scholarly journals Immunogenicity of an E1-deleted recombinant human adenovirus against rabies by different routes of administration

2001 ◽  
Vol 82 (9) ◽  
pp. 2191-2197 ◽  
Author(s):  
Ad Vos ◽  
Andreas Neubert ◽  
Elke Pommerening ◽  
Thomas Müller ◽  
Leopold Döhner ◽  
...  
Keyword(s):  
Immune Response ◽  
Oral Administration ◽  
Neutralizing Antibodies ◽  
Direct Injection ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Vaccine Virus ◽  
Strong Immune Response ◽  
Routes Of Administration ◽  
Immunogenic Properties

The immunogenic properties of an E1-deleted, human adenovirus type 5 (Ad5) vaccine virus with activity against rabies were examined in mice, foxes and dogs using different routes of administration. NMRI mice received 105·8, 105·3, 104·3, 103·3 and 102·3 TCID50 by peroral or intramuscular (i.m.) administration. Furthermore, six mice received 105·8 TCID50 intracerebrally (i.c.). The construct elicited marked seroconversion in mice after oral administration. Immunoreactivity in mice was even more pronounced i.m. and i.c. After direct oral administration (108·0 TCID50) in foxes, six of eight animals developed rabies virus-neutralizing antibodies (VNA). All foxes immunized by direct injection (107·7 TCID50) in the membrane of the jejunum were shown to seroconvert. Pre-existing immunity against canine adenovirus did not hinder the development of rabies VNA after oral application of the construct (108·0 TCID50). Fox cubs (24–29 days old) born from rabies-immune vixens were shown to develop very high levels of rabies VNA after i.m. administration (108·0 TCID50), indicating that the immunogenicity of the construct could surpass maternally transferred immunity. In dogs, the construct (108·0 TCID50) induced a very strong immune response after i.m. administration. However, no immune response was detectable in dogs after direct oral administration (108·3 TCID50) or after endoscopic deposition in the smaller intestine (108·0 TCID50). Hence, it must be concluded that the construct is not suitable for oral vaccination of dogs against rabies.

scholarly journals Structure-Based Modeling of Complement C4 Mediated Neutralization of Adenovirus

Viruses ◽  
2021 ◽  
Vol 13 (1) ◽  
pp. 111
Author(s):  
Corey C. Emerson ◽  
Phoebe L. Stewart
Keyword(s):  
Neutralizing Antibodies ◽  
Covalent Binding ◽  
Neutralizing Antibody ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Viral Escape ◽  
Structural Basis ◽  
Penton Base ◽  
Strong Immune Response ◽  
Complement Components

Adenovirus (AdV) infection elicits a strong immune response with the production of neutralizing antibodies and opsonization by complement and coagulation factors. One anti-hexon neutralizing antibody, called 9C12, is known to activate the complement cascade, resulting in the deposition of complement component C4b on the capsid, and the neutralization of the virus. The mechanism of AdV neutralization by C4b is independent of downstream complement proteins and involves the blockage of the release of protein VI, which is required for viral escape from the endosome. To investigate the structural basis underlying how C4b blocks the uncoating of AdV, we built a model for the complex of human adenovirus type-5 (HAdV5) with 9C12, together with complement components C1 and C4b. This model positions C4b near the Arg-Gly-Asp (RGD) loops of the penton base. There are multiple amino acids in the RGD loop that might serve as covalent binding sites for the reactive thioester of C4b. Molecular dynamics simulations with a multimeric penton base and C4b indicated that stabilizing interactions may form between C4b and multiple RGD loops. We propose that C4b deposition on one RGD loop leads to the entanglement of C4b with additional RGD loops on the same penton base multimer and that this entanglement blocks AdV uncoating.

scholarly journals Seroprevalence of neutralizing antibodies against human adenovirus type 55 in the South Korean military, 2018-2019

PLoS ONE ◽  
2020 ◽  
Vol 15 (7) ◽  
pp. e0236040
Author(s):  
So Yun Park ◽  
Jae-Hoon Ko ◽  
Sezim Monoldorova ◽  
Jonguk Jeong ◽  
Bo-Young Jeon ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
The South ◽  
South Korean

scholarly journals Recombinant Antigens Based on Non-Glycosylated Regions from RBD SARS-CoV-2 as Potential Vaccine Candidates against COVID-19

Vaccines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 928
Author(s):  
Leandro Núñez-Muñoz ◽  
Gabriel Marcelino-Pérez ◽  
Berenice Calderón-Pérez ◽  
Miriam Pérez-Saldívar ◽  
Karla Acosta-Virgen ◽  
...  
Keyword(s):  
Immune Response ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Polyclonal Antibodies ◽  
Igg Antibodies ◽  
Mice Model ◽  
Strong Immune Response ◽  
Recombinant Antigens ◽  
Glycosylation Sites ◽  
Potential Vaccine

The Receptor-Binding Domain (RBD) of the Spike (S) protein from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) has glycosylation sites which can limit the production of reliable antigens expressed in prokaryotic platforms, due to glycan-mediated evasion of the host immune response. However, protein regions without glycosylated residues capable of inducing neutralizing antibodies could be useful for antigen production in systems that do not carry the glycosylation machinery. To test this hypothesis, the potential antigens NG06 and NG19, located within the non-glycosylated S-RBD region, were selected and expressed in Escherichia coli, purified by FPLC and employed to determine their immunogenic potential through detection of antibodies in serum from immunized rabbits, mice, and COVID-19 patients. IgG antibodies from sera of COVID-19-recovered patients detected the recombinant antigens NG06 and NG19 (A450 nm = 0.80 ± 0.33; 1.13 ± 0.33; and 0.11 ± 0.08 for and negatives controls, respectively). Also, the purified antigens were able to raise polyclonal antibodies in animal models evoking a strong immune response with neutralizing activity in mice model. This research highlights the usefulness of antigens based on the non-N-glycosylated region of RBD from SARS-CoV-2 for candidate vaccine development.

scholarly journals Development and Assessment of Human Adenovirus Type 11 as a Gene Transfer Vector

2005 ◽  
Vol 79 (8) ◽  
pp. 5090-5104 ◽  
Author(s):  
Daniel Stone ◽  
Shaoheng Ni ◽  
Zong-Yi Li ◽  
Anuj Gaggar ◽  
Nelson DiPaolo ◽  
...  
Keyword(s):  
Gene Transfer ◽  
Neutralizing Antibodies ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Cell Types ◽  
Widespread Application ◽  
Human Cd34 ◽  
Immature Dendritic Cells

ABSTRACT Adenovirus vectors based on human serotype 5 (Ad5) have successfully been used as gene transfer vectors in many gene therapy-based approaches to treat disease. Despite their widespread application, many potential therapeutic applications are limited by the widespread prevalence of vector-neutralizing antibodies within the human population and the inability of Ad5-based vectors to transduce important therapeutic target cell types. In an attempt to circumvent these problems, we have developed Ad vectors based on human Ad serotype 11 (Ad11), since the prevalence of neutralizing antibodies to Ad11 in humans is low. E1-deleted Ad11 vector genomes were generated by homologous recombination in 293 cells expressing the Ad11-E1B55K protein or by recombination in Escherichia coli. E1-deleted Ad11 genomes did not display transforming activity in rodent cells. Transduction of primary human CD34+ hematopoietic progenitor cells and immature dendritic cells was more efficient with Ad11 vectors than with Ad5 vectors. Thirty minutes after intravenous injection into mice that express one of the Ad11 receptors (CD46), we found, in a pattern and at a level comparable to what is found in humans, Ad11 vector genomes in all analyzed organs, with the highest amounts in liver, lung, kidney, and spleen. Neither Ad11 genomes nor Ad11 vector-mediated transgene expression were, however, detected at 72 h postinfusion. A large number of Ad11 particles were also found to be associated with circulating blood cells. We also discovered differences in in vitro transduction efficiencies and in vivo biodistributions between Ad11 vectors and chimeric Ad5 vectors possessing Ad11 fibers, indicating that Ad11 capsid proteins other than fibers influence viral infectivity and tropism. Overall, our study provides a basis for the application of Ad11 vectors for in vitro and in vivo gene transfer and for gaining an understanding of the factors that determine Ad tropism.

scholarly journals Replication-Defective Vector Based on a Chimpanzee Adenovirus

2001 ◽  
Vol 75 (23) ◽  
pp. 11603-11613 ◽  
Author(s):  
Steven F. Farina ◽  
Guang-ping Gao ◽  
Z. Q. Xiang ◽  
John J. Rux ◽  
Roger M. Burnett ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Open Reading Frames ◽  
Hypervariable Regions ◽  
293 Cells ◽  
Coxsackievirus And Adenovirus Receptor ◽  
Cross Neutralization ◽  
Adenovirus Receptor ◽  
Adenovirus Type 5

ABSTRACT An adenovirus previously isolated from a mesenteric lymph node from a chimpanzee was fully sequenced and found to be similar in overall structure to human adenoviruses. The genome of this virus, called C68, is 36,521 bp in length and is most similar to subgroup E of human adenovirus, with 90% identity in most adenovirus type 4 open reading frames that have been sequenced. Substantial differences in the hexon hypervariable regions were noted between C68 and other known adenoviruses, including adenovirus type 4. Neutralizing antibodies to C68 were highly prevalent in sera from a population of chimpanzees, while sera from humans and rhesus monkeys failed to neutralize C68. Furthermore, infection with C68 was not neutralized from sera of mice immunized with human adenovirus serotypes 2, 4, 5, 7, and 12. A replication-defective version of C68 was created by replacing the E1a and E1b genes with a minigene cassette; this vector was efficiently transcomplemented by the E1 region of human adenovirus type 5. C68 vector transduced a number of human and murine cell lines. This nonhuman adenoviral vector is sufficiently similar to human serotypes to allow growth in 293 cells and transduction of cells expressing the coxsackievirus and adenovirus receptor. As it is dissimilar in regions such as the hexon hypervariable domains, C68 vector avoids significant cross-neutralization by sera directed against human serotypes.

scholarly journals Identification of a Critical and Conformational Neutralizing Epitope in Human Adenovirus Type 4 Hexon

2017 ◽  
Vol 92 (2) ◽  
Author(s):  
Xingui Tian ◽  
Hongling Qiu ◽  
Zhichao Zhou ◽  
Shouli Wang ◽  
Ye Fan ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Subunit Vaccine ◽  
Hypervariable Region ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Conformational Epitope ◽  
Therapeutic Treatment ◽  
Neutralizing Epitope ◽  
Small Surface ◽  
A Subunit

ABSTRACTHuman adenovirus type 4 (HAdV-4) is an epidemic virus that contributes to serious acute respiratory disease (ARD) in both pediatric and adult patients. However, no licensed drug or vaccine is currently available to the civilian population. The identification of neutralizing epitopes of HAdV-4 should allow the development of a novel antiviral vaccine and a novel gene transfer vector, and an effective neutralizing monoclonal antibody (MAb) will be useful in developing appropriate antiviral drugs. In this study, we report that MAb MN4b shows strong neutralizing activity against HAdV-4. MN4b recognizes a conformational epitope (418AGSEK422) within hypervariable region 7 (HVR7). Mutations within this site permitted HAdV-4 mutants to escape neutralization by MN4b and to resist neutralization by animal and human anti-HAdV-4 sera. A recombinant virus, rAd3-A4R7-1, containing the identified neutralizing epitope in the HVR7 region of HAdV-3 hexon, successfully induced antiserum that inhibited HAdV-4 infection. These results indicate that a small surface loop of HAdV-4 hexon is a critical neutralization epitope for this virus. The generation of MN4b and the identification of this neutralizing epitope may be useful in developing therapeutic treatment, a subunit vaccine, and a novel vector that can escape preexisting neutralization for HAdV-4.IMPORTANCENeutralizing antibodies are considered good tools for the prevention of human adenovirus type 4 (HAdV-4) infections. The identification of the epitopes recognized by such neutralizing antibodies is important for the generation of recombinant antiviral vaccines. However, until now, no neutralizing epitope has been reported for HAdV-4. Here, we developed a serotype-specific neutralizing MAb directed against HAdV-4, MN4b. We provide evidence that MN4b recognizes a conformational epitope within HVR7 of HAdV-4 hexon. Antisera generated to this conformational epitope displayed on HAdV-3 hexon inhibited infection of AD293 cells by HAdV-4. Our findings are very important for the development of therapeutic treatment, a subunit vaccine, and a novel vector for HAdV-4.

scholarly journals Review on Adeno Virus; As a Vaccine Vehicle

2017 ◽  
Vol 2 (3) ◽  
pp. 1-12
Author(s):  
Tadesse B
Keyword(s):  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Human Adenovirus ◽  
Antigen Expression ◽  
Adenovirus Type ◽  
Adenoviral Vectors ◽  
Vaccine Antigen ◽  
Mammalian Host ◽  
Antigen Delivery ◽  
Vaccine Vectors

Adenoviruses have moved to the forefront of vaccinology and are showing substantial prom ise as vehicles for antigen delivery for a number of vaccines currently being developed. Most studies to date have focused on human serotype adenoviruses, particularly human adenovirus type 5. Human serotype adenovirus vaccine vectors are particularly usef ul for development of veterinary vaccines as neutralizing antibodies to the vector will not usually be present in the vaccinates. Most vectors currently used as vaccine carriers are deleted in E1 gene. The original E1 deleted adenoviral vectors were constr ucted by homologous recombination. Replication incompetent vectors contain an antigen expression cassette substituted for the deleted E1A – E1B region. These replication incompitant adenoviruses can not replicate because of the deletion of the essential vir al E1 gene region containing two genes. Replication competent adenoviral vectors encode all of the remaining adenoviral antigens in addition to the transgene product, i.e., the vaccine antigen. The potential for adenoviruses to elicit powerful B cell and T cell responses in the mammalian host are the main reason for the use of these vectors in vaccine development. For effective veterinary use, extensive research on adenoviral vaccine vectors should be undertaken.

scholarly journals Nonclinical Safety and Immunogenicity of an rVSV-ΔG-SARS-CoV-2-S vaccine in mice, hamsters, rabbits and pigs

2021 ◽  
Author(s):  
Noa Madar-Balakirski ◽  
Amir Rosner ◽  
Sharon Melamed ◽  
Boaz Politi ◽  
Michal Steiner ◽  
...  
Keyword(s):  
Immune Response ◽  
Neutralizing Antibodies ◽  
Safety Concern ◽  
Regional Lymph Node ◽  
Clinical Stage ◽  
Clinical Signs ◽  
Vaccine Virus ◽  
Serum Samples ◽  
Vaccination Site ◽  
Viral Shedding

rVSV-ΔG-SARS-CoV-2-S is a clinical stage (Phase 2) replication competent recombinant vaccine against SARS-CoV-2. Nonclinical safety, immunogenicity and efficacy studies were conducted in 4 animal species, using multiple dose levels (up to 10e8 PFU/animal) and various dosing regimens. There were no treatment related mortalities in any study, or any noticeable clinical signs. Compared to unvaccinated controls, hematology and biochemistry parameters were unremarkable and no adverse histopathological findings gave cause for safety concern in any of the studies. There was no viral shedding in urine, nor viral RNA detected in whole blood or serum samples 7 days post vaccination. The rVSV-ΔG-SARS-CoV-2-S vaccine immune response gave rise to neutralizing antibodies, cellular immune response, and increased lymphocytic cellularity in the spleen germinal centers and regional lymph node. No evidence for neurovirulence was found in C57BL/6 immune competent mice or in highly sensitive IFNAR KO mice. Vaccine virus replication and distribution in K18 hACE2 transgenic mice showed a gradual clearance from the vaccination site with no vaccine virus recovered from the lungs. The rVSV-ΔG-SARS-CoV-2-S vaccine was well tolerated locally and systemically and elicited an effective immunogenic response up to the highest dose tested, supporting further clinical development.

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