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DeltaFLU

Universal Influenza Vaccine

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DeltaFLU SPRAY

Vivaldi Biosciences is developing its DeltaFLU universal influenza vaccine to protect against all influenza strains – seasonal and pandemic – for all ages, from infants to seniors.

DeltaFLU is an advanced, self-adjuvanting influenza vaccine, administered as a nasal spray. Immunization with DeltaFLU is simple, convenient and pain-free.

The European Union is funding clinical development of DeltaFLU universal influenza vaccine through FLUniversal, a consortium of Vivaldi Biosciences and leading academic and industry partners.

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UNIVERSAL PROTECTION

deltaFLU is a radical advance towards the first truly universal influenza vaccine. A single dose of deltaFLU shows potential to protect against a broad range of influenza type A and B strains. Studies in human volunteers show the deltaFLU vaccine approach generates immunity to widely different influenza viruses – diverse strains that cause seasonal flu, and even an influenza strain with pandemic potential (A/H5N1 “bird flu”).

Recent studies in the ferret model take these striking clinical results a step further, showing deltaFLU protects against “drifted” influenza strains exhibiting a decade’s worth of accumulated genetic changes, and even protects against a strain so genetically altered it’s considered “shifted.” Such shifted strains are the source of flu pandemics.

With a unique self-adjuvant effect achieved by inducing interferon, deltaFLU generates a rapid and robust immune response. Administered as a gentle nasal spray, deltaFLU launches its protective effect in the nasal passages to disable incoming influenza viruses, and establishes long-lasting and broad protection from circulating T cells and cross-reactive antibodies.

Universal Protection

With its unique mode of action, DeltaFLU achieves a robust and broad immune response to multiple influenza strains

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UNIVERSAL PROTECTION



DeltaFLU is a radical advance towards the first truly universal influenza vaccine. DeltaFLU shows potential to protect against a broad range of influenza type A and B strains. Studies in human volunteers show the DeltaFLU vaccine approach generates immunity to widely different influenza viruses – diverse strains that cause seasonal flu, and even an influenza strain with pandemic potential (A/H5N1 “bird flu”).

Recent preclinical studies take these striking clinical results a step further, showing DeltaFLU protects against “drifted” influenza strains exhibiting a decade’s worth of accumulated genetic changes, and even protects against a strain so genetically altered it’s considered “shifted.” Such shifted strains are the source of flu pandemics.

Administered as a gentle nasal spray, DeltaFLU rapidly induces interferon and cross-reactive mucosal antibodies, launching its protective effect in the nasal passages to disarm influenza viruses at their point of entry. The self-adjuvant effect of interferon enhances T- and B-cell activity for a broadly protective systemic immune response. Durability of protection is achievable because of the induction of interferon, memory T cells, and memory B cells.

Our approach to universal protection takes advantage of these unique immune-stimulating properties of DeltaFLU combined with a heterologous prime-boost immunization regimen that directs the immune response to the conserved stalk of the influenza hemagglutinin (HA) surface antigen.

In animal model studies we showed that heterologous prime-boost immunization with DeltaFLU completely protected against challenge with a broadly divergent influenza strain. Immunized animals were symptom-free, protected from fever and weight loss, and challenge virus in the nasal passages was reduced by over 99% vs placebo. We’ve demonstrated preclinical proof of concept for universal protection with DeltaFLU against all the types of influenza viruses that cause disease in humans: type A groups 1 and 2 and type B lineages. Our planned clinical challenge-protection studies aim to replicate in humans this proof of concept for universal protection.

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INNOVATIVE PRODUCTION

We’ve developed and implemented a proprietary high-yield, high-efficiency process for producing deltaFLU using Vero cells as the production substrate. Our Vero cell system is fast, efficient and economical. Vero cells are an advantageous production platform − they are widely used for manufacture of licensed vaccines, have a solid regulatory track record, and eliminate the problem of antigenic mutations caused by production in eggs, the most widely used substrate for production of licensed influenza vaccines.

deltaFLU is composed of selected influenza type A and B vaccine strains genetically modified by deletion of the gene for NS1 and optimized for high growth and efficient production in Vero cells. We’re able to generate deltaFLU vaccine strains in as little as one week. And we’re able to produce the finished deltaFLU vaccine product in just 7 weeks. Traditional egg-based production can take up to 6 months.

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Our 7-week production timeline is a game-changer in the event of a pandemic, and provides an important competitive advantage in the seasonal influenza vaccine market.

Our Vero cell system uses serum-free media and single-use bioreactors. The streamlined process and one-step purification protocol enhance the efficiency and ensure a potent and pure vaccine product. Our system can be scaled to meet the demand for broad protection against seasonal influenza, and the challenge of rapidly producing hundreds of millions of doses in the face of an emerging influenza pandemic. Rapid vaccine strain generation and production enable shifting from commercial production of deltaFLU for the seasonal influenza market to surge production of deltaFLU for pandemic influenza. With its nasal spray dosage form, immunization with deltaFLU is efficient and well suited to mass use in a pandemic situation.

Innovative Production 

DeltaFLU vaccines can be delivered with unprecedented speed using our cell-based production system

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INNOVATIVE PRODUCTION



We’ve developed and implemented a proprietary high-yield, high-efficiency process for producing Delta NS1 vaccines using Vero cells as the production substrate. Our Vero cell system is fast, efficient and economical. Vero cells are an advantageous production platform − they are widely used for manufacture of licensed vaccines, have a solid regulatory track record, and eliminate the problem of antigenic mutations caused by production in eggs, the most widely used substrate for production of licensed influenza vaccines.

DeltaFLU is composed of selected influenza type A and B vaccine strains genetically modified by deletion of the gene for NS1 and optimized for high growth and efficient production in Vero cells. We’re able to generate DeltaFLU vaccine strains in as little as one week. And we’re able to produce the finished deltaFLU vaccine product in just 7 weeks. Traditional egg-based production of influenza vaccines can take up to 6 months.

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Our 7-week production timeline is a game-changer in the event of a pandemic, and provides an important competitive advantage in the seasonal influenza vaccine market.

Our Vero cell system uses serum-free media and single-use bioreactors. The streamlined process and one-step purification protocol enhance the efficiency and ensure a potent and pure vaccine product. Our system can be scaled to meet the demand for broad protection against seasonal influenza, and the challenge of rapidly producing hundreds of millions of doses in the face of an emerging influenza pandemic. Rapid vaccine strain generation and production enable shifting from commercial production of DeltaFLU for the seasonal influenza market to surge production of DeltaFLU for pandemic influenza. With its nasal spray dosage form, immunization with DeltaFLU is efficient and well suited to mass use in a pandemic situation.

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CLINICAL TRIALS



The European Union has awarded a grant for clinical development of DeltaFLU Universal Influenza Vaccine. Through the FLUniversal program, leading experts in academia and industry are collaborating with Vivaldi on a Phase 1 clinical study of DeltaFLU to confirm safety and dose, and a clinical challenge study in healthy adult volunteers to demonstrate protective efficacy and proof of concept for universal protection.


The grant also funds studies of infection, transmission, and protection in animal models. The FLUniversal program’s synergistic combination of preclinical models, clinical challenge study, and integrated immunological analyses form a unique platform to pinpoint molecular signatures of protection.


Vivaldi already has demonstrated safety, immunogenicity, and broadly cross-neutralizing antibody activity of DeltaFLU vaccine strains in Phase 1 and 2 clinical trials involving a total of 245 volunteers. We’ve achieved proof of concept for universal protection against influenza A and B strains in animal models.


Universal protection uses the unique immune-stimulating properties of DeltaFLU in combination with an immunization strategy that drives the immune response to features of the hemagglutinin (HA) antigen displayed by all influenza viruses. Intranasal administration of DeltaFLU takes advantage of the cross-neutralizing properties of IgA antibodies in the nasal passages to provide broad protection directly at the point of entry of circulating viruses. DeltaFLU induces interferon, robust systemic immunity, and memory T and B cells for durable protection.

Clinical Trials

An EU grant is funding clinical development of DeltaFLU, including a clinical challenge study to demonstrate efficacy and proof of concept for universal protection

Read more...
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CLINICAL TRIALS



The European Union has awarded a grant for clinical development of DeltaFLU Universal Influenza Vaccine. Through the FLUniversal program, leading experts in academia and industry are collaborating with Vivaldi on a Phase 1 clinical study of DeltaFLU to confirm safety and dose, and a clinical challenge study in healthy adult volunteers to demonstrate protective efficacy and proof of concept for universal protection.


The grant also funds studies of infection, transmission, and protection in animal models. The FLUniversal program’s synergistic combination of preclinical models, clinical challenge study, and integrated immunological analyses form a unique platform to pinpoint molecular signatures of protection.


Vivaldi already has demonstrated safety, immunogenicity, and broadly cross-neutralizing antibody activity of DeltaFLU vaccine strains in Phase 1 and 2 clinical trials involving a total of 245 volunteers. We’ve achieved proof of concept for universal protection against influenza A and B strains in animal models.


Universal protection uses the unique immune-stimulating properties of DeltaFLU in combination with an immunization strategy that drives the immune response to features of the hemagglutinin (HA) antigen displayed by all influenza viruses. Intranasal administration of DeltaFLU takes advantage of the cross-neutralizing properties of IgA antibodies in the nasal passages to provide broad protection directly at the point of entry of circulating viruses. DeltaFLU induces interferon, robust systemic immunity, and memory T and B cells for durable protection.

 
 

The DeltaFLU Difference

DeltaFLU is the only vaccine in clinical development based on deletion of the influenza NS1 gene. Removing this influenza virulence gene gives DeltaFLU both its unique mode of attenuation and its highly effective mechanism of action. Lacking NS1, DeltaFLU rapidly induces interferon, a key component of the immune response to viral infection.

 

Deletion of NS1 achieves two highly advantageous properties of DeltaFLU:

Delivered into the nasal passages in a gentle spray, DeltaFLU introduces to the immune system natural viral antigens that stimulate multiple components of the immune system to achieve a broadly protective immune response. The effect is similar to infection with a circulating influenza strain, but with a crucial difference: DeltaFLU vaccine strains are replication-deficient. Because of this, DeltaFLU strains cannot cause disease and do not produce viral progeny. Individuals immunized with deltaFLU do not shed the vaccine virus. These are important safety aspects of the DeltaFLU approach, and significant advantages over live vaccines that are able to replicate.

DeltaFLU vaccine strains can’t fight off the body’s interferon response because unlike naturally occurring influenza viruses, they lack the ability to produce NS1. As a result, DeltaFLU rapidly induces high levels of interferon and IgA antibodies in the linings of the nasal passages, creating a first line of defense against circulating disease-causing influenza viruses directly at their point of entry. This potent interferon response generates a self-adjuvant effect that activates a broadly protective systemic immune response in the form of serum antibodies, T cells, and T cell-based memory to viral infection.

Rapid and robust interferon induction – and interferon’s self-adjuvant effect – are unique to DeltaFLU.

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The Need

Influenza is a serious public health threat. No infectious disease has higher rates of incidence and mortality. Worldwide, a third of all children and 10% of all adults are infected with influenza viruses every year. Influenza and its serious complications cause a half a million deaths annually.

 
data source: https://www.cdc.gov/flu/vaccines-work/past-seasons-estimates.html

data source: https://www.cdc.gov/flu/vaccines-work/past-seasons-estimates.html

 

Vaccination is the primary means of preventing influenza infections and their spread, but conventional influenza vaccines are only about 50% effective at best. Effectiveness of conventional vaccines relies on a good match between the strains on which the vaccines are based and strains circulating in populations. As influenza viruses replicate they undergo constant genetic change. The gradual accumulation of genetic changes results in “drifted” strains that can’t be recognized by antibodies generated by prior immunization or virus exposure. Conventional vaccine technologies require annual attempts to match influenza vaccines to the strains expected to dominate the coming flu season. Mismatches between vaccines and circulating strains frequently occur, resulting in poor protection.

Occasionally influenza viruses undergo an abrupt genetic change so significant that most people have no immunity to the new virus strain. Such “shifted” strains can cause an influenza pandemic. Rapid development, production and distribution of a new vaccine is paramount to protect the population and forestall the disease’s spread. Pandemic influenza is a relentless global threat. The 2009 influenza pandemic led to over a quarter of a million deaths. The three major influenza pandemics of the 20th century caused a combined total of over 50 million deaths.

DeltaFLU shows the potential to provide protection against all strains of influenza type A and B viruses, including drifted strains and emerging strains with pandemic potential. Clinical studies show DeltaFLU induces broadly cross-neutralizing antibodies in the nasal passages and serum that can block widely unmatched influenza strains. We have demonstrated the feasibility of universal protection with DeltaFLU in nonclinical models. These findings support our plans to evaluate universal protection with DeltaFLU in placebo-controlled studies in healthy volunteers. GMP production of DeltaFLU for these upcoming clinical studies is underway.

 

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