Intranasal gene therapy to prevent infection by SARS-CoV-2 variants

Sims, Joshua J.; Greig, Jenny A.; Michalson, Kristofer T.; Lian, Sharon; Martino, Recchia; Meggersee, Rosemary; Turner, Kevin B.; Nambiar, Kalyani; Dyer, Cecilia; Hinderer, Christian; Horiuchi, Makoto; Yan, Hanying; Huang, Xin; Chen, Shu‐Jen; Wilson, James M.

doi:10.1371/journal.ppat.1009544

Cited by 40 publications

(73 citation statements)

References 42 publications

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“…There are also other AAV based vaccines for COVID-19, like AAVhu68-ACE2 ( Sims et al., 2021 ) and AAVrh32.33-S ( Zabaleta et al., 2021 ). Compared with them, the pros for AAV9-RBD are (1) two linked RBDs are more efficient antigens to elicit immune responses than single S protein or S1 protein, which has been showed by recombinant protein vaccine study.…”

Section: Discussionmentioning

confidence: 99%

Development of an Adeno-Associated Virus-Vectored SARS-CoV-2 Vaccine and Its Immunogenicity in Mice

Qin

Li²,

et al. 2022

Front. Cell. Infect. Microbiol.

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Owing to the outbreak of the novel coronavirus (SARS-CoV-2) worldwide at the end of 2019, the development of a SARS-CoV-2 vaccine became an urgent need. In this study, we developed a type 9 adeno-associated virus vectored vaccine candidate expressing a dimeric receptor binding domain (RBD) of the SARS-CoV-2 spike protein (S protein) and evaluated its immunogenicity in a murine model. The vaccine candidate, named AAV9-RBD virus, was constructed by inserting a signal peptide to the N-terminus of two copies of RBD, spaced by a linker, into the genome of a type 9 adeno-associated virus. In vitro assays showed that HeLa cells infected by the recombinant AAV virus expressed high levels of the recombinant RBD protein, mostly found in the cell culture supernatant. The recombinant AAV9-RBD virus was cultured and purified. The genome titer of the purified recombinant AAV9-RBD virus was determined to be 2.4 × 1013 genome copies/mL (GC/mL) by Q-PCR. Balb/c mice were immunized with the virus by intramuscular injection or nasal drip administration. Eight weeks after immunization, neutralizing antibodies against the new coronavirus pseudovirus were detected in the sera of all mice; the mean neutralizing antibody EC50 values were 517.7 ± 292.1 (n=10) and 682.8 ± 454.0 (n=10) in the intramuscular injection group and nasal drip group, respectively. The results of this study showed that the recombinant AAV9-RBD virus may be used for the development of a SARS-CoV-2 vaccine.

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Section: Discussionmentioning

confidence: 99%

Development of an Adeno-Associated Virus-Vectored SARS-CoV-2 Vaccine and Its Immunogenicity in Mice

Qin

Li²,

et al. 2022

Front. Cell. Infect. Microbiol.

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“…Avid binding can mask differences in monovalent affinity (Zhang et al, 2022;Chan et al, 2020Chan et al, , 2021. We incubated cells expressing BA.1 omicron S with three monomeric sACE2(18-615) proteins: wild type, v2.4 (ACE2 mutations T27Y, L79T, and N330Y), and a second engineered decoy called CDY14 (ACE2 mutations K31M, E35K, S47A, L79F, L91P, and N330Y; this is the highest affinity decoy reported in published literature (Sims et al, 2021)). Cells were washed and bound proteins were detected by flow cytometry.…”

Section: Catalytic Activity Of Sace2 2 V24-igg1 Contributes To Therap...mentioning

confidence: 99%

An engineered ACE2 decoy receptor can be administered by inhalation and potently targets the BA.1 and BA.2 omicron variants of SARS-CoV-2

Zhang

Narayanan

Cooper

et al. 2022

Preprint

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Monoclonal antibodies targeting the SARS-CoV-2 spike (S) glycoprotein neutralize infection and are efficacious for the treatment of mild-to-moderate COVID-19. However, SARS-CoV-2 variants have emerged that partially or fully escape monoclonal antibodies in clinical use. Notably, the BA.2 sublineage of B.1.1.529/omicron escapes nearly all monoclonal antibodies currently authorized for therapeutic treatment of COVID-19. Decoy receptors, which are based on soluble forms of the host entry receptor ACE2, are an alternative strategy that broadly bind and block S from SARS-CoV-2 variants and related betacoronaviruses. The high-affinity and catalytically active decoy sACE22.v2.4-IgG1 was previously shown to be effective in vivo against SARS-CoV-2 variants when administered intravenously. Here, the inhalation of sACE22.v2.4-IgG1 is found to increase survival and ameliorate lung injury in K18-hACE2 transgenic mice inoculated with a lethal dose of the virulent P.1/gamma virus. Loss of catalytic activity reduced the decoy's therapeutic efficacy supporting dual mechanisms of action: direct blocking of viral S and turnover of ACE2 substrates associated with lung injury and inflammation. Binding of sACE22.v2.4-IgG1 remained tight to S of BA.1 omicron, despite BA.1 omicron having extensive mutations, and binding exceeded that of four monoclonal antibodies approved for clinical use. BA.1 pseudovirus and authentic virus were neutralized at picomolar concentrations. Finally, tight binding was maintained against S from the BA.2 omicron sublineage, which differs from S of BA.1 by 26 mutations. Overall, the therapeutic potential of sACE22.v2.4-IgG1 is further confirmed by inhalation route and broad neutralization potency persists against increasingly divergent SARS-CoV-2 variants.

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“…11 , 12 By employing a multi-dimensional approach, Gordon et al proposed a set of potential “pan” viral target for coronaviruses, but the druggability of these targets are yet to be evaluated. 13 ACE2 fusion proteins can act as decoy receptors to trap SARS-CoV-2, 14 , 15 but the affinity and developability of these proteins are generally less than antibodies. Recently, Rappazzo et al generated a set of monoclonal antibodies that bound to a large panel of coronaviruses, but their neutralizing abilities have not been tested yet.…”

Section: Introductionmentioning

confidence: 99%

ACE2-targeting monoclonal antibody as potent and broad-spectrum coronavirus blocker

Chen

Zhang

Yan

et al. 2021

Sig Transduct Target Ther

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The evolution of coronaviruses, such as SARS-CoV-2, makes broad-spectrum coronavirus preventional or therapeutical strategies highly sought after. Here we report a human angiotensin-converting enzyme 2 (ACE2)-targeting monoclonal antibody, 3E8, blocked the S1-subunits and pseudo-typed virus constructs from multiple coronaviruses including SARS-CoV-2, SARS-CoV-2 mutant variants (SARS-CoV-2-D614G, B.1.1.7, B.1.351, B.1.617.1, and P.1), SARS-CoV and HCoV-NL63, without markedly affecting the physiological activities of ACE2 or causing severe toxicity in ACE2 “knock-in” mice. 3E8 also blocked live SARS-CoV-2 infection in vitro and in a prophylactic mouse model of COVID-19. Cryo-EM and “alanine walk” studies revealed the key binding residues on ACE2 interacting with the CDR3 domain of 3E8 heavy chain. Although full evaluation of safety in non-human primates is necessary before clinical development of 3E8, we provided a potentially potent and “broad-spectrum” management strategy against all coronaviruses that utilize ACE2 as entry receptors and disclosed an anti-coronavirus epitope on human ACE2.

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Intranasal gene therapy to prevent infection by SARS-CoV-2 variants

Cited by 40 publications

References 42 publications

Development of an Adeno-Associated Virus-Vectored SARS-CoV-2 Vaccine and Its Immunogenicity in Mice

Development of an Adeno-Associated Virus-Vectored SARS-CoV-2 Vaccine and Its Immunogenicity in Mice

An engineered ACE2 decoy receptor can be administered by inhalation and potently targets the BA.1 and BA.2 omicron variants of SARS-CoV-2

ACE2-targeting monoclonal antibody as potent and broad-spectrum coronavirus blocker

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