Tag Archives: Lymph Node

Microbiology

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

Leave a comment

if (g_displayableSlots.mobileTopLeaderboard) {
pushDisplayAd(function() { googletag.display(‘div-gpt-mobile-top-leaderboard’); });
}

Reviewed by Lily Ramsey, LLMMay 25 2023

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.

if (g_displayableSlots.mobileMiddleMrec) {
pushDisplayAd(function() { googletag.display(‘div-gpt-mobile-middle-mrec’); });
}

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).

if (g_displayableSlots.mobileBottomLeaderboard) {
pushDisplayAd(function() { googletag.display(‘div-gpt-mobile-bottom-leaderboard’); });
}

Source:

Fred Hutchinson Cancer Center

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.

Microbiology

Healthy gut bacteria can travel to other parts of the body and boost antitumor immunity

Leave a comment

Reviewed by Emily Henderson, B.Sc.Mar 9 2023

Researchers at UT Southwestern Medical Center have discovered how healthy bacteria can escape the intestine, travel to lymph nodes and cancerous tumors elsewhere in the body, and boost the effectiveness of certain immunotherapy drugs. The findings, published in Science Immunology, shed light on why antibiotics can weaken the effect of immunotherapies and could lead to new cancer treatments.

Scientists have been stumped as to how bacteria inside your gut can have an impact on a cancer in your lungs, breasts, or skin. Now we understand that mechanism much better and, in the future, hope to use this knowledge to better fight cancer.”

Andrew Y. Koh, M.D., Associate Professor of Pediatrics, Microbiology, and in the Harold C. Simmons Comprehensive Cancer Center at UT Southwestern

Previous studies, including one led by Dr. Koh at UT Southwestern, have shown an association between the composition of gut microbiomes – the microorganisms found inside the digestive tract – and the effectiveness of cancer treatments that target the immune system, including pembrolizumab (Keytruda) and ipilimumab (Yervoy). However, researchers have reached conflicting conclusions about the ideal balance of microorganisms to optimize therapy, with studies pointing to different beneficial bacteria.

Dr. Koh and colleagues used mice with melanoma tumors to probe how the drugs, called immune checkpoint inhibitors, affected the movement of gut microbes through the body. They found that immune checkpoint inhibitors, which boost the activity of the immune system against tumors, also cause inflammation in the digestive system that leads to remodeling of lymph nodes in the gut.

Due to these changes, bacteria can leave the intestines and travel to lymph nodes near the tumor and the tumor itself, the researchers found. Here, the microbes activate a set of immune cells that act to kill tumor cells.

“Immune checkpoint inhibitors work by releasing the brakes on the immune system to target cancer,” said Dr. Koh, who is also Director of the Cellular and ImmunoTherapeutics Program at UTSW and Children’s Health. “What we think is that these microorganisms and the immune cells they’re activating are essentially pressing on the accelerator of the immune system at the same time.”

The findings suggest that a course of antibiotics, which can eliminate most gut microbes, is detrimental to immune checkpoint inhibitors because the bacteria can no longer play this role of immune accelerant. It also helps explain why researchers have found many types of bacteria in patient microbiomes that seem to be beneficial for treatment.

“As long as a subset of beneficial bacteria can translocate from the gut to the lymph node or tumor, it may not matter exactly which bacteria it is,” said Dr. Koh.

Dr. Koh’s team is now working toward the development of bacterial-based treatments to boost the efficacy of immune checkpoint inhibitors.

Other UTSW researchers who contributed to the study include first author and UTSW graduate student Yongbin Choi, Lora Hooper, Jake Lichterman, Laura Coughlin, Nicole Poulides, Wenling Li, Priscilla Del Valle, Suzette Palmer, Shuheng Gan, Jiwoong Kim, Xiaowei Zhan, Yajing Gao, and Bret Evers.

Dr. Hooper, a Howard Hughes Medical Institute Investigator, holds the Jonathan W. Uhr, M.D. Distinguished Chair in Immunology and is a Nancy Cain and Jeffrey A. Marcus Scholar in Medical Research, in honor of Dr. Bill S. Vowell.

The research was supported by funding from the National Institutes of Health (R01 CA231303, K24 AI123163, R01 DK070855), the Crow Family Fund, the UT Southwestern Medical Center and Children’s Health Cellular and ImmunoTherapeutics Program, National Research Service Award-Integrative Immunology Training Grant (5T32AI005284-43), The Welch Foundation (I-1874), and the Howard Hughes Medical Institute.

Source:

UT Southwestern Medical Center

Journal reference:

Choi, Y., et al. (2023) Immune checkpoint blockade induces gut microbiota translocation that augments extraintestinal antitumor immunity. Science Immunology. doi.org/10.1126/sciimmunol.abo2003.

Microbiology

Multi-stage HIV vaccine regimen shows promising results in Phase 1 clinical trial

Leave a comment

Reviewed by Emily Henderson, B.Sc.Dec 8 2022

The George Washington University Vaccine Research Unit in partnership with Scripps Research, IAVI, Fred Hutchinson Cancer Center (FHCC) and the National Institutes of Health, National Institute of Allergy and Infectious Diseases Vaccine Research Center published the results of their Phase 1 Clinical Trial in Science. The results show critical new insights into their novel vaccine strategy, which involves a stepwise approach to producing antibodies capable of targeting a wide range of HIV variants.

The trial, known as IAVI G001, tested the first stage in a multi-stage HIV vaccine regimen the researchers are developing. The trial results show that the vaccine had a favorable safety profile and induced the targeted response in 97% of people who were vaccinated. Importantly, the study also provides a detailed immunological analysis of the vaccine responses.

HIV has continued to be a difficult virus to create a vaccine for given its ability to mutate and quickly evade the immune system. The findings from this trial bring new hope to stopping HIV and may help find vaccines for other difficult infectious diseases as well.”

David Diemert, Professor of Medicine, GWU School of Medicine and Health Sciences

The novel vaccine strategy that was tested in this trial is focused on producing broadly neutralizing antibodies (“bnAbs”), which are a rare type of antibody that can fight and protect against many different variants of a virus, including HIV.

The researchers in the study are using a procedure known as ‘germline targeting’ to eventually produce bnAbs that can protect against HIV. The first step of germline targeting involves stimulating the rare immune cells-;known as bnAb-precursor B cells-;that can evolve into the cells that produce the bnAbs needed to block the virus. To accomplish this, the researchers designed a customized molecule-;known as an immunogen-;that would “prime” the immune system and elicit responses from these rare bnAb-precursor cells.

For this clinical trial, a novel method of sampling lymph nodes was developed by the clinical and biorepository teams at GW, FHCC and IAVI, which included ultrasound-guided fine needle aspiration of lymph nodes near the injection site. “This is the first time such a technique has been used routinely in a vaccine clinical trial,” Jeffrey Bethony, professor of microbiology, immunology and tropical medicine at GW SMHS said. “It enabled us to acquire a cell population critical to germline stimulation that do not circulate but remains sequestered in lymph node tissue.”

The GW VRU has partnered with IAVI on two other HIV vaccine-related Phase I clinical trials over the past five years, serving as a lead site, central biorepository and support unit. In addition, the unit has conducted a number of other clinical vaccine trials to date, including a Phase III trial to test the now FDA-authorized COVID-19 vaccine from biotechnology company Moderna; a Phase II clinical trial for a COVID-19 vaccine booster from the biopharmaceutical company Sanofi; and a Phase I trial of a vaccine to prevent Lassa fever, an acute, animal-borne viral disease endemic to parts of West Africa.

Source:

George Washington University

Microbiology

Monkeypox virus infection and its persistence in the testes of infected crab-eating macaques

Leave a comment

Bhavana KunkalikarBy Bhavana KunkalikarOct 22 2022Reviewed by Danielle Ellis, B.Sc.

In a recent study published in Nature Microbiology, researchers performed retrospective detection of the monkeypox virus (MPXV) in the testes of nonhuman primates (NHPs).

Study: Retrospective detection of monkeypox virus in the testes of nonhuman primate survivors. Image Credit: BalazsSebok/Shutterstock
Study: Retrospective detection of monkeypox virus in the testes of nonhuman primate survivors. Image Credit: BalazsSebok/Shutterstock

Background

Close sexual contact has been associated with the spread of (MPXV in the global pandemic in 2022. However, it is still unclear whether MPXV duplicates in the testicles or transmits through semen and results in an active infection. The team retrospectively examined crab-eating macaques infected with MPXV of clade I or clade II MPXV using immunostaining and ribonucleic acid (RNA) in situ hybridization.

About the study

In the present study, researchers examined MPXV infection and its persistence in the testes of infected crab-eating macaques, including MPXV-recovered macaques.

Crab-eating macaques infected with MPXV at the team’s institute were utilized to examine the pathogenesis of human MPVX or as a substitute animal model to study smallpox. MPXV infection was detected by screening formalin-fixed paraffin-embedded (FFPE) testicular, prostatic, and epididymal tissues from 21 male crab-eating macaques that died within six to 13 days of MPXV exposure via IT, IV, or AS inoculation route, without therapeutic intervention. This facilitated the understanding of the possibility of MPXV infection in the testes and shedding into semen.

The team created an RNA in situ hybridization (ISH) assay to identify the MPXV-specific transcript D1L, which causes smallpox. The study hypothesized that MPXV might linger in the testes of NHP survivors. Furthermore, the testicular tissues collected from 20 crab-eating macaques that had withstood the MPXV challenge without medical treatment were screened.

Results

 The team observed that 18 out of 21 animals possessed MPXV antigen in their testes, including 14 out of 16 animals with the clade I strain of MPXV and four out of five animals with the clade I strain. In seven of the 18 animals, the team detected the MPXV antigen in the epididymis, while six out of the 21 had MPXV antigen in their prostate glands. Compared to the uninfected control testicular tissue, MPXV antigen staining was multifocal and largely found in the testes’ interstitial tissue.

Intriguingly, MPXV antigen was occasionally found in the inflammatory cells and spermatozoa or in cellular debris present in the seminiferous tubules, which house sperm production as well as immune privilege. MPXV antigen was largely found in the duct epithelium and the lamina propria of the epididymis. Remarkably, MPXV antigen was also found in degenerated spermatozoa, cellular debris in the epididymal duct lumen, or inflammatory cells. In the regions of inflammation observed in the prostate of six of 21 animals, immunohistochemistry (IHC) staining was multifocal or focal.

The team employed antibodies to perform immunofluorescence staining on alpha-smooth muscle actin (SMA) and MPXV to show that these MPXV had spread to the lumen of the epididymal ducts and the seminiferous tubules of the testis, which are crucial for the generation, maturation, and transportation of sperm. These findings imply that MPX virions may be released in the semen during the acute stage of the infection in crab-eating macaques, albeit additional verification requires viral isolation from semen.

Two of the 20 survivors with testicular tissues stained positively by IHC survived to the end of the trial and their scheduled death. Crab-eating macaques that survived MPXV exposure typically displayed scabbed skin lesions around 20 days following infection with a viral deoxyribonucleic acid (DNA) level below the detection threshold. On the face, tail, arms, feet, and/or back, these two survivors frequently had scabs as well as desquamated or healed skin sores.

The necrotic seminiferous tubules present in the two survivors’ testes, as well as the necrotic center area of granulomas, were the main sites of IHC staining signal detection. With the exception of one survivor’s lung and the other survivor’s tracheobronchial lymph node and skeletal muscle, the IHC staining signal was not seen in the skin lesions or in the other organs. Additionally, MPXV-specific RNA ISH provided additional evidence of infection in the testicular granulomas. In addition to largely non-cell associated viral antigen in the necrotic center of granulomas, a small number of CD68+ monocytes/macrophages close to the necrotic areas also contained viral antigen.

The necrotic patches were also surrounded by lymphocytic, plasmacytic, and neutrophilic inflammation, as shown by the abundance of CD68+ monocytes/macrophages, CD3+ T cells, and myeloperoxidase (MPO)+ neutrophil granulocytes. Interestingly, CD8+ T cells account for most of the CD3+ T cells. These findings suggested that MPXV may be able to persist, especially in areas of inflammation and necrosis, in the testes of recovering crab-eating macaque survivors.

Our data provide evidence that monkeypox virus may be shed into semen during both acute and convalescent stages of the disease in crab-eating macaques.”

Conclusion

Overall, the study findings showed that crab-eating macaques may shed MPXV into their semen during both acute and convalescent stages of the infection.

Journal reference: