Vaccines safety tests

The U.S. standard pertussis vacciae is used to standardize the potency of the whole ceU pertussis vacciae. The number of protective units Hi the vaccine is estimated for each lot from the results of simultaneous intracerebral mouse-protection tests of the vaccine being studied and the U.S. reference standard (14,17). The potency of the aceUular vaccines is estimated by then abUity to produce antibodies to the proteins Hi the vaccine Hi a mouse model. These vaccines also undergo a series of animal safety tests to ensure that the iaactivation and toxoiding steps were carried out correctiy (14,17). 

Standardization and Testing. Potency is determined by titrating the amount of Hve vims using a suitable cell substrate. Safety testing is also performed on seed lots to assure proper attenuation and on vaccine to assure absence of unwanted contaminants. 

Standardization and Testing". The final vaccine is tested for safety, potency, and residual chemicals. Safety includes testing for endotoxin and stetihty. Potency is evaluated by quantitative determination of the amount of hemagglutinin in the vaccine. Antibody to this glycoprotein is associated with protection. The single radial immunodiffusion (SKID) technique is used to standardi2e the mass of this protein in comparison to a reference preparation. 

Vaccine Source materiai Processing Potency assay Safety tests... 

Safety tests. Beeause many vaccines are derived from basic materials of intense pathogenieity— the lethal dose of a tetanus toxin for a mouse is estimated to be 3 x 10 (ig—safety testing is of paramount importance. Effective testing provides a... 

Viral vaccines present problems of safety testing far more complex than those experienced with bacterial vaccines. With killed viral vaccines the potential hazards are those due to incomplete virus inactivation and the consequent presence of residual live virus in the preparation. The tests used to detect such live virus consist of the inoculation of susceptible tissue cultures and of susceptible animals. The cultures are examined for cytopathic effects and the animals for symptoms of disease and histological evidence of infection at autopsy. This test is of particular importance in inactivated poliomyelitis vaccine, the vaccine being injected intraspinally into monkeys. At autopsy, sections of brain and spinal cord are examined microscopically for the histological lesions indicative of proliferating poliovirus. 

The relevance of the target-animal safety test for batch safety testing of vaccines for veterinary use EU... 

Salk, I, U. Krech, and 1. Younger, Formaldehyde and safety testing of experimental poliomyelitis vaccines. Am 1 Publ Health, 1954. 44 563-70. 

This vaccine was tested for safety and immunogenicity in 24 human subjects. The injection elicited local moderate pain with no other notable physiologic abnormalities found. The vaccine increased antibody levels up to 12 months after the initial vaccination. Using functional tests such as activation of white cells ex vivo, cytokine generation, and bacterial clearance, the authors found a higher capacity for neutralizing bacteria and activating white cells (Cross et al., 2003). 

As a general rule, products that are used only once or a few times have to undergo fewer safety tests than products which will administered regularly or over a longer time. Less - if any - side reactions are tolerated for products intended to be used in healthy individuals (e.g. vaccines) than for products which are used in diseased individuals. In any case the benefits must clearly outreach any potential side-effects. 

Vaccine excipients (adjuvants and other substances used in the formulation) are treated in the same way as chemical substances. If new substances are introduced, a full safety assessment is required. It may be necessary to assess their toxic potential separately from the vaccine, since the vaccine formulation may interfere with a proper testing. In addition the normal pharmacological and safety tests for vaccines must be performed with the final, formulated product. 

Table 20 Special Safety Test Requirements for Attenuated Live Veterinary Vaccines...

Plasma-derived hepatitis B virus vaccine is prepared from the plasma of chronic HBsAg carriers, and consists of purified, inactivated 20-nm HBsAg particles adsorbed on to an aluminium adjuvant. The use of a vaccine produced with plasma derived from infected individuals represented a major departure from conventional approaches, and safety testing has therefore been designed to cover all possibilities of risk and to ensure freedom from transmission of residual HBV and other blood-borne agents. Various clinical trials (SEDA-10, 289) (SEDA-11, 289) have confirmed the safety of plasma-derived hepatitis B virus vaccines produced by different manufacturers. Fears that plasma-derived vaccine may transmit AIDS can be considered unfounded. 

Because many vaccines are derived from basic materials of intense pathogencity — the lethal dose of tetanus toxin for a mouse is estimated to be 3 x 10-5pg— safety testing is of paramount importance. Effective testing provides a guarantee of the safety of each batch of every product and most vaccines in the final container must pass one or more safety tests as prescribed in a pharmacopoeial monograph. This generality does not absolve a manufacturer from the need to perform in-process tests as required, but it is relaxed for those preparations that have a final formulation that makes safety tests on the final product either impractical or meaningless. 

Viral vaccines can present problems of safety testing far more complex than those experienced with most bacterial vaccines. With killed viral vac-... 

Figure 10.2-1 Maximizing the benefit-to-risk in vaccine development. No vaccine can be administered to humans without solid data showing safety. Product development and safety testing for these products relies very heavily on animal studies which are relied upon to predict both efficacy and safety. Toxicity assessments for vaccines are challenging because, in general, vaccines trigger complex immune reactions.There must be a balance between desired immunogenicity and unwanted adverse side effects.

The health status of animals from which starting materials are derived and of those used for quality control and safety testing should be monitored and recorded. Staff employed in animal quarters must be provided with special clothing, changing facilities and showers. Where monkeys are used for the production or quality control of biological products, special consideration is required, as laid down in the revised Requirements for Biological Substances No. 7 (Requirements for Polio-myelitis Vaccine (Oral))(5). 

Kulldorff M, Davis RL, Kolczak M. Lewis E, Lieu T, Platt R. 2011. A maximized sequential probability ratio test for drug and vaccine safety surveillance. Sequential Analysis Design, Methods and Applications. 30(l) 58-78. 

---