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

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.

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

10.1101/2020.10.10.331348 ◽

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.

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

Clinical and Vaccine Immunology ◽

10.1128/cvi.00207-14 ◽

2014 ◽

Vol 21 (8) ◽

pp. 1137-1144 ◽

Cited By ~ 7

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.

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

Clinical and Vaccine Immunology ◽

10.1128/cvi.00173-07 ◽

2007 ◽

Vol 14 (8) ◽

pp. 1053-1055 ◽

Cited By ~ 27

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.

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Designed recombinant adenovirus type 5 vector induced envelope-specific CD8+cytotoxic T lymphocytes and cross-reactive neutralizing antibodies against human immunodeficiency virus type 1

The Journal of Gene Medicine ◽

10.1002/jgm.1277 ◽

2009 ◽

Vol 11 (2) ◽

pp. 139-149 ◽

Cited By ~ 8

Author(s):

Takehiro Ura ◽

Atsushi Yoshida ◽

Ke-Qin Xin ◽

Shinji Yoshizaki ◽

Sayaka Yashima ◽

...

Keyword(s):

Human Immunodeficiency Virus ◽

T Lymphocytes ◽

Cytotoxic T Lymphocytes ◽

Human Immunodeficiency Virus Type ◽

Neutralizing Antibodies ◽

Recombinant Adenovirus ◽

Adenovirus Type ◽

Immunodeficiency Virus ◽

Adenovirus Type 5

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Reducing the Native Tropism of Adenovirus Vectors Requires Removal of both CAR and Integrin Interactions

Journal of Virology ◽

10.1128/jvi.75.23.11284-11291.2001 ◽

2001 ◽

Vol 75 (23) ◽

pp. 11284-11291 ◽

Cited By ~ 161

Author(s):

David A. Einfeld ◽

Rosanna Schroeder ◽

Peter W. Roelvink ◽

Alena Lizonova ◽

C. Richter King ◽

...

Keyword(s):

Adenovirus Type ◽

Wild Type ◽

Base Modification ◽

Model Following ◽

Vector Distribution ◽

High Level ◽

Adenovirus Type 5

ABSTRACT The development of tissue-selective virus-based vectors requires a better understanding of the role of receptors in gene transfer in vivo, both to rid the vectors of their native tropism and to introduce new specificity. CAR and αv integrins have been identified as the primary cell surface components that interact with adenovirus type 5 (Ad5)-based vectors during in vitro transduction. We have constructed a set of four vectors, which individually retain the wild-type cell interactions, lack CAR binding, lack αv integrin binding, or lack both CAR and αv integrin binding. These vectors have been used to examine the roles of CAR and αv integrin in determining the tropism of Ad vectors in a mouse model following intrajugular or intramuscular injection. CAR was found to play a significant role in liver transduction. The absence of CAR binding alone, however, had little effect on the low level of expression from Ad in other tissues. Binding of αv integrins appeared to have more influence than did binding of CAR in promoting the expression in these tissues and was also found to be important in liver transduction by Ad vectors. An effect of the penton base modification was a reduction in the number of vector genomes that could be detected in several tissues. In the liver, where CAR binding is important, combining defects in CAR and αv integrin binding was essential to effectively reduce the high level of expression from Ad vectors. While there may be differences in Ad vector tropism among species, our results indicate that both CAR and αv integrins can impact vector distribution in vivo. Disruption of both CAR and αv integrin interactions may be critical for effectively reducing native tropism and enhancing the efficacy of specific targeting ligands in redirecting Ad vectors to target tissues.

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Replication-Defective Vector Based on a Chimpanzee Adenovirus

Journal of Virology ◽

10.1128/jvi.75.23.11603-11613.2001 ◽

2001 ◽

Vol 75 (23) ◽

pp. 11603-11613 ◽

Cited By ~ 189

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.

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A single intranasal dose of chimpanzee adenovirus-vectored vaccine protects against SARS-CoV-2 infection in rhesus macaques

10.1101/2021.01.26.428251 ◽

2021 ◽

Author(s):

Ahmed O. Hassan ◽

Friederike Feldmann ◽

Haiyan Zhao ◽

David T. Curiel ◽

Atsushi Okumura ◽

...

Keyword(s):

Respiratory Tract ◽

Neutralizing Antibodies ◽

Lower Respiratory Tract ◽

Protective Efficacy ◽

Rhesus Macaques ◽

Angiotensin Converting Enzyme 2 ◽

Cell Responses ◽

Vectored Vaccine ◽

Dose Vaccine ◽

Intranasal Dose

SUMMARYThe deployment of a vaccine that limits transmission and disease likely will be required to end the Coronavirus Disease 2019 (COVID-19) pandemic. We recently described the protective activity of an intranasally-administered chimpanzee adenovirus-vectored vaccine encoding a pre-fusion stabilized spike (S) protein (ChAd-SARS-CoV-2-S) in the upper and lower respiratory tract of mice expressing the human angiotensin-converting enzyme 2 (ACE2) receptor. Here, we show the immunogenicity and protective efficacy of this vaccine in non-human primates. Rhesus macaques were immunized with ChAd-Control or ChAd-SARS-CoV-2-S and challenged one month later by combined intranasal and intrabronchial routes with SARS-CoV-2. A single intranasal dose of ChAd-SARS-CoV-2-S induced neutralizing antibodies and T cell responses and limited or prevented infection in the upper and lower respiratory tract after SARS-CoV-2 challenge. As this single intranasal dose vaccine confers protection against SARS-CoV-2 in non-human primates, it is a promising candidate for limiting SARS-CoV-2 infection and transmission in humans.

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

PLoS ONE ◽

10.1371/journal.pone.0037532 ◽

2012 ◽

Vol 7 (5) ◽

pp. e37532 ◽

Cited By ~ 4

Author(s):

Qiang Liu ◽

Jianhui Nie ◽

Weijin Huang ◽

Shufang Meng ◽

Baozhu Yuan ◽

...

Keyword(s):

High Throughput ◽

Neutralizing Antibodies ◽

Adenovirus Type ◽

Adenovirus Type 5

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

Journal of Virology ◽

10.1128/jvi.00866-09 ◽

2009 ◽

Vol 84 (1) ◽

pp. 630-638 ◽

Cited By ~ 43

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.

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