Immunogenicity of a new gorilla adenovirus vaccine candidate for COVID-19.
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ABSTRACT:
SUBMITTER: Capone S
PROVIDER: S-EPMC8062434 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:The coronavirus family member, SARS-CoV-2 has been identified as the causal agent for the pandemic viral pneumonia disease, COVID-19. At this time, no vaccine is available to control further dissemination of the disease. We have previously engineered a synthetic DNA vaccine targeting the MERS coronavirus Spike (S) protein, the major surface antigen of coronaviruses, which is currently in clinical study. Here we build on this prior experience to generate a synthetic DNA-based vaccine candidate targeting SARS-CoV-2 S protein. The engineered construct, INO-4800, results in robust expression of the S protein in vitro. Following immunization of mice and guinea pigs with INO-4800 we measure antigen-specific T cell responses, functional antibodies which neutralize the SARS-CoV-2 infection and block Spike protein binding to the ACE2 receptor, and biodistribution of SARS-CoV-2 targeting antibodies to the lungs. This preliminary dataset identifies INO-4800 as a potential COVID-19 vaccine candidate, supporting further translational study.
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Project description:Covid-19 pandemic has struck worldwide by end of 2019 and the use of various vaccine platforms was one of the main strategies to end this. To meet the needs for vaccine technology equality among many countries, we developed adenovirus-based Covid-19 vaccine candidate in Indonesia. SARS-CoV-2 Spike gene (S) was constructed into pAdEasy vector. The recombinant serotype 5 Adenovirus (AdV_S) genome was transfected into AD293 cells to produce recombinant adenovirus. Characterization using PCR confirmed the presence of spike gene. Transgene expression analysis showed the expression of S protein in AdV_S infected AD293 and A549 cells. Optimization of viral production showed the highest titer was obtained at MOI of 0.1 and 1 at 4 days. The in vivo study was performed by injecting Balb/c mice with 3.5 × 107 ifu of purified adenovirus. The result showed that S1-specific IgG was increased up to 56 days after single-dose administration of AdV_S. Interestingly, significant increase of S1 glycoprotein-specific IFN-γ ELISpot was observed in AdV_S treated Balb/c mice. In conclusion, the AdV_S vaccine candidate was successfully produced at laboratory scale, immunogenic, and did not cause severe inflammation in Balb/c mice. This study serves as initial step towards manufacturing of adenovirus-based vaccine in Indonesia.
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Project description:There are approximately 44,000 cases of human papillomavirus-associated (HPV-associated) cancer each year in the United States, most commonly caused by HPV types 16 and 18. Prophylactic vaccines successfully prevent healthy people from acquiring HPV infections via HPV-specific antibodies. In order to treat established HPV-associated malignancies, however, new therapies are necessary. Multiple recombinant gorilla adenovirus HPV vaccine constructs were evaluated in NSG-β2m-/- peripheral blood mononuclear cell-humanized mice bearing SiHa, a human HPV16+ cervical tumor, and/or in the syngeneic HPV16+ TC-1 model. PRGN-2009 is a therapeutic gorilla adenovirus HPV vaccine containing multiple cytotoxic T cell epitopes of the viral oncoproteins HPV 16/18 E6 and E7, including T cell enhancer agonist epitopes. PRGN-2009 treatment reduced tumor volume and increased CD8+ and CD4+ T cells in the tumor microenvironment of humanized mice bearing the human cervical tumor SiHa. PRGN-2009 monotherapy in the syngeneic TC-1 model also reduced tumor volumes and weights, generated high levels of HPV16 E6-specific T cells, and increased multifunctional CD8+ and CD4+ T cells in the tumor microenvironment. These studies provide the first evaluation to our knowledge of a therapeutic gorilla adenovirus HPV vaccine, PRGN-2009, showing promising preclinical antitumor efficacy and induction of HPV-specific T cells, along with the rationale for its evaluation in clinical trials.
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Project description:Mucosal-associated invariant T (MAIT) cells are innate sensors of viruses, which can augment early immune responses and contribute to protection from lethal infection. Thus, we reasoned MAIT cells may have an adjuvating role in the immunogenicity of replication-incompetent adenovirus vectors, which are novel vaccine platforms for pandemic pathogens such as Ebola virus and SARS-CoV-2. In both mice and human volunteers, immunization with ChAdOx1 (Chimpanzee Adenovirus Ox1) robustly activated MAIT cells. Activation required transduction of plasmacytoid dendritic cells and monocytes to produce IFN- and IL-18, respectively. IFN--induced monocyte-derived TNF was identified as a novel intermediate in this activation pathway, and activation required combinatorial signaling of all three cytokines both in vitro and in vivo. Strikingly, vaccine-induced activation of MAIT cells positively correlated with vaccine-induced T cell responses in human volunteers. Supporting a causal relationship, MAIT cell-deficient mice displayed impaired CD8+ T cell responses to multiple vaccine-encoded antigens. These findings define a novel role for MAIT cells in the immunogenicity of adenovirus vector vaccines, with potential implications for vaccine design.
2020-10-01 | GSE158835 | GEO
Project description:BackgroundThe spread of SARS-CoV-2 has caused a worldwide pandemic that has affected almost every aspect of human life. The development of an effective COVID-19 vaccine could limit the morbidity and mortality caused by infection and may enable the relaxation of social-distancing measures. Age is one of the most significant risk factors for poor health outcomes after SARS-CoV-2 infection; therefore, it is desirable that any new vaccine candidates elicit a robust immune response in older adults.MethodsHere, we use in-depth immunophenotyping to characterize the innate and adaptive immune response induced upon intramuscular administration of the adenoviral vectored ChAdOx1 nCoV-19 (AZD-1222) COVID-19 vaccine candidate in mice.FindingsA single vaccination generates spike-specific Th1 cells, Th1-like Foxp3+ regulatory T cells, polyfunctional spike-specific CD8+ T cells. and granzyme-B-producing CD8 effectors. Spike-specific IgG and IgM are generated from both the early extrafollicular antibody response and the T follicular helper cell-supported germinal center reaction, which is associated with the production of virus-neutralizing antibodies. A single dose of this vaccine generated a similar type of immune response in aged mice but of a reduced magnitude than in younger mice. We report that a second dose enhances the immune response to this vaccine in aged mice.ConclusionsThis study shows that ChAdOx1 nCoV-19 induces both cellular and humoral immunity in adult and aged mice and suggests a prime-boost strategy is a rational approach to enhance immunogenicity in older persons.FundingThis study was supported by BBSRC, Lister institute of Preventative Medicine, EPSRC VaxHub, and Innovate UK.
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Project description:Adenoviruses (AdV) broadly infect vertebrate hosts including a variety of primates. We identified a novel AdV in the feces of captive gorillas by isolation in cell culture, electron microscopy and PCR. From the supernatants of infected cultures we amplified DNA polymerase (DPOL), preterminal protein (pTP) and hexon gene sequences with generic pan primate AdV PCR assays. The sequences in-between were amplified by long-distance PCRs of 2-10 kb length, resulting in a final sequence of 15.6 kb. Phylogenetic analysis placed the novel gorilla AdV into a cluster of primate AdVs belonging to the species Human adenovirus B (HAdV-B). Depending on the analyzed gene, its position within the cluster was variable. To further elucidate its origin, feces samples of wild gorillas were analyzed. AdV hexon sequences were detected which are indicative for three distinct and novel gorilla HAdV-B viruses, among them a virus nearly identical to the novel AdV isolated from captive gorillas. This shows that the discovered virus is a member of a group of HAdV-B viruses that naturally infect gorillas. The mixed phylogenetic clusters of gorilla, chimpanzee, bonobo and human AdVs within the HAdV-B species indicate that host switches may have been a component of the evolution of human and non-human primate HAdV-B viruses.
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Project description:The pandemic of COVID-19 caused by SARS-CoV-2 has raised a new challenges to the scientific and industrious fields after over 1-year spread across different countries. The ultimate approach to end the pandemic is the timely application of vaccines to achieve herd immunity. Here, a novel SARS-CoV-2 receptor-binding domain (RBD) homodimer was developed as a SARS-CoV-2 vaccine candidate. Formulated with aluminum adjuvant, RBD dimer elicited strong immune response in both rodents and non-human primates, and protected mice from SARS-CoV-2 challenge with significantly reducing viral load and alleviating pathological injury in the lung. In the non-human primates, the vaccine could prevent majority of the animals from SARS-CoV-2 infection in the respiratory tract and reduce lung damage. In addition, antibodies elicited by this vaccine candidate showed cross-neutralization activities to SARS-CoV-2 variants. Furthermore, with our expression system, we provided a high-yield RBD homodimer vaccine without additional biosafety or special transport device supports. Thus, it may serve as a safe, effective, and low-cost SARS-CoV-2 vaccine candidate.
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Project description:Severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2) has emerged as the infectious agent causing the pandemic coronavirus disease 2019 (COVID-19) with dramatic consequences for global human health and economics. Previously, we reached clinical evaluation with our vector vaccine based on modified vaccinia virus Ankara (MVA) against the Middle East respiratory syndrome coronavirus (MERS-CoV), which causes an infection in humans similar to SARS and COVID-19. Here, we describe the construction and preclinical characterization of a recombinant MVA expressing full-length SARS-CoV-2 spike (S) protein (MVA-SARS-2-S). Genetic stability and growth characteristics of MVA-SARS-2-S, plus its robust expression of S protein as antigen, make it a suitable candidate vaccine for industrial-scale production. Vaccinated mice produced S-specific CD8+ T cells and serum antibodies binding to S protein that neutralized SARS-CoV-2. Prime-boost vaccination with MVA-SARS-2-S protected mice sensitized with a human ACE2-expressing adenovirus from SARS-CoV-2 infection. MVA-SARS-2-S is currently being investigated in a phase I clinical trial as aspirant for developing a safe and efficacious vaccine against COVID-19.
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Project description:ObjectivesMany vaccines require higher/additional doses or adjuvants to provide adequate protection for people with HIV (PWH). Our objective was to compare COVID-19 vaccine immunogenicity in PWH to HIV-negative individuals.DesignIn a Canadian multi-center prospective, observational cohort of PWH receiving at least two COVID-19 vaccinations, we measured vaccine-induced immunity at 3 and 6 months post 2nd and 1-month post 3rd doses.MethodsThe primary outcome was the percentage of PWH mounting vaccine-induced immunity [co-positivity for anti-IgG against SARS-CoV2 Spike(S) and receptor-binding domain proteins] 6 months post 2nd dose. Univariable and multivariable logistic regressions were used to compare COVID-19-specific immune responses between groups and within subgroups.ResultsData from 294 PWH and 267 controls were analyzed. Immunogenicity was achieved in over 90% at each time point in both groups. The proportions of participants achieving comparable anti-receptor-binding domain levels were similar between the group at each time point. Anti-S IgG levels were similar by group at month 3 post 2nd dose and 1-month post 3rd dose. A lower proportion of PWH vs. controls maintained vaccine-induced anti-S IgG immunity 6 months post 2nd dose [92% vs. 99%; odds ratio: 0.14 (95% confidence interval: 0.03, 0.80; P = 0.027)]. In multivariable analyses, neither age, immune non-response, multimorbidity, sex, vaccine type, or timing between doses were associated with reduced IgG response.ConclusionVaccine-induced IgG was elicited in the vast majority of PWH and was overall similar between groups. A slightly lower proportion of PWH vs. controls maintained vaccine-induced anti-S IgG immunity 6 months post 2nd dose demonstrating the importance of timely boosting in this population.
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Project description:In the last two years, the coronavirus disease 19 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has been a scientific and social challenge worldwide. Vaccines have been the most effective intervention for reducing virus transmission and disease severity. However, virus genetic variants are still circulating among vaccinated individuals with different symptomatology disease cases. Understanding the protective or disease associated mechanisms in vaccinated individuals is relevant to advance in vaccine development and implementation. To address this objective, serum protein profiles were characterized by quantitative proteomics and data analysis algorithms in four cohorts of vaccinated individuals uninfected and SARS-CoV-2 infected with asymptomatic, nonsevere and severe disease symptomatology. The results showed that immunoglobulins were the most overrepresented proteins in infected cohorts when compared to PCR-negative individuals. The immunoglobulin profile varied between different infected cohorts and correlated with protective or disease associated capacity. Overrepresented immunoglobulins in PCR-positive individuals correlated with protective response against SARS-CoV-2, other viruses, and thrombosis in asymptomatic cases. In nonsevere cases, correlates of protection against SARS-CoV-2 and HBV together with risk of myasthenia gravis and allergy and autoantibodies were observed. Patients with severe symptoms presented risk for allergy, chronic idiopathic thrombocytopenic purpura, and autoantibodies. The analysis of underrepresented immunoglobulins in PCR-positive compared to PCR-negative individuals identified vaccine-induced protective epitopes in various coronavirus proteins including the Spike receptor-binding domain RBD. Non-immunoglobulin proteins were associated with COVID-19 symptoms and biological processes. These results evidence host-associated differences in response to vaccination and the possibility of improving vaccine efficacy against SARS-CoV-2.
2022-10-14 | PXD031969 | Pride