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

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.

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Interleukin-6 and Interleukin-12 Participate in Induction of a Type 1 Protective T-Cell Response during Vaccination with a Tuberculosis Subunit Vaccine

Infection and Immunity ◽

10.1128/iai.67.11.5747-5754.1999 ◽

1999 ◽

Vol 67 (11) ◽

pp. 5747-5754 ◽

Cited By ~ 72

Author(s):

Irene S. Leal ◽

Birgitte Smedegård ◽

Peter Andersen ◽

Rui Appelberg

Keyword(s):

T Cells ◽

Interleukin 6 ◽

Neutralizing Antibodies ◽

Subunit Vaccine ◽

T Cell Response ◽

Interleukin 12 ◽

Cell Mediated Immunity ◽

Ifn Γ ◽

Dimethyldioctadecylammonium Bromide

ABSTRACT We examined the role of cytokines in the development of gamma interferon (IFN-γ)-secreting protective T cells following immunization with a culture filtrate subunit vaccine againstMycobacterium tuberculosis containing the adjuvant dimethyldioctadecylammonium bromide (DDA). Depletion of either interleukin-6 (IL-6) or IL-12 with specific neutralizing antibodies during vaccination reduced the priming of T cells for antigen-specific proliferation and IFN-γ secretion. Such reduction was also observed in IL-6 gene-disrupted mice as compared to wild-type animals. IL-6 was found to play a role in the initial differentiation of Th1 cells but not in their expansion. The defect found after IL-6 depletion or in IL-6-knockout mice was compensated by the inclusion of recombinant mouse IL-12 in the vaccine. The induction of protective immunity against an intravenous or an aerosol challenge with live, virulentM. tuberculosis was markedly reduced by neutralizing either IL-6 or IL-12 during immunization with the vaccine. Likewise, the effects of IL-6 neutralization were partially reversed by including IL-12 in the vaccine. Our data point to an important role of IL-6 and IL-12 in the generation of cell-mediated immunity to tuberculosis.

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787 Phase III clinical trial to test the safety and efficacy of autologous tumor lysate-loaded dendritic cells in patients with newly diagnosed glioblastoma

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0787 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A836-A836

Author(s):

Marnix Bosch ◽

Linda Liau ◽

Keyoumars Ashkan

Keyword(s):

Clinical Trial ◽

Dendritic Cells ◽

Tumor Cell ◽

Disease Progression ◽

Autologous Tumor ◽

Newly Diagnosed ◽

Tumor Lysate ◽

Phase 3 ◽

Link Type ◽

To Receive

BackgroundGlioblastoma (GBM) is an incurable form of brain cancer with a high mortality rate in which multiple treatment attempts over the past decade have proven unsuccessful at extending survival. Early stage data have suggested that immunization against tumor cell antigens may be effective in GBM. In this Phase 3 study we aimed to assess whether autologous dendritic cells (DCs) loaded with autologous tumor cell lysate, is able to improve survival in these patients.MethodsWe conducted a randomized, double-blind, placebo-controlled international Phase 3 clinical trial with autologous tumor lysate-loaded DCs (DCVax-L) in 331 patients with histologically confirmed newly diagnosed GBM. Following surgery and chemoradiation, patients were randomized 2:1 to receive temozolomide plus DCVax-L or temozolomide plus placebo (i.e., autologous PBMC). Eligibility criteria included an intent for significant tumor resection (not biopsy only), sufficient doses of DCVax-L manufactured for 5 or more immunizations, and no radiographic evidence of apparent disease progression at the end of chemoradiation. A crossover option allowed all patients to receive the autologous vaccine at the time of disease progression. As a result, 90% of the randomized patients received DCVax-L at some point during their participation in the trial. Study subjects received immunizations with 2.5 million DCs or placebo at days 0, 10 and 20, followed by immunizations at months 2, 4, 8, 12, 18, 24 and 30. All subjects were assessed for progression-free survival(PFS) and overall survival (OS). This trial is registered with clinicaltrials.gov, number NCT00045968.Trial RegistrationThe study was registered as NCT00045968Ethics ApprovalThe study was approved by all applicable Institutional Review Boards or Ethics Committees

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Contribution of Interleukin-12 (IL-12) and the CD28/B7 and CD40/CD40 Ligand Pathways to the Development of a Pathological T-Cell Response in IL-10-Deficient Mice

Infection and Immunity ◽

10.1128/iai.70.12.6940-6947.2002 ◽

2002 ◽

Vol 70 (12) ◽

pp. 6940-6947 ◽

Cited By ~ 12

Author(s):

Ulrike Wille ◽

Eric N. Villegas ◽

Linden Craig ◽

Robert Peach ◽

Christopher A. Hunter

Keyword(s):

T Cell ◽

T Cell Activation ◽

Cell Response ◽

Cd40 Ligand ◽

T Cell Response ◽

Interleukin 12 ◽

Cell Mediated Immunity ◽

Cell Functions ◽

Ifn Γ

ABSTRACT The ability of interleukin-10 (IL-10) to suppress accessory cell functions required for optimal T-cell activation makes it an important inhibitor of cell-mediated immunity. Thus, after infection with the protozoan parasite Toxoplasma gondii, IL-10 knockout (KO) mice develop a CD4+-T-cell-dependent shock-like reaction with high levels of IL-12 and gamma interferon (IFN-γ) in serum, leading to death of mice during the acute phase of infection. Previous studies from this laboratory have shown that simultaneous blockade of CD28 and CD40 can prevent this lethal reaction by inhibiting the production of IFN-γ. However, the blockade of costimulation did not affect systemic levels of IL-12. To better understand the relationship between IL-12 and the CD28 and CD40 pathways in mediating immune hyperactivity, antagonists of these factors were used to determine their effects on the development of a pathological T-cell response in IL-10 KO mice. Blockade of IL-12 or the CD28/B7 interaction alone did not affect survival; however, the combined blockade of both pathways resulted in decreased production of IFN-γ and the survival of IL-10 KO mice. To assess the role of the two ligands for CD28, B7.1 and B7.2, IL-10 KO mice were treated with αIL-12 plus αB7.1 or αB7.2 or the combination of all three antibodies. These studies revealed that blockade of both B7 molecules is required for decreased production of IFN-γ and survival of infected IL-10 KO mice, suggesting that B7.1 and B7.2 can contribute to the lethal shock-like reaction in IL-10 KO mice. In contrast, neutralization of IL-12 and blockade of the CD40/CD40 ligand (CD40L) interaction in vivo did not alter the production of IFN-γ and only resulted in a small delay in time to death of mice. Together, these data suggest that the CD28/B7 interaction has a central role in the development of a pathological T-cell response in IL-10 KO mice, which is distinct from the role of the CD40/CD40L and IL-12 pathways.

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Clinical effectiveness and safety of baricitinib for the treatment of juvenile idiopathic arthritis-associated uveitis or chronic anterior antinuclear antibody-positive uveitis: study protocol for an open-label, adalimumab active-controlled phase 3 clinical trial (JUVE-BRIGHT)

Trials ◽

10.1186/s13063-021-05651-5 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Athimalaipet V. Ramanan ◽

Catherine M. Guly ◽

Stuart Y. Keller ◽

Douglas E. Schlichting ◽

Stephanie de Bono ◽

...

Keyword(s):

Clinical Trial ◽

Juvenile Idiopathic Arthritis ◽

Antinuclear Antibody ◽

Clinical Effectiveness ◽

Janus Kinase ◽

Fixed Dose ◽

Open Label ◽

Phase 3 ◽

Bayesian Design ◽

Link Type

Abstract Background Juvenile idiopathic arthritis (JIA) is the most common pediatric rheumatic disease and the most common systemic disorder associated with uveitis in childhood. Uveitis is more common in JIA patients who are antinuclear antibody (ANA)-positive, have an early-onset disease, and have oligoarticular arthritis. JIA-associated uveitis (JIA-uveitis) is typically anterior, chronic, bilateral, nongranulomatous, and asymptomatic. Visual outcomes in JIA-uveitis have improved with current screening and treatment options; however, many patients fail to respond or do not achieve long-lasting remission. Baricitinib, an oral selective Janus kinase (JAK)1 and 2 inhibitor, may impact key cytokines implicated in the pathogenesis of JIA-uveitis or ANA-positive uveitis, representing a potential novel treatment option for disease management. Methods The multicenter, phase 3 trial will be conducted using an open-label Bayesian design. The study will enroll at least 20 and up to 40 patients aged 2 to <18 years with active JIA-uveitis or chronic ANA-positive uveitis without systemic features. At least 20 patients who have had an inadequate response or intolerance to methotrexate (MTX-IR), but not biologic disease-modifying antirheumatic drugs (bDMARDs), will be randomized (1:1) to open-label baricitinib or adalimumab. Approximately 20 additional patients who are MTX-IR or bDMARD inadequate responders will receive baricitinib treatment. Patients will be treated with once daily oral baricitinib at a fixed dose by age group (4 mg for patients aged ≥6 to <18 years and 2 mg for patients <6 years) or adalimumab (20 mg for patients weighing <30 kg and 40 mg for patients ≥30 kg) as a subcutaneous injection every 2 weeks. Treatment with stable background conventional synthetic DMARDs, low-dose corticosteroids, and/or nonsteroidal anti-inflammatory drugs is allowed. The primary endpoint is the proportion of patients with response at week 24. Patients may continue treatment for up to 5 years. Discussion This is the first pediatric clinical trial to assess the clinical effectiveness and safety of a JAK inhibitor in JIA-uveitis or chronic ANA-positive uveitis. A novel Bayesian design is used to assess the efficacy of baricitinib, including an adalimumab reference arm, in this small patient population with unmet medical need. Trial registration EudraCT 2019-000119-10. Registered on January 4, 2019; NCT04088409. Registered on September 12, 2019

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28 Retrospective pooled analysis of epacadostat clinical studies identifies doses required for maximal pharmacodynamic effect in anti-PD-1 combination studies

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-sitc2020.0028 ◽

2020 ◽

Vol 8 (Suppl 3) ◽

pp. A27-A27

Author(s):

Michael Smith ◽

Robert Newton ◽

Sherry Owens ◽

Xiaohua Gong ◽

Chuan Tian ◽

...

Keyword(s):

Mass Spectrometry ◽

Clinical Studies ◽

Reversible Inhibitor ◽

Double Blind Study ◽

List Type ◽

Phase 3 ◽

Double Blind ◽

Link Type ◽

Healthy Control ◽

Ifn Γ

BackgroundIDO1 is the initial rate-limiting enzyme in one breakdown pathway of tryptophan. It reduces tryptophan levels and generates metabolites (e.g., kynurenine [KYN]) that contribute to tumor-associated immune suppression. Epacadostat (EPA) is a novel, potent, selective, reversible inhibitor of IDO1 studied in clinical trials in combination with anti-PD-1 antibodies. Epacadostat-induced decreases in plasma KYN have been used as a pharmacodynamic measure of drug activity and have aided in dose selection for clinical studies. Despite encouraging signs of efficacy in combination with pembrolizumab (PMB) in the ECHO-202 study, a large phase 3 study in melanoma (ECHO-301) failed to reproduce this outcome.1MethodsLongitudinal plasma samples were obtained from participants in EPA clinical studies. Plasma KYN and EPA concentrations were measured by validated liquid chromatography tandem mass spectrometry. Quantitative mass spectrometry imaging (qMSI) of intratumoral tryptophan metabolites was also performed.ResultsAnalysis of plasma KYN levels demonstrated that PMB monotherapy significantly elevated KYN. While blocking the PMB-induced increase, EPA (100 mg BID) in combination with PMB failed to normalize KYN to healthy control levels as was reported for EPA monotherapy.2 Because anti-PD-1 treatment can induce interferon gamma (IFN-γ) production and IDO1 expression is IFNg inducible,3 we hypothesize that PMB-induced IFN-γ may be responsible for the observed increase of plasma KYN levels. Combined analysis of plasma KYN from additional EPA/anti-PD-1 combination (ECHO-202; EPA/PMB, ECHO-204; EPA/nivolumab) and monotherapy (ECHO-210) studies, with EPA doses ranging from 50 to 600 mg BID, suggested that higher EPA doses (≥600 mg BID) may be necessary to overcome the anti-PD-1–associated KYN elevation. Doses ≥600 mg BID are projected to cover the EPA IC90 value for 24h. The POD1UM-102 study is currently evaluating the combination of a novel anti-PD-1 monoclonal antibody (retifanlimab) plus EPA at doses up to 900 mg BID. Preliminary results from this study indicate that 600 mg BID is the maximally tolerated dose and is capable of maintaining suppression of KYN to healthy control levels through treatment cycle 4. Additionally, qMSI of paired pre-treatment and on-treatment biopsies demonstrated intratumoral suppression of KYN production with EPA 600 mg BID.ConclusionsUsing suppression of plasma KYN as a pharmacodynamic marker of EPA activity, we demonstrated that maximal blockade of IDO1 activity in the context of anti-PD-1 treatment requires doses of EPA substantially higher than those tested in prior clinical studies. These findings are now informing additional proof of concept clinical studies.AcknowledgementsThese studies were sponsored by Incyte Corporation (ECHO-210, POD1UM-102) and in collaboration with MSD (ECHO-301, ECHO-202) and Bristol Myers Squibb (ECHO-204).Trial RegistrationECHO-202 [NCT NCT02178722]; ECHO-204 [NCT02327078]; ECHO-210 [NCT01685255]; ECHO-301 [NCT02752074]; POD1UM-102 [NCT03589651]Ethics ApprovalThese studies were each approved by the institutional review board or independent ethics committee of participating institutions.ReferencesLong GV, Dummer R, Hamid O, et al. Epacadostat plus pembrolizumab versus placebo plus pembrolizumab in patients with unresectable or metastatic melanoma (ECHO-301/KEYNOTE-252): a phase 3, randomized, double-blind study. Lancet Oncol 2019;20:1083–1097Beatty GL, O’Dwyer PJ, Clark J, et al. First-in-human phase I study of the oral inhibitor of indoleamine 2,3-dioxygenase-1 epacadostat (INCB024360) in patients with advanced solid malignancies. Clin Cancer Res 2017;23:3269–3276.Munn, DH, Mellor AL. IDO in the tumor microenvironment: inflammation, counter-regulation, and tolerance. Trends Immunol 2016;37:193–207.

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Combination of thermally ablative focused ultrasound with gemcitabine controls breast cancer via adaptive immunity

Journal for ImmunoTherapy of Cancer ◽

10.1136/jitc-2020-001008 ◽

2020 ◽

Vol 8 (2) ◽

pp. e001008

Author(s):

Natasha D Sheybani ◽

Alexandra R Witter ◽

Eric A Thim ◽

Hideo Yagita ◽

Timothy N J Bullock ◽

...

Keyword(s):

Breast Cancer ◽

T Cell ◽

Adaptive Immunity ◽

Primary Tumor ◽

Focused Ultrasound ◽

T Cell Response ◽

Tumor Control ◽

Cell Mediated Immunity ◽

Link Type ◽

Tumor Outgrowth

BackgroundTriple-negative breast cancer (TNBC) remains recalcitrant to most targeted therapy approaches. However, recent clinical studies suggest that inducing tumor damage can render TNBC responsive to immunotherapy. We therefore tested a strategy for immune sensitization of murine TNBC (4T1 tumors) through combination of focused ultrasound (FUS) thermal ablation and a chemotherapy, gemcitabine (GEM), known to attenuate myeloid-derived suppressor cells (MDSCs).MethodsWe applied a sparse-scan thermally ablative FUS regimen at the tumor site in combination with systemically administered GEM. We used flow cytometry analysis to investigate the roles of monotherapy and combinatorial therapy in mediating local and systemic immunity. We also tested this combination in Rag1−/− mice or T cell-depleted wild-type mice to determine the essentiality of adaptive immunity. Further, we layered Programmed cell death protein 1 (PD-1) blockade onto this combination to evaluate its impact on tumor outgrowth and survival.ResultsThe immune-modulatory effect of FUS monotherapy was insufficient to promote a robust T cell response against 4T1, consistent with the dominant MDSC-driven immunosuppression evident in this model. The combination of FUS+GEM significantly constrained primary TNBC tumor outgrowth and extended overall survival of mice. Tumor control correlated with increased circulating antigen-experienced T cells and was entirely dependent on T cell-mediated immunity. The ability of FUS+GEM to control primary tumor outgrowth was moderately enhanced by either neoadjuvant or adjuvant treatment with anti-PD-1.ConclusionThermally ablative FUS in combination with GEM restricts primary tumor outgrowth, improves survival and enhances immunogenicity in a murine metastatic TNBC model. This treatment strategy promises a novel option for potentiating the role of FUS in immunotherapy of metastatic TNBC and is worthy of future clinical evaluation.Trial registration numbersNCT03237572 and NCT04116320.

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Cryptosporidium parvum-Specific CD4 Th1 Cells from Sensitized Donors Responding to Both Fractionated and Recombinant Antigenic Proteins

Infection and Immunity ◽

10.1128/iai.72.3.1306-1310.2004 ◽

2004 ◽

Vol 72 (3) ◽

pp. 1306-1310 ◽

Cited By ~ 15

Author(s):

Maria Angeles Gomez Morales ◽

Raffaella Mele ◽

Alessandra Ludovisi ◽

Fabrizio Bruschi ◽

Fabio Tosini ◽

...

Keyword(s):

T Cell ◽

Cryptosporidium Parvum ◽

Cellular Response ◽

Mononuclear Cells ◽

Early Stage ◽

T Cell Response ◽

Interleukin 4 ◽

Cell Mediated Immunity ◽

Human T Cell ◽

Ifn Γ

ABSTRACT T-cell-mediated immunity plays a central role in the host response to Cryptosporidium parvum. Human T-cell clones (TCC) were isolated from peripheral blood mononuclear cells of five healthy donors with prior cryptosporidiosis by use of a C. parvum crude extract, two antigen fractions obtained by ion-exchange chromatography (IEC1 and IEC2), and two recombinant peptides (SA35 and SA40) from C. parvum sporozoites. The T-cell lines derived from the one recently infected donor had a higher proportion (26 to 38%) of T cells exhibiting the γ/δ T-cell receptor (γ/δ-TCR) than those from donors who had recovered from cryptosporidiosis several years earlier, suggesting that the γ/δ T-cell population is involved in the early stage of the infection. The specific TCC had the α/β-TCR, had the phenotype CD45RO+ CD4+ CD8−, and were characterized by either hyperproduction of gamma interferon (IFN-γ) alone, with a Th1 profile, or IFN-γ hyperproduction together with interleukin-4 (IL-4) or IL-5 production, with a Th0 profile. SA35, SA40, IEC1, and IEC2 may be considered good targets of the cellular response against C. parvum and may play a role in maintaining the T-cell-mediated memory response to this parasite. Furthermore, the SA35 and SA40 peptides may be regarded as immunodominant antigens involved in the maintenance of the T-cell response in healthy C. parvum-sensitized persons.

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Efficacy and safety of fremanezumab in clinical trial participants aged ≥60 years with episodic or chronic migraine: pooled results from 3 randomized, double-blind, placebo-controlled phase 3 studies

The Journal of Headache and Pain ◽

10.1186/s10194-021-01351-2 ◽

2021 ◽

Vol 22 (1) ◽

Author(s):

Stephanie J. Nahas ◽

Steffen Naegel ◽

Joshua M. Cohen ◽

Xiaoping Ning ◽

Lindsay Janka ◽

...

Keyword(s):

Clinical Trial ◽

Adverse Events ◽

Chronic Migraine ◽

Preventive Treatment ◽

Efficacy And Safety ◽

Phase 3 ◽

Double Blind ◽

Double Blind Placebo ◽

Link Type ◽

Trial Participants

Abstract Background Although migraine is less common in older people, preventive treatment of migraine in these individuals may be more challenging due to the presence of multiple comorbidities and polypharmacy. Additionally, evidence for migraine treatment efficacy, safety, and tolerability is limited in this population. We evaluated efficacy, safety, and tolerability of fremanezumab, a fully humanized monoclonal antibody (IgG2Δa) that selectively targets calcitonin gene–related peptide (CGRP), in clinical trial participants aged ≥60 years with episodic migraine (EM) or chronic migraine (CM). Methods This analysis included data from 3 randomized, double-blind, placebo-controlled phase 3 studies: the HALO EM study, HALO CM study, and FOCUS study in participants with EM or CM and prior inadequate response to 2–4 migraine preventive medication classes. Participants in all studies were randomized 1:1:1 to receive 12 weeks of subcutaneous treatment with quarterly fremanezumab (Months 1/2/3: EM/CM, 675 mg/placebo/placebo), monthly fremanezumab (Months 1/2/3: EM, 225 mg/225 mg/225 mg; CM, 675 mg/225 mg/225 mg), or matched monthly placebo. Results These pooled analyses included 246 participants aged ≥60 years. Reductions in monthly migraine days from baseline over 12 weeks were significantly greater with fremanezumab (least-squares mean change from baseline [standard error]: quarterly fremanezumab, − 4.3 [0.59]; monthly fremanezumab, − 4.6 [0.54]) versus placebo (placebo, − 2.3 [0.57]; both P < 0.01 vs placebo). As early as Week 1, significant reductions from baseline in weekly migraine days were observed with fremanezumab versus placebo (both P < 0.01). With fremanezumab treatment versus placebo, a significantly higher proportion of participants achieved ≥50% reduction in monthly migraine days, and significant improvements in disability and quality-of-life outcomes were observed (P < 0.05). Proportions of participants experiencing serious adverse events and adverse events leading to discontinuation were low and similar in the fremanezumab and placebo groups. Efficacy and safety results were comparable to the overall pooled population (N = 2843). Conclusions This pooled subgroup analysis demonstrates that fremanezumab treatment is efficacious and well-tolerated over 12 weeks in participants aged ≥60 years with EM or CM. These data may help healthcare providers with clinical decision making and preventive treatment selection for older patients with migraine. Trial registration ClinicalTrials.gov identifiers: HALO CM: NCT02621931; HALO EM: NCT02629861; FOCUS: NCT03308968.

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

Clinical Infectious Diseases ◽

10.1093/cid/ciab823 ◽

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.

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