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Microneedle array delivered recombinant coronavirus vaccines: Immunogenicity and rapid translational development.
EBioMedicine. 2020 May; 55:102743.E

Abstract

BACKGROUND

Coronaviruses pose a serious threat to global health as evidenced by Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and COVID-19. SARS Coronavirus (SARS-CoV), MERS Coronavirus (MERS-CoV), and the novel coronavirus, previously dubbed 2019-nCoV, and now officially named SARS-CoV-2, are the causative agents of the SARS, MERS, and COVID-19 disease outbreaks, respectively. Safe vaccines that rapidly induce potent and long-lasting virus-specific immune responses against these infectious agents are urgently needed. The coronavirus spike (S) protein, a characteristic structural component of the viral envelope, is considered a key target for vaccines for the prevention of coronavirus infection.

METHODS

We first generated codon optimized MERS-S1 subunit vaccines fused with a foldon trimerization domain to mimic the native viral structure. In variant constructs, we engineered immune stimulants (RS09 or flagellin, as TLR4 or TLR5 agonists, respectively) into this trimeric design. We comprehensively tested the pre-clinical immunogenicity of MERS-CoV vaccines in mice when delivered subcutaneously by traditional needle injection, or intracutaneously by dissolving microneedle arrays (MNAs) by evaluating virus specific IgG antibodies in the serum of vaccinated mice by ELISA and using virus neutralization assays. Driven by the urgent need for COVID-19 vaccines, we utilized this strategy to rapidly develop MNA SARS-CoV-2 subunit vaccines and tested their pre-clinical immunogenicity in vivo by exploiting our substantial experience with MNA MERS-CoV vaccines.

FINDINGS

Here we describe the development of MNA delivered MERS-CoV vaccines and their pre-clinical immunogenicity. Specifically, MNA delivered MERS-S1 subunit vaccines elicited strong and long-lasting antigen-specific antibody responses. Building on our ongoing efforts to develop MERS-CoV vaccines, promising immunogenicity of MNA-delivered MERS-CoV vaccines, and our experience with MNA fabrication and delivery, including clinical trials, we rapidly designed and produced clinically-translatable MNA SARS-CoV-2 subunit vaccines within 4 weeks of the identification of the SARS-CoV-2 S1 sequence. Most importantly, these MNA delivered SARS-CoV-2 S1 subunit vaccines elicited potent antigen-specific antibody responses that were evident beginning 2 weeks after immunization.

INTERPRETATION

MNA delivery of coronaviruses-S1 subunit vaccines is a promising immunization strategy against coronavirus infection. Progressive scientific and technological efforts enable quicker responses to emerging pandemics. Our ongoing efforts to develop MNA-MERS-S1 subunit vaccines enabled us to rapidly design and produce MNA SARS-CoV-2 subunit vaccines capable of inducing potent virus-specific antibody responses. Collectively, our results support the clinical development of MNA delivered recombinant protein subunit vaccines against SARS, MERS, COVID-19, and other emerging infectious diseases.

Authors+Show Affiliations

Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, W1148 Biomedical Science Tower, 200 Lothrop St., Pennsylvania, PA 15213, USA.Department of Dermatology, University of Pittsburgh School of Medicine, W1150 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, PA 15213, USA.Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, W1148 Biomedical Science Tower, 200 Lothrop St., Pennsylvania, PA 15213, USA.Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, W1148 Biomedical Science Tower, 200 Lothrop St., Pennsylvania, PA 15213, USA.Department of Dermatology, University of Pittsburgh School of Medicine, W1150 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, PA 15213, USA.Department of Dermatology, University of Pittsburgh School of Medicine, W1150 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, PA 15213, USA.Department of Viroscience, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands.Department of Radiation Oncology, University of Pittsburgh, Pittsburgh, PA 15213, USA.Center for Vaccine Research, Department of Immunology, University of Pittsburgh, Pittsburgh, PA 15213, USA.Department of Viroscience, Erasmus Medical Center Rotterdam, Rotterdam, the Netherlands.Department of Dermatology, University of Pittsburgh School of Medicine, W1150 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, PA 15213, USA; Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15231, USA.Department of Dermatology, University of Pittsburgh School of Medicine, W1150 Biomedical Science Tower, 200 Lothrop St., Pittsburgh, PA 15213, USA; Department of Bioengineering, Swanson School of Engineering, University of Pittsburgh, Pittsburgh, PA 15231, USA; Clinical and Translational Science Institute, University of Pittsburgh, Pittsburgh, PA 15213, USA; The McGowan Institute for Regenerative Medicine, University of Pittsburgh, Pittsburgh, PA 15219, USA. Electronic address: lof2@pitt.edu.Department of Surgery, University of Pittsburgh School of Medicine, Pittsburgh, W1148 Biomedical Science Tower, 200 Lothrop St., Pennsylvania, PA 15213, USA. Electronic address: gambottoa@upmc.edu.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32249203

Citation

Kim, Eun, et al. "Microneedle Array Delivered Recombinant Coronavirus Vaccines: Immunogenicity and Rapid Translational Development." EBioMedicine, vol. 55, 2020, p. 102743.
Kim E, Erdos G, Huang S, et al. Microneedle array delivered recombinant coronavirus vaccines: Immunogenicity and rapid translational development. EBioMedicine. 2020;55:102743.
Kim, E., Erdos, G., Huang, S., Kenniston, T. W., Balmert, S. C., Carey, C. D., Raj, V. S., Epperly, M. W., Klimstra, W. B., Haagmans, B. L., Korkmaz, E., Falo, L. D., & Gambotto, A. (2020). Microneedle array delivered recombinant coronavirus vaccines: Immunogenicity and rapid translational development. EBioMedicine, 55, 102743. https://doi.org/10.1016/j.ebiom.2020.102743
Kim E, et al. Microneedle Array Delivered Recombinant Coronavirus Vaccines: Immunogenicity and Rapid Translational Development. EBioMedicine. 2020;55:102743. PubMed PMID: 32249203.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Microneedle array delivered recombinant coronavirus vaccines: Immunogenicity and rapid translational development. AU - Kim,Eun, AU - Erdos,Geza, AU - Huang,Shaohua, AU - Kenniston,Thomas W, AU - Balmert,Stephen C, AU - Carey,Cara Donahue, AU - Raj,V Stalin, AU - Epperly,Michael W, AU - Klimstra,William B, AU - Haagmans,Bart L, AU - Korkmaz,Emrullah, AU - Falo,Louis D,Jr AU - Gambotto,Andrea, Y1 - 2020/04/02/ PY - 2020/03/16/received PY - 2020/03/18/revised PY - 2020/03/18/accepted PY - 2020/4/7/pubmed PY - 2020/5/30/medline PY - 2020/4/7/entrez KW - COVID-19 KW - MERS-CoV S1 KW - Microneedle array KW - SARS-CoV-2 KW - Subunit vaccines KW - Trimerization SP - 102743 EP - 102743 JF - EBioMedicine JO - EBioMedicine VL - 55 N2 - BACKGROUND: Coronaviruses pose a serious threat to global health as evidenced by Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS), and COVID-19. SARS Coronavirus (SARS-CoV), MERS Coronavirus (MERS-CoV), and the novel coronavirus, previously dubbed 2019-nCoV, and now officially named SARS-CoV-2, are the causative agents of the SARS, MERS, and COVID-19 disease outbreaks, respectively. Safe vaccines that rapidly induce potent and long-lasting virus-specific immune responses against these infectious agents are urgently needed. The coronavirus spike (S) protein, a characteristic structural component of the viral envelope, is considered a key target for vaccines for the prevention of coronavirus infection. METHODS: We first generated codon optimized MERS-S1 subunit vaccines fused with a foldon trimerization domain to mimic the native viral structure. In variant constructs, we engineered immune stimulants (RS09 or flagellin, as TLR4 or TLR5 agonists, respectively) into this trimeric design. We comprehensively tested the pre-clinical immunogenicity of MERS-CoV vaccines in mice when delivered subcutaneously by traditional needle injection, or intracutaneously by dissolving microneedle arrays (MNAs) by evaluating virus specific IgG antibodies in the serum of vaccinated mice by ELISA and using virus neutralization assays. Driven by the urgent need for COVID-19 vaccines, we utilized this strategy to rapidly develop MNA SARS-CoV-2 subunit vaccines and tested their pre-clinical immunogenicity in vivo by exploiting our substantial experience with MNA MERS-CoV vaccines. FINDINGS: Here we describe the development of MNA delivered MERS-CoV vaccines and their pre-clinical immunogenicity. Specifically, MNA delivered MERS-S1 subunit vaccines elicited strong and long-lasting antigen-specific antibody responses. Building on our ongoing efforts to develop MERS-CoV vaccines, promising immunogenicity of MNA-delivered MERS-CoV vaccines, and our experience with MNA fabrication and delivery, including clinical trials, we rapidly designed and produced clinically-translatable MNA SARS-CoV-2 subunit vaccines within 4 weeks of the identification of the SARS-CoV-2 S1 sequence. Most importantly, these MNA delivered SARS-CoV-2 S1 subunit vaccines elicited potent antigen-specific antibody responses that were evident beginning 2 weeks after immunization. INTERPRETATION: MNA delivery of coronaviruses-S1 subunit vaccines is a promising immunization strategy against coronavirus infection. Progressive scientific and technological efforts enable quicker responses to emerging pandemics. Our ongoing efforts to develop MNA-MERS-S1 subunit vaccines enabled us to rapidly design and produce MNA SARS-CoV-2 subunit vaccines capable of inducing potent virus-specific antibody responses. Collectively, our results support the clinical development of MNA delivered recombinant protein subunit vaccines against SARS, MERS, COVID-19, and other emerging infectious diseases. SN - 2352-3964 UR - https://www.unboundmedicine.com/medline/citation/32249203/Microneedle_array_delivered_recombinant_coronavirus_vaccines:_Immunogenicity_and_rapid_translational_development_ L2 - https://linkinghub.elsevier.com/retrieve/pii/S2352-3964(20)30118-3 DB - PRIME DP - Unbound Medicine ER -