Can therapeutic vaccines fulfill their promise?
SummaryTherapeutic vaccines have faced numerous setbacks recently. The only three vaccines to reach the market so far have had insignificant sales, and have failed to gain approval in the critical US market. Meanwhile, numerous high-profile pipeline failures and the lack of new product launches have seriously dampened investor enthusiasm. However, the industry's fortunes could be set for a major change.
Therapeutic vaccines are defined as medications that can induce a new immune response in the patient to treat a pre-existing condition (in contrast to traditional, prophylactic vaccines administered to healthy individuals to prevent disease). By their nature, the most obvious applicability for such therapies is in diseases where the immune system needs to be activated and augmented: most notably in cancer and infectious diseases, including HIV.
Analysis shows that therapeutic vaccines development is currently heavily weighted towards cancer vaccines, which account for 60.6% of all 208 active pipeline projects. HIV and infectious disease projects are also relatively well-represented. In the early-stage pipeline greater interest is also starting to be shown in additional therapeutic areas, including nicotine addiction, and allergic, CNS and cardiovascular diseases.
A history of failures
The early days of the therapeutic vaccine industry have so far been characterized by clinical and commercial failures. Although some clinical trials have shown remarkable improvements in selected small populations, no therapeutic vaccine has yet gained regulatory approval in the commercially important market.
Numerous vaccines with apparently strong prospects have been hit by developmental delays and failures. These include CancerVax's Canvaxin, Aphton's Insegia, Progenics' GMK vaccine, Biomira's Theratope and VaxGen's AIDSVAX. With 12 therapeutic vaccines currently in phase III or phase II/III trials, the industry is reaching a critical point where regulatory success stories are desperately needed.
However, even if the numerous difficulties in clinical development can be overcome, commercial success is still proving elusive. The first three therapeutic vaccines to have reached the market - Avax Technologies' M-Vax, Intracel's OncoVax and Corixa's Melacine - have all sold poorly, each having been launched in only a small number of countries. Reasons for this lack of commercial success include their limited efficacy, high cost, and low acceptance of unproven therapeutic vaccines among physicians.
These poor commercial outcomes have damaged investor confidence, leading to the creation of a vicious circle, where a lack of adequate funding and pharmaceutical experience (from big pharma partnerships) has led to sub-optimal product development, leading to poor clinical results which have further damaged the industry's reputation.
Personalized or generalized vaccines?
Therapeutic vaccines are segmented into two basic types: patient-specific (personalized, or autologous) vaccines, created by using the patient's own tissue in the production of an individualized therapy; and non-patient-specific (generalized, or allogeneic) vaccines, which are 'off-the-shelf' mass-produced therapies.
Personalized vaccines have been well-represented among the first few therapeutic vaccines to be developed, because they offer the efficacy and specificity advantages of being formulated specifically for each patient and do not require such an in-depth understanding of the exact antigens involved. However, they present major commercial disadvantages that have limited their uptake: very high cost and low scalability of manufacture, logistical complications, concerns over sterility and more complex regulatory approval process.
Now, rapid scientific progress in genomics, proteomics and related areas means that antigen-specific, generalized, 'off-the-shelf' vaccines could soon offer comparable efficacy, to complement their strong commercial profile. As a result, generalized vaccines are now starting to dominate the pipeline. While both of the two currently marketed therapeutic vaccines are personalized - and almost half of phase III projects - only 10% of preclinical projects are personalized. This illustrates the dramatic shift in interest towards generalized vaccines.
Combinations could be key
There is an increasing trend in therapeutic vaccines development towards the use of multiple antigens (and adjuvants), to attack cancers or HIV from multiple angles. The generally low levels of side effects make this a viable option. Combinations of therapies, and novel approaches such as prime-boost regimens are expected to yield exciting results.
Because of the increasing focus on combining technologies and vaccines, partnerships will become much more important. There are around 85 companies or organizations involved in the development of therapeutic vaccines, yet many of these have no collaborations with rival companies. The low level of cooperation between vaccine players needs to be addressed in order to accelerate the development of effective vaccines.
Looking to the future, it is likely that the industry will be pushed forwards by the rapid technological evolution, increased understanding of antigens and mechanisms through genomics and proteomics, and especially by the accumulation of clinical experience with different types of therapeutic vaccines. A clear progression in underlying technology platforms can be seen: from early, simple vaccines using inactivated viruses or tumor cells and cell lysates; through to the identification of specific antigens to create more advanced viral vectors, dendritic cells, conjugated vaccines and anti-idiotype vaccines.
Among the newer technology types, DNA vaccines and prime-boost technologies can be singled out as two areas of particularly exciting potential, alongside the development of vaccine combinations.
Parallels with monoclonal antibodies
Parallels between the emerging therapeutic vaccines industry and the history of the monoclonal antibodies industry can also be seen. In the case of monoclonal antibodies, their eventual long-awaited success was driven by technology evolution from murine to chimeric, and ultimately humanized and fully human antibodies. Now the industry has exceeded $10 billion in annual sales, and is expected to continue to grow rapidly to over $30 billion by 2010.
Although the near-term prospects for therapeutic vaccines remain doubtful, with total sales not expected to surpass $500 million in 2010, technological evolution should ultimately enable therapeutic vaccines to make similar commercial breakthroughs after their initial disappointments.
A new wave of 'off-the-shelf' generalized vaccines driven by genomic advances promise to remedy the commercial drawbacks of early personalized vaccines. As clinical experience mounts, new antigen delivery technologies appear and combination vaccines gain favor, the prospect of new non-toxic therapies for cancer and HIV gets closer to being reality.