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- Data show that Vaxart’s HPV vaccine constructs stimulate specific T cell immune responses, reduce tumor size, and increase survival in an animal model of human papillomavirus (HPV)-related tumorigenesis - - Results suggest that Vaxart’s mucosal vaccine platform holds promise in enabling a novel, non-invasive treatment for HPV-related cervical dysplasia - SOUTH SAN FRANCISCO, Calif., Aug. 28, 2024 (GLOBE NEWSWIRE) -- Vaxart, Inc. (Nasdaq: VXRT) today announced the publication of preclinical data demonstrating the potential of its mucosal vaccine technology platform in enabling therapeutic vaccination against HPV-related cervical dysplasia. The data show that Vaxart’s HPV vaccine constructs can stimulate a potent immune response against the HPV16 proteins E6 and E7 that are known to transform healthy cells into malignant cells. The data, reported in the current issue of Vaccines, also shows that administration of a mucosal vaccine against these proteins in mice with HPV-expressing tumors led to reductions in tumor size and increased survival. Persistent HPV infection plays a causative role in most cases of cervical dysplasia, which leads to cervical cancers if left untreated. While prophylactic HPV vaccines are highly effective if administered prior to infection; they have not demonstrated a therapeutic effect on established infections. “The preclinical data published in Vaccines demonstrate that our mucosal vaccines stimulate T cells to destroy HPV-expressing cells, reducing the size of HPV-derived tumors and increasing the survival of mice bearing these tumors,” said Dr. Sean Tucker, Vaxart’s Founder and Chief Scientific Officer. “While additional studies are needed to further characterize the immune stimulating and anti-tumor activity of our HPV-vaccine, these initial findings suggest that our mucosal vaccine platform could open the door to a non-invasive approach designed to prevent the progression to cervical cancer. As our mucosal vaccine candidates can be administered easily and are stable at room temperature, they also have potential to address global inequities associated with the treatment of HPV-related cancers.” In this study published in Vaccines, the therapeutic potential of this platform was assessed in mice bearing HPV-expressing tumors. Animals were treated with vaccine candidates expressing wildtype E6 and E7 antigens from HPV16, engineered E6 and E7 that disrupt their malignant transformation potential, and fragments of E6 and E7 predicted to stimulate an immune response. Key findings from the study include: All vaccines generated a specific T cell response to HPV16 E6 and E7 in mice.All vaccines caused significant reductions in tumor volume and increased survival compared to control groups.Concurrent administration of anti-PD-1 with vaccination further increased animal survival in small and large tumor models compared to vaccination alone.Vaccination led to significant increases in intra-tumoral T cells, including T cells that create a cytotoxic tumor environment, compared with an empty control vaccine.Vaccination led to the generation of antigen-specific cytotoxic T cells. These results suggest that rAd5 vaccines delivered to a mucosal surface may have therapeutic potential in the treatment of HPV-derived cervical dysplasia and might be used to stimulate immune responses against other cancer-related proteins. Vaxart is continuing to evaluate its HPV vaccine candidates. About Vaxart Vaxart is a clinical-stage biotechnology company developing a range of oral recombinant vaccines based on its proprietary delivery platform. Vaxart vaccines are designed to be administered using pills that can be stored and shipped without refrigeration and eliminate the risk of needle-stick injury. Vaxart believes that its proprietary pill vaccine delivery platform is suitable to deliver recombinant vaccines, positioning the company to develop oral versions of currently marketed vaccines and to design recombinant vaccines for new indications. Vaxart’s development programs currently include pill vaccines designed to protect against coronavirus, norovirus and influenza, as well as a therapeutic vaccine for human papillomavirus (HPV), Vaxart’s first immune-oncology indication. Vaxart has filed broad domestic and international patent applications covering its proprietary technology and creations for oral vaccination using adenovirus and dsRNA agonists. Note Regarding Forward-Looking StatementsThis press release contains forward-looking statements that involve substantial risks and uncertainties. All statements, other than statements of historical facts, included in this press release regarding Vaxart’s strategy, prospects, plans and objectives, results from preclinical and clinical trials and the timing of such results, vaccine efficacy and safety, commercialization agreements and licenses, and beliefs and expectations of management are forward-looking statements. These forward-looking statements may be accompanied by such words as “should,” “believe,” “could,” “potential,” “will,” “expected,” “anticipate,” “plan,” and other words and terms of similar meaning. Examples of such statements include, but are not limited to, statements relating to Vaxart’s ability to develop and commercialize its product candidates, including its vaccine booster products; Vaxart’s expectations regarding clinical results and trial data, and the timing of receiving and reporting such clinical results and trial data; and Vaxart’s expectations with respect to the effectiveness of its product candidates. Vaxart may not actually achieve the plans, carry out the intentions, or meet the expectations or projections disclosed in the forward-looking statements, and you should not place undue reliance on these forward-looking statements. Actual results or events could differ materially from the plans, intentions, expectations, and projections disclosed in the forward-looking statements. Various important factors could cause actual results or events to differ materially from the forward-looking statements that Vaxart makes, including uncertainties inherent in research and development, including the ability to meet anticipated clinical endpoints, commencement, and/or completion dates for clinical trials, regulatory submission dates, regulatory approval dates, and/or launch dates, as well as the possibility of unfavorable new clinical data and further analyses of existing clinical data; the risk that clinical trial data are subject to differing interpretations and assessments by regulatory authorities; whether regulatory authorities will be satisfied with the design of and results from the clinical studies; decisions by regulatory authorities impacting labeling, manufacturing processes, and safety that could affect the availability or commercial potential of any product candidate, including the possibility that Vaxart’s product candidates may not be approved by the FDA or non-U.S. regulatory authorities; that, even if approved by the FDA or non-U.S. regulatory authorities, Vaxart’s product candidates may not achieve broad market acceptance; that a Vaxart collaborator may not attain development and commercial milestones; that Vaxart or its partners may experience manufacturing issues and delays due to events within, or outside of, Vaxart’s or its partners’ control; difficulties in production, particularly in scaling up initial production, including difficulties with production costs and yields, quality control, including stability of the product candidate and quality assurance testing, shortages of qualified personnel or key raw materials, and compliance with strictly enforced federal, state, and foreign regulations; that Vaxart may not be able to obtain, maintain, and enforce necessary patent and other intellectual property protection; that Vaxart’s capital resources may be inadequate; Vaxart’s ability to resolve pending legal matters; Vaxart’s ability to obtain sufficient capital to fund its operations on terms acceptable to Vaxart, if at all; the impact of government healthcare proposals and policies; competitive factors; and other risks described in the “Risk Factors” sections of Vaxart’s Quarterly and Annual Reports filed with the SEC. Vaxart does not assume any obligation to update any forward-looking statements, except as required by law. Contacts Vaxart Media Relations:Mark HerrVaxart, Incmherr@vaxart.com(203) 517-8957 Investor Relations:Matt SteinbergFINN PartnersIR@vaxart.com(646) 871-8481

Researchers have developed a model of Kaposi sarcoma that could expedite the development of new drugs to treat the disease, which is the most common cancer in people living with HIV. Researchers at UNC Lineberger Comprehensive Cancer Center, after decades of research efforts, have developed a mouse model of Kaposi sarcoma that could be key to the development of new drugs to treat the disease. Kaposi sarcoma is a cancer that is the most common cancer in people living with HIV. The findings appeared in Cell Host & Microbe. "This is an important development as we have created the first animal model ever of Kaposi sarcoma. Animal models are essential to move new drugs from the laboratory bench into clinical trials," said UNC Lineberger's Dirk Dittmer, PhD, senior corresponding author, co-leader of the UNC Lineberger Virology Research Program and director of the UNC Viral Genomics Core. "Before this, only repurposed drugs from other cancers were used to treat Kaposi sarcoma, but now we can start investigating entirely new compounds to help treat what can be a lethal cancer." About 20% of all human cancers arise from viruses or require viral infection as an essential cofactor. The Kaposi sarcoma-associated herpes virus (KSHV) was discovered in 1994 and is associated with Kaposi's sarcoma as well as B-cell cancers. KSHV-associated diseases affect internal organs and are ultimately fatal. In the U.S., the diseases are found primarily in immunosuppressed people such as those who are HIV-positive or are transplant patients. Worldwide, an estimated 34,270 cases of Kaposi sarcoma were diagnosed, and 15,086 deaths reported in 2020, with twice as many cases and deaths occurring in men compared to women. Africa accounted for 73% of new cases and 86.6% of the deaths from Kaposi sarcoma worldwide. The disease is endemic, and not HIV-related, in some southern and eastern African countries. Aside from animal models, one way to study cancer is to look at tumor cells in the lab. But according to Dittmer, Kaposi sarcoma tumor cells are very finicky and dependent on signaling molecules and blood supply, which is why they don't survive in a laboratory culture dish. Therefore, researchers have been focusing on developing animal models that would mimic, as closely as possible, the disease in humans. One of the challenges the researchers faced in developing their model was the fact that two types of genes are transcribed into proteins in the Kaposi sarcoma mouse model. Normally when a virus infects a cell, the cell dies as the virus replicates, which is a process called cell lysis; the genes that are needed for the virus to propagate itself are lytic genes. Cancer viruses are different as they enter a quiet state, called latency, where only the genes that help the infected cell survive are expressed. The mouse model the researchers developed is complex as a bit of both types of genes were needed. Cervical cancer and its related virus, HPV (human papilloma virus), offers a good comparison for the challenge of developing a Kaposi sarcoma mouse model. The KSHV genome is 20 times larger than HPV. HPV has two cancer-causing genes, E6 and E7, so to mimic the disease in animals, researchers only needed to design two mice, one for each gene. KSHV may have as many as 10 cancer-causing genes that all work together so it would be way too difficult to develop that many mice, hence the virtue of their single model, Dittmer noted. "Another of the key virtues of our new mouse model is that it helps us understand angiogenesis, or new blood vessel formation. Without angiogenesis cancer cells are deprived of oxygen and die," Dittmer said. "In this mouse model, we can study angiogenesis blocking drugs better than ever before. If new drugs work against Kaposi sarcoma, they will also likely work against lesser-angiogenic tumors, which would be a major plus." For next steps, the researchers hope that others will pursue drug and vaccine development based on a new understanding of fundamental aspects of KSHV provided by their mouse model, including possible development of a much-needed primate model for human KSHV and Kaposi sarcoma.

KANAZAWA, Japan, Jan. 10, 2024 /PRNewswire/ -- Researchers at Nano Life Science Institute (WPI-NanoLSI), Kanazawa University report in Nano Letters how the flexibility of a protein hinge plays a crucial role in the transfer of proteins in key cell processes. Ubiquitination – the addition of the protein ubiquitin - is a key stage in many cell processes, such as protein degradation, DNA repairs, and signal transduction. Using high-speed atomic force microscopy (HS-AFM) and molecular modelling, researchers led by Hiroki Konno and Holger Flechsig at WPI-NanoLSI, Kanazawa University have identified how the mobility of a ubiquitination related enzyme hinge allows ubiquitination to take place. Previous studies have identified a number of enzymes that facilitate ubiquitination, including an enzyme that activates ubiquitin (E1), an enzyme that conjugates it (E2), and an enzyme that catalyzes ubiquitin protein joining (i.e. a ligase, E3) to target protein (Fig. 1). The HECT-type E3 ligase is characterized by a HECT domain that comprises an N lobe with the E2-binding site and a C lobe with a catalytic Cys residue, a flexible hinge connects the two lobes, leading to the hypothesis that ubiquitination is facilitated by the rearrangement of the protein around this hinge. Konno and their collaborators deployed their high-speed atomic force microscope to hunt for evidence that this was the case. The researchers noted that when the HECT domain was crystallized with a type of E2 enzyme, it formed an L shape such that the distance between the catalytic Cys residue of the HECT domain and the catalytic Cys of the E2 enzyme was 41 Å – too far for the transfer of ubiquitin. However, in its catalytic conformation the HECT domain has a different shape where the distance between the two catalytic Cys residues is much closer – just 8 Å – so this is thought to be a 'catalytic conformation'. Analysis of HS-AFM images of a wild-type HECT domain of E6AP revealed two conformations – one of which looked spherical and the other oval (Fig. 2). Using AFM simulations they attributed the oval shapes to the L conformation and spherical shapes are either the catalytic conformation or the so called inverted T conformation, which had been observed in the another type of HECT domain where the distance between the Cys residues is 16 Å (Fig. 2). To overcome the spatio-temporal resolution limitations of imaging, the experiments were complemented by molecular modelling to visualize HECT domain conformational motions at the atomistic level. Simulation AFM was used to generate a corresponding pseudo AFM movie, which clearly showed the change from spherical to the oval shaped topography (Fig. 2). "Although experimental limitations do not allow us to resolve the intermediate conformations," explain the researchers in their report of the work. "The performed modeling provides evidence that the transitions between spherical and oval HECT domain shapes observed under HS-AFM correspond to functional conformational motions under which the C-lobe rotates relative to the N-lobe, thereby allowing the change between catalytic and L-shape HECT conformations." Further experiments with mutant HECT domains with less flexibility in the hinge revealed no flipping between conformations – the mutant HECT domains were locked in the catalytic conformation. They also found that while these mutant HECT domains could form two ubiquitin proteins joined together more efficiently than the wild type. E6AP, the HECT-type E3 in this study, interacts with E6 protein derived from human papillomavirus (HPV) and ubiquitinates p53, a tumor suppressor protein. It is also known that ubiquitination of p53 by E6AP and E6 is a major cause of cervical cancer. However, the mechanism of p53 ubiquitination by the interaction of E6AP and E6 proteins remains unclear. In the future, we will elucidate the structural dynamics of E6AP/E6, and the E6AP/E6/p53 complex with HS-AFM, and clarify how E6 increases the activity of p53 ubiquitination by E6AP. Figure 1 link: Fig 1 caption: Ubiquitination and degradation of protein by the ubiquitin-proteasome system. © 2023 Takeda, et al., Published by American Chemical Society Fig. 2 link: Fig 2 caption: High-speed AFM observation and simulation of the structural dynamics of the HECT domain of E6AP. (A) HS-AFM image of the HECT domain. Spherical (white dotted line) and oval (blue dotted line) conformational states were observed. (B) Simulated transition process of the structural state of the HECT domain and its pseudo AFM image. (C) Ubiquitin (Ub) is transferred from E2 to E3 (HECT domain). After the addition of ubiquitin-containing E2 (E2-Ub), E2-Ub (white arrow) binds to the HECT domain, and after E2 dissociates, a small particle (blue arrow) that appears to be ubiquitin is added to the HECT domain. © 2023 Takeda, et al., Published by American Chemical Society Glossary Ubiquitin The protein takes its name from the term 'ubiquitous' because it is found in almost all tissues. It can be added as a single protein or further proteins added into a chain. This 'ubiquitination' is an essential step in many cell processes. High-speed atomic force microscopy This imaging technique uses a nanosized tip at the end of a cantilever that is scanned over a sample. It can be used to determine the topography of a sample surface from the change in the strength of forces between the tip and the sample with distance, and the resulting deflection of the cantilever. It was first developed in the 1980s but a number of modifications have augmented the functionality of the technique since. It is better suited to imaging biological samples than the scanning tunnelling microscope developed that had been developed because it does not require a conducting sample. In the 2000s Toshio Ando at Kanazawa University was able to improve the scanning speed to such an extent that moving images could be captured. This allowed people to use the technique to visualize molecular processes for the first time. Reference Kazusa Takeda†, Holger Flechsig†, Ikumi Muro†, Romain Amyot, Fuminori Kobayashi, Noriyuki Kodera, Toshio Ando and Hiroki Konno, Structural Dynamics of E6AP E3 Ligase HECT Domain and Involvement of a Flexible Hinge Loop in the Ubiquitin Chain Synthesis Mechanism, Nano Letters, 2023, 23, 24, 11940–11948. †These authors contributed equally to this work DOI：10.1021/acs.nanolett.3c04150 URL: Contact Hiroe Yoneda Senior Specialist in Project Planning and Outreach NanoLSI Administration OfficeNano Life Science Institute (WPI-NanoLSI) Kanazawa University Kakuma-machi, Kanazawa 920-1192, Japan Email: [email protected] Tel: +81 (76) 234-4555 About Nano Life Science Institute (WPI-NanoLSI), Kanazawa University Understanding nanoscale mechanisms of life phenomena by exploring 'uncharted nano-realms'. Cells are the basic units of almost all life forms. We are developing nanoprobe technologies that allow direct imaging, analysis, and manipulation of the behavior and dynamics of important macromolecules in living organisms, such as proteins and nucleic acids, at the surface and interior of cells. We aim at acquiring a fundamental understanding of the various life phenomena at the nanoscale. About the World Premier International Research Center Initiative (WPI) The WPI program was launched in 2007 by Japan's Ministry of Education, Culture, Sports, Science and Technology (MEXT) to foster globally visible research centers boasting the highest standards and outstanding research environments. Numbering more than a dozen and operating at institutions throughout the country, these centers are given a high degree of autonomy, allowing them to engage in innovative modes of management and research. The program is administered by the Japan Society for the Promotion of Science (JSPS). About Kanazawa University As the leading comprehensive university on the Sea of Japan coast, Kanazawa University has contributed greatly to higher education and academic research in Japan since it was founded in 1949. The University has three colleges and 17 schools offering courses in subjects that include medicine, computer engineering, and humanities. The University is located on the coast of the Sea of Japan in Kanazawa – a city rich in history and culture. The city of Kanazawa has a highly respected intellectual profile since the time of the fiefdom (1598-1867). Kanazawa University is divided into two main campuses: Kakuma and Takaramachi for its approximately 10,200 students including 600 from overseas. SOURCE Kanazawa University