Vivaldi Biosciences’ DeltaFLU Universal Influenza Vaccine and the Influenza H5N1 Pandemic Threat

The highly pathogenic avian influenza virus H5N1 causes extensive outbreaks and deaths in wild and domestic birds. The virus is known to infect humans, typically individuals that work with infected poultry, and has a high fatality rate. An outbreak of the virus in US dairy herds began in 2024 and three dairy workers have been infected. The recent transmission of influenza H5N1 from birds to mammals, the persistence of genetic features associated with mammalian adaptation, and the continuing possibility of reassortment with other animal influenza viruses significantly raise the pandemic threat of this virus. Vivaldi Biosciences’ DeltaFLU universal influenza vaccine is in development to protect against all influenza virus strains, including the highly pathogenic H5N1 virus and variants arising from its rapid mutation. Protection with current influenza vaccine technologies, including development-stage mRNA influenza vaccines, relies on a close match between the vaccine and circulating influenza virus strains. This hit-or-miss approach often results in poor protection. DeltaFLU is produced in an efficient cell culture system and conveniently administered as a nasal spray, providing critical advantages in the event of a pandemic. As the first universal influenza vaccine, DeltaFLU provides the much-needed solution to the threat of pandemic influenza and the annual toll of morbidity and mortality of seasonal influenza.

The Risk of Pandemic Influenza

Pandemic influenza is a relentless global public health threat. Three influenza pandemics in the 20th century caused over 50 million deaths in total. The 2009 H1N1 influenza pandemic led to over a quarter of a million deaths worldwide. A highly pathogenic avian influenza (HPAI) H5N1 virus was first isolated in 1959, and the first human cases and deaths from this virus were reported in 19971. The World Health Organization has tallied 889 cases and 463 fatalities from human infection with H5N1 (cumulative case fatality rate of 52%) from 2004 to the present in 23 countries2. H5N1 in wildlife has now been detected on all continents except Australia. HPAI H5N1 viruses (clade [genetic group] are enzootic in Europe, where they have infected wild birds and mammals, including farmed mink. H5N1 clade reached North America by bird migration, and by 2024 the virus had spread from birds to multiple mammalian hosts including domestic cattle. The virus has been detected in dairy cattle in nine US states. Transmission among cattle has led to transmission to other domestic animals. With continued transmission in mammals, further mutations will arise affecting transmission efficiency, virulence, and pathogenicity, which in turn increase the risk of infection of human populations. From January 2022 to April 1, 2024 there were 14 reported human cases of H5N1 clade worldwide, with some having severe consequences, including mortality. Three confirmed H5 cases have been reported in dairy farm workers in the US from April to late May 2024. In the first two cases, which occurred in Texas and Michigan, the individuals experienced conjunctivitis. The third individual, a dairy farm worker in Michigan, was the first to report respiratory symptoms3. While human-to-human transmission of this virus has not been detected, influenza typically spreads through the respiratory route. The virus now has persistent genetic features associated with mammalian adaptation4. Humans have no pre-existing immunity to this virus. The risk of a pandemic will be significant if the virus acquires the ability for efficient direct human-to-human transmission.

DeltaFLU for Protection Against Influenza H5N1

Vivaldi Biosciences ( is developing the DeltaFLU universal influenza vaccine, a nasal spray vaccine for protection against all influenza virus strains: H5N1 and other emerging strains with pandemic potential, as well as seasonal influenza strains and variants that arise. DeltaFLU consists of genetically attenuated heterologous (unmatched) influenza strains in a prime-boost immunization regimen that generates a nearly immediate, broadly protective immune response in the nasal passages, and a robust systemic immune response of antibodies and T cells. 

Safe and immunogenic for H5N1 in humans: A component of DeltaFLU, a genetically attenuated vaccine strain based on HPAI H5N1 (A/Vietnam/1203/2004), was shown in a Phase 1 clinical trial to be safe and immunogenic, and to induce a superior antibody response compared with other H5N1 vaccine approaches. Seventy-five percent of the immunized study volunteers had serum HAI antibodies to H5N1 ≥1:40 after one intranasal dose of the vaccine, exceeding the FDA licensing threshold of 70%. After two doses, 92% met or exceeded this antibody response level. Antibody responses in the nasal mucosa also were observed among individuals with serum antibody responses5.

Universal protection against H5N1 and all potential pandemic and seasonal influenza viruses: Influenza viruses mutate rapidly. Co-infection of a host with different influenza viruses (e.g., a human infected with human and avian influenza viruses) can give rise to reassortment of viral RNA and yield a novel strain for which humans have no immunity. Universal protection requires effectiveness against all influenza type A and B viruses, consisting of at least 20 subtypes, innumerable variants and clades (genetic groups), and emerging strains with pandemic potential. Ferrets immunized intranasally with a genetically attenuated vaccine strain based on HPAI H5N1 (A/Vietnam/1203/04) similar to the DeltaFLU H5N1 component showed an immune response to multiple variants of influenza H5N1. Moreover, the immunized animals were protected from challenge with heterologous H5N1 viruses representing a range of clades, and also were protected from a H5N3 influenza virus6

Vivaldi has demonstrated proof of concept for universal protection with DeltaFLU in ferret and mouse models. With respect to H5N1 (a type A/group 1 virus), immunization with DeltaFLU vaccine strains for H5N1 and a second type A/group 1 strain (H1N1) protected ferrets from challenge with a broadly divergent H1N1 influenza strain, indicating potential for protection against all type A/group 1 strains. Additional studies gave similar results for type A/group 2 and type B viruses, providing strong evidence for DeltaFLU to protect against all influenza type A and B viruses, i.e., all influenza viruses that cause disease in humans.

Protection against transmission and disease spread: Influenza transmission between people primarily occurs via respiratory droplets. 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, especially in the event of a pandemic. Vivaldi is conducting studies in the ferret model to demonstrate the ability of DeltaFLU universal influenza vaccine to block transmission of all influenza virus types and prevent spread of infection and disease. The study specifically includes evaluation of DeltaFLU to block transmission of type A/group 1 strains representing H5N1. Final results of these studies are expected in June 2024.

Innovative, proprietary vaccine technology: DeltaFLU universal influenza vaccine combines two innovative concepts in the field of influenza virus vaccines: deletion of the influenza NS1 gene (delNS1), and heterologous prime-boost intranasal immunization with delNS1 vaccine strains. Deletion of the interferon antagonist NS1 results in the unique ability of DeltaFLU to rapidly induce interferon in the mucosal linings of the nasal passages. This creates a self-adjuvant effect, enhancing the generation of broadly cross-neutralizing antibodies in the nasal mucosa and systemic B and T cell-mediated immunity. Deletion of NS1 also makes DeltaFLU safe because the genetically modified vaccine strains are unable to replicate. Sequential immunization of heterologous delNS1 strains enables universal protection. The specific combination of delNS1 vaccine strains directs the immune response to highly conserved elements of the influenza virus shared by all influenza strain types, to confer protection against all influenza type A and B viruses. 

Preparation for an H5N1 pandemic: A pandemic vaccine must be capable of protecting against a known viral threat and also variant strains that may arise. Inactivated H5N1 vaccines for intramuscular injection have been developed and authorized for pandemic use. Because H5N1 is poorly immunogenic, a high dose or an adjuvant is used to boost the immune response (see table below). While adjuvants have the potential to improve the immune response and reduce the amount of antigen required in a vaccine, they also have important risk and drawbacks, including adverse reactions to immunization. A live attenuated vaccine for H5N1 A/Vietnam/1203/2004 for intranasal administration (2 doses) is produced by AstraZeneca. This vaccine is for pediatric use only (indicated for age 12 months to < 18 years). The vaccine virus must replicate to induce an immune response. The vaccine is produced in egg substrate. It was authorized in the EU in 2016 and re-authorized in 2023. None of the vaccines authorized by either the FDA or EMA use an H5N1 vaccine strain of clade 

Preliminary evaluations indicate the H5N1 vaccines retain cross-reactivity with currently circulating clade viruses, though it is uncertain how protective they will be. It is likely that the H5N1 vaccines will need to be updated to address the H5N1 threat7. mRNA vaccines are in early stages of clinical development. Moderna initiated a Phase 1 dose-escalation study of an H5N1 clade vaccine in July 2023, and in April 2024 Curevac and GSK began a Phase 1 dose-escalation study for their mRNA H5N1 vaccine. The low immunogenicity of H5N1 and reactogenicity of mRNA vaccines may be stumbling blocks to safety and efficacy. Although mRNA vaccine technology is vastly different from that of traditional inactivated influenza vaccines, both technologies produce strain-specific vaccines that require a close match to the circulating H5N1 strain, and likely will require frequent updating and reformulation as the H5N1 virus continues to mutate.

Inactivated Vaccines for H5N1 Authorized in the US and EU
ManufacturerVaccine NameH5N1 Vaccine StrainAdjuvantAge IndicationDosingProduction SubstrateAuthorized
GSKAdjupanrixA/Vietnam/1194/2004AS03≥ 6 months2 x 3.75 μgEgg2009 (EU)
GSKA/Indonesia/05/2005AS03≥ 6 months2 x 3.75 μgEgg2013 (US)
SanofiA/Vietnam/1203/2004(none)18-64 years2 x 90 μgEgg2007 (US)
Seqirus (CSL)FocliviaA/Vietnam/1194/2004MF59≥ 6 months 2 x 7.5 μgEgg2009 (EU)
Seqirus (CSL)AudenzA/Turkey/1/2005 NIBRG-23MF59≥ 6 months2 x 7.5 μgMDCK cells2020 (US)

Sanofi and GSK H5N1 vaccines are stockpiled by the US. The amount of vaccine stockpiled is only a fraction of what would be required to protect the population in the event of a pandemic. Doses sufficient for only about 50 million people could be available within 3-4 months7

To rapidly produce greater quantities of these H5N1 vaccines, the existing infrastructure for production of seasonal influenza vaccines would need to be diverted. Even if this were possible, production of H5N1 vaccines would be problematic. Most of the production infrastructure for influenza vaccines is dedicated to egg-substrate production, a cumbersome and time-consuming process. Over 90% of licensed influenza vaccines are produced in embryonated chicken eggs. Egg-based production may be unreliable due to the potentially limited supply of pathogen-free embryonated 10-day old chicken eggs needed as virus substrates, vulnerability of egg supply in the event of an outbreak of an HPAI virus affecting poultry or during a pandemic, the need to passage the vaccine virus to adapt to growth on eggs, growth optimization and scale-up, and problems with vaccine antigen yield and variability due to egg adaption. 

DeltaFLU diversifies the global vaccine pipeline with a reliable and sustainable Vero cell-based manufacturing system. Cell-based manufacture addresses strategic needs in the event of a pandemic, avoiding potential egg shortages that could occur with an HPAI pandemic, and providing greater speed and capacity than is possible with egg substrate production. With Vivaldi’s vaccine manufacturing system, the substrate is virtually unlimited, and the system is readily scalable8. Vivaldi’s high-yield system includes proprietary technologies to optimize vaccine strain growth, purity, and potency. Vaccines can be produced in as little as seven weeks.

Conclusion: DeltaFLU universal influenza vaccine is an innovative vaccine approach for pandemic preparedness and prevention of seasonal influenza. Broad and superior effectiveness, safety, convenient and pain-free administration, and efficient cell-based production should enable DeltaFLU to take a sizeable share the established market for seasonal influenza vaccines, which is dominated by inactivated, injectable vaccines produced in egg substrate. Availability of and immunization with DeltaFLU will not be restricted to certain months of the year, as are traditional vaccines with their long production lead-times. DeltaFLU is designed to protect against all influenza virus strains, including emerging strains with pandemic potential, seasonal strains, and variants that arise. Nasal spray administration of DeltaFLU is well-suited to mass administration in the threat of a pandemic, and avoids the need to produce, stockpile, handle, and dispose of hundreds of millions of syringes and needles. DeltaFLU is self-adjuvanting, avoiding the safety concerns of vaccine adjuvants. Immunization with DeltaFLU rapidly induces an immune response in the nasal passages, where antibodies neutralize the virus. The potential of DeltaFLU to block transmission of influenza viruses and reduce disease spread would be transformational. 


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  2. World Health Organization. 2024. Cumulative number of confirmed human cases for avian influenza A(H5N1) reported to WHO, 2023-2024, 3 May 2024. 
  3. CDC. 2024. CDC Confirms Second Human H5 Bird Flu Case in Michigan; Third Case Tied to Dairy Outbreak. 
  4. Uyeki, et al. 2024. Highly pathogenic avian influenza A(H5N1) virus infection in a dairy farm worker (Correspondence). NEJM. 3 May.
  5. Nicolodi, et al. 2019. Safety and immunogenicity of a replication-deficient H5N1 influenza virus vaccine lacking NS1. Vaccine 37(28): 3722-3729.
  6. Romanova, et al. 2009. Preclinical evaluation of a replication-deficient intranasal ΔNS1H5N1 influenza vaccine. PLOS ONE 4(6): e5984.
  7. Lovelace. 2024. Two possible bird flu vaccines could be available within weeks. NBC News. 1 May.
  8. Barrett, et al. 2009. Vero cell platform in vaccine production: moving towards cell culture-based viral vaccines. Expert Rev. Vaccines 8:607.