Vaccines must be held to a very high standard of safety. Stringent measures are taken to ensure quality and safety in the research and development, manufacturing, licensing, transport, storage, and use of vaccines, and in the disposal of needles and other equipment after vaccinations are carried out.
Like other pharmaceutical products, vaccines are first carefully evaluated for effectiveness and potential harmful effects in vitro and in animals. If good safety results are achieved, phased trials with humans begin.
Phase I clinical trials examine safety and immune responses to candidate vaccines. Such trials generally have 20 or fewer participants, usually healthy adults. These trials are meant to identify any obvious or commonly occurring adverse reactions. Phase II trials, which may have from 50 to several hundred participants, help researchers to determine the optimum vaccine composition for achieving protection while ensuring safety.
Phase III trials are designed to see if a vaccine actually prevents a disease as intended, and to provide further safety information. They serve as the final gate-keepers prior to vaccines' introduction for wider use in the general population. Phase III trials involve thousands to tens of thousands of people of the intended age. In general, Phase III trials include a control group receiving a placebo. Subsequent "adverse events" (or medical incidents which may or may not be the result of vaccination) and the rates of occurrence of target diseases are compared between the groups of vaccinated and unvaccinated persons. Should significant safety issues arise during a human trial at any phase, mechanisms are in place to stop the study and stop administration of the vaccine. If there are significant safety concerns, the vaccine does not go forward for licensure.
Once vaccines are licensed for general use and are administered to large populations, monitoring continues to identify less common adverse events, events that may occur after a long time, or events that may occur in specific subgroups of the target population.
Typically, monitoring of licensed vaccines is done through spontaneous reporting systems whereby adverse events that follow immunization are reported to health authorities. Sometimes post-licensure monitoring is conducted in more formal Phase IV trials.
Detection of an adverse event following immunization does not necessarily mean the event was caused by the vaccine. Determination of a cause and effect relationship requires further investigation.
Numerous regulations ensure the safety and quality of vaccines. They include the precise identification (characterization) of starting materials, compliance with the principles of good manufacturing practices, the use of detailed control procedures, and the independent release of vaccines on a lot-by-lot basis by national regulatory authorities. Responsibility for quality and safety rests with the national regulatory authority (NRA) in the country of manufacture and, where exported, with the NRAs of the receiving countries.
The World Health Organization (WHO) helps strengthen the regulatory capacities of NRAs through periodic assessments against a published set of indicators. WHO also provides technical support to NRAs where appropriate.
Vaccines supplied by United Nations agencies are pre-qualified by WHO. Pre-qualification is only possible for vaccines produced in countries where the NRA effectively exercises all the required oversight responsibilities, as verified by WHO. The manufacturer submits a product summary file detailing, among other things, production methods, vaccine composition, and quality controls. Consecutive lots of vaccines are independently tested by laboratories qualified by WHO, and WHO experts conduct site visits to ensure that vaccines and production methods conform to international standards. Random testing and regular reassessment procedures are also in place to ensure the continued quality of the product.
Vaccines must constantly be kept at optimal temperature, typically at between 2 °C and 8 °C, from the place of manufacture to the point of use. This is a logistical challenge, especially in developing countries. The network set up to ensure that the required temperature is maintained is called the "cold chain." Refrigerators, ice packs, and cold boxes are employed on airplanes, helicopters, trucks, in various storage locations, and, in areas not reached by road, chilled vaccine carriers are transported by hand to reach the point of use.
If electricity is not available, gas- or kerosene-run, or even solar-powered refrigerators or freezers may be used. Most refrigerators and related equipment can be selected to meet WHO-UNICEF Performance Quality and Safety standards. Staff at international, national, and local levels are trained to manage cold chain networks. They include technicians, shippers, customs officers, pilots, drivers, government officials, health workers, and community leaders. Among other things, they monitor the temperature of the vaccines and discard those that have exceeded the established limits.
Vaccine vial monitors (VVMs) ─ temperature-sensitive labels ─ can be attached to vaccine vials and indicate through a change in colour whether an individual vial has been exposed to heat which is likely to have damaged the vaccine. These labels have been successfully used to monitor vaccines taken beyond well- established cold chain settings, such as clinics, to field sites used for mass immunization campaigns. In these latter settings, which may be remote and without any access to refrigeration, the vaccines need to be kept in containers with cold packs. The VVM vial labels enable health care providers to determine at a glance if a vial has been kept within the needed temperature range or not.
WHO publishes thorough guidelines on the international packaging and shipping of vaccines, including the use of monitoring forms such as the "vaccine arrival report" to be completed when a shipment reaches its destination.
Many vaccines are delivered by injection. WHO promotes safe injection practices, as a priority. Vaccine-related injections are safe for the recipient when a health worker uses a sterile syringe, a sterile needle and sterile technique for each injection. They are safe for health workers when needle-stick injuries are avoided. They are safe for the community when used needles, injection equipment and vaccine waste are disposed of in such a way as to avoid injuries from potentially contaminated needles and to minimize pollution.
For immunization, WHO recommends the exclusive use of syringes with auto-disable features which prevent reuse; these are now available, inexpensive, and widely employed. In addition, WHO recommends immediate disposal of used needles and syringes into puncture-resistant safety boxes, a practice fast becoming the standard around the world. Equipment and safety procedures continue to be improved.
WHO provides recommendations on proper injection techniques and guidance on managing used injection equipment in a safe manner. It offers tools and technical assistance to countries to help them: (1) assess the quality of immunization services and systems for managing used injection equipment, and (2) develop and implement national safe injection and health-care waste management policies.
In 1999, WHO created the Global Advisory Committee on Vaccine Safety to provide rapid, reliable and independent scientific assessment of vaccine safety issues through:
The Committee publishes its conclusions and recommendations in English and French in the WHO Weekly Epidemiological Record. Recommendations and conclusions, together with additional information, are also translated into other WHO official languages and posted on the committee's website www.who.int/vaccine_safety/en/.
Examples of topics reviewed by the Committee include hepatitis B vaccine and multiple sclerosis; hepatitis B vaccine and leukaemia; and intranasal killed influenza vaccination and Bell's palsy.
No vaccine is "perfect" — that is, no vaccine provides full protection against its target disease for every person who receives it and no vaccine is completely risk-free for every person who receives it. Experience has shown that most "adverse events" are not actually caused by vaccines; the majority are coincidental (occur at the same time but are not related), while others are related to preventable errors in the storage, handling, or administration of vaccines.
While vaccines can cause reactions, these tend to be minor, such as a sore arm, redness or minor swelling at the injection site, or low-grade fever. Extremely rarely, there are more serious consequences. For example, anaphylaxis (immediate, severe allergic reaction leading to shock) has been noted at a rate one per 1 million persons receiving measles vaccine and vaccine-associated paralytic polio occur in approximately 1 in 2.5 million Oral Polio Vaccine (OPV) doses administered, The risk of these more serious reactions must always be weighed against the major benefits of protecting large numbers of people against serious and even life-threatening diseases.
Periodically, concerns about vaccine safety are raised that later prove to be unfounded. For example, there is no valid evidence of a causal link between measles vaccine and autism, a topic that has been extensively reviewed by the Global Advisory Committee on Vaccine Safety and several other expert bodies. Similarly, no valid evidence has been found to support an alleged link between whole-cell pertussis vaccine and brain damage, or hepatitis B vaccine and leukaemia or multiple sclerosis.
WHO has embarked on a number of additional activities to ensure vaccine quality and safety. They include: