SARS-CoV-2 mRNA Vaccine Development Enabled by Prototype Pathogen Preparedness

Abstract

39A SARS-CoV-2 vaccine is needed to control the global COVID-19 public health crisis. Atomic-40 level structures directed the application of prefusion-stabilizing mutations that improved 41 expression and immunogenicity of betacoronavirus spike proteins. Using this established 42 immunogen design, the release of SARS-CoV-2 sequences triggered immediate rapid 43 manufacturing of an mRNA vaccine expressing the prefusion-stabilized SARS-CoV-2 spike 44 trimer (mRNA-1273). Here, we show that mRNA-1273 induces both potent neutralizing antibody 45 and CD8 T cell responses and protects against SARS-CoV-2 infection in lungs and noses of 46 mice without evidence of immunopathology. mRNA-1273 is currently in a Phase 2 clinical trial 47 sequences (then known as "2019-nCoV") on January 10 th , the 2P mutations were substituted 98 into S positions aa986 and 987 to produce prefusion-stabilized SARS-CoV-2 S (S-2P) protein 99 for structural analysis 22 and serological assay development 23,24 in silico without additional 100 experimental validation. Within 5 days of sequence release, current Good Manufacturing 101

A Newcastle disease virus (NDV) expressing membrane-anchored spike as a cost-effective inactivated SARS-CoV-2 vaccine

“…Lung lobes of mice were collected and homogenized in PBS. A plaque assay was performed to measure viral titer in the lung homogenates as described previously (1,21). Geometric mean titers of plaque forming units (PFU) per lobe were calculated using GraphPad Prism 7.0.…”

“…A severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine is urgently needed to mitigate the current coronavirus disease 2019 (COVID-19) pandemic worldwide. Numerous vaccine approaches are being developed (1)(2)(3)(4), however, many of them are not likely to be cost-effective and affordable by low-income countries and under-insured populations. This could be of concern in the long run, as it is crucial to vaccinate a larger population than the high-income minority to establish herd immunity and effectively contain the spread of the virus.…”

Ad26-vector based COVID-19 vaccine encoding a prefusion stabilized SARS-CoV-2 Spike immunogen induces potent humoral and cellular immune responses

“…Our data demonstrate that the design of the S protein is critical for the characteristics of the immunogen and the resulting immune responses elicited by the vaccine. While SARS-CoV-2-binding antibodies and NAbs have been shown to be induced in animal models and humans by several vaccines using different vaccine platforms and different S protein designs (Corbett et al, 2020), we here examined different S protein designs side by side which revealed specific characteristics for each of them. We show here that the wt SP is best suited for correct cleavage, which is needed for natively folded protein and it enhanced the induction of S binding antibodies and virus NAbs in vivo.…”

“…Several vaccine approaches using different designs of the S protein (e.g. with or without stabilizing substitutions, using a wild type (wt) signal peptide (SP) or Tissue Plasminogen Activator (tPA) SP (Alharbi et al, 2017)), have been described, which induce neutralizing antibodies (NAbs) and protection in animal challenge models against SARS-CoV (Martin et al, 2008), MERS-CoV (Alharbi et al, 2017) and SARS-CoV-2 infections (Corbett et al, 2020;Smith et al, 2020;van Doremalen et al, 2020;Yu et al, 2020). It is assumed that an effective vaccine against coronavirus infections should induce NAbs and a Th1skewed immune response.…”

Capsid-like particles decorated with the SARS2-CoV-2 receptor-binding domain elicit strong virus neutralization activity

“…The urgent need of an effective SARS-CoV-2 vaccine, to contain the worldwide pandemic and prevent new viral outbreaks, has led to a global effort involving a wide range of vaccine technologies. These include genetic-based (mRNA and DNA) principles 16,17 , replicating/non-replicating viral vectors (measles 18 , adenovirus 19,20 , baculovirus) recombinant proteins or peptides 21 , virus-like particles (VLPs)/nanoparticles or inactivated and live-attenuated viral vaccines [22][23][24] . In fact, more than 120 SARS-CoV-2 candidate vaccines are currently registered by WHO, of which 21 are currently undergoing clinical testing 25 .…”