scholarly journals Safety and Immunogenicity of an Inactivated SARS-CoV-2 Vaccine in a Subgroup of Healthy Adults in Chile

2021 ◽  
Author(s):  
Susan M Bueno ◽  
Katia Abarca ◽  
Pablo A González ◽  
Nicolás M S Gálvez ◽  
Jorge A Soto ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adverse Reaction ◽  
Neutralizing Antibodies ◽  
Adverse Reactions ◽  
Age Group ◽  
Phase 3 ◽  
Blood Samples ◽  
Cell Responses ◽  
Global Priority ◽  
Neutralizing Capacity

Abstract Background The development of effective vaccines against COVID-19 is a global priority. CoronaVac is an inactivated SARS-CoV-2 vaccine with promising safety and immunogenicity profiles. This article reports safety and immunogenicity results obtained for healthy Chilean adults aged ≥18 in a phase 3 clinical trial. Methods Volunteers randomly received two doses of CoronaVac or placebo, separated by two weeks. 434 volunteers were enrolled, 397 aged 18-59 years, and 37 aged ≥60 years. Solicited and unsolicited adverse reactions were registered from all volunteers. Blood samples were obtained from a subset of volunteers and analyzed for humoral and cellular measures of immunogenicity. Results The primary adverse reaction in the 434 volunteers was pain at the injection site, with a higher incidence in the vaccine than in the placebo arm. Adverse reactions observed were mostly mild and local. No severe adverse events were reported. The humoral evaluation was performed on 81 volunteers. Seroconversion rates for specific anti-S1-RBD IgG were 86.67% in the 18-59 age group and 70.37% in the ≥60 age group, two and four weeks after the second dose. A significant increase in circulating neutralizing antibodies was detected two and four weeks after the second dose. The cellular evaluation was performed on 47 volunteers. We detected a significant induction of T cell responses characterized by the secretion of IFN-γupon stimulation with Mega Pools of peptides from SARS-CoV-2. Conclusions Immunization with CoronaVac in a 0-14 schedule in Chilean adults aged ≥18 is safe, induces anti-S1-RBD IgG with neutralizing capacity, activates T cells, and promotes the secretion of IFN-γupon stimulation with SARS-CoV-2 antigens.

scholarly journals Safety of Inulin and Sinistrin: Combining Several Sources for Pharmacovigilance Purposes

2021 ◽  
Vol 12 ◽  
Author(s):  
T-V. Bui ◽  
C. Prot-Bertoye ◽  
H. Ayari ◽  
S. Baron ◽  
J-P. Bertocchio ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Adverse Reaction ◽  
Anaphylactic Shock ◽  
Adverse Reactions ◽  
Fatal Outcome ◽  
Hypersensitivity Reactions ◽  
Multiple Sources ◽  
National Agency ◽  
Health Products ◽  
Pharmaceutical Industries

Introduction: Inulin and its analog sinistrin are fructose polymers used in the food and pharmaceutical industries. In 2018, The French National Agency for the Safety of Medicines and Health Products (ANSM) decided to withdraw products containing sinistrin and inulin due to several reports of serious hypersensitivity reactions, including a fatal outcome.Objective: To assess the safety of inulin and sinistrin use in France.Methods: We searched multiple sources to identify adverse reactions (ARs) to inulin or sinistrin: first, classical pharmacovigilance databases including the French Pharmacovigilance (FPVD) and the WHO Database (VigiBase); second, data from a clinical trial, MultiGFR; third, data regarding current use in an hospital. All potential ARs to inulin or sinistrin were analyzed with a focus on hypersensitivity reactions and relationships to batches of sinistrin.Results: From 1991 to 2018, 134 ARs to inulin or sinistrin were registered in the FPVD or VigiBase. Sixty-three cases (47%) were classified as serious, and 129 cases (96%) were hypersensitivity reactions. We found an association between a batch of sinistrin and the occurrence of hypersensitivity reactions. During the MultiGFR clinical trial, 7 patients (7/163 participants) had an Adverse reaction; of these, 4 were hypersensitivity reactions including one case of grade 4 anaphylactic shock. In the hospital, no ARs were observed. In the literature, ARs to inulin and sinistrin are very rarely reported and mostly benign.Conclusion: Most ARs to inulin and sinistrin are hypersensitivity reactions that appear to be associated with sinistrin batches.

scholarly journals Interim report: Safety and immunogenicity of an inactivated vaccine against SARS-CoV-2 in healthy chilean adults in a phase 3 clinical trial

2021 ◽  
Author(s):  
Susan M Bueno ◽  
Katia Abarca ◽  
Pablo A González ◽  
Nicolás MS Gálvez ◽  
Jorge A Soto ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Injection Site ◽  
Rapid Development ◽  
Seroconversion Rate ◽  
T Cell Response ◽  
Cell Mediated Immunity ◽  
Phase 3 ◽  
Link Type ◽  
Neutralizing Capacity ◽  
Ifn Γ

AbstractBackgroundThe ongoing COVID-19 pandemic has had a significant impact worldwide, with an incommensurable social and economic burden. The rapid development of safe and protective vaccines against this disease is a global priority. CoronaVac is a vaccine prototype based on inactivated SARS-CoV-2, which has shown promising safety and immunogenicity profiles in pre-clinical studies and phase 1/2 trials in China. To this day, four phase 3 clinical trials are ongoing with CoronaVac in Brazil, Indonesia, Turkey, and Chile. This article reports the safety and immunogenicity results obtained in a subgroup of participants aged 18 years and older enrolled in the phase 3 Clinical Trial held in Chile.MethodsThis is a multicenter phase 3 clinical trial. Healthcare workers aged 18 years and older were randomly assigned to receive two doses of CoronaVac or placebo separated by two weeks (0-14). We report preliminary safety results obtained for a subset of 434 participants, and antibody and cell-mediated immunity results obtained in a subset of participants assigned to the immunogenicity arm. The primary and secondary aims of the study include the evaluation of safety parameters and immunogenicity against SARS-CoV-2 after immunization, respectively. This trial is registered at clinicaltrials.gov (NCT04651790).FindingsThe recruitment of participants occurred between November 27th, 2020, until January 9th, 2021. 434 participants were enrolled, 397 were 18-59 years old, and 37 were ≥60 years old. Of these, 270 were immunized with CoronaVac, and the remaining 164 participants were inoculated with the corresponding placebo. The primary adverse reaction was pain at the injection site, with a higher incidence in the vaccine arm (55.6%) than in the placebo arm (40.0%). Moreover, the incidence of pain at the injection site in the 18-59 years old group was 58.4% as compared to 32.0% in the ≥60 years old group. The seroconversion rate for specific anti-S1-RBD IgG was 47.8% for the 18-59 years old group 14 days post immunization (p.i.) and 95.6% 28 and 42 days p.i. For the ≥60 years old group, the seroconversion rate was 18.1%, 100%, and 87.5% at 14, 28, and 42 days p.i., respectively. Importantly, we observed a 95.7% seroconversion rate in neutralizing antibodies for the 18-59 years old group 28 and 42 days p.i. The ≥60 years old group exhibited seroconversion rates of 90.0% and 100% at 28 and 42 days p.i. Interestingly, we did not observe a significant seroconversion rate of anti-N-SARS-CoV-2 IgG for the 18-59 years old group. For the participants ≥60 years old, a modest rate of seroconversion at 42 days p.i. was observed (37.5%). We observed a significant induction of a T cell response characterized by the secretion of IFN-γ upon stimulation with Mega Pools of peptides derived from SARS-CoV-2 proteins. No significant differences between the two age groups were observed for cell-mediated immunity.InterpretationImmunization with CoronaVac in a 0-14 schedule in adults of 18 years and older in the Chilean population is safe and induces specific IgG production against the S1-RBD with neutralizing capacity, as well as the activation of T cells secreting IFN-γ, upon recognition of SARS-CoV-2 antigens.FundingMinistry of Health of the Chilean Government; Confederation of Production and Commerce, Chile; Consortium of Universities for Vaccines and Therapies against COVID-19, Chile; Millennium Institute on Immunology and Immunotherapy.

Immunotransplant Expands Vaccine-Induced Memory T Cell Responses In Patients With Mantle Cell Lymphoma

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1816-1816 ◽  
Author(s):  
Debra K Czerwinski ◽  
Joshua Brody ◽  
Holbrook E Kohrt ◽  
Malek Faham ◽  
Etelka Gabriel ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Cell Lymphoma ◽  
T Cell Responses ◽  
Blood Samples ◽  
Post Transplant ◽  
Cell Responses ◽  
Mantle Cell ◽  
Over Time

Abstract Background Autologous transplant has been shown to prolong survival in patients with MCL, a disease which is known to have poor long-term survival. The purpose of this clinical trial is to reduce the relapse rate and prolong survival through the induction of anti-tumor T cells which can effectively survey, expand and eradicate tumor cells when and if they arise. In a murine model, T cells from CpG-tumor vaccinated donors were shown to expand preferentially in recipient mice following a myeloablative regimen and were effective in eradicating tumor in these mice (Goldstein, M. et al., Blood 2011). Consequently, we developed a clinical trial where patients with mantle cell lymphoma (MCL) are given a CpG-based cellular vaccine followed by an autologous stem cell transplant (Immunotransplant). T cells, harvested after vaccination prior to transplant, are reinfused post-transplant. Blood samples are taken prior to vaccine, post the initial vaccination, as well as post immunotransplant to study the CD4 and CD8 anti-tumor T cell responses. Blood samples are also drawn pre and 2 weeks post a vaccine boost given approximately 6 months post-transplant to assess the memory component of the anti-tumor T cells. Methods Peripheral blood lymphocytes (PBL) were cultured for 5 days with and without autologous CpG activated tumor. T cells were re-stimulated over-night with fresh activated tumor then analyzed by flow cytometry for phenotype (CD4+ T cells, CD8+/CD56- T cells and memory marker, CD45RO) as well as functionality (cytokine expression [IFN-g, TNF and IL-2], cytolitic activity [perforin and granzyme B expression] and activation markers, CD137 and ICOS [CD278]). In several cases, tumor-responsive T cells from co-cultures were sequenced to determine their TCRb repertoire. Clonotypes enriched over those found in PBL drawn pre-vaccine were deemed to be antigen-specific. These clones were compared to ones enriched directly in the blood after the original vaccine and later boost. Results To date, 21 MCL patients have been enrolled and have received the immunotransplant as well as final vaccine boost. 15 patients have been analyzed and have shown anti-tumor T cell responses following vaccine and immunotransplant. In most cases, the T cell responses were boosted post immunotransplant suggesting an expansion of anti-tumor T cells as predicted by the murine model. The phenotype of the responding T cells (CD4, CD8, or both CD4 and CD8) varied between patients. (Figure 1.) Also, in 11/15 patients, tumor-responsive T cells were still present at the time of the final vaccine, about 6 months post-transplant. The final vaccine boosted T cell responses, mostly in the CD8 compartment, suggesting an induced memory anti-tumor T cell response, which is durable over time. (Figure 2.) Finally, TCRb clonotypic analyses of the responding T cells demonstrated that these T cell clones were enriched in the blood post vaccine providing further proof that they were vaccine-induced. Conclusion Immunotransplant can induce and expand a population of tumor-responsive memory T cells, both CD4 and CD8, which can be detected as an expansion of specific TCRb clonotypes in whole blood. This response is durable over time and can be boosted suggesting a means by which the immune system can be enticed to maintain anti-tumor surveillance and eradicate tumor cells in the future. Disclosures: Faham: Sequenta, Inc.: Employment, Patents & Royalties.

scholarly journals mRNA-1273 vaccine induces neutralizing antibodies against spike mutants from global SARS-CoV-2 variants

2021 ◽  
Author(s):  
Kai Wu ◽  
Anne P. Werner ◽  
Juan I. Moliva ◽  
Matthew Koch ◽  
Angela Choi ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Human Subjects ◽  
Geometric Mean ◽  
Phase 3 ◽  
The United Kingdom ◽  
Global Pandemic ◽  
Fold Reduction ◽  
Neutralizing Capacity ◽  
Human Sera ◽  
Trial Participants

ABSTRACTSevere acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is the causative infection of a global pandemic that has led to more than 2 million deaths worldwide. The Moderna mRNA-1273 vaccine has demonstrated ~94% efficacy in a Phase 3 study and has been approved under Emergency Use Authorization. The emergence of SARS-CoV-2 variants with mutations in the spike protein, most recently circulating isolates from the United Kingdom (B.1.1.7) and Republic of South Africa (B.1.351), has led to lower neutralization from convalescent serum by pseudovirus neutralization (PsVN) assays and resistance to certain monoclonal antibodies. Here, using two orthogonal VSV and lentivirus PsVN assays expressing spike variants of 20E (EU1), 20A.EU2, D614G-N439, mink cluster 5, B.1.1.7, and B.1.351 variants, we assessed the neutralizing capacity of sera from human subjects or non-human primates (NHPs) that received mRNA-1273. No significant impact on neutralization against the B.1.1.7 variant was detected in either case, however reduced neutralization was measured against the mutations present in B.1.351. Geometric mean titer (GMT) of human sera from clinical trial participants in VSV PsVN assay using D614G spike was 1/1852. VSV pseudoviruses with spike containing K417N-E484K-N501Y-D614G and full B.1.351 mutations resulted in 2.7 and 6.4-fold GMT reduction, respectively, when compared to the D614G VSV pseudovirus. Importantly, the VSV PsVN GMT of these human sera to the full B.1.351 spike variant was still 1/290, with all evaluated sera able to fully neutralize. Similarly, sera from NHPs immunized with 30 or 100μg of mRNA-1273 had VSV PsVN GMTs of ~ 1/323 or 1/404, respectively, against the full B.1.351 spike variant with a ~ 5 to 10-fold reduction compared to D614G. Individual mutations that are characteristic of the B.1.1.7 and B.1.351 variants had a similar impact on neutralization when tested in VSV or in lentivirus PsVN assays. Despite the observed decreases, the GMT of VSV PsVN titers in human vaccinee sera against the B.1.351 variant remained at ~1/300. Taken together these data demonstrate reduced but still significant neutralization against the full B.1.351 variant following mRNA-1273 vaccination.

scholarly journals Donors for SARS-CoV-2 Convalescent Plasma for a Controlled Clinical Trial: Donor Characteristics, Content and Time Course of SARS-CoV-2 Neutralizing Antibodies

2021 ◽  
pp. 1-10
Author(s):  
Sixten Körper ◽  
Bernd Jahrsdörfer ◽  
Victor M. Corman ◽  
Jan Pilch ◽  
Patrick Wuchter ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Randomized Clinical Trial ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Controlled Clinical Trial ◽  
Neutralizing Capacity ◽  
Iga Antibodies ◽  
Antibody Titers ◽  
Antibody Levels ◽  
Over Time

<b><i>Background:</i></b> Convalescent plasma is one of the treatment options for COVID-19 which is currently being investigated in many clinical trials. Understanding of donor and product characteristics is important for optimization of convalescent plasma. <b><i>Methods:</i></b> Patients who had recovered from CO­VID-19 were recruited as donors for COVID-19 convalescent plasma (CCP) for a randomized clinical trial of CCP for treatment of severe COVID-19 (CAPSID Trial). Titers of neutralizing antibodies were measured by a plaque-reduction neutralization test (PRNT). Correlation of antibody titers with host factors and evolution of neutralizing antibody titers over time in repeat donors were analysed. <b><i>Results:</i></b> A series of 144 donors (41% females, 59% males; median age 40 years) underwent 319 plasmapheresis procedures providing a median collection volume of 850 mL and a mean number of 2.7 therapeutic units per plasmapheresis. The majority of donors had a mild or moderate course of COVID-19. The titers of neutralizing antibodies varied greatly between CCP donors (from &#x3c;1:20 to &#x3e;1:640). Donor factors (gender, age, ABO type, body weight) did not correlate significantly with the titer of neutralizing antibodies. We observed a significant positive correlation of neutralization titers with the number of reported COVID-19 symptoms and with the time from SARS-CoV-2 diagnosis to plasmapheresis. Neutralizing antibody levels were stable or increased over time in 58% of repeat CCP donors. Mean titers of neutralizing antibodies of first donation and last donation of repeat CCP donors did not differ significantly (1:86 at first compared to 1:87 at the last donation). There was a significant correlation of neutralizing antibodies measured by PRNT and anti-SARS-CoV-2 IgG and IgA antibodies which were measured by ELISA. CCP donations with an anti-SARS-CoV-2 IgG antibody content above the 25th percentile were substantially enriched for CCP donations with higher neutralizing antibody levels. <b><i>Conclusion:</i></b> We demonstrate the feasibility of collection of a large number of CCP products under a harmonized protocol for a randomized clinical trial. Titers of neutralizing antibodies were stable or increased over time in a subgroup of repeat donors. A history of higher number of COVID-19 symptoms and higher levels of anti-SARS-CoV-2 IgG and IgA antibodies in immunoassays can preselect donations with higher neutralizing capacity.

scholarly journals Assessment of neutralizing antibodies elicited by a vaccine (Nakayama) strain of Japanese encephalitis virus in Taiwan

1997 ◽  
Vol 119 (1) ◽  
pp. 79-83 ◽  
Author(s):  
W. R.-H. SHYU ◽  
Y.-C. WANG ◽  
C. CHIN ◽  
W.-J. CHEN
Keyword(s):  
Vaccine Strain ◽  
Japanese Encephalitis ◽  
Random Sampling ◽  
Neutralizing Antibodies ◽  
Neutralization Test ◽  
Protective Efficacy ◽  
Age Group ◽  
Blood Samples ◽  
Blood Specimens ◽  
Good Coverage

A total of 368 blood specimens were resampled from a serum collection containing 2914 blood samples which were collected by a random sampling in Taiwan in 1991. The plaque reduction neutralization test was applied to evaluate the neutralizing ability to two strains of Japanese encephalitis viruses, i.e. Nakayama (the present vaccine strain) and JE5 (a Taiwan isolate). The result revealed that antibodies against JE virus were present in each stratified age group. Antibody positive rates were both highest in the group older than 70 years although the lowest rates were located in different groups. In addition, the result showed that the immunogenicity potency of the antibody induced by the vaccine strain did not have a good coverage against JE5. The rate of neutralizing antibodies above the level of protective efficacy of the present vaccine was limited as low as 37·93%. Efficacy of the vaccine used at present was apparently not efficient. Consideration of a more promising vaccine may be necessary.

Analysis of PSA-Specific T-Cell Responses of Prostate Cancer Patients Given a PSA-Based Vaccine on a Clinical Trial

2003 ◽  
Author(s):  
James Gulley ◽  
William Dahut ◽  
Philip M. Arlen ◽  
Kwong Tsang ◽  
Jeffrey Schlom
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
T Cell ◽  
Cancer Patients ◽  
T Cell Responses ◽  
Cell Responses

scholarly journals 413 GEN-009, a personalized neoantigen vaccine, elicits robust immune responses in individuals with advanced or metastatic solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A438-A438
Author(s):  
Mara Shainheit ◽  
Devin Champagne ◽  
Gabriella Santone ◽  
Syukri Shukor ◽  
Ece Bicak ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Immune Responses ◽  
Solid Tumors ◽  
Ex Vivo ◽  
T Cell Responses ◽  
Checkpoint Blockade ◽  
T Cell Subsets ◽  
Cell Responses

BackgroundATLASTM is a cell-based bioassay that utilizes a cancer patient‘s own monocyte-derived dendritic cells and CD4+ and CD8+ T cells to screen their mutanome and identify neoantigens that elicit robust anti-tumor T cell responses, as well as, deleterious InhibigensTM.1 GEN-009, a personalized vaccine comprised of 4–20 ATLAS-identified neoantigens combined with Hiltonol®, harnesses the power of neoantigen-specific T cells to treat individuals with solid tumors. The safety and efficacy of GEN-009 is being assessed in a phase 1/2a clinical trial (NCT03633110).MethodsA cohort of 15 adults with solid tumors were enrolled in the study. During the screening period, patients received standard of care PD-1-based immunotherapies appropriate for their tumor type. Subsequently, patients were immunized with GEN-009 with additional doses administered at 3, 6, 12, and 24 weeks. Peripheral blood mononuclear cells (PBMCs) were collected at baseline, pre-vaccination (D1), as well as 29, 50, 92, and 176 days post first dose. Vaccine-induced immunogenicity and persistence were assessed by quantifying neoantigen-specific T cell responses in ex vivo and in vitro stimulation dual-analyte fluorospot assays. Polyfunctionality of neoantigen-specific T cells was evaluated by intracellular cytokine staining. Additionally, potential correlations between the ATLAS-identified profile and vaccine-induced immunogenicity were assessed.ResultsGEN-009 augmented T cell responses in 100% of evaluated patients, attributable to vaccine and not checkpoint blockade. Furthermore, neoantigen-induced secretion of IFNγ and/or TNFα by PBMCs, CD4+, and CD8+ T cells was observed in all patients. Responses were primarily from polyfunctional TEM cells and detectable in both CD4+ and CD8+ T cell subsets. Some patients had evidence of epitope spreading. Unique response patterns were observed for each patient with no apparent relationship between tumor types and time to emergence, magnitude or persistence of response. Ex vivo vaccine-induced immune responses were observed as early as 1 month, and in some cases, persisted for 176 days. Clinical efficacy possibly attributable to GEN-009 was observed in several patients, but no correlation has yet been identified with neoantigen number or magnitude of immune response.ConclusionsATLAS empirically identifies stimulatory neoantigens using the patient‘s own immune cells. GEN-009, which is comprised of personalized, ATLAS-identified neoantigens, elicits early, long-lasting and polyfunctional neoantigen-specific CD4+ and CD8+ T cell responses in individuals with advanced cancer. Several patients achieved clinical responses that were possibly attributable to vaccine; efforts are underway to explore T cell correlates of protection. These data support that GEN-009, in combination with checkpoint blockade, represents a unique approach to treat solid tumors.AcknowledgementsWe are grateful to the patients and their families who consented to participate in the GEN-009-101 clinical trial.Trial RegistrationNCT03633110Ethics ApprovalThis study was approved by Western Institutional Review Board, approval number 1-1078861-1. All subjects contributing samples provided signed individual informed consent.ReferenceDeVault V, Starobinets H, Adhikari S, Singh S, Rinaldi S, Classon B, Flechtner J, Lam H. Inhibigens, personal neoantigens that drive suppressive T cell responses, abrogate protection of therapeutic anti-tumor vaccines. J. Immunol 2020; 204(1 Supplement):91.15.

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