Vaccines as Biopharmaceuticals

Dr. Robert V. House
President and Chief Scientific Officer
DynPort Vaccine, Co.

Vaccines have contributed more to overall human health and quality of life than any other medicine. Diseases that formerly caused untold morbidity are now suppressed to the point of extinction (smallpox) or near extinction (polio), and so-called childhood diseases such as measles and mumps are not feared as they once were. Widespread epidemics are rare, at least in the developed world. And yet, as a species, we are still dying from infectious disease in untold numbers. Diseases are spread by insects, water, air and direct contact. Particularly in the developing world, the underlying conditions make eradication of these diseases difficult, if not intractable.

The developed world also faces the threat of infectious disease. In fact, a number of conditions are emerging to suggest that the specter of epidemic and even pandemic disease is actually becoming more, not less, urgent. First, the dynamics of treatment options are shifting. Bacteria once easily controlled in the past are gaining resistance to even the most potent antibiotics (for example, the advancing risk of methicillin-resistant S. aureus, MRSA). Drugs for parasitic and fungal maladies are generally associated with certain toxicities, and viruses remain essentially untreatable except for palliative measures. To this, add the complications of previously unknown (or at least un-encountered) diseases now becoming more common, the threat of pathogens being used as agents or warfare or terrorism, and the potentially apocalyptic consequences of engineered pathogens being released into the human population, and it is clear that we indeed live in dangerous times.

While anti-infective agents remain powerful tools in our armamentarium of weapons against infectious disease, it is axiomatic that prevention of morbidity is generally preferable to treatment. In this respect, vaccines will continue to be important tools for combating our microbial adversaries. By harnessing the intrinsic power and flexibility of the body’s own immune system, vaccination prevents infection, or at least limits the progression of infection to full-blown disease. More importantly, this protection lasts, in most cases, for the life of the individual…something not currently practical for therapeutic intervention. Thus, it is clear that vaccines are, and will remain, crucial for ensuring human health.

Regulatory considerations

Vaccines are unlike most other medicines in that they are given (in most cases) to relatively large numbers of healthy individuals. For this reason, the expectations of safety and quality tend to be higher than for most other biopharmaceuticals. Like any medicine, vaccines must be rigorously tested to demonstrate safety before ever going into humans; once clinical trials are initiated, safety is evaluated at all stages of testing. With very rare exceptions, vaccines are remarkably safe.

In the 210 years since Edward Jenner first demonstrated the concept of vaccination, our understanding of the science of vaccinology has increased. However, the greatest advances in product quality have been achieved within the past several decades. Regulatory guidelines for production of products such as biopharmaceuticals, such as Current Good Manufacturing Process guidelines, now ensure a high degree of standardization and reproducibility in vaccine manufacture, and industry standard testing procedures ensure that these products are fully characterized.

Of course, product safety and quality are for naught if the vaccine is not effective for its intended purpose. For most human vaccines, clinical trials can be conducted in which volunteers are exposed to the infectious agent of concern, either experimentally under tightly controlled conditions (in which protection is compared with untreated controls), or in field trials of human populations in which a certain level of infection would be expected to occur. However, for the most pernicious agents (including potential agents of bioterrorism including anthrax, smallpox and plague, among others), it is generally considered to be unethical to deliberately expose humans to such agents. To facilitate licensure of vaccines and therapeutics designed to protect against these threats, the FDA has established the so-called “Animal Rule”, in which demonstration of efficacy is based primarily on highly detailed animal data. This mechanism should greatly facilitate the licensure of many important vaccines in the coming years.

What’s next?

While current vaccines are effective for their intended use, it is necessary to anticipate how vaccines might be used in the future. As mentioned in the introduction, we are increasingly facing the possibility of natural or man-made epidemics – if not pandemics – of severe consequence. To address these future threats most effectively, novel paradigms will be required. It will be necessary to develop new ways of quickly identifying novel threats (detection), particularly for diseases of high pathogenicity. Once these threat agents have been identified, new expression systems and manufacturing technologies will be needed to produce large amounts of vaccine on a near-continuous and quick turnaround basis. At DVC, we have recently developed a totally closed cycle, disposable and validatable process for producing live viral vaccines; other institutions are developing platforms that could conceivably “bundle” multiple vaccines into one expression system. A combination of this bundled vector expression system with high-density manufacturing would represent a powerful tool for emergency vaccine production.

Just as important as manufacturing, however, will be advances in basic vaccinology as well. For example, most current vaccines deal with only a single agent; even multivalent vaccines at present are combinations of separate monovalent vaccines. In this case, the vaccines target the immune response to unique determinants of the threat. However, transformational medicine and advances in systems biology will rapidly shift the approach to a disease-centric approach rather than an organism-centric approach. That is, vaccines will take advantage of common features of disease-causing microbes (perhaps highly-conserved genetic sequences or pathogen-associated molecular patterns), leading to a single vaccine with multiple targets. Novel vaccine formulations will also increasingly take advantage of the body’s innate defense mechanisms to greatly boost the efficacy of vaccines. Finally, new technologies promise to break – or at least dramatically decrease – the cold chain necessary to ensure vaccine stability, providing products that can be stored at room temperature or above, rather than refrigerated or frozen. This exciting development should provide untold benefits for vaccines destined for developing nations.

With a two-century legacy, it may be credibly argued that vaccines represent one of the first biopharmaceutical products. It is also reasonable to state that vaccines are one of the most successful biopharmaceuticals in terms of improvement of overall human health. Recent advances in technology, and technology still in its infancy, will ensure that vaccines protect an even greater number of us in the future.