Currently marketed influenza vaccines are based on a development, production and vaccination strategy that has not changed significantly in the past five decades. Due to the seasonal nature of the disease and the genetic instability of the virus, it is necessary to formulate a new influenza vaccine each year based on an epidemiological prediction of the strains most likely to be circulating in the human population in the next winter's flu season. Current vaccines are formulated with hemagglutinin (HA) as the viral antigen (the component of the virus, usually a protein, that serves as a target for an immune response). Due to slow development and production cycles, there is general concern that traditional vaccines may not consistently meet the demands of seasonal influenza or potential pandemic virus outbreaks.

 

The novel approach championed by VaxInnate is designed to meet those demands by drawing upon breakthroughs in our knowledge of the way the immune system works and taking advantage of efficient manufacturing technology. By leveraging the two primary mechanisms of immune defense, referred to as "innate" and "adaptive" responses, VaxInnate's proprietary TLR technology leads to a more effective vaccine against both variable antigens, and antigens that remain conserved from one strain of virus to the next. Because the vaccines can be produced in bacteria, they can be developed and manufactured at a large scale within a short period of time.

Recently, a VaxInnate lead vaccine candidate against influenza HA demonstrated full protection against a lethal influenza challenge in mice, while production yields suggested enough vaccine could be produced in standard industrial-scale fermenters within several months.

VaxInnate's TLR technology is based on the ability of "toll-like receptors" (TLRs) to recognize certain molecular patterns, triggering a more robust adaptive immune response including the production of antibodies. The company's vaccines combine proteins of vaccine antigen (such as the influenza HA) and bacterial flagellin, a component of the long hair-like tails that help bacteria swim and one of the molecular patterns recognized by TLRs. Physically linking flagellin to antigens leads to a more potent vaccine than just administering a mixture of the two unattached components. The method has been demonstrated to produce robust protective immune responses in animal models to several pathogens including West Nile Virus, Japanese Encephalitis Virus and Listeria, in addition to influenza. Because flagellin is a stable bacterial protein, these fusion products are simple to make using recombinant DNA techniques. The ability to rapidly develop and manufacture large quantities of the fusion product vaccines makes them ideally suited for responding to seasonal variants of influenza, or emerging pandemic viruses.

In addition to rapid development and production, TLR vaccine technology offers a further advantage. The viral antigen-flagellin fusion product can generate a response even against targets that are not very immunogenic, including highly conserved regions of viral proteins. That means instead of developing a new vaccine for every seasonal variant or emerging strain of virus, one vaccine could be effective against a wider variety of strains and even pandemic viruses. Such a vaccine strategy could facilitate stockpiling for public health and biodefense purposes.

 

Current vaccine manufacturing is based on growing virus in live fertilized chicken eggs. In a laborious process, the virus is then harvested, purified and processed to recover viral antigens. Egg-based systems take six to nine months to manufacture and release a year's batch of vaccine, making it difficult to predict demand or respond quickly to public health emergencies.

VaxInnate's fusion vaccine can be efficiently and economically manufactured in bacteria. The technology for producing large quantities of proteins in bacteria has been practiced for over two decades, and many currently available protein-based drugs are manufactured in this way. The method involves the insertion of a circular DNA "vector" coding for the flagellin-antigen fusion product into bacteria. The DNA directs the synthesis of the fusion product, which either accumulates in the bacteria or is secreted into the surrounding media. The following purification steps to isolate the protein are very straightforward. Applied to vaccines, bacteria-based production avoids traditional egg-based manufacturing, lowers the cost of goods of the final product, and establishes a more rapidly scaleable manufacturing process. In addition, a bacteria-based manufacturing process avoids the risk that an avian flu pandemic will destroy egg-laying flocks.

The immune system takes two different, yet interdependent approaches to defeating a foreign pathogen such as a bacteria or a virus.

The innate immune system. This system mounts an immediate response to an infection without being specific to the pathogen in question. The innate immune system is the more primitive of the body's responses to infection. It is made up of immune cells and receptors (including so-called 'toll-like receptors' or TLRs) that immediately recognize certain molecular patterns uniquely associated with pathogens and then launch a first-line attack on the invaders. Because it recognizes only general molecular patterns on the surface of pathogens, and because some pathogens develop ways to evade its defenses, the innate immune system may have limited capability in holding back some infections.

The adaptive immune system. This system has the distinct advantage of highly specific recognition of virtually any pathogen the body might encounter, as well as providing immunological memory of infection. It is responsible for the production of antibodies and killer T cells. However, the adaptive system relies upon the innate systems recognition of a pathogen to initiate its own response to a pathogen. While the adaptive systems recognition of a pathogen is extremely precise, it is relatively slow compared to the timescale of an infection.

Together, these two systems provide a comprehensive immune response to infectious agents. It is precisely this biological partnership that has been harnessed to produce VaxInnate's highly specific and potent vaccines.

 

Hemagglutinin binds to sugars on the surface of host cells and helps the virus to fuse with, and enter the cell. Its essential role in the infection cycle has made HA an obvious and effective target (antigen) for traditional influenza vaccines. Another viral antigen, neuraminidase (NA), clips the sugars, preparing the virus to freely exit the cell, and continue the replication cycle by infecting other cells. There is considerable genetic variance among type A virus strains, and the variants are grouped according to the particular HA and NA sub-types present. Influenza A subtypes have designations such as H3N2 or H1N1, reflecting the identity of the particular HA and NA proteins variants expressed by the virus subtype. Most human influenza viruses have H1 or H3 hemagglutinins, while avian influenza viral strains characteristically have H5, H7 or H9.