Mounting interest in the use of viral vector technology for vaccine and gene therapy applications is being driven by recent developments in these industry sectors.
Widespread media attention on the potential for a global influenza pandemic linked to the spread of the H5N1 avian flu strain, approval of the first gene therapy product in China, and the expanded use of viral vector technology in vaccine production have all contributed to the enthusiasm in these fields.
Technological advances such as the development of novel viral-based gene delivery methods, improvements in the design and production of viral vectors, and advances in large-scale manufacturing and purification of vaccine and gene therapy products, have all helped broaden the use of viral vector technology.
Fears of a human influenza pandemic linked to the H5N1 avian flu strain among birds in Asia and Europe have led to intense scrutiny of global preparedness to prevent and treat a large-scale flu outbreak.
In an effort to respond to this concern, sanofi pasteur (Lyon, France and Swiftwater, PA) announced a $100 million contract with the U.S. Department of Health and Human Services (HHS) in September. The agreement focuses on production and storage, in bulk concentrate form, of a vaccine that would help protect against a mutated version of H5N1 influenza that could spread among humans. The U.S. government is currently testing an investigational vaccine developed using conventional egg-based techniques and delivered by Sanofi in May 2004.
Earlier this year, HHS awarded a contract to Sanofi Pasteur to accelerate the development of a cell culture-based production process for manufacturing influenza vaccine.
MedImmune (Gaithersburg, MD) as well has entered into a collaborative agreement with the National Institute of Allergy and Infectious Diseases (NIAID) to develop investigational pandemic influenza vaccines. The company will apply the same technology it used to develop its FluMist product, an FDA-approved intranasal, live, attenuated influenza vaccine.
The firm will produce vaccine seed lots "for a number of different virus strains that we would not normally see in an annual cycle," according to George Kemble, Ph.D., vp of vaccines research and development and general manager of MedImmune's California facilities. One of these vaccine seeds will be based on the H5N1 strain of avian influenza.
"We will be using a cDNA-based approach called plasmid rescue, in which we individually clone six of the gene segments of the vaccine strain and two of the wild-type strain and combine them; we then rescue [the virus] following introduction of the cDNAs into mammalian cells," explains Dr. Kemble. The company then produces the vaccine using conventional egg-based production techniques.
At the 2005 Williamsburg Bioprocessing "Viral Vectors and Vaccines" conference, held recently, Ajit Subramanian of MedImmune presented the company's early R&D work using alternative, cell-based methods to produce influenza virus.
In September, MedImmune filed with the FDA for approval of a refrigerator-stable form of FluMist for use in healthy individuals between 5 to 49 years. The company is hoping to gain approval of this CAIV-T (cold adapted influenza vaccine, trivalent) for use in younger children as well.
Earlier this year, MedImmune completed construction of a new bulk vaccine manufacturing facility in Speke, England. The facility has the capacity to produce up to 15 million bulk doses per month, or about 90 million doses per influenza manufacturing season.
In October, Crucell (Leiden, The Netherlands) announced that Merck & Co. would use Crucell's PER.C6 production technology to develop an adenovirus-based vaccine against hepatitis C.
Merck already uses the PER.C6 human cell line technology to produce its adenovirus-based HIV vaccine that is in Phase II proof-of-concept trials. Crucell is applying the technology to develop an inactivated split virus influenza vaccine and an inactivated whole virus West Nile vaccine.
Crucell is also leveraging its adenovirus-based AdVac vector technology to create recombinant vaccines against the Ebola virus and malaria. It has signed an agreement with the U.S. Navy to develop AdVac-based vaccines against anthrax and plague as well as to test them in nonhuman primates.
"We're seeing positive trends on the adenovirus side in terms of both gene therapy and vaccines," says Anthony Green, Ph.D., a scientist at Puresyn (Malvern, PA). Dr. Green points to the positive results of animal studies from both a safety and efficacy perspective and the growing number of companies using adenovirus as part of a vaccine or gene therapy strategy.
"The issues that were problematic in the gene therapy field forced researchers to go back and address safety as part of their development process," Dr. Green says. "How you make your material and how clean it is"the process, independent of the vector"can affect both biological activity and safety," of the product, he adds.
Specializing in technology for large-scale production and purification of recombinant adenoviral vectors for use in gene therapy and vaccine applications, Puresyn developed the Adenopure adenovirus purification kits. These can replace cesium chloride gradients and chromatographic methods used to separate and purify recombinant adenovirus.
Puresyn plans to expand its contract manufacturing services and to add GMP services within the next 12 to 15 months, according to Mickey Flynn, president of Puresyn.
Optimism that the gene therapy industry in the U.S. will see its first product come to market and realize commercial success, overcoming safety issues that plagued early product development efforts, stems from the growing number of gene therapy products advancing through the pipeline as well as the successful launch of a recombinant adenovirus-based gene therapy product in China in April 2004. Gendicine contains the human p53 gene and is approved for the treatment of head and neck squamous cell carcinoma.