Global surveillance has identified emerging SARS-CoV-2 variants of concern (VOC) associated with broadened host specificity, pathogenicity, and immune evasion to vaccine-induced immunity. Here we ...compared humoral and cellular responses against SARS-CoV-2 VOC in subjects immunized with the DNA vaccine, INO-4800. INO-4800 vaccination induced neutralizing antibodies against all variants tested, with reduced levels detected against B.1.351. IFNγ T cell responses were fully maintained against all variants tested.
VGX-3100 is an investigational DNA-based immunotherapy being developed as an alternative to surgery and ablation for cervical High-Grade Squamous Intraepithelial Lesion (HSIL) with the aim of ...preserving reproductive health while treating precancerous disease. Response durability up to 1.5 y following dosing is now reported.
Histologic regression and HPV16 and/or HPV 18 (HPV16/18) clearance were previously demonstrated in a randomized, placebo-controlled, double-blind trial and reported for 6 months after the last dose of VGX-3100 or placebo. The presence of HPV16/18, Pap smear diagnoses, and immunogenicity longer-term responses were assessed at 18 months after the last dose.
91% (32/35) VGX-3100-treated women, whose cervical HSIL regressed and avoided excision at 6 months following study treatment completion, had no detectable HPV16/18 at 18 months following treatment completion. These results were comparable to those for women who received placebo and then later underwent surgery. For VGX-3100 recipients who regressed at 6 months following study treatment completion and avoided excision during the trial, Pap testing showed no HSIL recurrence at 18 months following VGX-3100 treatment. VGX-3100-induced cellular immune responses specific for HPV 16/18 E6/E7 remained higher than for placebo control recipients at 18 months.
In women with cervical HSIL who responded to VGX-3100 and were able to avoid surgery, clinical outcomes were comparable to the placebo control group which underwent conventional surgical treatment. These findings extend the understanding of the durability of the treatment effect of VGX-3100 up to 1.5 y and support that VGX-3100 could be used as an alternative to surgery.
HPV remains the most common sexually transmitted disease worldwide, despite improvements in awareness, screening, prophylactic vaccination uptake, and surgical treatment. VGX-3100 is an immunotherapy ...that uses electroporation to introduce DNA encoding for modified HPV-16 and HPV-18, E6-and E7 proteins into myocytes to stimulate an effector T cell response. We now report immunogenicity and safety of VGX-3100 for a refrigeration-stable formulation, which improves patient-care setting usability.
This multi-arm, double-blinded, randomized trial enrolled 235 healthy men and women to receive either a refrigerated (RF) or frozen formulation (FF) of VGX-3100. Three doses were administered intramuscularly with electroporation at 0, 4, and 12 weeks. Non-inferiority of RF to FF was assessed by comparing the proportion of subjects who achieved a ≥2-fold increase from baseline to Week 14 in Spot Forming Units/10
6
PMBCs using an interferon-γ enzyme-linked immunospot assay.
There were no related SAEs. Injection site reactions were the most common adverse event (54%, RF; 66%, FF) the majority of which resolved within a few minutes following administration. The primary endpoint was met with 89.9% of RF recipients and 97.2% of FF recipients reaching a ≥2-fold rise in SFU/10
6
PBMC, 2 weeks following the last dose; RF was statistically non-inferior to FF (p = .022).
A systemic, immunologic approach has the potential to fill a critical gap in the ability to treat men and women with high grade HPV diseases. These safety and immunogenicity data are supportive of the continued development of a refrigerated formulation of VGX-3100.
Abstract
Despite advances in therapy, glioblastoma (GBM) remains one of the most deadly cancers, with five-year survival under 5%. Newer immunotherapies hold promise in the treatment of GBM, and T ...cell-enabling therapies may improve progression-free and overall survival for newly-diagnosed patients. Checkpoint inhibitors, such as PD-1 inhibitors, have increased response rates in many cancers, but not yet in GBM. In this study, a novel antigen-specific T cell-generating therapy, INO-5401, combined with INO-9012, together with a PD-1 checkpoint inhibitor, cemiplimab, will be given to patients with newly-diagnosed GBM in order to evaluate tolerability, immunogenicity and any activity of the combination. INO-5401 is a mixture of three synthetic plasmids that target Wilms tumor gene-1 (WT-1) antigen, prostate specific membrane antigen (PSMA), and human telomerase reverse transcriptase (hTERT) antigen. INO-9012 is a plasmid encoding human interleukin-12 (IL-12) p35 and p40 subunit proteins. In preclinical studies, targeting WT-1, PSMA and hTERT induced robust cellular immune responses and slowed tumor growth in murine tumor implantation and ALL models.
This is a Phase I/IIA, open-label, multi-center trial to evaluate the safety, immunogenicity and preliminary clinical efficacy of INO-5401 + INO-9012 delivered by intramuscular (IM) injection followed by electroporation (EP), in combination with cemiplimab, and radiation and chemotherapy, in participants with newly-diagnosed GBM. INO-5401 + INO-9012 will be administered Q3w for the first four doses, and then Q9w until disease progression. Cemiplimab will be administered Q3w until disease progression.
The trial population is divided into two cohorts: Cohort A are patients with an unmethylated O6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) promoter; and Cohort B are patients with a methylated O6-methylguanine-deoxyribonucleic acid (DNA) methyltransferase (MGMT) promoter. Both cohorts will receive radiation and temozolomide (TMZ), if clinically indicated, in combination with study therapies. Cohort B will continue TMZ for a total of 6 cycles.
A safety run-in will be performed with up to six participants (safety analysis participants) from Cohort A and Cohort B. Correlative studies include the assessment of antigen-specific cellular immune responses in peripheral blood and tumor tissue.
Fifty-two patients are estimated to be enrolled, 32 in Cohort A and 18 in Cohort B. Enrollment began in May of 2018 and the trial is continuing to accrue as planned.
Citation Format: David Reardon, Seema Nagpal, Scott Soltys, Steven Brem, Antonio Omuro, Macarena De La Fuente, Amy-Lee Bredlau, Isreal Lowy, Matthew Fury, Matthew Morrow, Kim Kraynyak, Trevor McMullan, Ashley L. Santo, Brian Sacchetta, Jeffrey Skolnik. INO-5401 and INO-9012 delivered by electroporation (EP) in combination with cemiplimab (REGN2810) in newly-diagnosed glioblastoma (GBM) (NCT03491683) abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr CT114.
This study evaluated the safety and immunogenicity of PENNVAX-B in 12 HIV infected individuals. PENNVAX-B is a combination of three optimized synthetic plasmids encoding for multiclade HIV Gag and ...Pol and a consensus CladeB Env delivered by electroporation. HIV infected individuals whose virus was effectively suppressed using highly active antiretroviral therapy (HAART) received PENNVAX-B DNA followed by electroporation with CELLECTRA-5P at study weeks 0, 4, 8, and 16. Local administration site and systemic reactions to PENNVAX-B were recorded after each treatment along with any adverse events. Pain of the treatment procedure was assessed using a Visual Analog Scale. Whole PBMCs were isolated for use in IFN ELISpot and Flow Cytometric assays. PENNVAX-B was generally safe and well tolerated. Overall, the four dose regimen was not associated with any serious adverse events or severe local or systemic reactions. A rise in antigen-specific SFU was detected in the INFγ ELISpot assay in all 12 participants. T cells from 8/12 participants loaded with both granzyme B and perforin in response to HIV antigen, an immune finding characteristic of long-term nonprogressors (LTNPs) and elite controllers (ECs). Thus administration of PENNVAX-B may prove useful adjunctive therapy to ART for treatment and control of HIV infection.
First identified in 2012, Middle East respiratory syndrome (MERS) is caused by an emerging human coronavirus, which is distinct from the severe acute respiratory syndrome coronavirus (SARS-CoV), and ...represents a novel member of the lineage C betacoronoviruses. Since its identification, MERS coronavirus (MERS-CoV) has been linked to more than 1372 infections manifesting with severe morbidity and, often, mortality (about 495 deaths) in the Arabian Peninsula, Europe, and, most recently, the United States. Human-to-human transmission has been documented, with nosocomial transmission appearing to be an important route of infection. The recent increase in cases of MERS in the Middle East coupled with the lack of approved antiviral therapies or vaccines to treat or prevent this infection are causes for concern. We report on the development of a synthetic DNA vaccine against MERS-CoV. An optimized DNA vaccine encoding the MERS spike protein induced potent cellular immunity and antigen-specific neutralizing antibodies in mice, macaques, and camels. Vaccinated rhesus macaques seroconverted rapidly and exhibited high levels of virus-neutralizing activity. Upon MERS viral challenge, all of the monkeys in the control-vaccinated group developed characteristic disease, including pneumonia. Vaccinated macaques were protected and failed to demonstrate any clinical or radiographic signs of pneumonia. These studies demonstrate that a consensus MERS spike protein synthetic DNA vaccine can induce protective responses against viral challenge, indicating that this strategy may have value as a possible vaccine modality against this emerging pathogen.
A vaccine against SARS-CoV-2 is of high urgency. Here the safety and immunogenicity induced by a DNA vaccine (INO-4800) targeting the full length spike antigen of SARS-CoV-2 are described.
INO-4800 ...was evaluated in two groups of 20 participants, receiving either 1.0 mg or 2.0 mg of vaccine intradermally followed by CELLECTRA® EP at 0 and 4 weeks. Thirty-nine subjects completed both doses; one subject in the 2.0 mg group discontinued trial participation prior to receiving the second dose. ClinicalTrials.gov identifier: NCT04336410.
The median age was 34.5, 55% (22/40) were men and 82.5% (33/40) white. Through week 8, only 6 related Grade 1 adverse events in 5 subjects were observed. None of these increased in frequency with the second administration. No serious adverse events were reported. All 38 subjects evaluable for immunogenicity had cellular and/or humoral immune responses following the second dose of INO-4800. By week 6, 95% (36/38) of the participants seroconverted based on their responses by generating binding (ELISA) and/or neutralizing antibodies (PRNT IC50), with responder geometric mean binding antibody titers of 655.5 95% CI (255.6, 1681.0) and 994.2 95% CI (395.3, 2500.3) in the 1.0 mg and 2.0 mg groups, respectively. For neutralizing antibody, 78% (14/18) and 84% (16/19) generated a response with corresponding geometric mean titers of 102.3 95% CI (37.4, 280.3) and 63.5 95% CI (39.6, 101.8), in the respective groups. By week 8, 74% (14/19) and 100% (19/19) of subjects generated T cell responses by IFN-ɣ ELISpot assay with the median SFU per 106 PBMC of 46 95% CI (21.1, 142.2) and 71 95% CI (32.2, 194.4) in the 1.0 mg and 2.0 mg groups, respectively. Flow cytometry demonstrated a T cell response, dominated by CD8+ T cells co-producing IFN-ɣ and TNF-α, without increase in IL-4.
INO-4800 demonstrated excellent safety and tolerability and was immunogenic in 100% (38/38) of the vaccinated subjects by eliciting either or both humoral or cellular immune responses.
Coalition for Epidemic Preparedness Innovations (CEPI).
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