This technology introduces a novel vaccine delivery system using thermosensitive hydrogels for sustained antigen release, aiming to improve immune response durability and breadth.

Researchers at the University of California, Davis have developed advanced compounds targeting neuraminidase activity to combat viral infections and understand cellular mechanisms.

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SARS-CoV-2(SC2) virus has been the cause of the most recent world-wide pandemic, COVID-19. With submission of over 16 million genomic sequences of its variants, it became the most sequenced genome of all known viruses. SARS-CoV-2 (SC2) is a positive-sense single-stranded RNA virus, which encodes about 27 proteins. So far tens of thousands of variants of SC2 with unique sequences, each appearing many times, have been identified.  A UCB researcher has created computational methods for designing pan-valent vaccines by examing, retrospectively, many variants together for their degree of sequence diversity, global demographic grouping, and differences in characteristics among the groups and others which may provide observational bases for understanding the various aspects of SC2 during its pandemic period and for predicting and preventing its possible future resurgence.

Researchers from UC San Diego developed an invention that enables protein expression to be upregulated using specific proteins and/or peptide sequences derived from SARS-CoV-2 proteins that are engineered to recognize specific mRNA transcripts by fusion to RNA-targeting modules such as CRISPR/Cas systems. They anticipate that these proteins can be fused or tethered to any engineered RNA-targeting moiety/module such as PUF/Pum, and pentatricopeptide proteins.

α-Fetoprotein (AFP) is a fetal glycoprotein produced by the majority of human hepatocellular carcinoma tumors and other tumor types. Delineating differences between fetal 'normal' AFP (nAFP) and tumor-derived AFP (tAFP), investigators at UCSF and the Parker Institute for Cancer Immunotherapy have uncovered a novel role for tAFP in altering metabolism via lipid-binding partners. They have developed a pharmaceutical composition comprising AFP bound by a fatty acid which, depending on the fatty acid used, can have an immunosuppressive effect allowing for the treatment of inflammatory diseases.  AFP bound to other fatty acids can eliminate the immune suppressive impact and have a neutral effect which allows for the development of dendritic cell (DC) vaccines presenting AFP epitopes which could be used to treat and prevent tumor AFP-expressing cancers.  

Listeria monocytogenes has been used as a therapeutic vaccine in more than 20 cancer clinical trials and administered to more than 1800 patients. However, Listeria monocytogenes vaccines have been less immunogenic in clinical trials. In rare cases, live bacteria were found in patients’ blood or on implants, after the administration of live vaccines. Additionally, even attenuated vaccine strains still caused severe adverse events and consequently put clinical trials on hold. Due, in part, to the safety and efficacy concerns of using Listeria monocytogenes as a live vector for cancer immunotherapy, there is a need for safer and more potent strains of Listeria monocytogenes.  UC Berkeley researchers have created a Listeria monocytogenes mutant strain that will likely be a safer and potentially more potent platform for the future development of cancer therapeutics. The strain is auxotrophic for adenosine, a purine nucleoside with extremely low levels in blood and healthy cells. The strain cannot grow in the host cell cytosol and is significantly attenuated in the mouse infection model. The improvement in the safety of this invention is further demonstrated by the poor growth of the mutant strain in host extracellular environments such as mouse gallbladders and human blood. Although attenuated, the invented strain elicits a robust effector CD8+ T cell response in mice and protects mice against lethal-dose challenges of wild-type L. monocytogenes. More importantly, the immunogenicity of this invention is more potent in mice than in previous Listeria monocytogenes vaccine strains. Another facet of this invention is that because of the high concentration of adenosine in tumor microenvironments, the mutant strain could potentially survive and multiply in tumors.  

Researchers at UC Irvine have identified and tested a molecular target that regulates T cell function during chronic viral infection and cancer. The molecular target is one of the high mobility group proteins (HMGB2). HMGB2 is a DNA binding protein that regulates transcriptional processes, meaning that its modulation will have profound effects on T cell differentiation and ultimate function by altering the expression of many genes.

Vaccine design is at the forefront of therapeutic development. Candidate proteins for recombinant vaccine design are expressed as soluble proteins lacking the native transmembrane domain. These proteins are often fused with multimerization domains to stabilize the native oligomeric state of the candidate protein. However, these multimerization domains can elicit off-target immune responses, raising concerns regarding risks of unintended immunogenicity. Thus, there is a need to eliminate potential off-target effects of recombinant vaccine candidates that contain multimerization domains such as the foldon domain.

Researchers at the University of California, Davis have developed a method to stop bacterial growth while maintaining desirable metabolic functions for therapeutic and biotechnological applications.

The inventors have developed an engineering approach to identify novel and nonobvious membrane-associated accessory protein (MAAP) sequence variants that confer increased Adeno-associated virus (AAV) secretion during packaging. The technique is based upon the iterative process of sequence diversification and selection of functional gene variants known as directed evolution. First, the inventors generated a library of more than 1E6 MAAP variants. The variants were subjected to five rounds of packaging into an AAV2 capsid for which MAAP expression was inactivated without altering the viral protein VP1 open reading frame (ORF) (AAV2-MAAP-null). Among each iterative packaging round, the inventors observed a progressive increase in both the overall titer and ratio of secreted vector genomes conferred by the bulk selected MAAP library population. Next-generation sequencing uncovered common mutational features that were enriched up to over 10,000-fold on the amino acid level. Individual MAAP variants were isolated and systematically tested for effect on recombinant AAV2-MAAP-null packaging in HEK293 cells. The inventors predict that this work may be applicable to increasing per-cell AAV output in industrial settings, potentially reducing global costs and increasing functional vector recovery in downstream manufacturing processes.BACKGROUNDParvoviruses are small, single-stranded DNA viruses that are ubiquitously found in many animal species. AAV is a prototypic dependoparvovirus whose replication cycle requires the function of helper genes from larger co-infected viruses such as Adenoviruses or Herpesviruses. The natural genome of AAV contains ~4.7 kb of ssDNA that encodes up to ten known proteins in a highly overlapped fashion. The rep gene encodes four protein products named based on their molecular weight: Rep72 and Rep68 facilitate genomic replication, whereas Rep52, and Rep40 play essential roles in loading nascent ssDNA genomes into assembled capsids. Downstream of rep lies the cap gene, which encodes three known protein products off of overlapping reading frames: VP1, VP2, and VP3 are structural proteins that assemble to form the capsid, the assembly activating protein (AAP) targets VP proteins to the nucleus and is involved in capsid assembly. The most recently discovered AAV-encoded gene is the membrane-associated accessory protein (MAAP). MAAP is encoded by an alternative ORF in the AAV cap gene that is found in all presently reported natural serotypes. Gene delivery by recombinant AAV (rAAV) have shown significant success in both research and clinical gene therapy applications. In the rAAV system, Rep and Cap are removed from between AAV’s 5’ and 3’ inverted terminal repeats (ITRs) and provided in trans. Instead, a transgene of interest is inserted between the ITRs and subsequently packaged into the nascent AAV capsids. However, manufacturing quantities of good manufacturing practice (GMP)-grade rAAVs necessary to achieve current and projected dosing requirements–particularly in a clinical context–presents a significant hurdle to expanding rAAV-based gene therapies. Recently, evidence has emerged supporting a functional role of MAAP in AAV egress. This led to the hypothesis that MAAP could be engineered to facilitate increased levels of secreted AAV produced from HEK293 cells. 

Researchers at the University of California, Irvine have developed a new vaccine which generates a targeted, specific immune response with fewer complications than currently available vaccines.

The inventors present a novel strategy for achieving pathogen opportunistic pathogenesis, with broad implications for treating infectious diseases. In a comprehensive analysis of Kaposi sarcoma associated herpesvirus (KSHV), a medically important virus, the inventors discovered novel antiviral targets and gene function, and identified opportunistic factors with dual functions of regulating both the immune environment/responses and viral reactivation/replication. This discovery includes:A collection of KSHV mutants with inactivation or deletion of each of the 91 predicted open reading frames (91 mutant strains). Methods and reagents (e.g. primers) for construction of the collection of KSHV mutants. The identity of 44 KSHV essential genes, which represent potential antiviral targets (including 27 newly identified essential genes). Methods for construction of gene-inactivation and rescued mutants, and for tagging and introducing foreign genes into the KSHV genome. These approaches can be used for vector and vaccine development. Growth properties of viral mutants with inactivation of non-essential genes.Methods for screening mutants in different human cell lines.Opportunistic factors of KSHV and all other animal viruses that have dual functions as both the modulators of immune environment/response and regulators of viral reactivation/replication.   

Following the pandemic, there is a clear need for improved technology in the area of vaccines. A pressing challenge is to enable a rapid response to emerging threats, using an established platform technology.

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Researchers at the University of California, Davis have developed a more cost effective and consistent method for producing capsular polysaccharides, a component of certain types of vaccines.

Researchers at UC Berkeley have developed methods to probe the conformational landscape of the SARS-CoV-2 Spike protein in the prefusion and ligand binding variations. The Spike protein from SARS-CoV-2 is the primary target for current vaccines against COVID-19 and is the focus of many therapeutic efforts. This large, heavily glycosylated trimeric protein is responsible for mediating cell entry via recognition of host cell receptors. A stabilized prefusion version of the structure of the Spike protein (termed S-2P) has been widely used for vaccine development and many structure/function studies, which have demonstrated that like other class 1 viral fusion proteins, the SARS-CoV-2 Spike protein is dynamic and samples several different conformations during its functional lifecycle. However, there are few experimental studies on the dynamics within the pre-fusion state of the SARS-CoV-2 Spike protein. The protein’s conformational landscape and the effects of perturbations, such as ligand binding (including receptor and antibody binding) or amino acid substitutions in emerging variants of concerns, are unknown. Stage of Research The inventors have developed hydrogen-deuterium exchange monitored by mass spectrometry (HDX-MS) methods to probe the conformational landscape of the soluble spike prefusion ectodomain, as well as the effects of ligand binding and sequence variation. They uncovered a stable alternative conformation that interconverts slowly with the canonical prefusion structure. This conformation is an open trimer, with easily accessible RBDs that expose the S2 trimer interface, providing new epitopes in a highly conserved region of the protein.

Streptococcus pyogenes (group A Streptococcus [GAS]) is a leading health and economic burden worldwide, with an estimated 700 million infections occurring annually. Among these are 18.1 million severe cases that result in over 500,000 deaths. Despite active research, a protective vaccine remains elusive, leaving antimicrobial agents as the sole pharmacological intervention against GAS. To date, penicillin remains a primary drug of choice for combating GAS infections. However, despite no apparent emergence of resistant isolates, the rate of treatment failures with penicillin has increased to nearly 40% in certain regions of the world. Due to the high prevalence of GAS infection and the decreasing efficacy of the available repertoire of countermeasures, it is critical to investigate alternative approaches against GAS infection. An emerging strategy for combating pathogenic bacteria involves targeting virulence. To avoid immune clearance, GAS expresses a wide variety of secreted and cell-associated virulence factors to facilitate survival during infection. Despite decades of inquiry into the role and regulation of GAS virulence factors, the function and potential importance of many proteins involved in pathogenicity remain unknown.

Though new therapeutics for the treatment of cancer are constantly being developed, they often show low efficiency for long-term remission, adverse side effects, and low immune response. Scientists at UCI have found a way to combat these issues with a combination therapy delivered by nanoparticle of both a vaccine, to prime the immune system, and a checkpoint inhibitor to shut down anti-cancer immune responses. This has been shown to prolong survival and promote immune response and immunological memory related to long-term survival.

UCLA researchers in the Department of Chemical and Biomolecular Engineering have developed a novel biomaterial that can be used as a therapeutic for cancer, wound healing and other diseases.

UCLA researchers in the Department of Medicine have developed a novel vaccine platform against Tier 1 Select Agents to prevent infectious diseases such as tularemia, anthrax, plague, and melioidosis.

UCLA researchers in the Department of Biological Chemistry have developed a novel nanoparticle based antiviral vaccine capable of targeting many viruses.

Leptospirosis is one of the most widespread diseases estimated to infect up to 7-10 million people per year worldwide (2014) that can be transmitted from animals to humans. The most common transmission is via the urine of rodents or domestic animals that contaminates water or soil. Unfortunately, it can cause severe infection and currently there is not an efficient vaccine present to combat this disease. The disease is caused by Leptospira, a genus of the spirochaete bacteria of which there are ~13 pathogenic species that effect humans. The signs and symptoms of the disease are quite variable and can range from mild headaches, muscle pains, and fevers to the more severe form which causes bleeding from the lungs.

UCLA researchers in the Department of Pharmacology have discovered a novel approach toward generating live attenuated influenza vaccines with improved immune response in vivo.

Effective and easily accepted system of oral delivery of therapeutic drugs.