Recombinant protein vaccines, a proven approach against coronavirus pandemics

Pollet, Jeroen; Chen, Wen‐Hsiang; Strych, Ulrich

doi:10.1016/j.addr.2021.01.001

Cited by 202 publications

(194 citation statements)

References 125 publications

(109 reference statements)

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“…Although other groups have followed a more direct approach (“antigen arrests” as well as “immunization”) to prevent RBD Spike binding to ACE2 through designing mini-proteins [ 116 ], peptide blockers [ 114 ], nanobodies [ 115 ], and vaccines [ 117 – 119 ], we have chosen a more indirect and unconventional (reverse) approach in our proposed bio-therapeutic design. The reasons for our choice are as follows:…”

Section: Resultsmentioning

confidence: 99%

Plausible blockers of Spike RBD in SARS-CoV2—molecular design and underlying interaction dynamics from high-level structural descriptors

et al. 2021

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COVID-19 is characterized by an unprecedented abrupt increase in the viral transmission rate (SARS-CoV-2) relative to its pandemic evolutionary ancestor, SARS-CoV (2003). The complex molecular cascade of events related to the viral pathogenicity is triggered by the Spike protein upon interacting with the ACE2 receptor on human lung cells through its receptor binding domain (RBD Spike ). One potential therapeutic strategy to combat COVID-19 could thus be limiting the infection by blocking this key interaction. In this current study, we adopt a protein design approach to predict and propose non-virulent structural mimics of the RBD Spike which can potentially serve as its competitive inhibitors in binding to ACE2. The RBD Spike is an independently foldable protein domain, resilient to conformational changes upon mutations and therefore an attractive target for strategic re-design. Interestingly, in spite of displaying an optimal shape fit between their interacting surfaces (attributed to a consequently high mutual affinity), the RBD Spike –ACE2 interaction appears to have a quasi-stable character due to a poor electrostatic match at their interface. Structural analyses of homologous protein complexes reveal that the ACE2 binding site of RBD Spike has an unusually high degree of solvent-exposed hydrophobic residues, attributed to key evolutionary changes, making it inherently “reaction-prone.” The designed mimics aimed to block the viral entry by occupying the available binding sites on ACE2, are tested to have signatures of stable high-affinity binding with ACE2 (cross-validated by appropriate free energy estimates), overriding the native quasi-stable feature. The results show the apt of directly adapting natural examples in rational protein design, wherein, homology-based threading coupled with strategic “hydrophobic ↔ polar” mutations serve as a potential breakthrough. Graphical Abstract Supplementary Information The online version contains supplementary material available at 10.1007/s00894-021-04779-0.

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Section: Resultsmentioning

confidence: 99%

Plausible blockers of Spike RBD in SARS-CoV2—molecular design and underlying interaction dynamics from high-level structural descriptors

et al. 2021

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“…These vaccine platforms are less demanding with respect to transport and storage and often come with a long history of successful global large-scale production capabilities and affordable use for other infectious diseases (Hotez and Bottazzi 2020). Particularly attractive in this aspect are recombinant protein antigens (Pollet et al 2021a), in particular those produced through microbial fermentation in yeast. For instance, recombinant hepatitis B vaccine has been administered to adults and children for decades (World Health Organization 2017).…”

Section: Introductionmentioning

confidence: 99%

“…For instance, recombinant hepatitis B vaccine has been administered to adults and children for decades (World Health Organization 2017). Currently, only a few protein-based COVID-19 vaccine candidates have advanced to phase 3 trials, namely from Novavax, Vector Institute in Russia, and Cuba's Finlay Vaccine Institute (Pollet et al 2021a), but in aggregate, it is promising to see more than 30 protein-based vaccines are actively in development (Zimmer et al 2021), which will greatly enable future access and distribution of safe, effective, and affordable COVID-19 vaccines for the world.…”

Section: Introductionmentioning

confidence: 99%

Process development and scale-up optimization of the SARS-CoV-2 receptor binding domain–based vaccine candidate, RBD219-N1C1

Lee

Liu

Chen

et al. 2021

Appl Microbiol Biotechnol

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A SARS-CoV-2 RBD219-N1C1 (RBD219-N1C1) recombinant protein antigen formulated on Alhydrogel® has recently been shown to elicit a robust neutralizing antibody response against SARS-CoV-2 pseudovirus in mice. The antigen has been produced under current good manufacturing practices (cGMPs) and is now in clinical testing. Here, we report on process development and scale-up optimization for upstream fermentation and downstream purification of the antigen. This includes production at the 1-L and 5-L scales in the yeast, Pichia pastoris, and the comparison of three different chromatographic purification methods. This culminated in the selection of a process to produce RBD219-N1C1 with a yield of >400 mg per liter of fermentation with >92% purity and >39% target product recovery after purification. In addition, we show the results from analytical studies, including SEC-HPLC, DLS, and an ACE2 receptor binding assay that were performed to characterize the purified proteins to select the best purification process. Finally, we propose an optimized upstream fermentation and downstream purification process that generates quality RBD219-N1C1 protein antigen and is fully scalable at a low cost. Key points • Yeast fermentation conditions for a recombinant COVID-19 vaccine were determined. • Three purification protocols for a COVID-19 vaccine antigen were compared. • Reproducibility of a scalable, low-cost process for a COVID-19 vaccine was shown. Graphical abstract

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“…This form of vaccine consists of synthetic peptides or recombinant antigenic proteins essential to emulate the immunogenicity of the original virus particle and consequently trigger a therapeutic immune response, such proteins may include the spike ‘S’ protein of SARS-CoV-2 which constitutes the most significant component in the nCOVID19 infection cycle. AdimrSC-2f by Adimmune [72] is such a vaccine that uses the spike protein antigenicity. It is currently within phase I of its study with 70 healthy volunteers.…”

Section: Immunotherapeutic Interventionsmentioning

confidence: 99%

Chemotherapy vs. Immunotherapy in combating nCOVID19: An update

Choudhury

Mukherjee

2021

Human Immunology

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The nCOVID-19 pandemic initiated its course of contagion from the city of Wuhan and now it has spread all over the globe. SARS-CoV-2 is the causative virus and the infection as well as its symptoms are distributed across the multi-organ perimeters. Interactions between the host and virus governs the induction of ‘cytokine storm’ resulting various immunopathological consequences leading to death. Till now it has caused tens of millions of casualties and yet no credible cure has emerged to vision. This article presents a comprehensive overview on the two most promising remedial approaches that are being attempted for the management, treatment, and plausible cure of nCOVID-19. In this context, chemotherapeutic approach primarily aims to interrupt the interactions between the host and the virus causing inhibition of its entry into the host cell and/or its proliferation and suppressing the inflammatory milieu in the infected patients. On the other side, immunotherapeutic approaches aim to modulate the host immunity by fine tuning the inflammatory signaling cascades to achieve phylaxis from the virus and restoring immune-homeostasis. Considering most of the path-breaking findings, combinatorial therapy involving of chemotherapeutics as well as vaccine could usher to be a hope for all of us to eradicate the crisis

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Recombinant protein vaccines, a proven approach against coronavirus pandemics

Cited by 202 publications

References 125 publications

Plausible blockers of Spike RBD in SARS-CoV2—molecular design and underlying interaction dynamics from high-level structural descriptors

Plausible blockers of Spike RBD in SARS-CoV2—molecular design and underlying interaction dynamics from high-level structural descriptors

Process development and scale-up optimization of the SARS-CoV-2 receptor binding domain–based vaccine candidate, RBD219-N1C1

Chemotherapy vs. Immunotherapy in combating nCOVID19: An update

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