scholarly journals Successful Topical Respiratory Tract Immunization of Primates against Ebola Virus

2007 ◽  
Vol 81 (12) ◽  
pp. 6379-6388 ◽  
Author(s):  
Alexander Bukreyev ◽  
Pierre E. Rollin ◽  
Mallory K. Tate ◽  
Lijuan Yang ◽  
Sherif R. Zaki ◽  
...  
Keyword(s):  
Respiratory Tract ◽  
Ebola Virus ◽  
Protective Efficacy ◽  
Hemorrhagic Fever ◽  
Surface Glycoprotein ◽  
Respiratory Pathogen ◽  
Viral Hemorrhagic Fever ◽  
Primate Model ◽  
Challenge Virus ◽  
Virus Challenge

ABSTRACT Ebola virus causes outbreaks of severe viral hemorrhagic fever with high mortality in humans. The virus is highly contagious and can be transmitted by contact and by the aerosol route. These features make Ebola virus a potential weapon for bioterrorism and biological warfare. Therefore, a vaccine that induces both systemic and local immune responses in the respiratory tract would be highly beneficial. We evaluated a common pediatric respiratory pathogen, human parainfluenza virus type 3 (HPIV3), as a vaccine vector against Ebola virus. HPIV3 recombinants expressing the Ebola virus (Zaire species) surface glycoprotein (GP) alone or in combination with the nucleocapsid protein NP or with the cytokine adjuvant granulocyte-macrophage colony-stimulating factor were administered by the respiratory route to rhesus monkeys—in which HPIV3 infection is mild and asymptomatic—and were evaluated for immunogenicity and protective efficacy against a highly lethal intraperitoneal challenge with Ebola virus. A single immunization with any construct expressing GP was moderately immunogenic against Ebola virus and protected 88% of the animals against severe hemorrhagic fever and death caused by Ebola virus. Two doses were highly immunogenic, and all of the animals survived challenge and were free of signs of disease and of detectable Ebola virus challenge virus. These data illustrate the feasibility of immunization via the respiratory tract against the hemorrhagic fever caused by Ebola virus. To our knowledge, this is the first study in which topical immunization through respiratory tract achieved prevention of a viral hemorrhagic fever infection in a primate model.

scholarly journals Induction of Immune Responses in Mice and Monkeys to Ebola Virus after Immunization with Liposome-Encapsulated Irradiated Ebola Virus: Protection in Mice Requires CD4+ T Cells

2002 ◽  
Vol 76 (18) ◽  
pp. 9176-9185 ◽  
Author(s):  
Mangala Rao ◽  
Mike Bray ◽  
Carl R. Alving ◽  
Peter Jahrling ◽  
Gary R. Matyas
Keyword(s):  
T Lymphocytes ◽  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Ebola Virus ◽  
Protective Efficacy ◽  
Hemorrhagic Fever ◽  
Surface Glycoprotein ◽  
Antibody Treatment ◽  
Amino Terminal ◽  
Monoclonal Antibody Treatment

ABSTRACT Ebola Zaire virus (EBO-Z) causes severe hemorrhagic fever in humans, with a high mortality rate. It is thought that a vaccine against EBO-Z may have to induce both humoral and cell-mediated immune responses to successfully confer protection. Because it is known that liposome-encapsulated antigens induce both antibody and cellular responses, we evaluated the protective efficacy of liposome-encapsulated irradiated EBO-Z [L(EV)], which contains all of the native EBO-Z proteins. In a series of experiments, mice immunized intravenously with L(EV) were completely protected (94/94 mice) against illness and death when they were challenged with a uniformly lethal mouse-adapted variant of EBO-Z. In contrast, only 55% of mice immunized intravenously with nonencapsulated irradiated virus (EV) survived challenge, and all became ill. Treatment with anti-CD4 antibodies before or during immunization with L(EV) eliminated protection, while treatment with anti-CD8 antibodies had no effect, thus indicating a requirement for CD4+ T lymphocytes for successful immunization. On the other hand, treatment with either anti-CD4 or anti-CD8 antibodies after immunization did not abolish the protection. After immunization with L(EV), antigen-specific gamma interferon (IFNγ)-secreting CD4+ T lymphocytes were induced as analyzed by enzyme-linked immunospot assay. Anti-CD4 monoclonal antibody treatment abolished IFNγ production (80 to 90% inhibition compared to that for untreated mice). Mice immunized with L(EV), but not EV, developed cytotoxic T lymphocytes specific to two peptides (amino acids [aa] 161 to 169 and aa 231 to 239) present in the amino-terminal end of the EBO-Z surface glycoprotein. Because of the highly successful results in the mouse model, L(EV) was also tested in three cynomolgus monkeys. Although immunization of the monkeys with L(EV)-induced virus-neutralizing antibodies against EBO-Z caused a slight delay in the onset of illness, it did not prevent death.

Viral hemorrhagic fever – a vascular disease?

2003 ◽  
Vol 89 (06) ◽  
pp. 967-972 ◽  
Author(s):  
Heinz Feldmann ◽  
Hans Schnittler
Keyword(s):  
Ebola Virus ◽  
Vascular System ◽  
Current Knowledge ◽  
Hemorrhagic Fever ◽  
Host Cells ◽  
Fluid Distribution ◽  
Target Cells ◽  
Viral Hemorrhagic Fever ◽  
Virus Infections ◽  
Cytokines And Chemokines

SummaryThe syndrome of “viral hemorrhagic fever” in man caused by certain viruses, such as Ebola, Lassa, Dengue, and Crimean-Congo hemorrhagic fever viruses, is often associated with a shock syndrome of undetermined pathogenesis. However, the vascular system, particularly the vascular endothelium, seems to be directly and indirectly targeted by all these viruses. Here we briefly summarize the current knowledge on Marburg and Ebola virus infections, the prototype viral hemorrhagic fever agents, and formulate a working hypothesis for the pathogenesis of viral hemorrhagic fever. Infections with filoviruses show lethality up to 89% and in severe cases lead to a shock syndrome associated with hypotension, coagulation disorders and an imbalance of fluid distribution between the intravascular and extravascular tissue space. The primary target cells for filovi-ruses are mononuclear phagocytotic cells which are activated upon infection and release certain cytokines and chemokines. These mediators indirectly target the endothelium and are thought to play a key role in the pathogenesis of filoviral hemorrhagic fever. In addition, direct infection and subsequent destruction of endothelial cells might contribute to the pathogenesis. Filoviruses, particularly Ebola virus, encode nonstructural glycoproteins which are released from infected host cells. Their function as potential determinants in pathogenicity remains to be investigated.

scholarly journals Macaque Monoclonal Antibodies Targeting Novel Conserved Epitopes within Filovirus Glycoprotein

2015 ◽  
Vol 90 (1) ◽  
pp. 279-291 ◽  
Author(s):  
Zhen-Yong Keck ◽  
Sven G. Enterlein ◽  
Katie A. Howell ◽  
Hong Vu ◽  
Sergey Shulenin ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Nonhuman Primates ◽  
Ebola Virus ◽  
Virus Disease ◽  
Protective Efficacy ◽  
Hemorrhagic Fever ◽  
Marburg Virus ◽  
Human Pathogens ◽  
Content Type ◽  
The Core

ABSTRACTFiloviruses cause highly lethal viral hemorrhagic fever in humans and nonhuman primates. Current immunotherapeutic options for filoviruses are mostly specific to Ebola virus (EBOV), although other members ofFiloviridaesuch as Sudan virus (SUDV), Bundibugyo virus (BDBV), and Marburg virus (MARV) have also caused sizeable human outbreaks. Here we report a set of pan-ebolavirus and pan-filovirus monoclonal antibodies (MAbs) derived from cynomolgus macaques immunized repeatedly with a mixture of engineered glycoproteins (GPs) and virus-like particles (VLPs) for three different filovirus species. The antibodies recognize novel neutralizing and nonneutralizing epitopes on the filovirus glycoprotein, including conserved conformational epitopes within the core regions of the GP1 subunit and a novel linear epitope within the glycan cap. We further report the first filovirus antibody binding to a highly conserved epitope within the fusion loop of ebolavirus and marburgvirus species. One of the antibodies binding to the core GP1 region of all ebolavirus species and with lower affinity to MARV GP cross neutralized both SUDV and EBOV, the most divergent ebolavirus species. In a mouse model of EBOV infection, this antibody provided 100% protection when administered in two doses and partial, but significant, protection when given once at the peak of viremia 3 days postinfection. Furthermore, we describe novel cocktails of antibodies with enhanced protective efficacy compared to individual MAbs. In summary, the present work describes multiple novel, cross-reactive filovirus epitopes and innovative combination concepts that challenge the current therapeutic models.IMPORTANCEFiloviruses are among the most deadly human pathogens. The 2014-2015 outbreak of Ebola virus disease (EVD) led to more than 27,000 cases and 11,000 fatalities. While there are five species ofEbolavirusand several strains of marburgvirus, the current immunotherapeutics primarily target Ebola virus. Since the nature of future outbreaks cannot be predicted, there is an urgent need for therapeutics with broad protective efficacy against multiple filoviruses. Here we describe a set of monoclonal antibodies cross-reactive with multiple filovirus species. These antibodies target novel conserved epitopes within the envelope glycoprotein and exhibit protective efficacy in mice. We further present novel concepts for combination of cross-reactive antibodies against multiple epitopes that show enhanced efficacy compared to monotherapy and provide complete protection in mice. These findings set the stage for further evaluation of these antibodies in nonhuman primates and development of effective pan-filovirus immunotherapeutics for use in future outbreaks.

scholarly journals Aerosolized Cidofovir Is Retained in the Respiratory Tract and Protects Mice against Intranasal Cowpox Virus Challenge

2003 ◽  
Vol 47 (9) ◽  
pp. 2933-2937 ◽  
Author(s):  
Chad J. Roy ◽  
Robert Baker ◽  
Kenneth Washburn ◽  
Mike Bray
Keyword(s):  
Respiratory Tract ◽  
Time Course ◽  
Low Dose ◽  
Tissue Concentration ◽  
Protective Efficacy ◽  
Antiviral Drug ◽  
Cowpox Virus ◽  
Virus Challenge ◽  
Prolonged Retention ◽  
Long Acting

ABSTRACT We employed a murine model to test the concept of using an aerosolized, long-acting antiviral drug to protect humans against smallpox. We previously showed that a low dose of aerosolized cidofovir (HPMPC [Vistide]) was highly protective against subsequent aerosolized cowpox virus challenge and was more effective than a much larger dose of drug given by injection, suggesting that aerosolized cidofovir is retained in the lung. Because the nephrotoxicity of cidofovir is a major concern in therapy, delivering the drug directly to the respiratory tract might be an effective prophylactic strategy that maximizes the tissue concentration at the site of initial viral replication, while minimizing its accumulation in the kidneys. In the present study, we found that treating mice with aerosolized 14C-labeled cidofovir (14C-cidofovir) resulted in the prolonged retention of radiolabeled drug in the lungs at levels greatly exceeding those in the kidneys. In contrast, subcutaneous injection produced much higher concentrations of 14C-cidofovir in the kidneys than in the lungs over the 96-h time course of the study. As further evidence of the protective efficacy of aerosolized cidofovir, we found that aerosol treatment before or after infection was highly protective in mice challenged intranasally with cowpox virus. All or nearly all mice that were treated once by aerosol, from 2 days before to 2 days after challenge, survived intranasal infection, whereas all placebo-treated animals died.

scholarly journals Passive Transfer of Antibodies Protects Immunocompetent and Immunodeficient Mice against Lethal Ebola Virus Infection without Complete Inhibition of Viral Replication

2001 ◽  
Vol 75 (10) ◽  
pp. 4649-4654 ◽  
Author(s):  
Manisha Gupta ◽  
Siddhartha Mahanty ◽  
Mike Bray ◽  
Rafi Ahmed ◽  
Pierre E. Rollin
Keyword(s):  
Virus Infection ◽  
Viral Replication ◽  
Ebola Virus ◽  
Protective Efficacy ◽  
Hemorrhagic Fever ◽  
Passive Transfer ◽  
Immune Serum ◽  
Immunodeficient Mice ◽  
Ebola Hemorrhagic Fever ◽  
Ebola Virus Infection

ABSTRACT Ebola hemorrhagic fever is a severe, usually fatal illness caused by Ebola virus, a member of the filovirus family. The use of nonhomologous immune serum in animal studies and blood from survivors in two anecdotal reports of Ebola hemorrhagic fever in humans has shown promise, but the efficacy of these treatments has not been demonstrated definitively. We have evaluated the protective efficacy of polyclonal immune serum in a mouse model of Ebola virus infection. Our results demonstrate that mice infected subcutaneously with live Ebola virus survive infection and generate high levels of anti-Ebola virus immunoglobulin G (IgG). Passive transfer of immune serum from these mice before challenge protected upto 100% of naive mice against lethal Ebola virus infection. Protection correlated with the level of anti-Ebola virus IgG titers, and passive treatment with high-titer antiserum was associated with a delay in the peak of viral replication. Transfer of immune serum to SCID mice resulted in 100% survival after lethal challenge with Ebola virus, indicating that antibodies alone can protect from lethal disease. Thus antibodies suppress or delay viral growth, provide protection against lethal Ebola virus infection, and may not require participation of other immune components for protection.

scholarly journals Human antibody cocktail deploys multiple functions to confer pan-ebolavirus protection

2018 ◽  
Author(s):  
Anna Z. Wec ◽  
Zachary A. Bornholdt ◽  
Shihua He ◽  
Andrew S. Herbert ◽  
Eileen Goodwin ◽  
...  
Keyword(s):  
Ebola Virus ◽  
Virus Disease ◽  
Protective Efficacy ◽  
Affinity Maturation ◽  
Surface Glycoprotein ◽  
Human Antibody ◽  
Human Mabs ◽  
Western Africa ◽  
Guinea Pig Model

During the unprecedented 2013–2016 Ebola virus disease (EVD) epidemic in Western Africa and in its aftermath, the passive administration of monoclonal antibodies (mAbs) emerged as a promising treatment approach1–7. However, all antibody-based therapeutics currently in advanced development are specific for a single member of the Ebolavirus genus, Ebola virus (EBOV), and ineffective against divergent outbreak-causing ebolaviruses, including Bundibugyo virus (BDBV) and Sudan virus (SUDV)2,3,5,7. Here we advance MBP134, a cocktail of two broadly neutralizing human mAbs targeting the filovirus surface glycoprotein, GP, as a candidate pan-ebolavirus therapeutic. One component of this cocktail is a pan-ebolavirus neutralizing mAb, ADI-15878, isolated from a human EVD survivor8,9. The second, ADI-23774, was derived by affinity maturation of a human mAb8,9 via yeast display to enhance its potency against SUDV. MBP134 afforded exceptionally potent pan-ebolavirus neutralization in vitro and demonstrated greater protective efficacy than ADI-15878 alone in the guinea pig model of lethal EBOV challenge. A second-generation cocktail, MBP134AF, engineered to effectively harness natural killer (NK) cells afforded additional, unprecedented improvements in protective efficacy against EBOV and SUDV in guinea pigs relative to both its precursor and to any mAbs or mAb cocktails tested previously. MBP134AF is a best-in-class mAb cocktail suitable for evaluation as a pan-ebolavirus therapeutic in nonhuman primates.

scholarly journals IgY antibodies against Ebola virus possess post-exposure protection in a murine pseudovirus challenge model and excellent thermostability

2021 ◽  
Vol 15 (3) ◽  
pp. e0008403
Author(s):  
Yuan Zhang ◽  
Yanqiu Wei ◽  
Yunlong Li ◽  
Xuan Wang ◽  
Yang Liu ◽  
...  
Keyword(s):  
Thermal Stability ◽  
Ebola Virus ◽  
Protective Efficacy ◽  
High Titer ◽  
Lethal Dose ◽  
Hemorrhagic Fever ◽  
High Dose ◽  
Excellent Thermal Stability ◽  
Post Exposure

Ebola virus (EBOV) is one of the most virulent pathogens that causes hemorrhagic fever and displays high mortality rates and low prognosis rates in both humans and nonhuman primates. The post-exposure antibody therapies to prevent EBOV infection are considered effective as of yet. However, owing to the poor thermal stability of mammalian antibodies, their application in the tropics has remained limited. Therefore, a thermostable therapeutic antibody against EBOV was developed modelled on the poultry(chicken) immunoglobulin Y (IgY). The IgY antibodies retaining their neutralising activity at 25°C for one year, displayed excellent thermal stability, opposed to conventional polyclonal antibodies (pAbs) or monoclonal antibodies (mAbs). Laying hens were immunised with a variety of EBOV vaccine candidates and it was confirmed that VSVΔG/EBOVGP encoding the EBOV glycoprotein could induce high titer neutralising antibodies against EBOV. The therapeutic efficacy of immune IgY antibodies in vivo was evaluated in the newborn Balb/c mice who have been challenged with the VSVΔG/EBOVGP model. Mice that have been challenged with a lethal dose of the pseudovirus were treated 2 or 24 h post-infection with different doses of anti-EBOV IgY. The group receiving a high dose of 106 NAU/kg (neutralising antibody units/kilogram) showed complete protection with no symptoms of a disease, while the low-dose group was only partially protected. Conversely, all mice receiving naive IgY died within 10 days. In conclusion, the anti-EBOV IgY exhibits excellent thermostability and protective efficacy. Anti-EBOV IgY shows a lot of promise in entering the realm of efficient Ebola virus treatment regimens.

scholarly journals A Live Attenuated Severe Acute Respiratory Syndrome Coronavirus Is Immunogenic and Efficacious in Golden Syrian Hamsters

2008 ◽  
Vol 82 (15) ◽  
pp. 7721-7724 ◽  
Author(s):  
Elaine W. Lamirande ◽  
Marta L. DeDiego ◽  
Anjeanette Roberts ◽  
Jadon P. Jackson ◽  
Enrique Alvarez ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Respiratory Tract ◽  
Protective Efficacy ◽  
Neutralizing Antibody ◽  
High Serum ◽  
Wild Type Virus ◽  
Live Attenuated Vaccine ◽  
Virus Challenge ◽  
Antibody Titers ◽  
Efficacious Vaccine

ABSTRACT The immunogenicity and protective efficacy of a live attenuated vaccine consisting of a recombinant severe acute respiratory syndrome (SARS) coronavirus lacking the E gene (rSARS-CoV-ΔE) were studied using hamsters. Hamsters immunized with rSARS-CoV-ΔE developed high serum-neutralizing antibody titers and were protected from replication of homologous (SARS-CoV Urbani) and heterologous (GD03) SARS-CoV in the upper and lower respiratory tract. rSARS-CoV-ΔE-immunized hamsters remained active following wild-type virus challenge, while mock-immunized hamsters displayed decreased activity. Despite being attenuated in replication in the respiratory tract, rSARS-CoV-ΔE is an immunogenic and efficacious vaccine in hamsters.

scholarly journals Protective Efficacy of Neutralizing Monoclonal Antibodies in a Nonhuman Primate Model of Ebola Hemorrhagic Fever

PLoS ONE ◽  
2012 ◽  
Vol 7 (4) ◽  
pp. e36192 ◽  
Author(s):  
Andrea Marzi ◽  
Reiko Yoshida ◽  
Hiroko Miyamoto ◽  
Mari Ishijima ◽  
Yasuhiko Suzuki ◽  
...  
Keyword(s):  
Monoclonal Antibodies ◽  
Nonhuman Primate ◽  
Protective Efficacy ◽  
Hemorrhagic Fever ◽  
Nonhuman Primate Model ◽  
Primate Model ◽  
Ebola Hemorrhagic Fever

scholarly journals A Single Intranasal Inoculation with a Paramyxovirus-Vectored Vaccine Protects Guinea Pigs against a Lethal-Dose Ebola Virus Challenge

2006 ◽  
Vol 80 (5) ◽  
pp. 2267-2279 ◽  
Author(s):  
Alexander Bukreyev ◽  
Lijuan Yang ◽  
Sherif R. Zaki ◽  
Wun-Ju Shieh ◽  
Pierre E. Rollin ◽  
...  
Keyword(s):  
Guinea Pigs ◽  
Ebola Virus ◽  
Lethal Dose ◽  
Vaccine Dose ◽  
Humoral Response ◽  
Hemorrhagic Fever ◽  
Vero Cells ◽  
Intranasal Inoculation ◽  
Virus Challenge ◽  
Vectored Vaccine

ABSTRACT To determine whether intranasal inoculation with a paramyxovirus-vectored vaccine can induce protective immunity against Ebola virus (EV), recombinant human parainfluenza virus type 3 (HPIV3) was modified to express either the EV structural glycoprotein (GP) by itself (HPIV3/EboGP) or together with the EV nucleoprotein (NP) (HPIV3/EboGP-NP). Expression of EV GP by these recombinant viruses resulted in its efficient incorporation into virus particles and increased cytopathic effect in Vero cells. HPIV3/EboGP was 100-fold more efficiently neutralized by antibodies to EV than by antibodies to HPIV3. Guinea pigs infected with a single intranasal inoculation of 105.3 PFU of HPIV3/EboGP or HPIV3/EboGP-NP showed no apparent signs of disease yet developed a strong humoral response specific to the EV proteins. When these animals were challenged with an intraperitoneal injection of 103 PFU of EV, there were no outward signs of disease, no viremia or detectable EV antigen in the blood, and no evidence of infection in the spleen, liver, and lungs. In contrast, all of the control animals died or developed severe EV disease following challenge. The highly effective immunity achieved with a single vaccine dose suggests that intranasal immunization with live vectored vaccines based on recombinant respiratory viruses may be an advantageous approach to inducing protective responses against severe systemic infections, such as those caused by hemorrhagic fever agents.

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