Vaccine Development: The Revolution Starts Tomorrow

Vaccine development is again enjoying a renaissance, buoyed in part by the need to meet the challenge of a global influenza pandemic and though the largesse of private donors committed to finding better vaccines and means for their deployment in the developing world. 

Having either worked in or actively followed the vaccine industry for over 20 years, I’m struck by the apparent paradox between the amount of intellectual effort invested in vaccine development and the absence of truly revolutionary products which have made it into common use. That’s not to say that there have not been significant evolutionary improvements, such as the shift towards cell-based production methods and the approval of virus-like particle and attenuated virus vaccines, but there is little in routine vaccination that would greatly surprise Edward Jenner.  

There has never been a shortage of grand revolutionary concepts, including fully-synthetic, rationally-defined vaccines incorporating all the right epitopes to give both antibody and cellular immune responses; naked DNA vaccines, where the recipient’s own cells are coaxed into manufacturing vaccine components in situ, plus the often ingenious needle-free delivery systems ranging from vaccine patches, through to the use of ultrasound to drive vaccines through the skin and oral vaccines, conveniently grown in bananas or other edible plants.

Along with technological inventiveness has come the truly revolutionary notion that, as potent manipulators of the immune system, vaccines can treat rather than simply prevent disease states. Substantial effort is being applied to vaccines, or more accurately, immunotherapies, for cancer, chronic viral and bacterial infections, and metabolic disease and CNS conditions.

Cancer vaccines have been a particular disappointment. It’s taken 15 years for the first cancer immunotherapy approval in the form of Dendreon’s “Provenge®", a prostate cancer treatment which utilizes the patient’s own antigen-presenting cells in a complex treatment resembling autologousstem cell therapy. Dendreon was rightly applauded for tenacity, but whether the estimated $93,000 cost for a 4 month survival benefit will prove acceptable to prescribers and taxpayers is unknown. 

Why the apparent disconnect between effort, ingenuity and revolutionary vaccines? One reason, also touted as a cause of declining productivity across the pharmaceutical industry, is that all of the easy targets are gone.  All in all, vaccines have been remarkably effective in dealing with infectious conditions involving uncomplicated microorganisms, although we still struggle a bit with  ‘flu viruses which change from year to year. Challenging targets, where vaccines have still to find success, include bacteria, parasites and viruses which have learned to hijack our immune systems (HIV, TB and malaria, for example) or otherwise deflect the immune response. A better understanding of the subtleties of the complex host-pathogen interaction is the rate-limiting step for vaccine success.

Cancer and other immunotherapy targets are even more complex. Tumours are designed not to provoke or to otherwise shrug off host immune responses and vaccines have yet to effectively master the trick of making non-immunogenic targets stand out. Metabolic diseases such as diabetes and hypertension arise through multiple mechanisms but the receptors or hormones selected as targets for vaccine development are not only difficult immunogens, but often have multiple biological roles and complete abrogation of their function may bring its own effects..

While a shift to pain-free vaccination is highly desirable (ask any parent), the reality is that syringe and needle, prime and boost is an extremely effective means of generating reliable, potent and long-lasting immune responses in the majority of individuals. More sophisticated intradermal delivery might bring the advantage of requiring lower concentrations of expensive vaccine but investigational systems have yet to prove to be as effective as the needle, or even the needle-free spray injectors developed in the 1930s. Oral vaccines have struggled to find an application that does not depend only on short-duration mucosal immunity.

The fruits of vaccine development face an increasingly tough regulatory and commercial environment. Vaccines constitute a unique drug class: they are almost exclusively intended for people who are not sick. Despite the remarkable safety record of vaccines, vaccination scares are never far from the headlines and have caused tangible harm with respect to MMR vaccine and HPV vaccine uptake. In the minds of many, fear of disease has been replaced by fear of vaccination and regulators have no choice but to set the safety bar high enough to minimize the risk of future safety issues. 

The number of vaccine purchasers is small, being governments, international health organizations or very large health care providers. Vaccine suppliers face increasing resistance when trying to convince cost conscious purchasers to pay more for slender incremental improvements in vaccine efficacy and safety. The recent wrangle over pandemic vaccine oversupply and underuse is likely to make both manufactures and buyers more wary in their dealings. Therapeutic vaccines must compete with existing or investigational small molecule or biologic approaches for the same indication and will only thrive if differentiated through superior outcomes and cost-benefit.

As to the vaccine revolution, we can greatly improve the odds of fulfilling unmet needs by tempering ingenuity and effort with an earlier recognition that successful vaccine products must cross substantial economic and regulatory hurdles and be truly competitive against other novel pharmaceutical and biopharmaceutical products. 
 

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