scholarly journals Single-dose intranasal administration of AdCOVID elicits systemic and mucosal immunity against SARS-CoV-2 in mice

2020 ◽  
Author(s):  
Rodney G King ◽  
Aaron Silva-Sanchez ◽  
Jessica N. Peel ◽  
Davide Botta ◽  
Selene Meza-Perez ◽  
...  
Keyword(s):  
Mucosal Immunity ◽  
Neutralizing Antibodies ◽  
Vaccine Development ◽  
Adenovirus Type ◽  
First Line ◽  
Viral Spread ◽  
Cytokine Expression Profile ◽  
Preventive Vaccination ◽  
Vectored Vaccine ◽  
Adenovirus Type 5

AbstractThe coronavirus disease 2019 (COVID-19) pandemic has highlighted the urgent need for effective preventive vaccination to reduce burden and spread of severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) in humans. Intranasal vaccination is an attractive strategy to prevent COVID-19 as the nasal mucosa represents the first-line barrier to SARS-CoV-2 entry before viral spread to the lung. Although SARS-CoV-2 vaccine development is rapidly progressing, the current intramuscular vaccines are designed to elicit systemic immunity without conferring mucosal immunity. Here, we show that AdCOVID, an intranasal adenovirus type 5 (Ad5)-vectored vaccine encoding the receptor binding domain (RBD) of the SARS-CoV-2 spike protein, elicits a strong and focused immune response against RBD through the induction of mucosal IgA, serum neutralizing antibodies and CD4+ and CD8+ T cells with a Th1-like cytokine expression profile. Therefore, AdCOVID, which promotes concomitant systemic and local mucosal immunity, represents a promising COVID-19 vaccine candidate.

scholarly journals Single-Dose Intranasal Administration of AdCOVID Elicits Systemic and Mucosal Immunity against SARS-CoV-2 and Fully Protects Mice from Lethal Challenge

Vaccines ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 881
Author(s):  
R. Glenn King ◽  
Aaron Silva-Sanchez ◽  
Jessica N. Peel ◽  
Davide Botta ◽  
Alexandria M. Dickson ◽  
...  
Keyword(s):  
Mucosal Immunity ◽  
Neutralizing Antibodies ◽  
Adenovirus Type ◽  
Lethal Challenge ◽  
Cytokine Expression Profile ◽  
Prophylactic Vaccination ◽  
Vectored Vaccine ◽  
High Level ◽  
Adenovirus Type 5 ◽  
Intranasal Dose

The coronavirus disease 2019 (COVID-19) pandemic has highlighted the urgent need for effective prophylactic vaccination to prevent the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Intranasal vaccination is an attractive strategy to prevent COVID-19 as the nasal mucosa represents the first-line barrier to SARS-CoV-2 entry. The current intramuscular vaccines elicit systemic immunity but not necessarily high-level mucosal immunity. Here, we tested a single intranasal dose of our candidate adenovirus type 5-vectored vaccine encoding the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein (AdCOVID) in inbred, outbred, and transgenic mice. A single intranasal vaccination with AdCOVID elicited a strong and focused immune response against RBD through the induction of mucosal IgA in the respiratory tract, serum neutralizing antibodies, and CD4+ and CD8+ T cells with a Th1-like cytokine expression profile. A single AdCOVID dose resulted in immunity that was sustained for over six months. Moreover, a single intranasal dose completely protected K18-hACE2 mice from lethal SARS-CoV-2 challenge, preventing weight loss and mortality. These data show that AdCOVID promotes concomitant systemic and mucosal immunity and represents a promising vaccine candidate.

scholarly journals Hexon Hypervariable Region-Modified Adenovirus Type 5 (Ad5) Vectors Display Reduced Hepatotoxicity but Induce T Lymphocyte Phenotypes Similar to Ad5 Vectors

2014 ◽  
Vol 21 (8) ◽  
pp. 1137-1144 ◽  
Author(s):  
Jeffrey E. Teigler ◽  
Pablo Penaloza-MacMaster ◽  
Rebecca Obeng ◽  
Nicholas M. Provine ◽  
Rafael A. Larocca ◽  
...  
Keyword(s):  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Hypervariable Region ◽  
Adenovirus Type ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Cytokines And Chemokines ◽  
Programmed Death 1 ◽  
Lymphocyte Phenotypes ◽  
Adenovirus Type 5

ABSTRACTHexon modification of adenovirus type 5 (Ad5) vectors with the hypervariable regions (HVRs) of Ad48 has been shown to allow Ad5HVR48 vectors to circumvent the majority of the preexisting Ad5-neutralizing antibodies. However, it remains unclear whether modifying hexon HVRs impacts innate or adaptive immune responses elicited by this vector. In this study, we investigated the influence of the HVR substitution of Ad5 on innate and adaptive immune responses following vaccination. Ad5HVR48 displayed an intermediate level of innate immune cytokines and chemokines relative to those of Ad5 and Ad48, consistent with its chimeric nature. Hepatotoxicity was observed after Ad5 immunization but not after Ad5HVR48 or Ad48 immunization. However, the CD8+T-cell responses elicited by Ad5HVR48 vectors displayed a partially exhausted phenotype, as evidenced by the sustained expression of programmed death 1 (PD-1), decreased effector-to-central memory conversion, and reduced memory recall responses, similar to those elicited by Ad5 vectors and in contrast to those induced by Ad48 vectors. Taken together, these results indicate that although Ad5HVR48 largely bypasses preexisting Ad5 neutralizing antibodies and shows reduced hepatotoxicity compared to that of Ad5, it induces adaptive immune phenotypes that are functionally exhausted similar to those elicited by Ad5.

scholarly journals Seroprevalence of Neutralizing Antibodies to Adenovirus Type 5 among Children in India: Implications for Recombinant Adenovirus-Based Vaccines

2007 ◽  
Vol 14 (8) ◽  
pp. 1053-1055 ◽  
Author(s):  
Mohan Babu Appaiahgari ◽  
Ravindra Mohan Pandey ◽  
Sudhanshu Vrati
Keyword(s):  
Neutralizing Antibodies ◽  
Recombinant Adenovirus ◽  
Adenovirus Type ◽  
Age Group ◽  
Specific Immunity ◽  
Age Dependent ◽  
Adenovirus Type 5 ◽  
Adenovirus 5

ABSTRACT We determined the levels of adenovirus 5 (Ad5) neutralizing antibodies in children in India less than 2 years of age. The results clearly show an age-dependent increase in Ad5-specific immunity, with 7- to 12-month-old children having the lowest levels of Ad5 immunity. This opens up the scope for the use of recombinant Ad5-based vaccines in this age group.

scholarly journals Genetic Identification of Adenovirus Type 5 Genes That Influence Viral Spread

2006 ◽  
Vol 80 (4) ◽  
pp. 2000-2012 ◽  
Author(s):  
T. Subramanian ◽  
S. Vijayalingam ◽  
G. Chinnadurai
Keyword(s):  
Dna Sequences ◽  
Control Cell ◽  
Cancer Cell Line ◽  
Adenovirus Type ◽  
Viral Proteins ◽  
Genetic Identification ◽  
Large Plaque ◽  
Viral Spread ◽  
Leader Protein ◽  
Adenovirus Type 5

ABSTRACT The mechanisms that control cell-to-cell spread of human adenoviruses (Ad) are not well understood. Two early viral proteins, E1B-19K and E3-ADP, appear to have opposing effects since viral mutants that are individually deficient in E1B-19K produce large plaques (G. Chinnadurai, Cell 33:759-766, 1983), while mutants deficient in E3-ADP produce small plaques (A. E. Tollefson et al., J. Virol. 70:2296-2306, 1996) on infected cell monolayers. We have used a genetic strategy to identify different viral genes that influence adenovirus type 5 (Ad5) spread in an epithelial cancer cell line. An Ad5 mutant (dl327; lacking most of the E3 region) with the restricted-spread (small-plaque) phenotype was randomly mutagenized with UV, and 27 large-plaque (lp) mutants were isolated. A combination of analyses of viral proteins and genomic DNA sequences have indicated that 23 mutants contained lesions in the E1B region affecting either 19K or both 19K and 55K proteins. Four other lp mutants contained lesions in early regions E1A and E4, in the early L1 region that codes for the i-leader protein, and in late regions that code for the viral structural proteins, penton base, and fiber. Our results suggest that the requirement of E3-ADP for Ad spread could be readily compensated for by abrogation of the functions of E1B-19K and provide genetic evidence that these two viral proteins influence viral spread in opposing manners. In addition to E1B and E3 proteins, other early and late proteins that regulate viral replication and infectivity also influence lateral viral spread. Our studies have identified novel mutations that could be exploited in designing efficient oncolytic Ad vectors.

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 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 Comparison of Two High-Throughput Assays for Quantification of Adenovirus Type 5 Neutralizing Antibodies in a Population of Donors in China

PLoS ONE ◽  
2012 ◽  
Vol 7 (5) ◽  
pp. e37532 ◽  
Author(s):  
Qiang Liu ◽  
Jianhui Nie ◽  
Weijin Huang ◽  
Shufang Meng ◽  
Baozhu Yuan ◽  
...  
Keyword(s):  
High Throughput ◽  
Neutralizing Antibodies ◽  
Adenovirus Type ◽  
Adenovirus Type 5

scholarly journals Differential Specificity and Immunogenicity of Adenovirus Type 5 Neutralizing Antibodies Elicited by Natural Infection or Immunization

2009 ◽  
Vol 84 (1) ◽  
pp. 630-638 ◽  
Author(s):  
Cheng Cheng ◽  
Jason G. D. Gall ◽  
Martha Nason ◽  
C. Richter King ◽  
Richard A. Koup ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Recombinant Adenovirus ◽  
Natural Infection ◽  
Vaccine Trial ◽  
Adenovirus Type ◽  
Aids Vaccine ◽  
Increased Risk ◽  
Adenovirus Type 5 ◽  
Induced Immunity ◽  
Hiv 1

ABSTRACT A recent clinical trial of a T-cell-based AIDS vaccine delivered with recombinant adenovirus type 5 (rAd5) vectors showed no efficacy in lowering viral load and was associated with increased risk of human immunodeficiency virus type 1 (HIV-1) infection. Preexisting immunity to Ad5 in humans could therefore affect both immunogenicity and vaccine efficacy. We hypothesized that vaccine-induced immunity is differentially affected, depending on whether subjects were exposed to Ad5 by natural infection or by vaccination. Serum samples from vaccine trial subjects receiving a DNA/rAd5 AIDS vaccine with or without prior immunity to Ad5 were examined for the specificity of their Ad5 neutralizing antibodies and their effect on HIV-1 immune responses. Here, we report that rAd5 neutralizing antibodies were directed to different components of the virion, depending on whether they were elicited by natural infection or vaccination in HIV vaccine trial subjects. Neutralizing antibodies elicited by natural infection were directed largely to the Ad5 fiber, while exposure to rAd5 through vaccination elicited antibodies primarily to capsid proteins other than fiber. Notably, preexisting immunity to Ad5 fiber from natural infection significantly reduced the CD4 and CD8 cell responses to HIV Gag after DNA/rAd5 vaccination. The specificity of Ad5 neutralizing antibodies therefore differs depending on the route of exposure, and natural Ad5 infection compromises Ad5 vaccine-induced immunity to weak immunogens, such as HIV-1 Gag. These results have implications for future AIDS vaccine trials and the design of next-generation gene-based vaccine vectors.

scholarly journals Adenovirus Type 6: Subtle Structural Distinctions from Adenovirus Type 5 Result in Essential Differences in Properties and Perspectives for Gene Therapy

Pharmaceutics ◽  
2021 ◽  
Vol 13 (10) ◽  
pp. 1641
Author(s):  
Margarita Romanenko ◽  
Ivan Osipov ◽  
Sergey V. Netesov ◽  
Julia Davydova
Keyword(s):  
Gene Therapy ◽  
Vaccine Development ◽  
Viral Vector ◽  
Human Adenovirus ◽  
Adenovirus Type ◽  
Structural Features ◽  
Blood Proteins ◽  
Multiple Cancer ◽  
Oncolytic Therapy ◽  
Adenovirus Type 5

Adenovirus vectors are the most frequently used agents for gene therapy, including oncolytic therapy and vaccine development. It’s hard to overestimate the value of adenoviruses during the COVID-19 pandemic as to date four out of four approved viral vector-based SARS-CoV-2 vaccines are developed on adenovirus platform. The vast majority of adenoviral vectors are based on the most studied human adenovirus type 5 (HAdV-C5), however, its immunogenicity often hampers the clinical translation of HAdV-C5 vectors. The search of less seroprevalent adenovirus types led to another species C adenovirus, Adenovirus type 6 (HAdV-C6). HAdV-C6 possesses high oncolytic efficacy against multiple cancer types and remarkable ability to induce the immune response towards carrying antigens. Being genetically very close to HAdV-C5, HAdV-C6 differs from HAdV-C5 in structure of the most abundant capsid protein, hexon. This leads to the ability of HAdV-C6 to evade the uptake by Kupffer cells as well as to distinct opsonization by immunoglobulins and other blood proteins, influencing the overall biodistribution of HAdV-C6 after systemic administration. This review describes the structural features of HAdV-C6, its interaction with liver cells and blood factors, summarizes the previous experiences using HAdV-C6, and provides the rationale behind the use of HAdV-C6 for vaccine and anticancer drugs developments.

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