scholarly journals EXTH-39. HEXON SWAPPING MITIGATES ANTI-VIRAL IMMUNE RESPONSE DURING BRAIN TUMOR VIROTHERAPY

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii95-ii95
Author(s):  
Dong Ho Shin ◽  
Teresa Nguyen ◽  
Hong Jiang ◽  
Sagar Sohoni ◽  
Sumit Gupta ◽  
...  
Keyword(s):  
Immune Response ◽  
Brain Tumor ◽  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Phase 1 ◽  
Malignant Gliomas ◽  
Oncolytic Viruses ◽  
Comparable Efficacy ◽  
Host Immune System ◽  
Serotype 5

Abstract Cancer virotherapy is a paradigm-shifting treatment modality based on the capabilities of virus-mediated oncolysis to elicit an anti-tumor immune response. Phase 1 and 2 clinical trials have demonstrated the safety and efficacy of our oncolytic adenovirus DNX-2401 (Delta-24-RGD) for patients with recurrent malignant gliomas. While a subset of the patients showed significant benefits, our goal is to improve the response rate. Clearance of the therapeutic virus by dominant anti-viral immune responses may contribute to the observed limits of the virotherapy. Adenovirus serotype 5 that provides the backbone of most oncolytic adenoviruses is highly prevalent in the human population and neutralizing antibodies against the capsid protein hexon may inhibit viral infection and replication. In this study, we showed using immunofluorescence that in mice bearing orthotopic syngeneic glioblastoma GSC005 treated with Delta-24-RGD, IgG antibodies crossed the disrupted blood-brain barrier and infiltrated the brain tumor parenchyma to colocalize with the viral hexon, suggesting that the systemic immune response may eradicate the virus within the infected tumor. To overcome this obstacle, we generated a chimeric virus called Delta-24-RGD-H43m with hexon hypervariable regions replaced with those from a lesser prevalent serotype 43 to avoid recognition by antibodies generated against serotype 5. The molecular swapping of the hexon did not significantly interfere with virion assembly nor attenuate its anti-glioma effect. Thus, the two viruses showed comparable efficacy in vitro (P= 0.568) and in vivo for animals without prior virus exposures (P= 0.228). Importantly, Delta-24-RGD-H43m evaded neutralizing antibodies generated against Delta-24-RGD and maintained its oncolytic ability (P< 0.0001). We conclude that hexon swapping strategies may improve virotherapy by alleviating the dominant immune response against the virus. Despite limited understanding of the interaction between oncolytic viruses and the host immune system, further research on strategies to circumvent virus-specific immune responses should aid the development of enhanced, glioma-targeted virotherapies.

scholarly journals Combining Oncolytic Viruses and Small Molecule Therapeutics: Mutual Benefits

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3386
Author(s):  
Bart Spiesschaert ◽  
Katharina Angerer ◽  
John Park ◽  
Guido Wollmann
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Tumor Cells ◽  
Small Molecule ◽  
Antiviral Immunity ◽  
Oncolytic Viruses ◽  
Antitumor Immune Response ◽  
Antiviral Responses ◽  
Small Molecule Therapeutics ◽  
Immunosuppressive Factors

The focus of treating cancer with oncolytic viruses (OVs) has increasingly shifted towards achieving efficacy through the induction and augmentation of an antitumor immune response. However, innate antiviral responses can limit the activity of many OVs within the tumor and several immunosuppressive factors can hamper any subsequent antitumor immune responses. In recent decades, numerous small molecule compounds that either inhibit the immunosuppressive features of tumor cells or antagonize antiviral immunity have been developed and tested for. Here we comprehensively review small molecule compounds that can achieve therapeutic synergy with OVs. We also elaborate on the mechanisms by which these treatments elicit anti-tumor effects as monotherapies and how these complement OV treatment.

scholarly journals Optimized Adenovirus-Antibody Complexes Stimulate Strong Cellular and Humoral Immune Responses against an Encoded Antigen in Naïve Mice and Those with Preexisting Immunity

2011 ◽  
Vol 19 (1) ◽  
pp. 84-95 ◽  
Author(s):  
Jin Huk Choi ◽  
Joe Dekker ◽  
Stephen C. Schafer ◽  
Jobby John ◽  
Craig E. Whitfill ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cell ◽  
Immune Responses ◽  
Neutralizing Antibodies ◽  
T Cell Responses ◽  
Transduction Efficiency ◽  
Virus Antibody ◽  
Cell Responses

ABSTRACTThe immune response to recombinant adenoviruses is the most significant impediment to their clinical use for immunization. We test the hypothesis that specific virus-antibody combinations dictate the type of immune response generated against the adenovirus and its transgene cassette under certain physiological conditions while minimizing vector-induced toxicity.In vitroandin vivoassays were used to characterize the transduction efficiency, the T and B cell responses to the encoded transgene, and the toxicity of 1 × 1011adenovirus particles mixed with different concentrations of neutralizing antibodies. Complexes formed at concentrations of 500 to 0.05 times the 50% neutralizing dose (ND50) elicited strong virus- and transgene-specific T cell responses. The 0.05-ND50formulation elicited measurable anti-transgene antibodies that were similar to those of virus alone (P= 0.07). This preparation also elicited very strong transgene-specific memory T cell responses (28.6 ± 5.2% proliferation versus 7.7 ± 1.4% for virus alone). Preexisting immunity significantly reduced all responses elicited by these formulations. Although lower concentrations (0.005 and 0.0005 ND50) of antibody did not improve cellular and humoral responses in naïve animals, they did promote strong cellular (0.005 ND50) and humoral (0.0005 ND50) responses in mice with preexisting immunity. Some virus-antibody complexes may improve the potency of adenovirus-based vaccines in naïve individuals, while others can sway the immune response in those with preexisting immunity. Additional studies with these and other virus-antibody ratios may be useful to predict and model the type of immune responses generated against a transgene in those with different levels of exposure to adenovirus.

scholarly journals SARS-CoV-2 Serology Status Detected by Commercialized Platforms Distinguishes Previous Infection and Vaccination Adaptive Immune Responses

2021 ◽  
Author(s):  
Raymond T. Suhandynata ◽  
Nicholas J. Bevins ◽  
Jenny T. Tran ◽  
Deli Huang ◽  
Melissa A. Hoffman ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Natural Infection ◽  
Adaptive Immune Response ◽  
Antibody Assay ◽  
Adaptive Immune Responses ◽  
Adaptive Immune ◽  
Previous Infection ◽  
A Cell

AbstractBackgroundThe severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected over 110 million individuals and led to 2.5 million deaths worldwide. As more individuals are vaccinated, the clinical performance and utility of SARS-CoV-2 serology platforms needs to be evaluated.MethodsThe ability of four commercial SARS-CoV-2 serology platforms to detect previous infection or vaccination were evaluated using a cohort of 53 SARS-CoV-2 PCR-positive patients, 89 SARS-CoV-2-vaccinated healthcare workers (Pfizer or Moderna), and 127 SARS-CoV-2 negative patients. Serology results were compared to a cell based SARS-CoV-2 pseudovirus (PSV) neutralizing antibodies assay.ResultsThe Roche S-(spike) antibody and Diazyme neutralizing antibodies (NAbs) assays detected adaptive immune response in 100.0% and 90.1% of vaccinated individuals who received two-doses of vaccine (initial and booster), respectively. The Roche N-(nucleocapsid) antibody assay and Diazyme IgG assay did not detect adaptive immune response in vaccinated individuals. The Diazyme Nabs assay correlated with the PSV SARS-CoV-2 ID50 neutralization titers (R2= 0.70), while correlation of the Roche S-antibody assay was weaker (R2= 0.39). Median PSV SARS-CoV-2 ID50 titers more than doubled in vaccinated individuals who received two-doses of the Moderna vaccine (ID50: 597) compared to individuals that received a single dose (ID50: 284).ConclusionsThe Roche S-antibody and Diazyme NAbs assays robustly detected adaptive immune responses in SARS-CoV-2 vaccinated individuals and SARS-CoV-2 infected individuals. The Diazyme NAbs assay strongly correlates with the PSV SARS-CoV-2 NAbs in vaccinated individuals. Understanding the reactivity of commercially available serology platforms is important when distinguishing vaccination response versus natural infection.SummaryThe Roche S (spike protein)-antibody and Diazyme neutralizing-antibodies (NAbs) assays were evaluated for their clinical utility in the detection of SARS-CoV-2 related adaptive immune responses by testing SARS-CoV-2 PCR-confirmed patients, SARS-CoV-2-vaccinated individuals, and SARS-CoV-2-negative individuals. Commercial serology results were compared to results generated using a cell-based SARS-CoV-2 pseudovirus (PSV) NAbs assay and previously validated SARS-CoV-2 commercial serology assays (Roche N (nucleocapsid protein) antibody and Diazyme IgG). We demonstrate that the Roche S-antibody and Diazyme NAbs assays detected adaptive immune response in SARS-CoV-2 vaccinated individuals and the presence of SARS-CoV-2 PSV NAbs. The Roche S-antibody assay had an observed positive percent agreement (PPA) of 100% for individuals who received two doses of the Pfizer or Moderna vaccine. By contrast, the Roche N assay and Diazyme IgG assay did not detect vaccine adaptive immune responses. Our findings also indicate that the Diazyme NAbs assay correlates strongly with the levels of SARS-CoV-2 ID50 neutralization titers using the PSV Nab assay in vaccinated individuals.

scholarly journals Protective and Pathogenic Immune Responses to Cutaneous Leishmaniasis

2021 ◽  
Author(s):  
Elina Panahi ◽  
Danielle I. Stanisic ◽  
Christopher S. Peacock ◽  
Lara J. Herrero
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Cutaneous Leishmaniasis ◽  
Adaptive Immune Response ◽  
Leishmania Parasite ◽  
Host Immune System ◽  
Phagocytic Cells ◽  
Host Immune Responses ◽  
Outcome Severity ◽  
Common Clinical Presentation

Leishmania (Kinetoplastida: Trypanosomatidae) parasites are known to cause a broad spectrum of clinical diseases in humans, collectively known as the leishmaniases. Cutaneous leishmaniasis is the most common clinical presentation with varying degrees of severity largely driven by host immune responses, specifically the interplay between innate and adaptive immune response. The establishment of a T lymphocyte driven cell-mediated immune response, leading to activated phagocytic cells, leading to Leishmania parasite killing and control of infection. Alternatively, the Leishmania parasite manipulates the host immune system, enabling parasite proliferation and clinical disease. Here we review how the cumulative interactions of different aspects of the host immune response determines disease outcome, severity, and immunity to re-infection.

scholarly journals MVA Vectored Vaccines Encoding Rift Valley Fever Virus Glycoproteins Protect Mice against Lethal Challenge in the Absence of Neutralizing Antibody Responses

Vaccines ◽  
2020 ◽  
Vol 8 (1) ◽  
pp. 82 ◽  
Author(s):  
Elena López-Gil ◽  
Sandra Moreno ◽  
Javier Ortego ◽  
Belén Borrego ◽  
Gema Lorenzo ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Cellular Immunity ◽  
Rift Valley ◽  
Neutralizing Antibodies ◽  
Rift Valley Fever ◽  
Rift Valley Fever Virus ◽  
Fever Virus ◽  
Valley Fever

In vitro neutralizing antibodies have been often correlated with protection against Rift Valley fever virus (RVFV) infection. We have reported previously that a single inoculation of sucrose-purified modified vaccinia Ankara (MVA) encoding RVFV glycoproteins (rMVAGnGc) was sufficient to induce a protective immune response in mice after a lethal RVFV challenge. Protection was related to the presence of glycoprotein specific CD8+ cells, with a low-level detection of in vitro neutralizing antibodies. In this work we extended those observations aimed to explore the role of humoral responses after MVA vaccination and to study the contribution of each glycoprotein antigen to the protective efficacy. Thus, we tested the efficacy and immune responses in BALB/c mice of recombinant MVA viruses expressing either glycoprotein Gn (rMVAGn) or Gc (rMVAGc). In the absence of serum neutralizing antibodies, our data strongly suggest that protection of vaccinated mice upon the RVFV challenge can be achieved by the activation of cellular responses mainly directed against Gc epitopes. The involvement of cellular immunity was stressed by the fact that protection of mice was strain dependent. Furthermore, our data suggest that the rMVA based single dose vaccination elicits suboptimal humoral immune responses against Gn antigen since disease in mice was exacerbated upon virus challenge in the presence of rMVAGnGc or rMVAGn immune serum. Thus, Gc-specific cellular immunity could be an important component in the protection after the challenge observed in BALB/c mice, contributing to the elimination of infected cells reducing morbidity and mortality and counteracting the deleterious effect of a subneutralizing antibody immune response.

scholarly journals Safety and Immunogenicity of Heterologous and Homologous 2-Dose Regimens of Adenovirus Serotype 26– and Modified Vaccinia Ankara–Vectored Ebola Vaccines: A Randomized, Controlled Phase 1 Study

2020 ◽  
Author(s):  
Neil Goldstein ◽  
Viki Bockstal ◽  
Stephan Bart ◽  
Kerstin Luhn ◽  
Cynthia Robinson ◽  
...  
Keyword(s):  
Immune Responses ◽  
Neutralizing Antibodies ◽  
Ebola Virus ◽  
Phase 1 ◽  
Booster Vaccination ◽  
Controlled Study ◽  
Adenovirus Serotype ◽  
Cellular Immune Responses ◽  
High Doses ◽  
Cellular Immune

Abstract Background This phase 1 placebo-controlled study assessed the safety and immunogenicity of 2-dose regimens of Ad26.ZEBOV (adenovirus serotype 26 [Ad26]) and MVA-BN-Filo (modified vaccinia Ankara [MVA]) vaccines with booster vaccination at day 360. Methods Healthy US adults (N = 164) randomized into 10 groups received saline placebo or standard or high doses of Ad26 or MVA in 2-dose regimens at 7-, 14-, 28-, or 56-day intervals; 8 groups received booster Ad26 or MVA vaccinations on day 360. Participants reported solicited and unsolicited reactogenicity; we measured immunoglobulin G binding, neutralizing antibodies and cellular immune responses to Ebola virus glycoprotein. Results All regimens were well tolerated with no serious vaccine-related adverse events. Heterologous (Ad26,MVA [dose 1, dose 2] or MVA,Ad26) and homologous (Ad26,Ad26) regimens induced humoral and cellular immune responses 21 days after dose 2; responses were higher after heterologous regimens. Booster vaccination elicited anamnestic responses in all participants. Conclusions Both heterologous and homologous Ad26,MVA Ebola vaccine regimens are well tolerated in healthy adults, regardless of interval or dose level. Heterologous 2-dose Ad26,MVA regimens containing an Ebola virus insert induce strong, durable humoral and cellular immune responses. Immunological memory was rapidly recalled by booster vaccination, suggesting that Ad26 booster doses could be considered for individuals at risk of Ebola infection, who previously received the 2-dose regimen.

scholarly journals Phase 1 Clinical Trial of a Replication-Defective Human Cytomegalovirus (CMV) Vaccine

2017 ◽  
Vol 4 (suppl_1) ◽  
pp. S308-S309 ◽  
Author(s):  
Stuart Adler ◽  
Nicole Lewis ◽  
Anthony Conlon ◽  
Mark Christiansen ◽  
Mohamed S Al-Ibrahim ◽  
...  
Keyword(s):  
Immune Responses ◽  
Injection Site ◽  
Neutralizing Antibodies ◽  
Phase 1 ◽  
Aluminum Phosphate ◽  
Post Dose ◽  
Viral Shedding ◽  
Vaccine Type ◽  
Dose Levels ◽  
Research Grant

Abstract Background Congenital CMV remains an unmet medical need worldwide. Naturally acquired CMV immunity in women prior to pregnancy has been shown effective in reducing maternal-fetal transmission. V160 is engineered as a replication-defective CMV, and its replication in culture is controlled by a synthetic chemical. V160 can’t replicate in humans but it maintains all virological properties for presentation of viral antigens, including gH/gL/pUL128-131 pentameric complex, important for potent neutralizing antibodies (NABs). Methods Approximately 190 CMV seronegative and seropositive adults at study entry received 3 doses of V160 or placebo administered via intramuscular (IM) or intradermal (ID) route on Day 1, Month 1, and Month 6. Four antigen levels (10, 30, 100, and 250 units per dose) formulated with or without aluminum phosphate adjuvant were evaluated. In each vaccination group, approximately 10 and 4 subjects received study vaccine and placebo, respectively. Injection site and systemic adverse events (AEs) were collected for 14 days after each vaccination. Serious AEs (SAEs) were assessed up to Month 18. Viral shedding (urine and saliva) were monitored up to Month 12. CMV-specific NABs and cell-mediated immune responses (CMI) were measured prior and 1 month after each vaccination, and at Months 12 and 18. Results During the study, no serious AEs were reported and only one CMV seropositive subject had non-vaccine type viral shedding. In both seronegative and seropositive cohorts, proportion of subjects who reported injection site AEs was higher in V160 recipients than placebo controls. Proportion of subjects who reported systemic AEs was comparable across V160 doses/formulations and placebo. In the CMV seronegative cohort, immune responses increased with incremental dosing. More importantly, recipients of V160 from several dose levels mounted NAB and CMI responses at 1 month post dose 3 (PD3) that were comparable to baseline levels measured in seropositive subjects. Conclusion V160 had acceptable safety profile across all dose levels and formulations studied; Vaccine was immunogenic and elicited NAB and CMI responses at 1 month PD3 that were comparable to natural CMV infection. Disclosures S. Adler, Merck: Investigator, Research grant. N. Lewis, Merck: Employee, Salary. A. Conlon, Merck: Employee, Salary. M. Christiansen, Merck: Investigator, Research grant. M. S. Al-Ibrahim, Merck: Investigator, Research grant R. Rupp, Merck: Investigator, Research grant. T. M. Fu, Merck: Employee, Salary. O. Bautista, Merck: Employee, Salary. H. Tang, Merck: Employee, Salary.T. Culp, Merck: Employee, Salary. R. Das, Merck: Employee, Salary. K. Beck, Merck: Employee, Salary. G. Tamms, Merck: Employee, Salary. L. Musey, Meck: Employee, Salary.

scholarly journals Immunization with DNA Plasmids Coding for Crimean-Congo Hemorrhagic Fever Virus Capsid and Envelope Proteins and/or Virus-Like Particles Induces Protection and Survival in Challenged Mice

2017 ◽  
Vol 91 (10) ◽  
Author(s):  
Jorma Hinkula ◽  
Stéphanie Devignot ◽  
Sara Åkerström ◽  
Helen Karlberg ◽  
Eva Wattrang ◽  
...  
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Dna Vaccine ◽  
Neutralizing Antibodies ◽  
Hemorrhagic Fever ◽  
Fever Virus ◽  
Vaccine Candidates ◽  
Th1 Response ◽  
Crimean Congo Hemorrhagic Fever ◽  
Hemorrhagic Fever Virus

ABSTRACT Crimean-Congo hemorrhagic fever virus (CCHFV) is a bunyavirus causing severe hemorrhagic fever disease in humans, with high mortality rates. The requirement of a high-containment laboratory and the lack of an animal model hampered the study of the immune response and protection of vaccine candidates. Using the recently developed interferon alpha receptor knockout (IFNAR−/−) mouse model, which replicates human disease, we investigated the immunogenicity and protection of two novel CCHFV vaccine candidates: a DNA vaccine encoding a ubiquitin-linked version of CCHFV Gc, Gn, and N and one using transcriptionally competent virus-like particles (tc-VLPs). In contrast to most studies that focus on neutralizing antibodies, we measured both humoral and cellular immune responses. We demonstrated a clear and 100% efficient preventive immunity against lethal CCHFV challenge with the DNA vaccine. Interestingly, there was no correlation with the neutralizing antibody titers alone, which were higher in the tc-VLP-vaccinated mice. However, the animals with a lower neutralizing titer, but a dominant cell-mediated Th1 response and a balanced Th2 response, resisted the CCHFV challenge. Moreover, we found that in challenged mice with a Th1 response (immunized by DNA/DNA and boosted by tc-VLPs), the immune response changed to Th2 at day 9 postchallenge. In addition, we were able to identify new linear B-cell epitope regions that are highly conserved between CCHFV strains. Altogether, our results suggest that a predominantly Th1-type immune response provides the most efficient protective immunity against CCHFV challenge. However, we cannot exclude the importance of the neutralizing antibodies as the surviving immunized mice exhibited substantial amounts of them. IMPORTANCE Crimean-Congo hemorrhagic fever virus (CCHFV) is responsible for hemorrhagic diseases in humans, with a high mortality rate. There is no FDA-approved vaccine, and there are still gaps in our knowledge of the immune responses to infection. The recently developed mouse models mimic human CCHF disease and are useful to study the immunogenicity and the protection by vaccine candidates. Our study shows that mice vaccinated with a specific DNA vaccine were fully protected. Importantly, we show that neutralizing antibodies are not sufficient for protection against CCHFV challenge but that an extra Th1-specific cellular response is required. Moreover, we describe the identification of five conserved B-cell epitopes, of which only one was previously known, that could be of great importance for the development of diagnostics tools and the improvement of vaccine candidates.

scholarly journals Strong immunogenicity of heterologous prime-boost immunizations with the experimental vaccine GRAd-COV2 and BNT162b2 or ChAdOx1-nCOV19

2021 ◽  
Author(s):  
Chiara Agrati ◽  
Stefania Capone ◽  
Concetta Castilletti ◽  
Eleonora Cimini ◽  
Giulia Matusali ◽  
...  
Keyword(s):  
Immune Response ◽  
Single Dose ◽  
Neutralizing Antibodies ◽  
Small Sample Size ◽  
Phase 1 ◽  
Vaccination Campaign ◽  
Small Sample ◽  
Vaccine Platform ◽  
Ideal Tool ◽  
Cellular Immune

Here we report on the humoral and cellular immune response in eight volunteers who autonomously chose to adhere to the Italian national COVID-19 vaccination campaign more than 3 months after receiving a single administration GRAd-COV2 vaccine candidate in the context of the phase 1 clinical trial. We observed a clear boost of both binding/neutralizing antibodies as well as T cell responses upon receipt of the heterologous BNT162b2 or ChAdOx1-nCOV19 vaccines. These results, despite the limitation of the small sample size, support the concept that a single-dose of an adenoviral vaccine may represent an ideal tool to effectively prime a balanced immune response, which can be boosted to high levels by a single dose of a different vaccine platform.

scholarly journals Host immune response to infection with porcine circoviruses

2021 ◽  
Vol 1 (1) ◽  
Author(s):  
Ruihan Shi ◽  
Lei Hou ◽  
Jue Liu
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Inflammatory Responses ◽  
Porcine Circovirus Type ◽  
Porcine Circovirus Type 2 ◽  
Immune Defense ◽  
Porcine Circovirus ◽  
Future Research ◽  
Host Immune System

AbstractPorcine circovirus type 2 (PCV2), which serves as a major causative agent of PCV2-associated diseases and causes severe loss to the pig industry worldwide, can dysregulate the immune response and induce immunosuppression in PCV2-infected pigs. Similar to PCV2, porcine circovirus type 3 (PCV3), a newly identified swine circovirus which might be closely associated with porcine dermatitis and nephropathy syndrome, reproductive disorder, and multisystemic inflammatory responses, also interferes with host immune defense. Interaction between host immune system and PCVs is considered to be a crucial determinant of pathogenicity in pigs. Here, we sought to briefly discuss the current knowledge regarding the interaction of porcine circovirus type 2 and/or 3 with host immune cells and immune responses to better depict the viral immunomodulatory capacity, pathogenic mechanisms, and the future research direction in host immune responses to infection with PCV2 and PCV3.

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