Mechanism of a COVID-19 nanoparticle vaccine candidate that elicits a broadly neutralizing antibody response to SARS-CoV-2 variants

AbstractThere is a great need for the development of vaccines for preventing SARS-CoV-2 infection and mitigating the COVID-19 pandemic. Here, we developed two modified vaccinia Ankara (MVA) based vaccines which express either a membrane anchored full-length spike protein (MVA/S) stabilized in a prefusion state or the S1 region of the spike (MVA/S1) which forms trimers and is secreted. Both immunogens contained the receptor-binding domain (RBD) which is a known target of antibody-mediated neutralization. Following immunizations with MVA/S or MVA/S1, both spike protein recombinants induced strong IgG antibodies to purified full-length SARS-CoV-2 spike protein. The MVA/S induced a robust antibody response to purified RBD, S1 and S2 whereas MVA/S1 induced an antibody response to the S1 region outside of the RBD region. Both vaccines induced an antibody response in the lung and that was associated with induction of bronchus-associated lymphoid tissue. MVA/S but not MVA/S1 vaccinated mice generated robust neutralizing antibody responses against SARS-CoV-2 that strongly correlated with RBD antibody binding titers. Mechanistically, S1 binding to ACE-2 was strong but reduced following prolonged pre-incubation at room temperature suggesting confirmation changes in RBD with time. These results demonstrate MVA/S is a potential vaccine candidate against SARS-CoV-2 infection.

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Inactivation of Zika Virus by Photoactive Iodonaphthyl Azide Preserves Immunogenic Potential of the Virus

Pathogens ◽

10.3390/pathogens8040188 ◽

2019 ◽

Vol 8 (4) ◽

pp. 188

Author(s):

Austin ◽

Galasso ◽

Nickens ◽

Knollmann-Ritschel ◽

Sharma

Keyword(s):

Public Health ◽

Monoclonal Antibodies ◽

Antibody Response ◽

Vaccine Candidate ◽

Binding Capacity ◽

Neutralizing Antibody ◽

Vero Cells ◽

Productive Infection ◽

Public Health Importance ◽

Significant Public Health

Zika virus’s (ZIKV) emergence as a pathogen of significant public health importance has accelerated efforts to develop a ZIKV vaccine. To date, the need for an effective ZIKV vaccine is unmet. In this study, we report inactivation of ZIKV using a hydrophobic photoactive compound: 1, 5 iodonaphthyl azide (INA). 50 and 100 µM of INA completely inactivated ZIKV (INA-ZIKV). Western blot and ELISA analysis show some loss of the binding capacity of INA-iZIKV to anti-ZIKV monoclonal antibodies; however, immunization of mice with INA-iZIKV demonstrated seroconversion and ZIKV-neutralizing antibody response. RNA isolated from INA-iZIKV did not induce productive infection in Vero cells, suggesting inactivation of ZIKV RNA. These results suggest that in the absence of an approved ZIKV vaccine, INA-iZIKV can be pursued as a viable ZIKV vaccine candidate.

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CoV-RBD121-NP Vaccine Candidate Protects against Symptomatic Disease Following SARS-CoV-2 Challenge in K18-hACE2 Mice and Induces Protective Responses That Prevent COVID-19-Associated Immunopathology

Vaccines ◽

10.3390/vaccines9111346 ◽

2021 ◽

Vol 9 (11) ◽

pp. 1346

Author(s):

Jennifer K. DeMarco ◽

Joshua M. Royal ◽

William E. Severson ◽

Jon D. Gabbard ◽

Steve Hume ◽

...

Keyword(s):

Antibody Response ◽

Neutralizing Antibodies ◽

Potential Role ◽

Vaccine Candidate ◽

Severe Disease ◽

Neutralizing Antibody ◽

Antibody Responses ◽

Receptor Binding Domain ◽

Symptomatic Disease ◽

Human Igg1

We developed a SARS-CoV-2 vaccine candidate (CoV-RBD121-NP) comprised of a tobacco mosaic virus-like nanoparticle conjugated to the receptor-binding domain of the spike glycoprotein of SARS-CoV-2 fused to a human IgG1 Fc domain. CoV-RBD121-NP elicits strong antibody responses in C57BL/6 mice and is stable for up to 12 months at 2–8 or 22–28 °C. Here, we showed that this vaccine induces a strong neutralizing antibody response in K18-hACE2 mice. Furthermore, we demonstrated that immunization protects mice from virus-associated mortality and symptomatic disease. Our data indicated that a sufficient pre-existing pool of neutralizing antibodies is required to restrict SARS-CoV-2 replication upon exposure and prevent induction of inflammatory mediators associated with severe disease. Finally, we identified a potential role for CXCL5 as a protective cytokine in SARS-CoV-2 infection. Our results suggested that disruption of the CXCL5 and CXCL1/2 axis may be important early components of the inflammatory dysregulation that is characteristic of severe cases of COVID-19.

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Priming a broadly neutralizing antibody response to HIV-1 using a germline-targeting immunogen

Science ◽

10.1126/science.aac5894 ◽

2015 ◽

Vol 349 (6244) ◽

pp. 156-161 ◽

Cited By ~ 220

Author(s):

J. G. Jardine ◽

T. Ota ◽

D. Sok ◽

M. Pauthner ◽

D. W. Kulp ◽

...

Keyword(s):

Antibody Response ◽

Neutralizing Antibody ◽

Broadly Neutralizing Antibody ◽

Hiv 1

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Respiratory tract immunization of non-human primates with a Newcastle disease virus-vectored vaccine candidate against Ebola virus elicits a neutralizing antibody response

Vaccine ◽

10.1016/j.vaccine.2010.10.024 ◽

2010 ◽

Vol 29 (1) ◽

pp. 17-25 ◽

Cited By ~ 63

Author(s):

Joshua M. DiNapoli ◽

Lijuan Yang ◽

Siba K. Samal ◽

Brian R. Murphy ◽

Peter L. Collins ◽

...

Keyword(s):

Antibody Response ◽

Respiratory Tract ◽

Newcastle Disease Virus ◽

Disease Virus ◽

Newcastle Disease ◽

Ebola Virus ◽

Vaccine Candidate ◽

Neutralizing Antibody ◽

Vectored Vaccine

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Chemoenzymatic Synthesis and Antibody Binding of HIV-1 V1/V2 Glycopeptide-Bacteriophage Qβ Conjugates as a Vaccine Candidate

International Journal of Molecular Sciences ◽

10.3390/ijms222212538 ◽

2021 ◽

Vol 22 (22) ◽

pp. 12538

Author(s):

Guanghui Zong ◽

Christian Toonstra ◽

Qiang Yang ◽

Roushu Zhang ◽

Lai-Xi Wang

Keyword(s):

Vaccine Candidate ◽

Click Reaction ◽

Neutralizing Antibody ◽

Antibody Binding ◽

Promising Candidate ◽

Design Synthesis ◽

Gp120 Envelope ◽

Binding Analysis ◽

Broadly Neutralizing Antibody ◽

Hiv 1

The broadly neutralizing antibody PG9 recognizes a unique glycopeptide epitope in the V1V2 domain of HIV-1 gp120 envelope glycoprotein. The present study describes the design, synthesis, and antibody-binding analysis of HIV-1 V1V2 glycopeptide-Qβ conjugates as a mimic of the proposed neutralizing epitope of PG9. The glycopeptides were synthesized using a highly efficient chemoenzymatic method. The alkyne-tagged glycopeptides were then conjugated to the recombinant bacteriophage (Qβ), a virus-like nanoparticle, through a click reaction. Antibody-binding analysis indicated that the synthetic glycoconjugates showed significantly enhanced affinity for antibody PG9 compared with the monomeric glycopeptides. It was also shown that the affinity of the Qβ-conjugates for antibody PG9 was dependent on the density of the glycopeptide antigen display. The glycopeptide-Qβ conjugates synthesized represent a promising candidate of HIV-1 vaccine.

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The Type-Specific Neutralizing Antibody Response Elicited by a Dengue Vaccine Candidate Is Focused on Two Amino Acids of the Envelope Protein

PLoS Pathogens ◽

10.1371/journal.ppat.1003761 ◽

2013 ◽

Vol 9 (12) ◽

pp. e1003761 ◽

Cited By ~ 29

Author(s):

Laura A. VanBlargan ◽

Swati Mukherjee ◽

Kimberly A. Dowd ◽

Anna P. Durbin ◽

Stephen S. Whitehead ◽

...

Keyword(s):

Amino Acids ◽

Antibody Response ◽

Envelope Protein ◽

Vaccine Candidate ◽

Neutralizing Antibody ◽

Dengue Vaccine

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Mechanism of a COVID-19 nanoparticle vaccine candidate that elicits a broadly neutralizing antibody response to SARS-CoV-2 variants

10.1101/2021.03.26.437274 ◽

2021 ◽

Author(s):

Yi-Nan Zhang ◽

Jennifer Paynter ◽

Tatiana Fourfouris ◽

Cindy Sou ◽

Timothy Ngo ◽

...

Keyword(s):

Lymph Node ◽

Germinal Center ◽

Vaccine Candidate ◽

Neutralizing Antibody ◽

Follicular Dendritic Cell ◽

Antibody Responses ◽

Transmission Electron ◽

Protein Nanoparticles ◽

Broadly Neutralizing Antibody ◽

Induced Immunity

Vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) are essential for combating the coronavirus disease 2019 (COVID-19) pandemic. Neutralizing antibody responses to the original Wuhan-Hu-1 strain that were generated during infection and vaccination showed lower effectiveness against variants of concern. Here, we demonstrated that mouse plasma induced by protein nanoparticles that present rationally designed S2GΔHR2 spikes can neutralize the B.1.1.7, B.1.351, and P.1 variants with comparable titers. The mechanism of nanoparticle vaccine-induced immunity was examined in mice for an I3-01v9 60-mer that presents 20 stabilized spikes. Compared with the soluble spike, this nanoparticle showed 6-fold longer retention, 4-fold greater presentation on follicular dendritic cell dendrites, and 5-fold higher germinal center reactions in lymph node follicles. Intact nanoparticles in lymph node tissues were visualized by transmission electron microscopy. In conclusion, spike-presenting protein nanoparticles that induce robust long-lived germinal centers may provide a vaccine solution for emerging SARS-CoV-2 variants.

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