Dieter Mielke
A5056348093- HIV Research and Treatment
- vaccines and immunoinformatics approaches
- Monoclonal and Polyclonal Antibodies Research
- SARS-CoV-2 and COVID-19 Research
- Immune Cell Function and Interaction
- Viral gastroenteritis research and epidemiology
- T-cell and B-cell Immunology
- Hepatitis C virus research
- HIV/AIDS drug development and treatment
- Viral Infections and Outbreaks Research
- COVID-19 Clinical Research Studies
- SARS-CoV-2 detection and testing
- Vaccine Coverage and Hesitancy
- Cytomegalovirus and herpesvirus research
- Viral Infections and Immunology Research
- Bacteriophages and microbial interactions
- Hepatitis B Virus Studies
- HIV/AIDS Research and Interventions
- Immunotherapy and Immune Responses
Duke Medical Center
2019-2025
Duke University
2019-2025
University of Cape Town
2019-2023
Ongoing SARS-CoV-2 vaccine development is focused on identifying stable, cost-effective, and accessible candidates for global use, specifically in low middle-income countries. Here, we report the efficacy of a rapidly scalable, novel yeast expressed specific receptor-binding domain (RBD) based rhesus macaques. We formulated RBD immunogen alum, licensed an emerging alum adsorbed TLR-7/8 targeted, 3M-052-alum adjuvants. The RBD+3M-052-alum adjuvanted promoted better binding effector...
Abstract Coronavirus vaccines that are highly effective against current and anticipated SARS-CoV-2 variants needed to control COVID-19. We previously reported a receptor-binding domain (RBD)-sortase A-conjugated ferritin nanoparticle (scNP) vaccine induced neutralizing antibodies pre-emergent sarbecoviruses protected non-human primates (NHPs) from WA-1 infection. Here, we find the RBD-scNP in NHPs pseudoviruses of SARS-CoV including 614G, Beta, Delta, Omicron BA.1, BA.2, BA.2.12.1,...
The VRC01 Antibody Mediated Prevention (AMP) efficacy trials conducted between 2016 and 2020 showed for the first time that passively administered broadly neutralizing antibodies (bnAbs) could prevent HIV-1 acquisition against bnAb-sensitive viruses. viruses isolated from AMP participants who acquired infection during study in sub-Saharan African (HVTN 703/HPTN 081) Americas/European 704/HPTN 085) represent a panel of currently circulating strains offer unique opportunity to investigate...
Antibodies perform both neutralizing and non-neutralizing effector functions that protect against certain pathogen-induced diseases. A human antibody directed at the SARS-CoV-2 Spike N-terminal domain (NTD), DH1052, was recently shown to be non-neutralizing, yet it protected mice cynomolgus macaques from severe disease. The mechanisms of NTD antibody-mediated protection are unknown. Here we show Fc mediate (non-nAb) MA10 viral challenge in mice. Though non-nAb prophylactic infusion did not...
Immune responses to SARS-CoV-2 primarily target the receptor binding domain of spike protein, which continually mutates escape acquired immunity. Other regions in S2 subunit, such as stem helix and segment encompassing residues 815-823 adjacent fusion peptide, are highly conserved across sarbecoviruses recognized by broadly reactive antibodies, providing hope that vaccines targeting these epitopes could offer protection against both current emergent viruses. Here we employ computational...
The correlation of HIV-specific antibody-dependent cellular cytotoxicity (ADCC) responses with protection from and delayed progression HIV-1 infection provides a rationale to leverage ADCC-mediating antibodies for treatment purposes. We evaluated ADCC mediated by different combinations 2 6 neutralizing non-neutralizing anti–HIV-1 Envelope (Env) mAbs, using concentrations ≤ 1 μg/mL, identify effective at targeting latent reservoir viruses 10 individuals. found that within hours, 3 mAbs more...
Background: The RV144 trial in Thailand is the only HIV-1 vaccine efficacy to date demonstrate any efficacy. Genetic signatures suggested that antibodies targeting variable loop 2 (V2) of envelope played an important protective role. ALVAC prime and protein boost follow-up southern Africa (HVTN702) failed show One hypothesis for this greater diversity subtype C viruses relative CRF01_AE Thailand. Methods: Here, we determined whether with computationally selected gp120 immunogens maximizing...
Abstract: Robust assay technologies and reference reagents are essential components in efforts to develop safe effective antibody-mediated prevention strategies for HIV-1. Here, we de-scribe current approaches used conduct standardized assessments of neutralizing, binding, Fc receptor-mediated effector functions vaccine-elicited antibodies, with an emphasis on recent developments that enable early precursors intermediates broadly neutralizing antibodies (bnAbs) be monitored. We also describe...
Abstract Background SARS-CoV-2 infection results in greater disease severity among immunocompromised individuals compared to healthy individuals. However, there is conflicting information about the impact of chronic HIV on immune responses and vaccination. Method We used a combination machine learning approaches network analysis explore 56 markers comprehensively profile humoral cellular immunity cross-sectional observational cohort people without (PWOH; n = 216) living with (PLWH; 43) who...
Both neutralization and antibody-dependent cellular cytotoxicity (ADCC) may be required for effective protection against HIV-1 infection. While there is extensive information on the targets of early neutralizing antibody (nAb) responses, much less known about ADCC which are more difficult to characterize. In four individuals recruited during acute HIV-infection, responses were detected 3-7 weeks prior nAb responses. To determine relative influence virus evolution, we performed an in-depth...
Neutralizing antibodies (nAbs) to highly variable viral pathogens show remarkable diversification during infection, resulting in an "arms race" between virus and host. Studies of nAb lineages have shown how somatic hypermutation (SHM) immunoglobulin (Ig)-variable regions enables maturing neutralize emerging escape variants. However, the Ig-constant region (which determines isotype) can also influence epitope recognition. Here, we use longitudinal deep sequencing HIV-directed lineage,...
Over one million people become infected with HIV-1 each year, making the development of an efficacious vaccine important unmet medical need. The RV144 human regimen is only clinical trial to date demonstrate efficacy. An area focus has been on identifying ways by which improve upon RV305 was a follow-up boost recipients that occurred 6 8 years after conclusion RV144. Our study focused effect delayed boosting in humans vaccine-induced Env constant region 1 and 2 (C1C2)-specific antibody...
Antibody-dependent cellular cytotoxicity (ADCC) responses were found to correlate with reduced risk of infection in the RV144 trial only human HIV-1 vaccine show any efficacy date. However, reagents understand breadth and magnitude these across preclinical clinical trials remain underdeveloped.
Despite antibody-dependent cellular cytotoxicity (ADCC) responses being implicated in protection from HIV-1 infection, there is limited evidence that they control virus replication. The high mutability of enables the to rapidly adapt, and thus viral escape a very sensitive approach demonstrate importance this response. To enable us deconvolute ADCC neutralizing antibody (nAb) escape, we identified individuals soon after infection with detectable responses, but no nAb responses. We evaluated...
Abstract Anti-HIV envelope broadly neutralizing antibodies (bnAbs) are alternatives to conventional antiretrovirals with the potential prevent and treat infection, reduce latent reservoirs, and/or mediate a functional cure. Clinical trials “first generation” bnAbs used alone or in combination show promising antiviral effects but also highlight that additional engineering of “enhanced” will be required for optimal clinical utility, while preserving enhancing cGMP manufacturing capability....
Coronavirus vaccines that are highly effective against SARS-CoV-2 variants needed to control the current pandemic. We previously reported a receptor-binding domain (RBD) sortase A-conjugated ferritin nanoparticle (RBD-scNP) vaccine induced neutralizing antibodies and pre-emergent sarbecoviruses protected monkeys from WA-1 infection. Here, we demonstrate RBD-scNP immunization induces potent in non-human primates (NHPs) all eight tested including Beta, Delta, Omicron variants. The variant was...
Since the beginning of SARS-CoV-2 pandemic, antibody responses and effector functions targeting SARS-CoV-2-infected cells have been understudied. Consequently, role these types antibodies in disease (COVID-19) immunity is still undetermined. To provide tools to study responses, we used plasma from individuals (n = 50) naive healthy controls 20) develop four specific reproducible flow cytometry-based assays: (i) two assessing binding to, antibody-mediated NK cell degranulation against, (ii)...
Coronavirus vaccines that are highly effective against SARS-CoV-2 variants needed to control the current pandemic. We previously reported a receptor-binding domain (RBD) sortase A-conjugated ferritin nanoparticle (RBD-scNP) vaccine induced neutralizing antibodies and pre-emergent sarbecoviruses protected monkeys from WA-1 infection. Here, we demonstrate RBD-scNP immunization induces potent in non-human primates (NHPs) all eight tested including Beta, Delta, Omicron variants. The variant was...
Background: The RV144 trial in Thailand is the only HIV-1 vaccine efficacy to date demonstrate any efficacy. Genetic signatures suggested antibodies targeting variable loop 2 (V2) of Envelope played an important protective role. ALVAC prime and protein boost follow-up southern Africa (HVTN702) failed show One hypothesis for this greater diversity subtype C viruses relative CRF01_AE Thailand. Methods: Here, we determined whether with computationally selected gp120 immunogens maximizing...
Abstract Induction of protective antibodies is a critical goal HIV-1 vaccine development. One strategy to induce non-neutralizing that kill virus-infected cells as these antibody specificities have been implicated in slowing disease progression and protection. Env constant region 1 2 (C1C2) frequently contain potent dependent cellular cytotoxicity (ADCC) making them target. Here we explore the effect delayed repetitive boosting RV144 vaccinee recipients with ALVAC/AIDSVAX B/E on...
Immune responses to SARS-CoV-2 primarily target the receptor binding domain of spike protein, which continually mutates escape acquired immunity. Other regions in S2 subunit, such as stem helix and segment encompassing residues 815-823 adjacent fusion peptide, are highly conserved across sarbecoviruses recognized by broadly reactive antibodies, providing hope that vaccines targeting these epitopes could offer protection against both current emergent viruses. Here we employed computational...