Tag Archives: Nanoparticle

First-in-human nanoparticle HIV vaccine induces broad and publicly targeted helper T cell responses

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Researchers from Fred Hutchinson Cancer Center in Seattle, Scripps Research in La Jolla, California, IAVI and other collaborating institutions have characterized robust T-cell responses in volunteers participating in the IAVI G001 Phase 1 clinical trial to test the safety and immune response of a self-assembling nanoparticle HIV vaccine.

Their work, published in Science Translational Medicine, signals a major step toward development of a vaccine approach to end the HIV/AIDS epidemic worldwide. The antigen used in this study was jointly developed by IAVI and Scripps Research and has been shown in previous analyses to stimulate VRC01-class B cells, an immune response considered promising enough for boosting in further studies.

We were quite impressed that this vaccine candidate produced such a vigorous T-cell response in almost all trial participants who received the vaccine. These results highlight the potential of this HIV-1 nanoparticle vaccine approach to induce the critical T-cell help needed for maturing antibodies toward the pathway of broadly neutralizing against HIV.”

Julie McElrath, MD, PhD, senior vice president and director of Fred Hutch’s Vaccine and Infectious Disease Division and co-senior author of the study

However, she added, this is the first step, and heterologous booster vaccines will still be needed to eventually produce VRC01-class broadly neutralizing antibodies, which in previous studies have demonstrated the ability to neutralize approximately 90% of HIV strains.

“We showed previously that this vaccine induced the desired B-cell responses from HIV broadly neutralizing antibody precursors. Here we demonstrated strong CD4 T-cell responses, and we went beyond what is normally done by drilling down to identify the T cell epitopes and found several broadly immunogenic epitopes that might be useful for developing boosters and for other vaccines,” William Schief, PhD, executive director of vaccine design for IAVI’s Neutralizing Antibody Center at Scripps Research and professor, Department of Immunology and Microbiology, at Scripps Research, who is co-senior author of the study.

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The trial is a phase 1, randomized, double-blind and placebo-controlled study to evaluate the safety and effectiveness of a nanoparticle HIV vaccine in healthy adult volunteers without HIV. It was comprised of two groups with 18 vaccine and six placebo recipients per group, with 48 total enrollees. Participants were given two doses of the vaccine or placebo eight weeks apart.

McElrath acknowledged the groundbreaking work of her lab team, the biostatistical team and Fred Hutch’s Vaccine Trials Unit for their invaluable contributions to the study. The Vaccine Trials Unit conducts multiple vaccine trials and was one of only two sites for this study.

Findings from the study include:

  • Vaccine-specific CD4 T cells were induced in almost all vaccine recipients.
  • Lymph node GC T follicular helper cells increased after vaccination compared to placebo.
  • Lumazine synthase protein, needed for self-assembly of the particle, also induced T-cell responses that can provide additional help to ultimately enhance efficacy in a sequential vaccine strategy.
  • Vaccine-specific CD4 T cells were polyfunctional and had diverse phenotypes.
  • LumSyn-specific CD8 T cells were highly polyfunctional and had a predominantly effector memory phenotype.
  • CD4 T-cell responses were driven by immunodominant epitopes with diverse and promiscuous HLA restriction.
  • CD8 T-cell responses to LumSyn were driven by HLA-A*02-restricted immunodominant epitopes B- and T-cell responses correlated within but not between LN and peripheral blood compartments.

This study was funded by the Bill & Melinda Gates Foundation Collaboration for AIDS Vaccine Discovery; IAVI Neutralizing Antibody Center; National Institute of Allergy and Infectious Diseases; and Ragon Institute of MGH, MIT and Harvard.

Study authors WRS and SM are inventors on a patent filed by Scripps and IAVI on the eOD-GT8 monomer and 60-mer immunogens (patent number 11248027, “Engineered outer domain (eOD) of HIV gp 120 and mutants thereof”). WRS, KWC and MJM are inventors on patents filed by Scripps, IAVI and Fred Hutch on immunodominant peptides from LumSyn (Title: Immunogenic compositions; filing no. 63127975).

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Journal reference:

Cohen, K. W., et al. (2023) A first-in-human germline-targeting HIV nanoparticle vaccine induced broad and publicly targeted helper T cell responses. Science Translational Medicine. doi.org/10.1126/scitranslmed.adf3309.

Inspired by nature: Silencing bacteria

Bacteria love moist surfaces. Once they have settled there, they do not live as solitary organisms but form larger communities that are embedded in a protective film. These biofilms are found on various surfaces, for example at home on light switches, in the bathroom, on toys or keyboards, on shopping carts or ATMs that many people touch with their hands. This can lead to contact infections. The bacteria, such as the pathogenic bacterium Pseudomonas aeruginosa, are often persistent and defy the body’s own immune system or chemical biocides. Current research approaches are therefore trying to prevent bacterial colonization of material surfaces or at least to make it more difficult. A team from Johannes Gutenberg University Mainz (JGU) and the German Federal Institute of Hydrology (BfG) in Koblenz has now developed a new approach using ceria nanoparticles.

Modified signaling molecules prevent the formation of biofilms

For bacterial life in communities, it is important that the individual cells “talk” to each other. Communication proceeds nonverbally with the help of signaling molecules that are continuously emitted to the environment, whereby different “languages” and “dialects” can occur depending on the specific bacterium. As bacterial concentration increases so does the concentration of the signaling molecules. This allows bacteria to detect the number of other bacteria in their environment and activate processes that enable the formation of biofilms.

To prevent colonization with bacterial biofilms, various hosts defend themselves with a strategy that ” silences” the bacteria by enzymatically modifying the signaling molecules. This is done, for example, with the help of haloperoxidases, a group of enzymes that halogenate signaling molecules through a complex reaction chain.

These modified signaling molecules have a similar structure as the original molecules and can still bind to receptors. However, they can no longer activate the process chains that lead to biofilm formation. This interference in bacterial gene regulation is also of pharmacological interest, because pathogenic bacteria can evade the attack of the immune defense or the effect of antibiotics by forming biofilms.

Ceria nanoparticles take over the function of natural enzymes

The researchers from Mainz and Koblenz mimic these processes with nanoparticles of cerium dioxide (CeO2). CeO2 nanoparticles are, as the researchers explain in their recent article in ACS Nano, a functional substitute for haloperoxidase enzymes. However, the molecular mechanisms underlying biofilm inhibition are difficult to unravel in detail, because not only do many competitive reactions occur in bacterial cultures, but vast numbers of other biomolecules are also present in addition to the halogenated signaling molecules.

The cooperation partners from Mainz and Koblenz demonstrate the enzyme-analog catalytic participation of the CeO2 nanoparticles via an analysis of the reaction cascade at the molecular level. The halogenated signaling molecules were first identified in model reactions. In bacterial cultures, their detection was not possible directly because the products are being degraded too quickly. However, chromatographic workup and mass spectrometric analysis unexpectedly revealed the formation of further halogenated signaling molecules from the family of so-called quinolones. This shows that the CeO2 nanoparticles interfere with biological processes just like native enzymes by modifying and inactivating signaling molecules.

Antibacterial surfaces without the risk of resistance formation made possible

“Cerium dioxide is non-toxic, chemically very stable, and it is contained, for example, in modern vehicle exhaust catalytic converters,” stated Dr. Eva Pütz, who carried out her doctoral thesis on this project. She is convinced that cerium dioxide is a viable and cost-effective alternative to conventional biocides. “One practical application of our findings is to block bacterial growth and prevent bacterial infections,” she said. The quinolone signaling molecules lead to the formation of small colony variants in the multidrug-resistant bacterium Staphylococcus aureus, which are often diagnostically undetectable. Since the halogenated quinolone signal molecules suppress colony formation, dangerous infections by P. aeruginosa and S. aureus, for example, can be prevented with the help of paint dispersions containing CeO2 nanoparticles,” added Dr. Athanasios Gazanis, who investigated the microbiological aspects in his doctoral thesis.

“Here we have an environmentally compatible component for a new generation of antibacterial surfaces that mimic nature’s defense system. Most importantly, it works not only in the lab, but also in everyday use,” emphasized Nils Keltsch, who performed the biological trace analysis in his doctoral thesis.

The danger in combating biofilms with biocides and antibiotics is the formation of resistance. However, this could be effectively circumvented in an environmentally friendly way by coating polymers with CeO2 nanoparticles.

Story Source:

Materials provided by Johannes Gutenberg Universitaet Mainz. Note: Content may be edited for style and length.

Journal Reference:

  • Eva Pütz, Athanasios Gazanis, Nils Gert Keltsch, Olga Jegel, Felix Pfitzner, Ralf Heermann, Thomas A. Ternes, Wolfgang Tremel. Communication Breakdown: Into the Molecular Mechanism of Biofilm Inhibition by CeO2 Nanocrystal Enzyme Mimics and How It Can Be Exploited. ACS Nano, 2022; 16 (10): 16091 DOI: 10.1021/acsnano.2c04377
  • Johannes Gutenberg Universitaet Mainz