scholarly journals A phase 1/2 randomized, double-blinded, placebo controlled ascending dose trial to assess the safety, tolerability and immunogenicity of ARCT-021 in healthy adults

2021 ◽  
Author(s):  
Jenny G Low ◽  
Ruklanthi de Alwis ◽  
Shiwei Chen ◽  
Shirin Kalimuddin ◽  
Yan Shan Leong ◽  
...  
Keyword(s):  
Older Adults ◽  
T Cell ◽  
Seroconversion Rate ◽  
Phase 1 ◽  
T Cell Responses ◽  
Neutralizing Antibody ◽  
Post Inoculation ◽  
Cell Responses ◽  
Dose Trial ◽  
Double Blinded

Background The pandemic of coronavirus disease-19 (Covid-19) continues to afflict the lives and livelihoods of many as global demand for vaccine supply remains unmet. Methods Phase 1 of this trial (N=42) assessed the safety, tolerability and immunogenicity of ascending levels of one-dose ARCT-021, a self-amplifying mRNA vaccine against Covid-19. Phase 2 (N=64) tested two-doses of ARCT-021 given 28 days apart. Both young and older adults were enrolled. The primary safety outcomes were local and systemic solicited adverse events (AEs) reported immediately and up to 7 days post-inoculation and unsolicited events reported up to 56 days after inoculation. Secondary and exploratory outcomes were antibody and T cell responses to vaccination, respectively. Results ARCT-021 was well tolerated up to one 7.5 μg dose and two 5.0 μg doses. Local solicited AEs, namely injection-site pain and tenderness, as well as systemic solicited AEs, such as fatigue, headache and myalgia, were more common in ARCT-021 than placebo recipients, and in younger than older adults. Seroconversion rate for anti-S IgG was 100% in all cohorts except for the 1 μg one-dose in younger adults and the 7.5 μg one-dose in older adults, which were each 80%. Neutralizing antibody titers increased with increasing dose although the responses following 5.0 μg and 7.5 μg ARCT-021 were similar. Anti-S IgG titers overlapped with those in Covid-19 convalescent plasma. ARCT-021 also elicited T-cell responses against the S glycoprotein. Conclusion Taken collectively, the favorable safety and immunogenicity profiles support further clinical development of ARCT-021.

scholarly journals Safety and immunogenicity of a recombinant DNA COVID-19 vaccine containing the coding regions of the spike and nucleocapsid proteins: Preliminary results from an open-label, phase 1 trial in healthy adults aged 19-55 years

2021 ◽  
Author(s):  
Jin Young Ahn ◽  
Jeongsoo Lee ◽  
You Suk Suh ◽  
Young Goo Song ◽  
Yoon-Jeong Choi ◽  
...  
Keyword(s):  
T Cell ◽  
Plasmid Dna ◽  
Phase 1 ◽  
T Cell Responses ◽  
Neutralizing Antibody ◽  
Dna Encoding ◽  
Open Label ◽  
Cell Responses ◽  
Open Label Phase ◽  
Trial Participants

Background : We investigated the safety and immunogenicity of two recombinant COVID-19 DNA vaccine candidates in first-in-human trials. GX-19 contains plasmid DNA encoding SARS-CoV-2 spike protein, and GX-19N contains plasmid DNA encoding SARS-CoV-2 receptor binding domain (RBD) foldon and nucleocapsid protein (NP) as well as plasmid DNA encoding SARS-CoV-2 spike protein. Methods : Two open-label phase 1 trials of GX-19 and GX-19N safety and immunogenicity were performed in healthy adults aged 19-55 years. GX-19 trial participants received two vaccine injections (1.5 mg or 3.0 mg, 1:1 ratio) four weeks apart. GX-19N trial participants received two 3.0 mg vaccine injections four weeks apart. Findings : Between June 17 and July 30 and December 28 and 31, 2020, 40 and 21 participants were enrolled in the GX-19 and GX-19N trials, respectively. Thirty-two participants (52.5%) reported 80 treatment-emergent adverse events (AE) after vaccination. All solicited AEs were mild except one case of moderate fatigue reported in the 1.5 mg GX-19 group. Binding antibody responses increased after vaccination in all groups. The geometric mean titers (GMTs) of spike-binding antibodies on day 57 were 85.74, 144.20, and 201.59 in the 1.5 mg, 3.0 mg GX-19 groups and the 3.0 mg GX-19N group, respectively. In GX-19N group, neutralizing antibody response (50% neutralizing titer using FRNT) significantly increased after vaccination, but GMT of neutralizing antibody on day 57 (37.26) was lower than those from human convalescent serum (288.78). GX-19N induced stronger T cell responses than GX-19. The magnitude of GX-19N-induced T cell responses was comparable to those observed in the convalescent PBMCs. GX-19N induced both SARS-CoV-2 spike- and NP-specific T cell responses, and the amino acid sequences of 15-mer peptides containing NP-specific T cell epitopes identified in GX-19N-vaccinated participants were identical with those of diverse SARS-CoV-2 variants Interpretation : GX-19N is safe, tolerated and induces humoral and broad SARS-CoV-2-specific T cell response which may enable cross-reactivity to emerging SARS-CoV-2 variants. Funding : This research was supported by Korea Drug Development Fund funded by Ministry of Science and ICT, Ministry of Trade, Industry, and Energy, and Ministry of Health and Welfare (HQ20C0016, Republic of Korea).

scholarly journals A Randomized, Double-Blinded, Placebo-Controlled, Phase 1 Study of a Replication-Defective Herpes Simplex Virus (HSV) Type 2 Vaccine, HSV529, in Adults With or Without HSV Infection

2019 ◽  
Vol 220 (6) ◽  
pp. 990-1000 ◽  
Author(s):  
Lesia K Dropulic ◽  
Makinna C Oestreich ◽  
Harlan L Pietz ◽  
Kerry J Laing ◽  
Sally Hunsberger ◽  
...  
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
T Cell ◽  
T Cell Responses ◽  
Neutralizing Antibody ◽  
Cd4 T Cell ◽  
Cell Responses ◽  
Systemic Reactions ◽  
Simplex Virus ◽  
Double Blinded

Abstract Background Herpes simplex virus 2 (HSV2) causes genital herpes in >400 million persons worldwide. Methods We conducted a randomized, double-blinded, placebo-controlled trial of a replication-defective HSV2 vaccine, HSV529. Twenty adults were enrolled in each of 3 serogroups of individuals: those negative for both HSV1 and HSV2 (HSV1−/HSV2−), those positive or negative for HSV1 and positive for HSV2 (HSV1±/HSV2+), and those positive for HSV1 and negative for HSV2 (HSV1+/HSV2−). Sixty participants received vaccine or placebo at 0, 1, and 6 months. The primary end point was the frequency of solicited local and systemic reactions to vaccination. Results Eighty-nine percent of vaccinees experienced mild-to-moderate solicited injection site reactions, compared with 47% of placebo recipients (95% confidence interval [CI], 12.9%–67.6%; P = .006). Sixty-four percent of vaccinees experienced systemic reactions, compared with 53% of placebo recipients (95% CI, −17.9% to 40.2%; P = .44). Seventy-eight percent of HSV1−/HSV2− vaccine recipients had a ≥4-fold increase in neutralizing antibody titer after 3 doses of vaccine, whereas none of the participants in the other serogroups had such responses. HSV2-specific CD4+ T-cell responses were detected in 36%, 46%, and 27% of HSV1−/HSV2−, HSV1±/HSV2+, and HSV1+/HSV2− participants, respectively, 1 month after the third dose of vaccine, and CD8+ T-cell responses were detected in 14%, 8%, and 18% of participants, respectively. Conclusions HSV529 vaccine was safe and elicited neutralizing antibody and modest CD4+ T-cell responses in HSV-seronegative vaccinees. Clinical Trials Registration NCT01915212.

scholarly journals Soluble Spike DNA Vaccine Provides Long-Term Protective Immunity against SARS-CoV-2 in Mice and Nonhuman Primates

Vaccines ◽  
2021 ◽  
Vol 9 (4) ◽  
pp. 307
Author(s):  
Yong Bok Seo ◽  
You Suk Suh ◽  
Ji In Ryu ◽  
Hwanhee Jang ◽  
Hanseul Oh ◽  
...  
Keyword(s):  
T Cell ◽  
Nonhuman Primates ◽  
Vaccine Candidate ◽  
T Cell Responses ◽  
Neutralizing Antibody ◽  
Dependent Manner ◽  
Viral Loads ◽  
Cell Responses ◽  
Rapid Spread

The unprecedented and rapid spread of SARS-CoV-2 (severe acute respiratory syndrome-coronavirus-2) has motivated the need for a rapidly producible and scalable vaccine. Here, we developed a synthetic soluble SARS-CoV-2 spike (S) DNA-based vaccine candidate, GX-19. In mice, immunization with GX-19 elicited not only S-specific systemic and pulmonary antibody responses but also Th1-biased T cell responses in a dose-dependent manner. GX-19-vaccinated nonhuman primates seroconverted rapidly and exhibited a detectable neutralizing antibody response as well as multifunctional CD4+ and CD8+ T cell responses. Notably, when the immunized nonhuman primates were challenged at 10 weeks after the last vaccination with GX-19, they had reduced viral loads in contrast to non-vaccinated primates as a control. These findings indicate that GX-19 vaccination provides a durable protective immune response and also support further development of GX-19 as a vaccine candidate for SARS-CoV-2.

scholarly journals HIV mRNA Vaccines—Progress and Future Paths

Vaccines ◽  
2021 ◽  
Vol 9 (2) ◽  
pp. 134
Author(s):  
Zekun Mu ◽  
Barton F. Haynes ◽  
Derek W. Cain
Keyword(s):  
T Cell ◽  
Neutralizing Antibodies ◽  
Vaccination Strategy ◽  
T Cell Responses ◽  
Neutralizing Antibody ◽  
Cytotoxic T Cell ◽  
Therapeutic Vaccines ◽  
Cell Responses ◽  
Broadly Neutralizing Antibody ◽  
Cytotoxic T Cell Responses

The SARS-CoV-2 pandemic introduced the world to a new type of vaccine based on mRNA encapsulated in lipid nanoparticles (LNPs). Instead of delivering antigenic proteins directly, an mRNA-based vaccine relies on the host’s cells to manufacture protein immunogens which, in turn, are targets for antibody and cytotoxic T cell responses. mRNA-based vaccines have been the subject of research for over three decades as a platform to protect against or treat a variety of cancers, amyloidosis and infectious diseases. In this review, we discuss mRNA-based approaches for the generation of prophylactic and therapeutic vaccines to HIV. We examine the special immunological hurdles for a vaccine to elicit broadly neutralizing antibodies and effective T cell responses to HIV. Lastly, we outline an mRNA-based HIV vaccination strategy based on the immunobiology of broadly neutralizing antibody development.

418 A phase 1, dose escalation and dose expansion study of SQZ PBMC HPV as monotherapy and in combination with atezolizumab in HLA-A*02+ Patients with HPV16+ recurrent, or metastatic solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A444-A444
Author(s):  
Cathy Eng ◽  
Joaquina Baranda ◽  
Matthew Taylor ◽  
Michael Gordon ◽  
Ursula Matulonis ◽  
...  
Keyword(s):  
T Cell ◽  
Solid Tumors ◽  
Cancer Vaccine ◽  
Phase 1 ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Dose Effect ◽  
Statistical Hypothesis ◽  
Mhc I ◽  
Cell Responses

BackgroundSQZ-PBMC-HPV is a therapeutic cancer vaccine created with Cell Squeeze®, a proprietary cell-engineering system. SQZ-PBMC-HPV is a novel cancer vaccine generated from peripheral blood mononuclear cells (PBMC) squeezed with HPV16 E6 and E7 antigens, resulting in delivery into the cytosol. The resulting antigen presenting cells (APCs) provide enhanced antigen presentation on MHC-I to potentially elicit robust, antigen-specific CD8+ T cell responses. Importantly, SQZ-PBMC-HPV are neither genetically modified nor immune effector cells.Studies in MHC-I knockout mice demonstrated that activation of antigen specific CD8+ tumor infiltrating lymphocytes (TILs) was a direct effect of cytosolic antigen delivery to PBMCs. In the murine TC-1 tumor model, tumor regression correlated with an influx of HPV16-specific CD8+ TILs. In vitro studies with human volunteer PBMCs demonstrated that each subset is capable of inducing CD8+ T cell responses. The Phase 1 study includes a significant biomarker program to investigate whether pharmacodynamic effects observed in non-clinical studies correlate with potential clinical benefit. Immunogenic and pharmacodynamic endpoints include Elispot assays to measure frequency of interferon gamma secreting cells, as well as quantification and characterization of TILs and tumor microenvironment. In addition, various cytokine responses and circulating cell-free HPV16 DNA levels in plasma are measured.MethodsSQZ-PBMC-HPV-101 (NCT04084951) is open for enrollment to HLA A*02+ patients with HPV16+ recurrent, locally advanced or metastatic solid tumors and includes escalation cohorts for monotherapy and in combination with atezolizumab. After initial demonstration of safety, the study assesses dose effect by testing different cell dose levels, the effect of prolonged antigen priming in Cycle 1 [APC administration on Day 1 only compared to Days 1 and 2 (double priming)] and the impact of treatment duration to identify the optimal dose regimen. The cycle length is 3 weeks, and patients will receive SQZ-PBMC-HPV for up to 1 year or until available autologous drug product is exhausted. Atezolizumab will be administered for up to 1 year. Eligible patients including but not limited to anal, cervical and head and neck tumors will undergo a single leukapheresis at the study site. The manufacturing process includes a maturation step and takes less than 24 hours. The vein-to-vein time for the 1st administration is approximately one week. Patients must have a lesion that can be biopsied with acceptable clinical risk and agree to have a fresh biopsy at Screening and on study. A Study Safety Committee is in place. No formal statistical hypothesis testing will be performed.ResultsN/AConclusionsN/ATrial RegistrationNCT04084951Ethics ApprovalThe study is registered on clinicaltrials.gov was approved by the Ethics Board of all institution listed as recruiting.

scholarly journals Marburg virus survivor immune responses are Th1 skewed with limited neutralizing antibody responses

2017 ◽  
Vol 214 (9) ◽  
pp. 2563-2572 ◽  
Author(s):  
Spencer W. Stonier ◽  
Andrew S. Herbert ◽  
Ana I. Kuehne ◽  
Ariel Sobarzo ◽  
Polina Habibulin ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Ebola Virus ◽  
T Cell Responses ◽  
Neutralizing Antibody ◽  
Cd8 T Cell ◽  
Marburg Virus ◽  
Antibody Responses ◽  
Cd4 T Cell ◽  
Cell Responses

Until recently, immune responses in filovirus survivors remained poorly understood. Early studies revealed IgM and IgG responses to infection with various filoviruses, but recent outbreaks have greatly expanded our understanding of filovirus immune responses. Immune responses in survivors of Ebola virus (EBOV) and Sudan virus (SUDV) infections have provided the most insight, with T cell responses as well as detailed antibody responses having been characterized. Immune responses to Marburg virus (MARV), however, remain almost entirely uncharacterized. We report that immune responses in MARV survivors share characteristics with EBOV and SUDV infections but have some distinct differences. MARV survivors developed multivariate CD4+ T cell responses but limited CD8+ T cell responses, more in keeping with SUDV survivors than EBOV survivors. In stark contrast to SUDV survivors, rare neutralizing antibody responses in MARV survivors diminished rapidly after the outbreak. These results warrant serious consideration for any vaccine or therapeutic that seeks to be broadly protective, as different filoviruses may require different immune responses to achieve immunity.

scholarly journals Cytotoxic polyfunctionality maturation of cytomegalovirus-pp65-specific CD4 + and CD8 + T-cell responses in older adults positively correlates with response size

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Yen-Ling Chiu ◽  
Chung-Hao Lin ◽  
Bo-Yi Sung ◽  
Yi-Fang Chuang ◽  
Jonathan P. Schneck ◽  
...  
Keyword(s):  
Older Adults ◽  
T Cell ◽  
T Cell Responses ◽  
Cd8 T Cell ◽  
Cell Responses

Neutralizing Antibody-Independent SARS-CoV-2 Control Correlated with Intranasal Vaccine-Induced CD8 + T-Cell Responses

2021 ◽  
Author(s):  
Hiroshi Ishii ◽  
Takushi Nomura ◽  
Hiroyuki Yamamoto ◽  
Masako Nishizawa ◽  
Trang Thi Thu Hau ◽  
...  
Keyword(s):  
T Cell ◽  
T Cell Responses ◽  
Neutralizing Antibody ◽  
Cell Responses ◽  
Intranasal Vaccine

scholarly journals CD8 T Cell Responses to an Immunodominant Epitope within the Nonstructural Protein NS1 Provide Wide Immunoprotection against Bluetongue Virus in IFNAR−/−Mice

2018 ◽  
Vol 92 (16) ◽  
Author(s):  
Alejandro Marín-López ◽  
Eva Calvo-Pinilla ◽  
Diego Barriales ◽  
Gema Lorenzo ◽  
Alejandro Brun ◽  
...  
Keyword(s):  
T Cell ◽  
Bluetongue Virus ◽  
Neutralizing Antibodies ◽  
Nonstructural Protein ◽  
T Cell Responses ◽  
Neutralizing Antibody ◽  
Cd8 T Cell ◽  
T Cell Response ◽  
Cell Responses ◽  
N Terminus

ABSTRACTThe development of vaccines against bluetongue, a prevalent livestock disease, has been focused on surface antigens that induce strong neutralizing antibody responses. Because of their antigenic variability, these vaccines are usually serotype restricted. We now show that a single highly conserved nonstructural protein, NS1, expressed in a modified vaccinia Ankara virus (MVA) vector can provide multiserotype protection in IFNAR−/−129 mice against bluetongue virus (BTV) that is largely dependent on CD8 T cell responses. We found that the protective antigenic capacity of NS1 resides within the N terminus of the protein and is provided in the absence of neutralizing antibodies. The protective CD8 T cell response requires the presence of a specific peptide within the N terminus of NS1, since its deletion ablates the efficacy of the vaccine formulation. These data reveal the importance of the nonstructural protein NS1 in CD8 T cell-mediated protection against multiple BTV serotypes when vectorized as a recombinant MVA vaccine.IMPORTANCEConventional vaccines have controlled or limited BTV expansion in the past, but they cannot address the need for cross-protection among serotypes and do not allow distinguishing between infected and vaccinated animals (DIVA strategy). There is a need to develop universal vaccines that induce effective protection against multiple BTV serotypes. In this work we have shown the importance of the nonstructural protein NS1, conserved among all the BTV serotypes, in CD8 T cell-mediated protection against multiple BTV serotypes when vectorized as a recombinant MVA vaccine.

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