 1818.
[49]	Schlake, T., Thess, A., Fotin-Mleczek, M.,Kallen, K.J., 2012. Developing mRNA-vaccine technologies. RNA Biol. 9, 1319−1330.
[50]	Shan, C., Yao, Y.F., Yang, X.L., Zhou, Y.W., Gao, G., Peng, Y., Yang, L., Hu, X., Xiong, J., Jiang, R.D., et al., 2020. Infection with novel coronavirus (SARS-CoV-2) causes pneumonia in rhesus macaques. Cell Res. 30, 670−677.
[51]	Shi, R., Shan, C., Duan, X., Chen, Z., Liu, P., Song, J., Song, T., Bi, X., Han, C., Wu, L., et al., 2020. A human neutralizing antibody targets the receptor binding site of SARS-CoV-2. Nature 584, 120−124.
[52]	Smith, T.R.F., Patel, A., Ramos, S., Elwood, D., Zhu, X., Yan, J., Gary, E.N., Walker, S.N., Schultheis, K., Purwar, M., et al., 2020. Immunogenicity of a DNA vaccine candidate for COVID-19. Nat. Commun. 11, 2601.
[53]	Su, S., Du, L., Jiang, S., 2021. Learning from the past: Development of safe and effective COVID-19 vaccines. Nat. Rev. Microbiol. 19, 211−219.
[54]	Sullenger, B.A., Nair, S., 2016. From the RNA world to the clinic. Science 352, 1417−1420.
[55]	Sun, S.H., Chen, Q., Gu, H.J., Yang, G., Wang, Y.X., Huang, X.Y., Liu, S.S., Zhang, N.N., Li, X.F., Xiong, R., et al., 2020. A mouse model of SARS-CoV-2 infection and pathogenesis. Cell host microbe 28, 124−133.
[56]	Tang, Z., Kong, N., Zhang, X., Liu, Y., Hu, P., Mou, S., Liljestrom, P., Shi, J., Tan, W., Kim, J.S., et al., 2020. A materials-science perspective on tackling COVID-19. Nat. Rev. Mater. 5, 847−860.
[57]	Ulmer, J.B., Geall, A.J., 2016. Recent innovations in mRNA vaccines. Curr. Opin. Immunol. 41, 18−22.
[58]	V'Kovski, P., Kratzel, A., Steiner, S., Stalder, H.,Thiel, V., 2021. Coronavirus biology and replication: Implications for SARS-CoV-2. Nat. Rev. Microbiol. 19, 155−170.
[59]	Walls, A.C., Park, Y.J., Tortorici, M.A., Wall, A., McGuire, A.T., Veesler, D., 2020. Structure, function, and antigenicity of the SARS-CoV-2 spike glycoprotein. Cell 181, 281−292.
[60]	Walsh, E.E., Frenck, R.W., Jr., Falsey, A.R., Kitchin, N., Absalon, J., Gurtman, A., Lockhart, S., Neuzil, K., Mulligan, M.J., Bailey, R., et al., 2020. Safety and immunogenicity of two RNA-based COVID-19 vaccine candidates. N. Engl. J. Med. 383, 2439−2450.
[61]	Wang, Q., Zhang, Y., Wu, L., Niu, S., Song, C., Zhang, Z., Lu, G., Qiao, C., Hu, Y., Yuen, K.Y., et al., 2020. Structural and functional basis of SARS-CoV-2 entry by using human ace2. Cell 181, 894−904.
[62]	Watanabe, Y., Allen, J.D., Wrapp, D., McLellan, J.S., Crispin, M., 2020. Site-specific glycan analysis of the SARS-CoV-2 spike. Science 369, 330−333.
[63]	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., et al., 2021. Durability of responses after SARS-CoV-2 mRNA-1273 vaccination. N. Engl. J. Med. 384, 80−82.
[64]	Wolff, J.A., Malone, R.W., Williams, P., Chong, W., Acsadi, G., Jani, A., Felgner, P.L., 1990. Direct gene transfer into mouse muscle in vivo. Science 247, 1465−1468.
[65]	Wouters, O.J., Shadlen, K.C., Salcher-Konrad, M., Pollard, A.J., Larson, H.J., Teerawattananon, Y., Jit, M., 2021. Challenges in ensuring global access to COVID-19 vaccines: Production, affordability, allocation, and deployment. Lancet .
[66]	Wrapp, D., De Vlieger, D., Corbett, K.S., Torres, G.M., Wang, N., Van Breedam, W., Roose, K., van Schie, L., Hoffmann, M., Pohlmann, S., et al., 2020a. Structural basis for potent neutralization of betacoronaviruses by single-domain camelid antibodies. Cell 181, 1004−1015.
[67]	Wrapp, D., Wang, N., Corbett, K.S., Goldsmith, J.A., Hsieh, C.L., Abiona, O., Graham, B.S., McLellan, J.S., 2020b. Cryo-em structure of the 2019-nCoV spike in the prefusion conformation. Science 367, 1260−1263.
[68]	Wu, Y., Li, C., Xia, S., Tian, X., Kong, Y., Wang, Z., Gu, C., Zhang, R., Tu, C., Xie, Y., et al., 2020a. Identification of human single-domain antibodies against SARS-CoV-2. Cell Host Microbe 27, 891−898.
[69]	Wu, Y., Wang, F., Shen, C., Peng, W., Li, D., Zhao, C., Li, Z., Li, S., Bi, Y., Yang, Y., et al., 2020b. A noncompeting pair of human neutralizing antibodies block COVID-19 virus binding to its receptor ACE2. Science 368, 1274−1278.
[70]	Xia, S., Liu, M., Wang, C., Xu, W., Lan, Q., Feng, S., Qi, F., Bao, L., Du, L., Liu, S., et al., 2020. Inhibition of SARS-CoV-2 (previously 2019-nCoV) infection by a highly potent pan-coronavirus fusion inhibitor targeting its spike protein that harbors a high capacity to mediate membrane fusion. Cell Res. 30, 343−355.
[71]	Xu, Y., Kang, L., Shen, Z., Li, X., Wu, W., Ma, W., Fang, C., Yang, F., Jiang, X., Gong, S., Zhang, L.,Li, M., 2020. Dynamics of SARS-CoV-2 genome variants in the feces during convalescence. J. Genet. Genomics 47, 610−617.
[72]	Yang, J., Wang, W., Chen, Z., Lu, S., Yang, F., Bi, Z., Bao, L., Mo, F., Li, X., Huang, Y., et al., 2020. A vaccine targeting the RBD of the S protein of SARS-CoV-2 induces protective immunity. Nature 586, 572−577.
[73]	Yu, J., Tostanoski, L.H., Peter, L., Mercado, N.B., McMahan, K., Mahrokhian, S.H., Nkolola, J.P., Liu, J., Li, Z., Chandrashekar, A., et al., 2020. DNA vaccine protection against SARS-CoV-2 in rhesus macaques. Science 369, 806−811.
[74]	Yuan, M., Wu, N.C., Zhu, X., Lee, C.D., So, R.T.Y., Lv, H., Mok, C.K.P., Wilson, I.A., 2020. A highly conserved cryptic epitope in the receptor-binding domains of SARS-CoV-2 and SARS-CoV. Science 368, 630−633.
[75]	Zhang, N.N., Li, X.F., Deng, Y.Q., Zhao, H., Huang, Y.J., Yang, G., Huang, W.J., Gao, P., Zhou, C., Zhang, R.R., et al., 2020. A thermostable mRNA vaccine against COVID-19. Cell 182, 1271−1283.
[76]	Zhou, P., Yang, X.L., Wang, X.G., Hu, B., Zhang, L., Zhang, W., Si, H.R., Zhu, Y., Li, B., Huang, C.L., et al., 2020. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 579, 270−273.
[77]	Zhu, F.C., Guan, X.H., Li, Y.H., Huang, J.Y., Jiang, T., Hou, L.H., Li, J.X., Yang, B.F., Wang, L., Wang, W.J., et al., 2020a. Immunogenicity and safety of a recombinant adenovirus type-5-vectored COVID-19 vaccine in healthy adults aged 18 years or older: A randomised, double-blind, placebo-controlled, phase 2 trial. Lancet 396, 479−488.
[78]	Zhu, F.C., Li, Y.H., Guan, X.H., Hou, L.H., Wang, W.J., Li, J.X., Wu, S.P., Wang, B.S., Wang, Z., Wang, L., et al., 2020b. Safety, tolerability, and immunogenicity of a recombinant adenovirus type-5 vectored COVID-19 vaccine: A dose-escalation, open-label, non-randomised, first-in-human trial. Lancet 395, 1845−1854.
[79]	Zhu, N., Zhang, D., Wang, W., Li, X., Yang, B., Song, J., Zhao, X., Huang, B., Shi, W., Lu, R., et al, 2020c. A novel coronavirus from patients with pneumonia in china, 2019. N. Engl. J. Med. 382, 727−733.