Biology subjects

Dora, E. G.

Publications and source records attributed to Dora, E. G..

5 recordsLinked to original sources

bioRxiv2024

Elimination of human papillomavirus 16-induced tumors by a mucosal rAd5 therapeutic vaccination in a pre-clinical study

Therapeutic vaccination can harness the bodys cellular immune system to target and destroy cancerous cells. Several invasive treatments are currently used to eliminate cancerous lesions caused by human papillomaviruses (HPV), however therapeutic vaccination may offer and effective and minimally intrusive alternative. We have developed recombinant, non-replicating human adenovirus type 5 (rAd5) vaccines that encode the HPV16 oncogenic proteins E6 and E7 alongside a molecular dsRNA adjuvant. The potency of these vaccines were examined in a mouse model of HPV tumorigenesis where E6E7-expressing and transformed cells were implanted subcutaneously into C57BL/6 mice. After tumor growth, mice were treated via intranasal administration with E6E7-encoding rAd5 vaccines expressing either a mutant form of E6E7 (rAd5-16/E6E7m), or predicted T cell epitopes of E6E7 (rAd5-16/E6E7epitopes). Animals receiving therapeutic treatments of rAd5-16/E6E7m and rAd5-16/E6E7epitopes had significant reductions in tumor volume and increased survival compared to animals treated with an empty rAd5 or left untreated. Further, antigen-specific CD8+ T effector memory cells (TEM) were observed in the animals treated with E6E7-encoding rAd5, but not in rAd5-empty group. The work described here demonstrates that mucosal rAd5 can be used in a therapeutic capacity to elicit antigen-specific cellular immunity and further identifies a clinical candidate with immense potential for the treatment and prevention of human cervical cancer.

immunology↗

bioRxiv2022

Adenoviral-Based Vaccine Elicits Robust Systemic and Mucosal Cross-Reactive Responses in African Green Monkeys and Reduces Shedding after SARS-CoV-2 Challenge

As new SARS-CoV-2 variants continue to emerge and impact communities worldwide, efforts to develop next generation vaccines that enhance mucosal immunity would be beneficial for protecting individuals and reducing community transmission. We have developed a non-replicating recombinant adenovirus vector (rAd5) vaccine delivered by mucosal administration engineered to express both a protein antigen and a novel molecular adjuvant in the same cell. Here we describe the immunogenicity of three unique SARS-CoV-2 rAd5 vaccine preclinical candidates and their efficacy following viral challenge in African green monkeys. Animals were prime and boost immunized intranasally twenty-nine days apart with rAd5 vaccine candidates containing viral SARS-CoV-2 spike protein alone or in combination with viral nucleocapsid. Mucosal immunization elicited significant increases in antigen-specific serum antibody responses and functional neutralizing activity against multiple variants of concern. Robust antigen specific mucosal IgA responses were observed after a single administration of rAd5 and generated strong cross-reactive neutralizing antibodies against multiple variants including delta. Importantly, all vaccinated animals exhibited a significant reduction in viral loads and infectious particle shedding in both the nasal passages and lower airways compared to unvaccinated controls following challenge with SARS-CoV-2. These findings demonstrate that mucosal immunization using rAd5 is highly immunogenic, confers protective cross-reactive humoral responses in both the circulation and mucosa, and reduces viral loads and shedding upon challenge with multiple SARS-CoV-2 variants.

immunology↗

bioRxiv2022

Mucosal Immunization of Cynomolgus Macaques with Adenoviral Vector Vaccine Elicits Neutralizing Nasal and Serum Antibody to Several SARS-CoV-2 Variants

The emergence of SARS-CoV-2 variants continues to be a major obstacle for controlling the global pandemic. Despite the currently authorized SARS-CoV-2 vaccines ability to reduce severe disease and hospitalization, new immunization strategies are needed that enhance mucosal immune responses, inhibit community transmission, and provide protection against emerging variants. We have developed a mucosally delivered, non-replicating recombinant adenovirus vector (rAd5) vaccine, that has proven efficacy in the clinic against other respiratory viruses [1]. Here we evaluated the immunogenicity of three candidate SARS-CoV-2 vaccines in cynomolgus macaques that contained spike (S) and/or nucleocapsid (N) from either the Wuhan or the beta variant to select a candidate for future clinical development. Mucosal immunization with the Wuhan specific S vaccine (ED90) induced significant cross-reactive serum IgG responses against to Wuhan, beta, gamma and delta lineages, and generated substantial serum neutralizing activity. In nasal samples, ED90 immunization induced 1000-fold increases in IgA to all variants of concern tested and had neutralizing activity against Wuhan and delta. While immunization with the beta specific vaccine (ED94) enhanced IgG and IgA responses to homologous beta variant S and RBD, this approach resulted in less cross-reactive responses to other variants in the serum and nasal passages compared to ED90. As ED90 immunization induced the most robust cross-reactive systemic and mucosal antibody responses, this candidate was chosen for future clinical development.

immunology↗

bioRxiv2021

Oral and intranasal Ad5 SARS-CoV-2 vaccines decrease disease and viral transmission in a golden hamster model

Transmission-blocking strategies that slow the spread of SARS-CoV-2 and protect against COVID-19 are needed. We have developed a shelf-stable, orally-delivered Ad5-vectored SARS-CoV-2 vaccine candidate that expresses the spike protein. Here we demonstrated that oral and intranasal SARS-CoV-2 vaccination of this candidate protected against disease in index hamsters, and decreased aerosol transmission to unvaccinated, naive hamsters. We confirmed that mucosally-vaccinated hamsters had robust antibody responses. We then induced a post-vaccination infection by inoculating vaccinated index hamsters with SARS-CoV-2. Oral and IN-vaccinated hamsters had decreased viral RNA and infectious virus in the nose and lungs and experienced less lung pathology compared to mock-vaccinated hamsters post challenge. Naive hamsters exposed in a unidirectional air flow chamber to mucosally-vaccinated, SARS-CoV-2-infected hamsters had lower nasal swab viral RNA and exhibited less clinical symptoms of disease than control animals. Our data demonstrate that oral immunization is a viable strategy to decrease SARS-CoV-2 disease and aerosol transmission.

immunology↗

bioRxiv2020

Pre-clinical studies of a recombinant adenoviral mucosal vaccine to prevent SARS-CoV-2 infection

There is an urgent need to develop efficacious vaccines against SARS-CoV-2 that also address the issues of deployment, equitable access, and vaccine acceptance. Ideally, the vaccine would prevent virus infection and transmission as well as preventing COVID-19 disease. We previously developed an oral adenovirus-based vaccine technology that induces both mucosal and systemic immunity in humans. Here we investigate the immunogenicity of a range of candidate adenovirusbased vaccines, expressing full or partial sequences of the spike and nucleocapsid proteins, in mice. We demonstrate that, compared to expression of the S1 domain or a stabilized spike antigen, the full length, wild-type spike antigen induces significantly higher neutralizing antibodies in the periphery and in the lungs, when the vaccine is administered mucosally. Antigen-specific CD4+ and CD8+ T cells were induced by this leading vaccine candidate at low and high doses. This fulllength spike antigen plus nucleocapsid adenovirus construct has been prioritized for further clinical development.

immunology↗