The proof-of-concept is evaluated in the early stages of vaccine discovery, followed by a few years of preclinical studies with lead vaccine candidates prior to clinical testing in humans. Once approved for clinical development, the vaccine will undergo defined stages of clinical testing and monitoring, often over a decade or longer, before being licensed and marketed. Following the introduction of a vaccine on to the market, post market surveillance and safety monitoring continues.
Pre-clinical studies use tissue-culture or cell-culture systems and animal testing to assess the safety of the candidate vaccine and its immunogenicity, or ability to provoke an immune response. Animal studies usually include animal models such as mice and rabbits. These studies give researchers an idea of the cellular responses they might expect in humans. They may also suggest a safe starting dose for the next phase of research as well as a safe method of administering the vaccine.
Researchers may adapt the candidate vaccine during the pre-clinical state to try to make it more effective. They may also do challenge studies with the animals, meaning that they vaccinate the animals and then try to infect them with the target pathogen. Challenge studies are not normally conducted in humans.
Many candidate vaccines do not progress beyond this stage because they fail to produce the desired immune response or are demonstrated unsafe. The pre-clinical stages often lasts 1-2 years.
This first attempt to assess the candidate vaccine in humans involves a small group of adults, usually less than 20 subjects. If the vaccine is intended for children, researchers will first test adults, and then gradually step down the age of the test subjects until they reach their target. Phase 1 trials may be non-blinded (also known as open-label in that the researchers and perhaps subjects know whether a vaccine or placebo is used).
The goals of phase 1 testing are to assess the safety of the candidate vaccine and to determine the type and extent of immune response that the vaccine provokes. A promising phase 1 trial will progress to the next stage.
A larger group of at least several hundred individuals participates in phase 2 testing. Some of the individuals may belong to groups at risk of acquiring the disease. These trials are randomised and well controlled, and often include a placebo group.
The goals of phase 2 testing are to study the candidate vaccine’s safety, immunogenicity, proposed doses, schedule of immunisations, and method of delivery.
Successful phase 2 candidate vaccines move on to larger trials, involving thousands to tens of thousands of people. These phase 3 tests are randomised and double blind and involve the experimental vaccine being tested against a control (the control may be a placebo may be a saline solution, a vaccine for another disease, or some other substance).
One phase 3 goal is to assess vaccine safety in a large group of people. Certain rare side effects might not surface in the smaller groups of subjects tested in earlier phases. For example, suppose that an adverse event related to a candidate vaccine might occur in 1 of every 10,000 people. To detect a significant difference for a low-frequency event, the trial would have to include 60,000 subjects, half of them in the control, or no vaccine, group.
Vaccine efficacy is tested as well. This will involve comparing the rates of infection or disease in the candidate vaccine group compared with the control group.
After a successful phase 3 trial, the vaccine developer will submit a Biologics License Application to the licencing body such as the Federal Drug Administration (FDA) in the US or the European Medicines Agency in Europe (EMA). In New Zealand it is Medsafe that handle applications for licensure. After licensure, agencies such as the FDA will continue to monitor the production of the vaccine, including inspecting facilities and reviewing the manufacturer’s tests of lots of vaccines for potency, safety and purity. The FDA has the right to conduct its own testing of manufacturers’ vaccines.
Phase 4 trials are optional studies that drug companies may conduct after a vaccine is released. The manufacturer may continue to test the vaccine for safety, efficacy, and other potential uses.
Vaccine safety is monitored through voluntary reporting of adverse events, passive monitoring, and formal systems that require reporting, active monitoring. All reports received through both passive and active reporting systems are investigated to determine if the reported adverse event was actually caused by the vaccine or a component of the vaccine. Not all adverse events after immunisation are caused by the vaccine.
Passive monitoring systems receive reports of adverse events following immunisation. They utilise a voluntary reporting system and anyone, such as a parent, a health care provider, or friend of the patient, who suspect an association between a vaccination and an adverse event may report that event and information about it.
The Centre for Adverse Reactions Monitoring (CARM) in Dunedin is New Zealand's national monitoring centre for adverse reactions. It collects and evaluates spontaneous reports of adverse reactions to medicines, vaccines, herbal products and dietary supplements from health professionals in New Zealand. Currently the CARM database holds over 80 000 reports and provides New Zealand-specific information on adverse reactions to these products, and serves to support clinical decision making when unusual symptoms are thought to be therapy related.
CARM as New Zealand's national monitoring centre, collaborates with and pools anonymised data, together with other national monitoring centres, into the database of the World Health Organisation's International Drug Monitoring Programme based in Uppsala, Sweden. Through this network, New Zealand is able to keep abreast of the latest concerns around drug safety as they emerge, whilst access to the international database serves to complement the local experience of adverse reactions to medicines.
The Therapeutic Goods Administration (TGA) collects and reviews reported adverse events following immunisation within the national system monitoring the safety of medicines.
The Centres for Disease Control and Prevention (CDC) and the Food and Drug Administration (FDA), both in the US, established the Vaccine Adverse Event Reporting System (VAERS) in 1990.
The Public Health Agency of Canada monitor the safety of vaccines administered in Canada through the Canadian Adverse Events Following Immunisation Surveillance System (CAEFISS).
Vaccine safety monitoring is done by the Medicines and Healthcare products Regulatory Agency (MHRA), within the system monitoring the safety of medicines.
Individual European countries passively monitor vaccine safety within the systems monitoring medicine safety.
Formal monitoring systems may be put in place when relatively new vaccines start being used in a community. Mandatory reporting of all presentations for medical treatment within a defined period after receipt of a specified vaccine may detect adverse events that occur too infrequently to have been captured in clinical trials where participant numbers are significantly smaller than the number of vaccine recipients in whole communities.
Post-licensure clinical trials and the use of data in large linked vaccine safety data bases are also active methods of vaccine safety monitoring.
The Centres for Disease Control and Prevention (CDC) established the Vaccines Safety Datalink (VSD) system in 1990. The VSD is a collection of linked databases containing information from large medical groups. The linked databases allow officials to gather data about vaccination among the populations served by the medical groups. Researchers can access the data by proposing studies to the CDC and having them approved.
Adapted with permission from history of vaccines
The Vaccine Adverse Event Surveillance and Communication (VAESCO) is a collaborative network that collects and reviews information from vaccine safety monitoring agencies in individual European member countries. They use the collected information to provide high quality vaccine safety information.