Skip to main content
U.S. Department of Energy
Office of Scientific and Technical Information

Crimean Congo hemorrhagic fever virus nucleoprotein and GP38 subunit vaccine combination prevents morbidity in mice

Journal Article · · npj Vaccines
 [1];  [2];  [2];  [2];  [2];  [3];  [2];  [2];  [2];  [4];  [2];  [2];  [2];  [5]
  1. Centers for Disease Control and Prevention (CDC), Atlanta, GA (United States); University of California, Riverside, CA (United States)
  2. Centers for Disease Control and Prevention (CDC), Atlanta, GA (United States)
  3. Centers for Disease Control and Prevention (CDC), Atlanta, GA (United States); US Dept. of Agriculture (USDA), Manhattan, KS (United States). Agricultural Research Service (ARS)
  4. University of California, Riverside, CA (United States)
  5. Centers for Disease Control and Prevention (CDC), Atlanta, GA (United States); University of Georgia, Athens, GA (United States)
Immunizing mice with Crimean-Congo hemorrhagic fever virus (CCHFV) nucleoprotein (NP), glycoprotein precursor (GPC), or with the GP38 domain of GPC, can be protective when the proteins are delivered with viral vectors or as a DNA or RNA vaccine. Subunit vaccines are a safe and cost-effective alternative to some vaccine platforms, but Gc and Gn glycoprotein subunit vaccines for CCHFV fail to protect despite eliciting high levels of neutralizing antibodies. Here, we investigated humoral and cellular immune responses and the protective efficacy of recombinant NP, GP38, and GP38 forms (GP85 and GP160) associated with the highly glycosylated mucin-like (MLD) domain, as well as the NP + GP38 combination. Vaccination with GP160, GP85, or GP38 did not confer protection, and vaccination with the MLD-associated GP38 forms blunted the humoral immune responses to GP38, worsened clinical chemistry, and increased viral RNA in the blood compared to the GP38 vaccination. In contrast, NP vaccination conferred 100% protection from lethal outcome and was associated with mild clinical disease, while the NP + GP38 combination conferred even more robust protection by reducing morbidity compared to mice receiving NP alone. Thus, recombinant CCHFV NP alone is a promising vaccine candidate conferring 100% survival against heterologous challenge. Moreover, incorporation of GP38 should be considered as it further enhances subunit vaccine efficacy by reducing morbidity in surviving animals.
Research Organization:
Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)
Sponsoring Organization:
Defense Threat Reduction Agency (DTRA); National Institutes of Health (NIH); USDOE Office of Science (SC)
Grant/Contract Number:
SC0014664
OSTI ID:
2471344
Journal Information:
npj Vaccines, Journal Name: npj Vaccines Journal Issue: 1 Vol. 9; ISSN 2059-0105
Publisher:
Springer NatureCopyright Statement
Country of Publication:
United States
Language:
English

References (85)

Hemagglutinin Functionalized Liposomal Vaccines Enhance Germinal Center and Follicular Helper T Cell Immunity journal March 2021
Vaccine molecules targeting Xcr1 on cross‐presenting DCs induce protective CD8+ T‐cell responses against influenza virus journal December 2014
Recombinant nucleoprotein‐based serological diagnosis of Crimean–Congo hemorrhagic fever virus infections journal December 2004
Identification of T cell responses to the nonstructural glycoproteins in survivors of Crimean‐Congo hemorrhagic fever in South Africa journal October 2023
Production of CCHF virus-like particle by a baculovirus-insect cell expression system journal October 2011
Recombinant Trivalent Influenza Vaccine (Flublok®): A Review of Its Use in the Prevention of Seasonal Influenza in Adults journal August 2013
Over a decade of experience with a yeast recombinant hepatitis B vaccine journal August 1999
Safety and immunogenicity of SARS-CoV-2 recombinant protein vaccine formulations in healthy adults: interim results of a randomised, placebo-controlled, phase 1–2, dose-ranging study journal September 2021
Recombinant protein vaccines, a proven approach against coronavirus pandemics journal March 2021
Crimean-Congo hemorrhagic fever: History, epidemiology, pathogenesis, clinical syndrome and genetic diversity journal October 2013
The role of ticks in the maintenance and transmission of Crimean-Congo hemorrhagic fever virus: A review of published field and laboratory studies journal August 2017
Heterologous protection against Crimean-Congo hemorrhagic fever in mice after a single dose of replicon particle vaccine journal October 2019
Crimean-Congo Hemorrhagic Fever Virus Suppresses Innate Immune Responses via a Ubiquitin and ISG15 Specific Protease journal September 2017
Rapid Germinal Center and Antibody Responses in Non-human Primates after a Single Nanoparticle Vaccine Immunization journal November 2019
Fc-mediated pan-sarbecovirus protection after alphavirus vector vaccination journal April 2023
Resolving adjuvant mode of action to enhance vaccine efficacy journal August 2022
Crimean–Congo hemorrhagic fever virus: new outbreaks, new discoveries journal April 2012
Replicating RNA vaccination elicits an unexpected immune response that efficiently protects mice against lethal Crimean-Congo hemorrhagic fever virus challenge journal August 2022
Co-immunization with hemagglutinin stem immunogens elicits cross-group neutralizing antibodies and broad protection against influenza A viruses journal December 2022
Cytokine levels in Crimean-Congo hemorrhagic fever journal August 2006
Assessment of IgG avidity against pertussis toxin and filamentous hemagglutinin via an adapted enzyme-linked immunosorbent assay (ELISA) using ammonium thiocyanate journal January 2013
A high-throughput, bead-based, antigen-specific assay to assess the ability of antibodies to induce complement activation journal October 2019
Human defined antigenic region on the nucleoprotein of Crimean-Congo hemorrhagic fever virus identified using truncated proteins and a bioinformatics approach journal November 2013
Evolution of Crimean-Congo Hemorrhagic Fever virus journal September 2009
A DNA vaccine encoding ubiquitinated Rift Valley fever virus nucleoprotein provides consistent immunity and protects IFNAR−/− mice upon lethal virus challenge journal June 2011
RTS,S: Toward a first landmark on the Malaria Vaccine Technology Roadmap journal December 2015
N-linked glycosylation of Gn (but not Gc) is important for Crimean Congo hemorrhagic fever virus glycoprotein localization and transport journal May 2007
Accelerated DNA vaccine regimen provides protection against Crimean-Congo hemorrhagic fever virus challenge in a macaque model journal February 2023
Structure of the Ebola virus glycoprotein bound to an antibody from a human survivor journal July 2008
Non-neutralizing antibodies elicited by recombinant Lassa–Rabies vaccine are critical for protection against Lassa fever journal October 2018
Structural characterization of protective non-neutralizing antibodies targeting Crimean-Congo hemorrhagic fever virus journal November 2022
A Lassa virus mRNA vaccine confers protection but does not require neutralizing antibody in a guinea pig model of infection journal September 2023
Nucleocapsid protein-specific monoclonal antibodies protect mice against Crimean-Congo hemorrhagic fever virus journal February 2024
Enhanced germinal center reaction by targeting vaccine antigen to major histocompatibility complex class II molecules journal February 2019
A CCHFV DNA vaccine protects against heterologous challenge and establishes GP38 as immunorelevant in mice journal March 2021
Antibody avidity, persistence, and response to antigen recall: comparison of vaccine adjuvants journal May 2021
GP38 as a vaccine target for Crimean-Congo hemorrhagic fever virus journal May 2023
A novel Schmallenberg virus subunit vaccine candidate protects IFNAR-/- mice against virulent SBV challenge journal November 2020
Optimal reference genes for RNA tissue analysis in small animal models of hemorrhagic fever viruses journal November 2023
Induction of Caspase Activation and Cleavage of the Viral Nucleocapsid Protein in Different Cell Types during Crimean-Congo Hemorrhagic Fever Virus Infection journal December 2010
Understanding modern-day vaccines: what you need to know journal November 2017
A Crimean-Congo hemorrhagic fever (CCHF) viral vaccine expressing nucleoprotein is immunogenic but fails to confer protection against lethal disease journal August 2015
Evaluation of Serum Levels of Interleukin (IL)–6, IL‐10, and Tumor Necrosis Factor–α in Patients with Crimean‐Congo Hemorrhagic Fever journal April 2006
Crimean-Congo Hemorrhagic Fever Virus Subunit Vaccines Induce High Levels of Neutralizing Antibodies But No Protection in STAT1 Knockout Mice journal December 2015
Impact and Effectiveness of the Quadrivalent Human Papillomavirus Vaccine: A Systematic Review of 10 Years of Real-world Experience journal May 2016
Crimean-Congo Hemorrhagic Fever in Humanized Mice Reveals Glial Cells as Primary Targets of Neurological Infection journal May 2017
A Simple Method of Estimating Fifty per cent Endpoints12 journal May 1938
First serological evidence of Crimean–Congo haemorrhagic fever virus in transhumant bovines in Italy journal October 2022
GP38-targeting monoclonal antibodies protect adult mice against lethal Crimean-Congo hemorrhagic fever virus infection journal July 2019
A bivalent Epstein-Barr virus vaccine induces neutralizing antibodies that block infection and confer immunity in humanized mice journal May 2022
Interacting Roles of Immune Mechanisms and Viral Load in the Pathogenesis of Crimean-Congo Hemorrhagic Fever journal May 2010
Recombinant Nucleoprotein-Based Enzyme-Linked Immunosorbent Assay for Detection of Immunoglobulin G Antibodies to Crimean-Congo Hemorrhagic Fever Virus journal May 2002
Altered Glycosylation Patterns Increase Immunogenicity of a Subunit Hepatitis C Virus Vaccine, Inducing Neutralizing Antibodies Which Confer Protection in Mice journal December 2016
Structure, Function, and Evolution of the Crimean-Congo Hemorrhagic Fever Virus Nucleocapsid Protein journal August 2012
Crimean-Congo Hemorrhagic Fever Virus Glycoprotein Processing by the Endoprotease SKI-1/S1P Is Critical for Virus Infectivity journal September 2007
Structure and Characterization of Crimean-Congo Hemorrhagic Fever Virus GP38 journal March 2020
Characterization of the Glycoproteins of Crimean-Congo Hemorrhagic Fever Virus journal July 2002
Human MxA Protein Inhibits the Replication of Crimean-Congo Hemorrhagic Fever Virus journal March 2004
Cellular Localization and Antigenic Characterization of Crimean-Congo Hemorrhagic Fever Virus Glycoproteins journal April 2005
Crimean-Congo Hemorrhagic Fever Virus Glycoprotein Precursor Is Cleaved by Furin-Like and SKI-1 Proteases To Generate a Novel 38-Kilodalton Glycoprotein journal December 2005
Nucleoside-Modified mRNA Vaccines Protect IFNAR –/– Mice against Crimean-Congo Hemorrhagic Fever Virus Infection journal February 2022
Determination of a Statistically Valid Neutralization Titer in Plasma That Confers Protection against Simian-Human Immunodeficiency Virus Challenge following Passive Transfer of High-Titered Neutralizing Antibodies journal March 2002
Comprehensive Functional Analysis of N-Linked Glycans on Ebola Virus GP1 journal January 2014
Self-assembling influenza nanoparticle vaccines drive extended germinal center activity and memory B cell maturation journal May 2020
A DNA vaccine for Crimean-Congo hemorrhagic fever protects against disease and death in two lethal mouse models journal September 2017
Long-lived CD8+ T cell responses following Crimean-Congo haemorrhagic fever virus infection journal December 2017
Nucleocapsid protein-based vaccine provides protection in mice against lethal Crimean-Congo hemorrhagic fever virus challenge journal July 2018
ISG15 overexpression compensates the defect of Crimean-Congo hemorrhagic fever virus polymerase bearing a protease-inactive ovarian tumor domain journal September 2020
Evaluation of the cell culture based and the mouse brain derived inactivated vaccines against Crimean-Congo hemorrhagic fever virus in transiently immune-suppressed (IS) mouse model journal November 2020
Fine Epitope Mapping of the Central Immunodominant Region of Nucleoprotein from Crimean-Congo Hemorrhagic Fever Virus (CCHFV) journal November 2014
Recovery of Recombinant Crimean Congo Hemorrhagic Fever Virus Reveals a Function for Non-structural Glycoproteins Cleavage by Furin journal May 2015
Probing the impact of nairovirus genomic diversity on viral ovarian tumor domain protease (vOTU) structure and deubiquitinase activity journal January 2019
Fluorescent Crimean-Congo hemorrhagic fever virus illuminates tissue tropism patterns and identifies early mononuclear phagocytic cell targets in Ifnar-/- mice journal December 2019
The interplays between Crimean-Congo hemorrhagic fever virus (CCHFV) M segment-encoded accessory proteins and structural proteins promote virus assembly and infectivity journal September 2020
The host inflammatory response contributes to disease severity in Crimean-Congo hemorrhagic fever virus infected mice journal May 2022
Crimean-Congo Hemorrhagic Fever, Spain, 2013–2021 journal February 2023
Vaccination with the Crimean-Congo hemorrhagic fever virus viral replicon vaccine induces NP-based T-cell activation and antibodies possessing Fc-mediated effector functions journal August 2023
A Sample-Sparing Multiplexed ADCP Assay journal August 2019
Systematic Review on Crimean–Congo Hemorrhagic Fever Enzootic Cycle and Factors Favoring Virus Transmission: Special Focus on France, an Apparently Free-Disease Area in Europe journal July 2022
Co-Delivery Effect of CD24 on the Immunogenicity and Lethal Challenge Protection of a DNA Vector Expressing Nucleocapsid Protein of Crimean Congo Hemorrhagic Fever Virus journal January 2019
Bovine Herpesvirus Type 4 (BoHV-4) Vector Delivering Nucleocapsid Protein of Crimean-Congo Hemorrhagic Fever Virus Induces Comparable Protective Immunity against Lethal Challenge in IFNα/β/γR−/− Mice Models journal March 2019
Molecular Insights into Crimean-Congo Hemorrhagic Fever Virus journal April 2016
Immunological Analysis of a CCHFV mRNA Vaccine Candidate in Mouse Models journal September 2019
Immunogenicity of a DNA-Based Sindbis Replicon Expressing Crimean–Congo Hemorrhagic Fever Virus Nucleoprotein journal December 2021
Crimean-Congo Hemorrhagic Fever journal June 2014

Similar Records

Structure and Characterization of Crimean-Congo Hemorrhagic Fever Virus GP38
Journal Article · Mon Mar 30 20:00:00 EDT 2020 · Journal of Virology · OSTI ID:1839757

Crimean-Congo hemorrhagic fever survivors elicit protective non-neutralizing antibodies that target 11 overlapping regions on glycoprotein GP38
Journal Article · Fri Jul 12 20:00:00 EDT 2024 · Cell Reports · OSTI ID:2470075

Structural characterization of protective non-neutralizing antibodies targeting Crimean-Congo hemorrhagic fever virus
Journal Article · Fri Nov 25 19:00:00 EST 2022 · Nature Communications · OSTI ID:2423642