Novavax' Recombinant Protein Nanoparticle Vaccine Technology
Novavax is a leading innovator of recombinant vaccines. Novavax' proprietary vaccine technology combines the power and the speed of genetic engineering to efficiently produce a new class of highly immunogenic particles addressing urgent unmet medical needs. The power of this technology is highlighted by our program to address respiratory syncytial virus (RSV), a leading cause of infant and elderly hospitalization. Attempts to develop an RSV vaccine have been stymied despite 60 years of research by vaccinologists. Our scientific breakthrough in the development of an RSV nanoparticle vaccine candidate and our rapid advances in clinical development are excellent examples of the power of our technology.
Genetic Engineering in Insect Cells
We produce our vaccine nanoparticles in cells originally isolated in the 1970s from the ovaries of the fall armyworm (Spodoptera frugiperda). In the early 1980s, scientists at Texas A&M (Smith, et al. 1983) discovered that one of these "Sf" insect cell lines, Sf9, could grow in apparent perpetuity in a special culture medium and could be made to produce recombinant proteins by infecting them with a baculovirus (BV), a virus that infects only insects. Because a baculovirus can be engineered to carry one or more foreign genes of interest, it can be used to "program" (infect) the Sf9 cells to efficiently produce the desired protein or proteins that, unlike simple bacteria or yeast-cell expression technology, are correctly folded and biologically active when made in these more highly evolved insect cell lines. Novavax uses the Sf9 system to construct two types of immunogenic nanoparticles that form the basis of our vaccine candidates:
- Recombinant protein nanoparticles that are tailored toward a single type of recombinant protein, and;
- Virus-like particles (or VLPs), which enable the incorporation of multiple antigens onto a single particle.
Recombinant Protein Nanoparticles
Our RSV vaccine candidate illustrates how Novavax scientists use our Sf9/baculovirus recombinant technology platform to create new product candidates.
We start by identifying a specific surface protein with favorable immunogenic properties. The RSV fusion protein (F-protein) is an important surface protein central to the disease process. We first identified the genetic sequence of the F-protein, and then employed sophisticated recombinant techniques to clone the gene into the BV. The engineered BV is then used to infect the Sf9 cells where it utilizes the Sf9 cell internal machinery to make the RSV F-protein. As the Sf9 cells produce recombinant RSV F-proteins, the proteins properly fold, undergo a series of programmed modifications, and are ultimately transported to the cell surface. Correctly folded and modified RSV F-proteins are then extracted from the cell surface and purified to maintain their three-dimensional structure and biological activity, ultimately serving as the immunogenic molecule in our vaccine.
In the native RSV virus, the F-protein is unstable and does not appear to induce fully protective immune responses. However, Novavax scientists introduced specific modifications to ensure the recombinant F-protein in the vaccine candidate is more stable. Our scientists have also designed the recombinant F-proteins to self-assemble into nanoparticle constructs that approximate the size of the RSV virus, a strategy that has been shown to enhance the immune response. We believe this recombinant vaccine engineering approach provides robust and functional immunity, and can be applied to a wide variety of viral, bacterial and parasitic diseases.
Virus Like Particles (VLPs)
Another example of the power of Novavax' Sf9/BV platform is our ability to produce influenza virus-like particles (VLPs) using similar techniques. However, instead of producing single-target protein nanoparticles, as with our RSV vaccine, Novavax scientists incorporated the gene sequences of multiple immunogenic proteins, together with universal matrix (M1) assembly proteins, to produce more complex envelope particle vaccines. Our influenza VLP vaccines incorporate the genetic sequences of the strain specific hemagglutinin (HA) and neuraminidase (NA) surface proteins. Traditional egg-based vaccines contain meaningful levels of HA protein, but little to no NA or M1, which may make them less immunogenic and effective. The HA sequence in our VLPs is the same as in the wild-type virus and could prove to be more effective or immunogenic than influenza vaccines produced using egg or mammalian cell-lines, which alter HA. In addition, the NA and M1 in our VLPs may play a role in reducing the severity of the disease by inducing antibody responses and cell mediated immunity. NA and M1 are both highly conserved, and immunity to these viral components may help provide additional protection throughout an entire influenza season, even as strains mutate.
Once expressed, the HA, NA and M1 proteins self-assemble and bud off the insect cell. The end result is highly immunogenic spherical structures that are roughly the same size as influenza viruses, with a lipid bilayer membrane expressing the HA and NA proteins on the surface, stabilized by the matrix assembly protein. Because there is no genetic material (DNA or RNA) in these VLPs, it is impossible for them to infect host cells and cause disease. Instead, their virus-like qualities activate the immune system to stimulate both antibody B-cell and cellular T-cell responses. Finally, because of the structure and components of our VLPs, they may have greater immunogenicity in two vulnerable populations – pediatrics and the elderly.
The insect cell/BV recombinant platform is well-established in the biopharmaceutical industry and is the basis for several licensed biologic products and vaccines, including a vaccine licensed for Human Papilloma Virus (HPV), which showed >95% effectiveness in reducing the incidence of cervical cancer. Novavax can use its insect cell/BV technology to produce a wide range of vaccine candidates derived from viruses, bacteria and protozoan parasites.
Advantages of Novavax' Manufacturing Technology
Our manufacturing platform has a number of important advantages:
- Our carefully designed genetic constructs allow us to tailor our vaccines to key components of pathogens, which we believe enhances functional immunity and leads to better protection against infection and disease.
- Our Sf9/BV platform efficiently expresses large antigens and particles, which in turn promote superior immunogenicity and better functional immunity.
- Our manufacturing platform can produce proteins that are properly folded and modified, which can be critical for functional, protective immunity.
- Unlike traditional influenza vaccine manufacturing, we do not need to grow an actual influenza virus, obtain embryonated chicken eggs, adapt the virus or optimize new strains to grow in eggs. This 50-year old method requires four to six months lead time to produce a new strain of virus and significant investment in fixed production facilities.
Our Sf9/BV recombinant technology platform is the basis for a portfolio of novel vaccines that represent important advances and address current unmet medical needs. Our innovation introduces a significant immunologic advantage, embodied by the presentation of antigens as highly immunogenic particles in their native configuration, and sound principles of development, as a scalable, efficient recombinant vaccine production system.