Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults

Mulligan, Mark J.; Lyke, Kirsten E.; Kitchin, Nicholas; Absalon, Judith; Gurtman, Alejandra; Lockhart, Stephen; Neuzil, Kathleen M.; Raabe, Vanessa; Bailey, Richard; Swanson, Kena A.; Li, Ping; Koury, Kenneth; Kalina, Warren V.; Cooper, David A.; Fontes-Garfias, Camila R.; Shi, Pei Yong; Türeci, Özlem; Tompkins, Kristin; Walsh, Edward E.; Frenck, Robert W.; Falsey, Ann R.; Dormitzer, Philip R.; Gruber, William C.; Şahin, Uğur; Jansen, Kathrin U.

doi:10.1038/s41586-020-2639-4

“…Effect of spike mutation D614G on neutralization susceptibility. All of the COVID-19 vaccines currently in clinical trials are based on the original D614 spike sequence 19,20 . An important question is whether substitution D614G could reduce vaccine e cacy, assuming G614 virus continues to circulate.…”

Section: Resultsmentioning

confidence: 99%

Spike mutation D614G alters SARS-CoV-2 fitness and neutralization susceptibility

Shi

¹

,

Plante

²

,

Liu

³

et al. 2020

Preprint

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A spike protein mutation D614G became dominant in SARS-CoV-2 during the COVID-19 pandemic. However, the mutational impact on viral spread and vaccine efficacy remains to be defined. Here we engineer the D614G mutation in the SARS-CoV-2 USA-WA1/2020 strain and characterize its effect on viral replication, pathogenesis, and antibody neutralization. The D614G mutation significantly enhances SARS-CoV-2 replication on human lung epithelial cells and primary human airway tissues, through an improved infectivity of virions with the spike receptor-binding domain in an “up” conformation for binding to ACE2 receptor. Hamsters infected with D614 or G614 variants developed similar levels of weight loss. However, the G614 virus produced higher infectious titers in the nasal washes and trachea, but not lungs, than the D614 virus. The hamster results confirm clinical evidence that the D614G mutation enhances viral loads in the upper respiratory tract of COVID-19 patients and may increases transmission. For antibody neutralization, sera from D614 virus-infected hamsters consistently exhibit higher neutralization titers against G614 virus than those against D614 virus, indicating that (i) the mutation may not reduce the ability of vaccines in clinical trials to protect against COVID-19 and (ii) therapeutic antibodies should be tested against the circulating G614 virus before clinical development.

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“…vaccines currently in clinical trials are based on the original D614 spike sequence 19,20 . An important question is whether substitution D614G could reduce vaccine efficacy, assuming G614 virus continues to circulate.…”

Section: Effect Of Spike Mutation D614g On Neutralization Susceptibilmentioning

confidence: 99%

Spike mutation D614G alters SARS-CoV-2 fitness and neutralization susceptibility

Plante

¹

,

Liu

²

,

Liu

³

et al. 2020

Preprint

Self Cite

View full text Add to dashboard Cite

A spike protein mutation D614G became dominant in SARS-CoV-2 during the COVID-19 pandemic. However, the mutational impact on viral spread and vaccine efficacy remains to be defined. Here we engineer the D614G mutation in the SARS-CoV-2 USA-WA1/2020 strain and characterize its effect on viral replication, pathogenesis, and antibody neutralization. The D614G mutation significantly enhances SARS-CoV-2 replication on human lung epithelial cells and primary human airway tissues, through an improved infectivity of virions with the spike receptor-binding domain in an “up” conformation for binding to ACE2 receptor. Hamsters infected with D614 or G614 variants developed similar levels of weight loss. However, the G614 virus produced higher infectious titers in the nasal washes and trachea, but not lungs, than the D614 virus. The hamster results confirm clinical evidence that the D614G mutation enhances viral loads in the upper respiratory tract of COVID-19 patients and may increases transmission. For antibody neutralization, sera from D614 virus-infected hamsters consistently exhibit higher neutralization titers against G614 virus than those against D614 virus, indicating that (i) the mutation may not reduce the ability of vaccines in clinical trials to protect against COVID-19 and (ii) therapeutic antibodies should be tested against the circulating G614 virus before clinical development.ImportanceUnderstanding the evolution of SARS-CoV-2 during the COVID-19 pandemic is essential for disease control and prevention. A spike protein mutation D614G emerged and became dominant soon after the pandemic started. By engineering the D614G mutation into an authentic wild-type SARS-CoV-2 strain, we demonstrate the importance of this mutation to (i) enhanced viral replication on human lung epithelial cells and primary human airway tissues, (ii) improved viral fitness in the upper airway of infected hamsters, and (iii) increased susceptibility to neutralization. Together with clinical findings, our work underscores the importance of this mutation in viral spread, vaccine efficacy, and antibody therapy.

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“…Multiple studies employing a variety of vaccine formulations and modalities have now demonstrated that SARS-CoV-2 viral neutralization titers in small animals including mice and guinea pigs are predictive of immunogenicity in macaques and humans ( Figure 5E) [17][18][19][20]22,23,[33][34][35][36][37][40][41][42][43]45 . Despite promising immunogenicity in several cases, all of the above liquid formulations were either refrigerated or frozen prior to use.…”

Section: Discussionmentioning

confidence: 99%

“…Over 150 vaccine candidates are under development globally 16 . Some vaccine candidates that have entered rapidly into clinical phase testing include mRNA vaccine candidates by Moderna (mRNA-1273), BioNTech (BNT162b1) 17 , and CureVac (CVnCoV), a Chimpanzee Adenovirus vector vaccine by University of Oxford and AstraZeneca (ChAdOx1-S) 18 , a non-replicating adenovirus type-5 (Ad5) vaccine by Cansino (Ad5-nCoV) 19 , a DNA vaccine by Inovio (INO-4800) 20 , inactivated virus vaccines by Sinovac (PiCoVacc) 21 and Bharat Biotech (COVAXIN), a native like trimeric subunit spike protein vaccine by Clover Biopharmaceuticals /GSK/Dynavax (SCB-2019), and a full length recombinant glycoprotein nanoparticle vaccine by Novavax (NVX-CoV2373) 16,22 .…”

Section: Introductionmentioning

confidence: 99%

Design of a highly thermotolerant, immunogenic SARS-CoV-2 spike fragment immunogen

Malladi

¹

,

Singh

²

,

Pandey

³

et al. 2020

Preprint

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Virtually all SARS-CoV-2 vaccines currently in clinical testing are stored in a refrigerated or frozen state prior to use. This is a major impediment to deployment in resource-poor settings. Several use viral vectors or mRNA. In contrast to protein subunit vaccines, there is limited manufacturing expertise for these novel, nucleic acid based modalities, especially in the developing world. Neutralizing antibodies, the clearest known correlate of protection against SARS-CoV-2, are primarily directed against the Receptor Binding Domain (RBD) of the viral spike protein. We describe a monomeric, glycan engineered RBD protein fragment that is expressed at a purified yield of 200mg/L in unoptimized, mammalian cell culture and in contrast to a stabilized spike ectodomain, is tolerant of exposure to temperatures as high as 100°C when lyophilized, and upto 70°C in solution. In prime:boost guinea pig immunizations, when formulated with the MF59 like adjuvant AddaVax™, the RBD derivative elicited neutralizing antibodies with an endpoint geometric mean titer of ~415 against replicative virus, comparing favourably with several vaccine formulations currently in the clinic. These features of high yield, extreme thermotolerance and satisfactory immunogenicity suggest that such RBD subunit vaccine formulations hold great promise to combat COVID-19.

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Phase I/II study of COVID-19 RNA vaccine BNT162b1 in adults

Cited by 1,360 publications

References 24 publications

Spike mutation D614G alters SARS-CoV-2 fitness and neutralization susceptibility

Spike mutation D614G alters SARS-CoV-2 fitness and neutralization susceptibility

Spike mutation D614G alters SARS-CoV-2 fitness and neutralization susceptibility

Design of a highly thermotolerant, immunogenic SARS-CoV-2 spike fragment immunogen

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