Prime-boost vaccination regimens with INO-4800 and INO-4802 augment and broaden immune responses against SARS-CoV-2 in nonhuman primates

Walters, Jewell; Schouest, Blake; Patel, Ami; Reuschel, Emma L.; Schultheis, Katherine; Parzych, Elizabeth M.; Maricic, Igor; Gary, E.; Purwar, Mansi; Andrade, Viviane M; Doan, Arthur; Elwood, Dustin; Eblimit, Zeena; Nguyen, Brian; Frase, Drew; Zaidi, Faraz I; Kulkarni, Abhijeet J; Generotti, Alison; Kim, J Joseph; Humeau, Laurent; Ramos, Stephanie; Smith, Trevor R.F.; Weiner, David B.; Broderick, Kate E.

doi:10.1016/j.vaccine.2022.03.060

Cited by 6 publications

(11 citation statements)

References 61 publications

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“…The B.1.1.529 (Omicron) variant, along with its subvariants BA.1–5, contain a large number of escape mutations in the RBD (G339D, S371L, S373P, S375F, K417N, N440K, G446S, S477N, T478K, E484A, Q493R, G496S, Q498R, N501Y, Y505H) [ 19 , 20 ] that enabled it to outcompete previous variants and become the most prevalent circulating variant in the United States in early 2022 [ 21 , 22 , 23 ]. Several cross-reactive mAbs targeting the RBD have been isolated [ 9 , 24 , 25 ], and efforts are underway to develop broadly protective vaccines [ 26 , 27 ].…”

Section: Introductionmentioning

confidence: 99%

Unglycosylated Soluble SARS-CoV-2 Receptor Binding Domain (RBD) Produced in E. coli Combined with the Army Liposomal Formulation Containing QS21 (ALFQ) Elicits Neutralizing Antibodies against Mismatched Variants

et al. 2022

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The emergence of novel potentially pandemic pathogens necessitates the rapid manufacture and deployment of effective, stable, and locally manufacturable vaccines on a global scale. In this study, the ability of the Escherichia coli expression system to produce the receptor binding domain (RBD) of the SARS-CoV-2 spike protein was evaluated. The RBD of the original Wuhan-Hu1 variant and of the Alpha and Beta variants of concern (VoC) were expressed in E. coli, and their biochemical and immunological profiles were compared to RBD produced in mammalian cells. The E. coli-produced RBD variants recapitulated the structural character of mammalian-expressed RBD and bound to human angiotensin converting enzyme (ACE2) receptor and a panel of neutralizing SARS-CoV-2 monoclonal antibodies. A pilot vaccination in mice with bacterial RBDs formulated with a novel liposomal adjuvant, Army Liposomal Formulation containing QS21 (ALFQ), induced polyclonal antibodies that inhibited RBD association to ACE2 in vitro and potently neutralized homologous and heterologous SARS-CoV-2 pseudoviruses. Although all vaccines induced neutralization of the non-vaccine Delta variant, only the Beta RBD vaccine produced in E. coli and mammalian cells effectively neutralized the Omicron BA.1 pseudovirus. These outcomes warrant further exploration of E. coli as an expression platform for non-glycosylated, soluble immunogens for future rapid response to emerging pandemic pathogens.

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Section: Introductionmentioning

confidence: 99%

Unglycosylated Soluble SARS-CoV-2 Receptor Binding Domain (RBD) Produced in E. coli Combined with the Army Liposomal Formulation Containing QS21 (ALFQ) Elicits Neutralizing Antibodies against Mismatched Variants

et al. 2022

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“…In general, the only DNA used for gene therapy is plasmid DNA (pDNA). Compared to other therapeutics, pDNA is stable, easy to produce, and easy to store and transport . pDNA is widely used in protein replacement therapy, which introduce the wild-type transgenes into specific cells with defective or under-expressed endogenous gene to upregulate the synthesis or expression of failed proteins. , It is well-known that it is enough for RNA to reach the cytoplasm, whereas the final destination of pDNA is the nucleus, entering the transcription process. , To this end, scientists have optimized DNA in various ways, including codon optimization, ,, backbone simplification, , and plasmid endlessness .…”

Section: Novel Dna Materials In Gene Therapymentioning

confidence: 99%

“…Using the CELLECTRA device for drug delivery helps ensure that the DNA drug is effectively delivered directly to the body's cells where it can function to drive the immune response. INOVIO currently has a number of clinical-stage pipelines, such as INO-4800,20,177 INO-9012,178 and INO-3107,179 all dedicated to the electroporation delivery of naked plasmids for the treatment of disease, all of which have made encouraging progress.Also, electroporation can cooperate with chemical carriers to deliver DNA material.Kanazawa et al…”

mentioning

confidence: 99%

DNA-Based Nonviral Gene Therapy─Challenging but Promising

Guan,

Pei,

Song

2024

Mol. Pharmaceutics

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Over the past decades, significant progress has been made in utilizing nucleic acids, including DNA and RNA molecules, for therapeutic purposes. For DNA molecules, although various DNA delivery systems have been established, viral vector systems are the go-to choice for large-scale commercial applications. However, viral systems have certain disadvantages such as immune response, limited payload capacity, insertional mutagenesis and pre-existing immunity. In contrast, nonviral systems are less immunogenic, not size limited, safer, and easier for manufacturing compared with viral systems. What's more, nonviral DNA vectors have demonstrated their capacity to mediate specific protein expression in vivo for diverse therapeutic objectives containing a wide range of diseases such as cancer, rare diseases, neurodegenerative diseases, and infectious diseases, yielding promising therapeutic outcomes. However, exogenous plasmid DNA is prone to degrade and has poor immunogenicity in vivo. Thus, various strategies have been developed: (i) designing novel plasmids with special structures, (ii) optimizing plasmid sequences for higher expression, and (iii) developing more efficient nonviral DNA delivery systems. Based on these strategies, many interesting clinical results have been reported. This Review discusses the development of DNA-based nonviral gene therapy, including novel plasmids, nonviral delivery systems, clinical advances, and prospects. These developments hold great potential for enhancing the efficacy and safety of nonviral gene therapy and expanding its applications in the treatment of various diseases.

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“…In light of the emergence of VOC against which many vaccines show lower effectiveness, Inovio Pharmaceuticals began to develop a new vaccine with the goal of improving robustness against known and future VOC ( 74 ). Known as INO-4802, this vaccine was designed to express a pan-spike immunogen ( 75 ). Booster studies in rodents ( 76 ) and nonhuman primates ( 75 ) suggest that it may be more effective than INO-4800 in providing immunity to VOC such as Delta and Omicron when administered as part of a heterologous boost regimen, although boosting with INO-4800 was also very effective in increasing immunity in rhesus macaques ( 75 ).…”

Section: Dna Vaccine Platformsmentioning

confidence: 99%

“…Known as INO-4802, this vaccine was designed to express a pan-spike immunogen ( 75 ). Booster studies in rodents ( 76 ) and nonhuman primates ( 75 ) suggest that it may be more effective than INO-4800 in providing immunity to VOC such as Delta and Omicron when administered as part of a heterologous boost regimen, although boosting with INO-4800 was also very effective in increasing immunity in rhesus macaques ( 75 ). Therefore, boosting is likely to be an important strategy for this vaccine, especially as the virus continues to evolve.…”

Section: Dna Vaccine Platformsmentioning

confidence: 99%