Vaccines have been an incredibly important tool in improving public health preventing millions of deaths each year from tuberculosis, diphtheria, tetanus, pertussis, polio, measles, hepatitis B, and Hib disease (WHO 2009 Fact Sheet). For that reason governments, multi-lateral health agencies, private donor organizations, NGOs, and companies have invested considerable time, effort, and money in creating a pipeline from discovery to delivery. But clearly, there are major challenges to their wider use of immunization in both preventing and treating disease. Foremost, current multilateral programs to subsidize the purchase and delivery of vaccinations, like UNICEF and the GAVI Alliance, are not funded sufficiently to meet the all need in the low- and lower-middle income countries (a total of 107 countries). WHO estimates the cost gap to be about $2 billion per year, or almost the amount that is spent now ($2.5 billion) (WHO Immunization Challenges). Technical and scientific challenges to inventing new vaccines are multiple including the selection of antigens and adjuvants to induce an immunological response, especially against target organisms with multiple subtypes or those with high rates of evolution (Oyston and Robinson 2012 and the 2011 BVGH report, Vaccine Landscape for Neglected Disease). The clinical testing of vaccines, since they are used in otherwise healthy people and often children, is extensive and expensive (CDC Vaccine Testing ). The manufacturing of vaccines poses a host of technical issues including assuring the safety of inactivated viral vaccines, purification, and product characterization (Rathore et al. 2012). There are also technical challenges in the delivery of vaccines, such as managing a long supply chain, keeping the doses cool, and administering via injection, all difficult in resource-constrained areas, (PATH Project Optimize).
Fortunately, academics, product development programs (PDPs), research institutes, and companies, large and small, are working on solutions (a good way to keep up with progress is through the FierceVaccines newsletter). I wondered which technologies that had reached a point where the major vaccine companies were willing to investment in them, thus suggesting which may eventually be deployed in global immunization programs.
Earlier last month I posted about the acquisition of Inviragen by the Japanese pharma company, Takeda (“More Toes in the Water”). I surmised the purchase may have been motivated by Inviragen’s lead candidate, a Dengue fever vaccine which had advanced into the next stage of a Phase II trial recently, and others in the pipeline, and not its technology. I also noted that Takeda purchased another privately-held vaccine company in 2012, Montana-based Ligocyte (Takeda press release). Ligocyte has proprietary technology for making VLP (virus-like particle) vaccines, several of which are in development. VLP vaccines have the protein structure of the target virus but lack its genetic material and therefore are non-replicating but can represent the all of the external structures needed to stimulate an immune response. Their production is simpler in that multiple types of expression platforms (including plant cells) can be used to make VLPs rather than growing a virus in its natural target cell (Pharma Tech article). Takeda’s investment in VPL technology is a relatively safe bet; four VLP vaccines have been approved and marketed (GlaxoSmithKline’s Engerix against hep B and Cervarix against HPV and Merck’s Recombivax HB and Gardasil, also HepB and HPV [Mellado et al. 2010]). I am guessing Takeda may combine the Ligocyte technology for designing vaccines for developing world diseases and Inviragen’s experience in testing them.
GlaxoSmithKline (GSK) went farther afield into new technology than Takeda when it bought Okairos, a venture-capital-backed Swiss firm, in late May for $325 million (FierceBiotech press release). Okairos’s approach is to stimulate a T-cell immune response rather than a B-cell (antibody-producing) response which is needed for effective response to some infections (e.g., influenza, HIV, and hepatitis C) using an antigen produced by the body cells (typically muscle cells) after infection by an adenovirus genetically engineered to include the antigen’s genes (Okairos Fact Sheet and Platform). The company, which spun out from Merck in 2007, developed its technology on relatively little funding, less than $20 million (FierceBiotech article) and has advanced it into the clinic. The company’s pipeline includes clinical stage candidates for malaria, hepatitis C, HIV, and respiratory syncytial virus (Pipeline). Okairos seems to be a good fit for GSK’s interests in global vaccines markets.
Also in a publication last month, scientists at Novartis, the Venter Institute, Synthetic Genomics, Inc., the US Biomedical Advanced Research and Development Authority, and the German Institut für Virologie, described a practical method of applying synthetic biology to the rapid design and production of vaccines to pandemic-type viruses (Dormitzer et al. 2013). Specifically, the scientists designed a vaccine to a new strain of influenza that had appeared in China last year and had it ready to be put into production cell lines in less than two weeks. According to the Venter Institute press release (JCVI press release): “The researchers focused on three technological areas–speedy synthesis of DNA cassettes to produce influenza RNA genome segments, improved accuracy of rapid gene synthesis by improving error correction technology, and increased yields of hemagglutinin (HA), which is the essential vaccine antigen.” Also as noted in the release, the team developed a new technique that may reduce manufacturing complexity by reproducing the synthetic virus in the same cell line that can be used in vaccine antigen production. The implication is that world health agencies could mount a response to a emerging disease in that a central facility could rapidly generate a cell line for distribution and production in multiple countries. In an article in the Boston Globe (Globe article), Marc Lipsitch, an epidemiologist and director at the Harvard School of Public Health, said “It’s a big deal if it works on a large scale.” The Globe also had a nice graphic comparing timelines of the new approach and that used by Novartis to make a H1N1 vaccine in 2009 (Globe graphic).
Technology marches on.