Randomized, Blinded, Dose-Ranging Trial of an Ebola Virus Glycoprotein Nanoparticle Vaccine With Matrix-M Adjuvant in Healthy Adults

Abstract Background Ebola virus (EBOV) epidemics pose a major public health risk. There currently is no licensed human vaccine against EBOV. The safety and immunogenicity of a recombinant EBOV glycoprotein (GP) nanoparticle vaccine formulated with or without Matrix-M adjuvant were evaluated to support vaccine development. Methods A phase 1, placebo-controlled, dose-escalation trial was conducted in 230 healthy adults to evaluate 4 EBOV GP antigen doses as single- or 2-dose regimens with or without adjuvant. Safety and immunogenicity were assessed through 1-year postdosing. Results All EBOV GP vaccine formulations were well tolerated. Receipt of 2 doses of EBOV GP with adjuvant showed a rapid increase in anti-EBOV GP immunoglobulin G titers with peak titers observed on Day 35 representing 498- to 754-fold increases from baseline; no evidence of an antigen dose response was observed. Serum EBOV-neutralizing and binding antibodies using wild-type Zaire EBOV (ZEBOV) or pseudovirion assays were 3- to 9-fold higher among recipients of 2-dose EBOV GP with adjuvant, compared with placebo on Day 35, which persisted through 1 year. Conclusions Ebola virus GP vaccine with Matrix-M adjuvant is well tolerated and elicits a robust and persistent immune response. These data suggest that further development of this candidate vaccine for prevention of EBOV disease is warranted.

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Safety, pharmacokinetics, and immunogenicity of a co-formulated cocktail of three human monoclonal antibodies targeting Ebola virus glycoprotein in healthy adults: a randomised, first-in-human phase 1 study

The Lancet Infectious Diseases ◽

10.1016/s1473-3099(18)30397-9 ◽

2018 ◽

Vol 18 (8) ◽

pp. 884-893 ◽

Cited By ~ 42

Author(s):

Sumathi Sivapalasingam ◽

Mohamed Kamal ◽

Rabih Slim ◽

Romana Hosain ◽

Weiping Shao ◽

...

Keyword(s):

Monoclonal Antibodies ◽

Ebola Virus ◽

Phase 1 ◽

Healthy Adults ◽

Human Monoclonal Antibodies ◽

Phase 1 Study ◽

Virus Glycoprotein

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Transcriptional analysis of lymphoid tissues from infected nonhuman primates reveals the basis for attenuation and immunogenicity of an Ebola virus encoding a mutant VP35 protein

Journal of Virology ◽

10.1128/jvi.01995-20 ◽

2021 ◽

Author(s):

Amanda Pinski ◽

Courtney Woolsey ◽

Allen Jankeel ◽

Robert Cross ◽

Christopher F. Basler ◽

...

Keyword(s):

Immune Response ◽

Nonhuman Primates ◽

Ebola Virus ◽

Transcriptional Response ◽

Transcriptional Analysis ◽

Lymphoid Tissues ◽

High Dose ◽

Type I ◽

Wild Type ◽

Transcriptional Responses

Infection with Zaire ebolavirus (EBOV), a member of the Filoviridae family, causes a disease characterized by high levels of viremia, aberrant inflammation, coagulopathy, and lymphopenia. EBOV initially replicates in lymphoid tissues and disseminates via dendritic cells (DCs) and monocytes to liver, spleen, adrenal gland and other secondary organs. EBOV protein VP35 is a critical immune evasion factor that inhibits type I interferon signaling and DC maturation. Nonhuman primates immunized with a high dose (5x105 PFU) of recombinant EBOV containing a mutated VP35 (VP35m) are protected from challenge with wild-type (wt)EBOV. This protection is accompanied by a transcriptional response in the peripheral blood reflecting a regulated innate immune response and a robust induction of adaptive immune genes. However, the host transcriptional response to VP35m in lymphoid tissues has not been evaluated. Therefore, we conducted a transcriptional analysis of axillary and inguinal lymph nodes, and spleen tissues of NHPs infected with a low dose (2x104 PFU) of VP35m and then backchallenged with a lethal dose of wtEBOV. VP35m induced early transcriptional responses in lymphoid tissues that are distinct from those observed in wtEBOV challenge. Specifically, we detected robust antiviral innate and adaptive responses and fewer transcriptional changes in genes with roles in angiogenesis, apoptosis and inflammation. Two of three macaques survived wtEBOV backchallenge, with only the nonsurvivor displaying a transcriptional response reflecting Ebola virus disease. These data suggest that VP35 is a key modulator of early host responses in lymphoid tissues, thereby regulating disease progression and severity following EBOV challenge. IMPORTANCE Zaire Ebola virus (EBOV) infection causes a severe and often fatal disease characterized by inflammation, coagulation defects, and organ failure driven by a defective host immune response. Lymphoid tissues are key sites of EBOV pathogenesis and generation of an effective immune response to infection. A recent study demonstrated that infection with an EBOV encoding a mutant VP35, a viral protein that antagonizes host immunity, can protect nonhuman primates (NHPs) against lethal EBOV challenge. However, no studies have examined the response to this mutant EBOV in lymphoid tissues. Here, we characterize the gene expression of lymphoid tissues from NHPs challenged with the mutant EBOV and subsequently with wild-type EBOV to identify signatures of a protective host response. Our findings are critical for elucidating viral pathogenesis, mechanisms of host antagonism and the role of lymphoid organs in protective responses to EBOV to improve the development of antivirals and vaccines against EBOV.

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Safety and immunogenicity of SARS-CoV-2 recombinant protein vaccine formulations in healthy adults: interim results of a randomised, placebo-controlled, phase 1–2, dose-ranging study

The Lancet Infectious Diseases ◽

10.1016/s1473-3099(21)00147-x ◽

2021 ◽

Cited By ~ 1

Author(s):

Paul A Goepfert ◽

Bo Fu ◽

Anne-Laure Chabanon ◽

Matthew I Bonaparte ◽

Matthew G Davis ◽

...

Keyword(s):

Recombinant Protein ◽

Phase 1 ◽

Healthy Adults ◽

Protein Vaccine ◽

Dose Ranging ◽

Recombinant Protein Vaccine

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Phase 1 safety and pharmacokinetics studies of BRII-196 and BRII-198, SARS-CoV-2 spike-targeting monoclonal antibodies

10.1101/2021.07.21.21260964 ◽

2021 ◽

Author(s):

Yao Zhang ◽

Xiaohua Hao ◽

Ji Ma ◽

Mingming Wang ◽

Yanyan Li ◽

...

Keyword(s):

Adverse Events ◽

Neutralizing Antibodies ◽

Phase 1 ◽

Clinical Results ◽

Healthy Adults ◽

Serious Adverse Events ◽

Infusion Reactions ◽

Human Igg1 ◽

Further Development ◽

Single Intravenous Infusion

Background. BRII-196 and BRII-198 are two anti-SARS-CoV-2 monoclonal neutralizing antibodies with modified Fc region that extends half-life and are being developed as cocktail therapy for the treatment of COVID-19. Safety, tolerability, pharmacokinetics, and immunogenicity of BRII-196 and BRII-198 were investigated in healthy adults. Methods. Single ascending doses of BRII-196 and BRII-198 were evaluated in parallel in the first-in-human, placebo-controlled phase 1 studies. A total of 32 healthy adults were randomized and received a single intravenous infusion of 750, 1500, and 3000 mg of BRII-196 (n=12), BRII-198 (n=12), or placebo (n=8) and were followed for 180 days. Results. All infusions were well tolerated at infusion rates between 0.5 mL/min to 4 mL/min with no dose-limiting adverse events, deaths, serious adverse events, or any systemic or local infusion reactions. Most treatment-emergent adverse events were isolated asymptomatic laboratory abnormalities of Grade 1-2 in severity. Each mAb displayed pharmacokinetics expected of Fc-engineered human IgG1 with mean terminal half-lives of approximately 46 days and 76 days, respectively, with no evidence of significant anti-drug antibody development. Conclusions. BRII-196 and BRII-198 were well-tolerated. Clinical results support further development as therapeutic or prophylactic options for SARS-CoV-2 infection.

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Attenuated dengue viruses are genetically more diverse than their respective wild-type parents

npj Vaccines ◽

10.1038/s41541-021-00340-5 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Amanda Makha Bifani ◽

Milly M. Choy ◽

Hwee Cheng Tan ◽

Eng Eong Ooi

Keyword(s):

Clinical Trials ◽

Vaccine Development ◽

Infectious Clone ◽

Phase 1 ◽

Genomic Diversity ◽

Genome Diversity ◽

Wild Type ◽

Safety Outcome ◽

Significant Burden

AbstractDengue poses a significant burden of individual health, health systems and the economy in dengue endemic regions. As such, dengue vaccine development has been an active area of research. Previous studies selected attenuated vaccine candidates based on plaque size. However, these candidates led to mixed safety outcome in clinical trials, suggesting it is insufficiently informative as an indicator of dengue virus (DENV) attenuation. In this study, we examined the genome diversity of wild-type DENVs and their attenuated derivatives developed by Mahidol University and tested in phase 1 clinical trials. We found that the attenuated DENVs, in particular the strain under clinical development by Takeda Vaccines, DENV2 PDK53, showed significantly higher genome diversity than its wild-type parent, DENV2 16681. The determinant of genomic diversity was intrinsic to the PDK53 genome as infectious clone of PDK53 showed greater genomic diversity after a single in vitro passage compared to 16681 infectious clone. Similar trends were observed with attenuated DENV1 and DENV4, both of which were shown to be attenuated clinically, but not DENV3 that was not adequately attenuated clinically. Taken together, evidence presented here suggests that genome diversity could be developed into a marker of DENV attenuation.

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