Treatment with the PPARα agonist fenofibrate improves the efficacy of CD8 T cell therapy for melanoma.

Adoptive transfer of tumor antigen-specific CD8 T cells can limit tumor progression but is hampered by the T cells' rapid functional impairment within the tumor microenvironment (TME). This is in part caused by metabolic stress due to lack of oxygen and glucose. Here, we report that fenofibrate treatment of human expanded tumor-infiltrating lymphocytes (TILs) improves their ability to limit melanoma progression in a patient-derived xenograft (PDX) mouse model.

Circumventing B Cell Responses to Allow for Redosing of Adeno-Associated Virus Vectors.

Adeno-associated virus (AAV)-mediated gene therapy has made significant progress in the last few decades. Nevertheless, challenges imposed by the immune system remain. The very high doses of AAV vectors used for some disorders have resulted in serious adverse events (SAEs) or even deaths, demonstrating that AAV vector doses that can safely be injected into patients are limited and for some indications below the therapeutic dose.

Intranasal multivalent adenoviral-vectored vaccine protects against replicating and dormant M.tb in conventional and humanized mice.

Viral-vectored vaccines are highly amenable for respiratory mucosal delivery as a means of inducing much-needed mucosal immunity at the point of pathogen entry. Unfortunately, current monovalent viral-vectored tuberculosis (TB) vaccine candidates have failed to demonstrate satisfactory clinical protective efficacy. As such, there is a need to develop next-generation viral-vectored TB vaccine strategies which incorporate both vaccine antigen design and delivery route.

Mitigating Serious Adverse Events in Gene Therapy with AAV Vectors: Vector Dose and Immunosuppression.

Gene transfer with high doses of adeno-associated viral (AAV) vectors has resulted in serious adverse events and even death of the recipients. Toxicity could most likely be circumvented by repeated injections of lower and less toxic doses of vectors. This has not been pursued as AAV vectors induce potent neutralizing antibodies, which prevent cell transduction upon reinjection of the same vector.

Heterologous chimpanzee adenovirus vector immunizations for SARS-CoV-2 spike and nucleocapsid protect hamsters against COVID-19.

Available COVID-19 vaccine only provide protection for a limited time due in part to the rapid emergence of viral variants with spike protein mutations, necessitating the generation of new vaccines to combat SARS-CoV-2. Two serologically distinct replication-defective chimpanzee-origin adenovirus (Ad) vectors (AdC) called AdC6 and AdC7 expressing early SARS-CoV-2 isolate spike (S) or nucleocapsid (N) proteins, the latter expressed as a fusion protein within herpes simplex virus glycoprotein D (gD), were tested individually or as a mixture in a hamster COVID-19 SARS-CoV-2 challenge model. The S protein expressing AdC (AdC-S) vectors induced antibodies including those with neutralizing activity that in part cross-reacted with viral variants.

Immunogenicity and toxicity of AAV gene therapy.

Gene transfer using adeno-associated viral (AAV) vectors has made tremendous progress in the last decade and has achieved cures of debilitating diseases such as hemophilia A and B. Nevertheless, progress is still being hampered by immune responses against the AAV capsid antigens or the transgene products. Immunosuppression designed to blunt T cell responses has shown success in some patients but failed in others especially if they received very high AAV vectors doses.

Safety and immunogenicity of a simian-adenovirus-vectored rabies vaccine: an open-label, non-randomised, dose-escalation, first-in-human, single-centre, phase 1 clinical trial.

Background: Rabies kills around 60 000 people each year. ChAdOx2 RabG, a simian adenovirus-vectored rabies vaccine candidate, might have potential to provide low-cost single-dose pre-exposure rabies prophylaxis. This first-in-human study aimed to evaluate its safety and immunogenicity in healthy adults.

PD-1 directed immunotherapy alters Tfh and humoral immune responses to seasonal influenza vaccine.

Anti-programmed death-1 (anti-PD-1) immunotherapy reinvigorates CD8 T cell responses in patients with cancer but PD-1 is also expressed by other immune cells, including follicular helper CD4 T cells (Tfh) which are involved in germinal centre responses. Little is known, however, about the effects of anti-PD-1 immunotherapy on noncancer immune responses in humans. To investigate this question, we examined the impact of anti-PD-1 immunotherapy on the Tfh-B cell axis responding to unrelated viral antigens.

A One Medicine Mission for an Effective Rabies Therapy.

Despite the disease's long history, little progress has been made toward a treatment for rabies. The prognosis for patient recovery remains dire. For any prospect of survival, patients require aggressive critical care, which physicians in rabies endemic areas may be reluctant or unable to provide given the cost, clinical expertise required, and uncertain outcome.

Immunological biomarker discovery in cure regimens for chronic hepatitis B virus infection.

There have been unprecedented advances in the identification of new treatment targets for chronic hepatitis B that are being developed with the goal of achieving functional cure in patients who would otherwise require lifelong nucleoside analogue treatment. Many of the new investigational therapies either directly target the immune system or are anticipated to impact immunity indirectly through modulation of the viral lifecycle and antigen production. While new viral biomarkers (HBV RNA, HBcAg, small, middle, large HBs isoforms) are proceeding through validation steps in clinical studies, immunological biomarkers are non-existent outside of clinical assays for antibodies to HBs, HBc and HBe.

The Effect of Rapamycin and Ibrutinib on Antibody Responses to Adeno-Associated Virus Vector-Mediated Gene Transfer.

Adeno-associated virus (AAV) vector-mediated gene transfer is lessening the impact of monogenetic disorders. Human AAV gene therapy recipients commonly mount immune responses to AAV or the encoded therapeutic protein, which requires transient immunosuppression. Most efforts to date have focused on blunting AAV capsid-specific T cell responses, which have been implicated in elimination of AAV-transduced cells.

Hepatitis B virus polymerase-specific T cell epitopes shift in a mouse model of chronic infection.

Background: Chronic hepatitis B virus (HBV) infection (CHB) is a significant public health problem that could benefit from treatment with immunomodulators. Here we describe a set of therapeutic HBV vaccines that target the internal viral proteins.

Methods: Vaccines are delivered by chimpanzee adenovirus vectors (AdC) of serotype 6 (AdC6) and 7 (AdC7) used in prime only or prime-boost regimens.

The Natural Stilbenoid (-)-Hopeaphenol Inhibits Cellular Entry of SARS-CoV-2 USA-WA1/2020, B.1.1.7, and B.1.351 Variants.

Antivirals are urgently needed to combat the global SARS-CoV-2/COVID-19 pandemic, supplement existing vaccine efforts, and target emerging SARS-CoV-2 variants of concern. Small molecules that interfere with binding of the viral spike receptor binding domain (RBD) to the host angiotensin-converting enzyme II (ACE2) receptor may be effective inhibitors of SARS-CoV-2 cell entry. Here, we screened 512 pure compounds derived from natural products using a high-throughput RBD/ACE2 binding assay and identified (-)-hopeaphenol, a resveratrol tetramer, in addition to vatalbinoside A and vaticanol B, as potent and selective inhibitors of RBD/ACE2 binding and viral entry.

PPARα Agonist Fenofibrate Enhances Cancer Vaccine Efficacy.

Reducing metabolic stress within the tumor microenvironment (TME) could be essential for improving the efficacy of cancer immunotherapy. Using a mouse model of melanoma, we show here that appropriately timed treatment with the PPARα agonist fenofibrate improves the ability of a T cell-inducing cancer vaccine to delay tumor progression. Fenofibrate reduced the use of glucose by tumor and stromal cells in the TME and promoted the use of fatty acids for their metabolic needs.

Vaccine-induced ICOSCD38 circulating Tfh are sensitive biosensors of age-related changes in inflammatory pathways.

Humoral immune responses are dysregulated with aging, but the cellular and molecular pathways involved remain incompletely understood. In particular, little is known about the effects of aging on T follicular helper (Tfh) CD4 cells, the key cells that provide help to B cells for effective humoral immunity. We performed transcriptional profiling and cellular analysis on circulating Tfh before and after influenza vaccination in young and elderly adults.

T Cell-Mediated Immune Responses to AAV and AAV Vectors.

Adeno-associated virus (AAV)-mediated gene transfer has benefited patients with inherited diseases, such as hemophilia B, by achieving long-term expression of the therapeutic transgene. Nevertheless, challenges remain due to rejection of AAV-transduced cells, which in some, but not all, patients can be prevented by immunosuppression. It is assumed that CD8 T cells induced by natural infections with AAVs are recalled by the AAV vector's capsid and upon activation eliminate cells expressing the degraded capsid antigens.

Towards rabies elimination in the Asia-Pacific region: From theory to practice.

Rabies is a major neglected zoonotic disease and causes a substantial burden in the Asian region. Currently, Pacific Oceania is free of rabies but enzootic areas throughout southeast Asia represent a major risk of disease introduction to this region. On September 25-26, 2019, researchers, government officials and related stakeholders met at an IABS conference in Bangkok, Thailand to engage on the topic of human rabies mediated by dogs.

The Effect of CpG Sequences on Capsid-Specific CD8 T Cell Responses to AAV Vector Gene Transfer.

Transfer of genes by adeno-associated virus (AAV) vectors is benefiting patients with particular genetic defects. Challenges remain by rejection of AAV-transduced cells, which may be caused by CD8 T lymphocytes directed to AAV capsid antigens. Reducing the number of CpG motifs from the genome of AAV vectors reduces expansion of naive T cells directed against an epitope within the capsid.

Age-related changes in B cell metabolism.

Antibody responses to vaccinations or infections decline upon aging. In this study we tested if metabolic changes in B cells may contribute to attenuation of responses to influenza vaccination in aged humans. Our data show that aging affects mitochondrial functions in B cells leading to increases in mitochondrial reactive oxygen species (MROS) and mitochondrial mass (MM) in some aged B cell subsets and decreases in expression levels of Sirtuin 1 (SIRT1), Forkhead box protein (FOX)O1 and carnitine palmitoyltransferase 1 (CPT-1).

New Rabies Vaccines for Use in Humans.

Although vaccines are available, rabies still claims more than 55,000 human lives each year. In most cases, rabies vaccines are given to humans after their exposure to a rabid animal; pre-exposure vaccination is largely reserved for humans at high risk for contacts with the virus. Most cases of human rabies are transmitted by dogs.