Regulation of Vaccines: Strengthening the Science Base
Source: Journal of Public Health Policy
In 1944, Dr. Pittman was, by
intracerebral injection, able to infect mice with pertussis, a method that became the basis for the mouse protection test. The test measures the 50% dose-the dose of vaccine that would result in the
survival of 50% of mice infected with a certain number of pertussis bacteria. She also developed an opacity standard to estimate the number of bacteria in a certain volume of vaccine. The US and other countries and the WHO ECBS then adopted biological standards for pertussis vaccines, having assigned potency units (10).
Unfortunately, to date, no better method for determining pertussis potency has been validated, yet this test is fraught with variability. A summary of testing results for biological products at the National Institute of Biological Standards and Control in 1994- 1995 (7) showed the highest rate of noncompliant results, over 8%, for the bacterial vaccines.
Many question the relevance of the abnormal toxicity test as its importance has been diminished by required compliance with Good Manufacturing Practice; it is nonspecific; and it is not mandatory for most pharmaceutical products (11). Many pharmacopeias now omit it (most European countries) but others retain
Better characterized and more highly purified vaccines. Products recently developed, such as component acellular pertussis vaccines, contain purified antigens, and others, such as the conjugated polysaccharide vaccines, depend on sophisticated chemical conjugation reactions and precise physical characterization. Products using recombinant DNA and viral vector technology are common. We often characterize these by physical techniques such as gel electrophoresis, mass spectroscopy, and polymerase chain reaction tests. Although unlikely to demonstrate potency directly, these tests show consistency of the products tested, compared to lots that have been shown to be safe and effective in clinical trials (13).
Limitations of testing. As a quality control method, testing vaccines has its limitations. For a sterility test, for example, it may be difficult to test enough samples to get a truly representative result. To test a product for a particular characteristic, a portion of that product must be used up. To test for a potential sporadic contaminant, the amount of sample that must be tested is defined by the formula, 0.4[radical]N, where N is the number of vials in a lot. Testing that number of samples does not assure that a "contamination event" would be picked up; for that reason strict process controls
are also imposed to ensure sterility of biological products.
Regulators are defining new tests that have enhanced sensitivity, but they may be difficult to interpret. For example, new sensitive tests can detect potential reverse transcriptase activity in some chicken- cell derived vaccines or DNA tumor virus, SV40, in poliovaccine (14,15,16). No evidence has indicated a public health relevance of these findings (12). For some products (e.g. acellular pertussis vaccine) and for potential contaminants, such as transmissible spongiform encephalopathies (TSE), no single test has been found to predict clinical efficacy or safety (12). Finally, any test method must be appropriately validated to ensure the reliability of the
results on which public health decisions might be based.
Therefore, to summarize, laboratory tests on vaccines are important, but they must be standardized and validated. But tests alone cannot predict clinical efficacy or safety of these products.