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Infection with Zika virus in pregnancy can lead to neurological disorders, fetal abnormalities and fetal death. Until now, how the virus manages to cross the placenta, which nurtures the developing fetus and forms a strong barrier against microbes and chemicals that could harm the fetus, has not been clear. Researchers now report a strategy Zika virus uses to covertly spread in placental cells, raising little alarm in the immune system. Infection with Zika virus in pregnancy can lead to neurological disorders, fetal abnormalities and fetal death. Until now, how the virus manages to cross the placenta, which nurtures the developing fetus and forms a strong barrier against microbes and chemicals that could harm the fetus, has not been clear. Researchers at Baylor College of Medicine with collaborators at Pennsylvania State University report in Nature Communications a strategy Zika virus uses to covertly spread in placental cells, raising little alarm in the immune system. "The Zika virus, which is transmitted by mosquitoes, triggered an epidemic in the Americas that began in 2015 and by 2018 had reached as many as 30 million cases," said co-senior author Dr. Indira Mysorekar, E.I. Wagner Endowed, M.D., Chair Internal Medicine II, chief of basic and translational research and professor of medicine -- infectious diseases at Baylor. "Understanding how Zika virus spreads through the human placenta and reaches the fetus is critical to prevent or control this devastating condition." The researchers discovered that Zika virus builds underground tunnels, a series of tiny tubes called tunneling nanotubes, that facilitate the transfer of viral particles to neighboring uninfected cells. "We discovered that the formation of these tiny tunnels is driven exclusively by a Zika protein called NS1," said first author Dr. Rafael T. Michita, postdoctoral research associate in the Mysorekar lab. "Exposure of placental cells to the NS1 protein of Zika virus triggers tunnel formation. As the tunnels develop and connect neighboring cells, a path opens for the virus to invade new cells." "Zika is the only virus in its family, which includes dengue and West Nile viruses among others, whose NS1 protein triggers the formation of tunnels in multiple cell types," Michita said. "Other viruses unrelated to Zika, such as HIV, herpes, influenza A and SARS-CoV-2, the virus that causes COVID-19, also can induce tiny tunnels in cells they infect and use the tunnels to spread to uninfected cells. This is the first time that tunneling has been shown by Zika virus infection in placental cells." Interestingly, the tiny conduits provided a means to transport not only viral particles, but also RNA, proteins and mitochondria, a cell's main source of energy, from infected to neighboring cells. "We propose that transporting mitochondria through the tunnels may provide an energetic boost to virus-infected cells to promote viral replication," said co-author Long B. Tran, a graduate student in the Mysorekar lab. "We also show that travelling through the tiny tunnels can potentially help Zika virus avoid the activation of large-scale antiviral responses, such as interferon lambda (IFN-lambda) defenses implemented by the placenta," Michita said. "Mutant Zika viruses that do not make tiny tunnels induce robust antiviral IFN-lambda response that can potentially limit the spread of the virus." "Altogether, we show that Zika virus uses a tunneling strategy to covertly spread the infection in the placenta while hijacking mitochondria to augment its propagation and survival. We propose that this strategy also protects the virus from the immune response," Mysorekar said. "These findings offer vital insights that could be used to develop therapeutic strategies targeted against this stealth transmission mode." Steven J. Bark and Deepak Kumar at Baylor College of Medicine and Shay A. Toner, Joyce Jose and co-senior author Anoop Narayanan at Pennsylvania State University are key members of the research team. This work was supported in part by grants from NIH/NIAID (R01AI176505), NIH/NICHD (R01HD091218) and Pennsylvania State University startup funds. This project was also supported by the Cytometry and Cell Sorting Core at Baylor College of Medicine with funding from the CPRIT Core Facility Support Award CPRIT-RP180672 and the NIH (CA125123 and RR024574).

FORT COLLINS, Colorado and VIENNA, Austria – December 18, 2023 – Vivaldi Biosciences today announced it has received a grant from Flu Lab to evaluate the potential of its DeltaFLU universal influenza vaccine, administered by nasal spray, to block influenza virus transmission and spread of infection and disease. Vivaldi Biosciences is a clinical-stage biotechnology company developing vaccines for viral respiratory diseases. Flu Lab, based in Palo Alto, CA, is a philanthropic organization founded to fuel bold approaches to defeat influenza. A vaccine that both protects against all influenza strains and blocks or reduces transmission would be a significant advance in preventing influenza and reducing the disease burden. The transmission study builds on successful clinical trials of DeltaFLU vaccine strains, and preclinical studies showing the potential for DeltaFLU to provide protection against all influenza virus strains causing disease in humans. Vivaldi Biosciences plans to begin the transmission study in early 2024. The study will include evaluations of immune response and protection of DeltaFLU-immunized ferrets against infection by broadly divergent wild-type influenza type A and B strains transmitted by experimentally infected ferrets. The ferret is the most well-characterized and relevant animal model of human influenza infection and immune response. Influenza is a contagious respiratory disease and a serious public health problem. Influenza viruses are transmitted between individuals by tiny droplets that enter the nose, mouth or lungs, where they replicate and cause disease. Each year, influenza infects as many as 30% of children and 10% of adults worldwide, and results in as many as 500,000 deaths. Vaccination is the best way to prevent influenza, but conventional vaccines provide only modest protection. Available vaccines are designed to protect against just three or four selected influenza virus strains and do not prevent transmission of influenza viruses from person to person. Vivaldi Biosciences’ DeltaFLU provides important advantages of needle-free administration and rapid protection in the nasal passages, where it generates a first line of defense at the point of entry of circulating flu viruses. DeltaFLU also activates T cells and antibody-producing B cells for a broadly protective systemic immune response. Vivaldi has secured funding from the National Institute of Allergy and Infectious Diseases (NIAID) and the European Union to conduct clinical trials to demonstrate universal protection with DeltaFLU in adult volunteers. About Vivaldi Biosciences Vivaldi Biosciences develops genetically engineered nasal spray vaccines for epidemic and pandemic viral respiratory diseases. The company’s patented technology centers on eliminating the influenza NS1 gene to generate self-adjuvanting vaccines. Vivaldi Biosciences’ Vero cell-based vaccine manufacturing system uses patented advances in production and purification for high yields and reduced costs. Data from completed Phase 1 and 2 clinical trials of DeltaFLU vaccine strains demonstrate safety and broadly cross-neutralizing antibodies in the serum and nasal mucosa. Studies in animal models provide proof of concept for protection against all influenza virus strain types causing disease in humans, including emerging strains with pandemic potential. Vivaldi Biosciences has received grants for further clinical studies of DeltaFLU universal influenza vaccine from the National Institute of Allergy and Infectious Diseases’ (NIAID) Collaborative Influenza Vaccine Innovation Centers (CIVICs) and the European Union’s Horizon Europe research and innovation program under grant agreement No. 101080692. Vivaldi Biosciences is a venture-backed company with operations at the Research Innovation Center at Colorado State University, Fort Collins, Colorado, and in Vienna, Austria. NGN Capital LLC is the company’s lead investor. Learn more at Connect with Vivaldi Biosciences on Linkedin. Contact Bill Wick, CEO, Vivaldi Biosciences Tel: +1 650-400-8915 bill.wick@vivaldibiosciences.com Forward-Looking Statements This release contains forward-looking statements relating to Vivaldi Biosciences, which are not historical facts and are forward-looking statements within the meaning of the Private Securities Litigation Reform Act of 1995. All statements included in this communication concerning activities, events or developments that we expect, believe or anticipate will or may occur in the future are forward-looking statements. Our actual results, performance or achievements may differ materially from those expressed or implied by these forward-looking statements. 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Leiden, The Netherlands – 5 June 2023 – A consortium of eight academic and industry partners is advancing the development of a universal influenza vaccine with a €7.6 million grant from the European Union. Through its FLUniversal programme, the consortium will conduct clinical trials of DeltaFLU, a rapid-acting universal influenza vaccine for intranasal administration. FLUniversal also will seek to elucidate molecular and immunological mechanisms of protection, and identify potential new correlates of protection using data from clinical trials and preclinical models. The partners will develop a novel controlled human infection model (CHIM) and influenza challenge strain which they will use to evaluate protective efficacy of DeltaFLU in a clinical challenge study. Ed Schmidt, PhD, Project Manager at consortium member Leiden University Medical Center (LUMC) remarked, “Influenza is a major public health problem globally. A universal influenza vaccine that provides protection against all seasonal influenza strains and emerging strains with pandemic potential is an urgent goal. The FLUniversal consortium unites world-leading experts with the tools and knowledge to develop a novel universal influenza vaccine that already has surmounted key hurdles of novel vaccines: demonstration of safety and robust immunogenicity in humans and manufacturability. Our synergistic combination of preclinical models, a CHIM to produce results similar to wild-type infection, clinical samples, and integrated complex immunological analyses form a unique platform to identify molecular signatures of protection and reduce the timeline and risks involved in clinical development.” DeltaFLU universal influenza vaccine, developed and owned by FLUniversal partner Vivaldi Biosciences, is based on influenza virus strains genetically modified to eliminate the NS1 gene. This genetic modification results in the ability of DeltaFLU to rapidly induce interferon and broadly cross-neutralising antibodies in the nasal passages, generating protection at the point of entry of influenza viruses, and establishing tissue-resident memory T cells for protection against repeat infection. The self-adjuvanting effect of interferon enhances T and B cell activity for a broadly protective systemic immune response. Deletion of NS1 also makes DeltaFLU safe because the genetically modified strains are unable to produce viral progeny and are not shed by vaccine recipients. Vivaldi has demonstrated safety and broad immunogenicity of DeltaFLU vaccine strains in clinical trials, and achieved proof of concept for universal protection against influenza A and B strains in animal models. LUMC and the Centre for Human Drug Research are responsible for the clinical studies in the FLUniversal programme: a Phase 1 study of safety and immunogenicity of DeltaFLU, a clinical study to characterise the novel influenza challenge strain and validate the CHIM, and a clinical challenge study of DeltaFLU in healthy adult volunteers to demonstrate protective efficacy. Vivaldi is responsible for GMP manufacture of the DeltaFLU vaccines and novel challenge strain using its high-yield Vero cell production system. The Medicines and Healthcare Products Regulatory Agency of the UK, participating in FLUniversal as an associate partner, is responsible for the isolation, selection and characterisation of the novel influenza virus challenge strain. MediTox, a GLP-certified contract research organisation with extensive expertise in nonclinical pharmacology and toxicology studies, will conduct the preclinical studies of DeltaFLU. Studies in the ferret model will include evaluations of safety, immunogenicity and challenge-protection. MediTox will further study DeltaFLU in the Syrian golden hamster model to identify immune fingerprints that correlate with protection against transmission of influenza virus from infected to immunised animals. Statens Serum Institut, an infectious disease research institute under the Danish Ministry of Health, will use state of the art techniques to evaluate samples from the preclinical and clinical studies, including cellular analyses of samples from the blood and nasal mucosa, to identify correlates of protection. VisMederi, a leader in validating immunological assay services, with unique competence in GCLPaccredited qualified sample analysis, will carry out integrated complex immunological assays for the identification of molecular signatures of protection. Zafiro Business Solutions, a consulting and advisory organisation specialising in EU programmes, serves as the FLUniversal programme coordinator, with responsibility for project management and compliance with ethics requirements. FLUniversal (Project Name: Intranasal, rapid-acting vaccine for all seasonal and pandemic influenza viruses) is funded under the European Union’s Horizon Europe Framework Programme (HORIZON). For further information, please contact: E.D.L. (Ed) Schmidt, Ph.D. Project Manager Department of Medical Microbiology Leiden University Medical Center e.d.l.schmidt@lumc.nl Funded by the European Union. Views and opinions expressed are however those of the author(s) only and do not necessarily reflect those of the European Union or the European Health and Digital Executive Agency (HADEA). Neither the European Union nor HADEA can be held responsible for them.