Will that be hollandaise with your egg, or a side of vaccine?

The second wave of the H1N1 flu sweeping the world is now officially classified by the WHO as a pandemic. Its second coming has sensitized the medical community, governments, and to a lesser extent, the general public to the real and perceived limitations of rapid responses by vaccine manufacturers to a worldwide public health crisis. It gets more confusing when the ‘experts’ on television discuss vaccine manufacturing, almost always accompanied by a roving health or medical correspondent who interviews a technician at a vaccine production facility. In the background are numerous staff wearing ‘bunny suits’ and hair nets, pushing around rack upon rack of chicken eggs. While some consumers may be worried more about the shortage of eggs for their breakfast than the vaccine shortage, these images in the context of a worldwide pandemic cause many to ask, what is the difference between a vaccine and a drug?

There is a simple and fundamental physical distinction between vaccines and drugs that has implications for discovery, development, manufacturing, and clinical testing of both products: drugs are synthetic, chemical entities and vaccines are protein products, analogous to eggs and milk (ie, they ‘go bad’ if they are not properly handled). In clinical use, there is also a relevant distinction between vaccines and drugs. For example, people with hypertension will take drugs (an ACE inhibitor, calcium-channel blocker, or diuretic) for the rest of their lives, but the hypertension will be neither prevented nor cured, just controlled. However, to obtain protection from a viral infection such as polio, smallpox, or hepatitis, one or two vaccinations will confer, in most instances, life-long protection. As an example, the rate of acute viral hepatitis B infections has dropped 88% from 1982 to 2006 because of vaccination, while smallpox has been totally eradicated due to vaccination.

Manufacturing processes are a point of significant departure between vaccines and drugs. For many drugs classes (eg, statins to control cholesterol or triptans for treating migraines), there may be several drugs with subtle but patentable differences; each of them generally represents one structurally-related class of synthetic organic compound for each therapeutic indication. On the other hand, since Jenner developed the first vaccine in 1796, we now have at least 8 different key vaccine forms:

• Toxoid
• Live-attenuated (recombinant; killed, metabolically active)
• Virus-like particles
• Inactivated
• Subunit (purified or recombinant)
• DNA
• Vector
• Prime-boost combinations

These 8 different vaccine forms each require their own unique method of vaccine manufacturing. And, while a vaccine might start out in cell culture or fermentation, the downstream processes can be as varied as the 8 different forms noted above. The combinatorial explosion of downstream processes necessary to produce a vaccine compared to a drug is best illustrated by the comparison of drug and vaccine/biologics key properties (Table 1).

Table 1. Physical differences between vaccines and drugs

As one can see, the differences between vaccines and drugs are rather profound, especially when comparing their physical properties. As noted above, a drug is a synthetic, organic chemical; a vaccine is extracted from living organisms, processed further, and becomes a very complex substance(s). Most vaccines in the USA, especially vaccines for influenza (seasonal and H1N1), are started in cell cultures and then grown in tiny incubators: chicken eggs. This slow and labor-intensive process has not changed in over 4 decades. As there is a long history for this production process, regulatory agencies such as the FDA are hesitant to switch manufacturing processes until product safety can be established for any new process, such as cell-based methodology. Demonstrating product safety takes time, but so does producing vaccines using chicken eggs — typically many months. A more recent concern with chicken-egg incubators – which did not exist a decade ago — is the consequence of avian flu re-emerging on a large scale, which might kill significant numbers of the chickens that produce the eggs used in vaccine production: no eggs, no vaccines.

Furthermore, these physical differences between vaccines and drugs lead to further differences in preclinical clinical studies – differences in the body’s reaction to the vaccine and the way the vaccine induces an immunogenic response. Because a vaccine is not a synthetic chemical, even preclinical evaluation methods are still a ‘work in progress’ with many unknowns regarding biological responses to new vaccinology modalities, such as subunit-, recombinant-, and vector-based agents.

There are some not-so-subtle differences among vaccines that must be taken into consideration when evaluating vaccines preclinically and clinically (Table 2).

Table 2. Clinical differences between vaccines and drugs.

All of the above drug characteristics lend themselves to being quantified rather easily and quickly by an analytical chemist. For example, there may be more than one way to attach methyl groups to a chemical structure but NMR can tell you exactly where it is attached and the body will respond the same way each time. Even if that synthetic process is changed to optimize it or improve the product yield, the end product will be the same. It has to be, because the end product has been patented and part of the patent process is showing how the drug was made. In addition, part of the regulatory burden is showing that the process is reproducible.

However, in vaccine production, if the method of cell culture is changed or an extra downstream filtration, chromatography, or centrifugation step during purification is added, the complex physicochemical structure of the final product may change. Thus, the bottom line for vaccines is that the process defines the product. Change the process and the product might be changed, which could change its immunogenicity, which can significantly affect what degree of protection to the disease the patient receives. Considering all of the above differences and the limited similarities between vaccines and drugs, the conundrum the vaccine industry faces at every stage of development becomes apparent. Speedier vaccine production would be nice, but quality and the expected immunogenic response cannot be sacrificed. Change is difficult and the processes, even modern ones for new vaccines, are fraught with sometimes more art than science. So, will that be hollandaise with your soft-boiled egg, sir, or a side of hepatitis A vaccine?