Article

VACCINE DEVELOPMENT, TESTING & REGULATION: WHAT WE SHOULD KNOW

Nik Norliza Nik Hassan School of Health Sciences Health Campus, Universiti Sains Malaysia 16150 Kelantan

Vaccination is a simple, safe and effective way of protecting human against harmful diseases, before human come into contact with them. To date, there are vaccines available to protect against at least 20 diseases, such as diphtheria, tetanus, pertussis, influenza and measles. Together, these vaccines save the lives of up to 3 million people every year [1,2].

Vaccination uses human body’s natural defenses to build resistance to specific infections and makes the immune system stronger. However, because vaccines contain only killed or weakened forms of germs like viruses or bacteria, they do not cause the disease or put us at risk of its complications. Vaccination is not just about protecting ourselves, but also those around us. However, seriously ill people are advised against getting certain vaccines - so they depend on the rest of us to get vaccinated and help reduce the spread of disease.

Our immune systems are designed to remember. Once exposed to one or more doses of a vaccine, we typically remain protected against a disease for years, decades or even a lifetime. This is what makes vaccines so effective. As more people in a community get vaccinated, fewer people remain vulnerable, and there is less possibility for passing the pathogen on from person to person. Lowering the possibility for a pathogen to circulate in the community protects those who cannot be vaccinated due to other serious health conditions are known as “herd immunity.” However, Herd immunity does not protect against all vaccinepreventable diseases. For example, tetanus that is caught from bacteria in the environment, not from other people [1,2].

During the COVID-19 pandemic, vaccination continues to be critically important. WHO has urged countries to ensure that essential immunization and health services continue, despite the challenges posed by COVID-19. WHO is one of the leaders of a global effort known as COVAX, which is speeding up the search for safe and effective COVID-19 vaccines by pooling resources from many different countries. This includes the COVAX Facility, a global risk-sharing mechanism for pooled procurement and equitable distribution of eventual COVID-19 vaccines. In addition to the investment for vaccine R & D, COVAX also helps in scale up vaccine manufacturing capabilities and commiting to buy vaccine doses if vaccines are shown to be safe and effective, with the goal of distributing 2 billion doses where they’re needed most, worldwide, by the end of 2021. Thus, COVAX is the vaccine pillar of the Access to COVID-19 tools (ACT) accelerator, a global collaboration to accelerate development, production, and equitable access to COVID-19 tests, treatments, and vaccines. A Solidarity clinical trials setup by WHO helps in the evaluation of the potential COVID-19 vaccines at sites across the globe. In general, the vaccine development is a long, complex process, often lasting 10-15 years and involving a combination of public and private involvement. The current system for developing, testing, and regulating vaccines developed during the 20th century as the groups involved standardized their procedures and regulations. At the end of the 19th century, several vaccines for humans had been developed. They were smallpox, rabies, plague, cholera, and typhoid vaccines. However, no regulation of vaccine production existed.

In general, stages of vaccine development and testing involved few steps.

a) LABORATORY AND ANIMAL STUDIES

Exploratory Stage This stage involves basic laboratory research and often lasts 2-4 years. At this phase, federally funded academic and governmental scientists identify natural or synthetic antigens that might help prevent or treat a disease. These antigens could include virus-like particles, weakened viruses, bacteria, bacterial toxins, or other substances derived from pathogens.

Pre-Clinical Stage A stage that give researchers an idea of the cellular responses they might expect in humans. A tissue-culture or cell-culture systems and animal testing involved in the assessing the safety of the candidate vaccine and its immunogenicity, or ability to provoke an immune response. Animal subjects may include mice and monkeys. A safe starting dose and method for administering the vaccine in the next phase of research also will be suggested. The pre-clinical stages often lasts 1-2 years and usually involves researchers in private industry. Before the vaccine is subject to three phases of testing, an approval from the U.S. Food and Drug Administration (FDA) are needed.

b) CLINICAL STDIES WITH HUMAN SUBJECTS

Phase I Vaccine Trials It involves a small group of subjects, usually between 20-80 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 I trials may be nonblinded (researchers and subjects know whether a vaccine or placebo is used). The goals of the phase are to assess the safety of the candidate vaccine and to determine the type and extent of immune response that the vaccine provokes. Researchers may use the challenge model, attempting to infect participants with the pathogen after the experimental group has been vaccinated. The participants in these studies are carefully monitored and conditions are carefully controlled. The promising results will ensure the next stage of trials.

Phase II Vaccine Trials This phase involved larger group of subjects in Phase II testing. Some of the individuals may belong to groups at risk of acquiring the disease. These trials are randomized and well controlled and include a placebo group. The goals of Phase II testing are to study the candidate vaccine’s safety, immunogenicity, proposed doses, schedule of immunizations, and method of delivery.

Phase III Vaccine Trials Successful Phase II candidate vaccines move on to larger trials, involving thousands to tens of thousands of subjects. They are randomized and double blind and involve the experimental vaccine being tested against a placebo (the placebo may be a saline solution, a vaccine for another disease, or some other substance). Major goal of the phase is to assess vaccine safety in a large group of people. Certain rare side effects might not be seen 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.

Vaccine efficacy is tested as well. These factors might include 1) Does the candidate vaccine prevent disease? 2) Does it prevent infection with the pathogen? 3) Does it lead to production of antibodies or other types of immune responses related to the pathogen?

c) Approval and Licensure

Data from a successful Phase III trial will be submit to the Biologics License Application. FDA later will perform factory inspection where the vaccine will be made before approving the labeling of the vaccine. After licensure, 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. At this stage, the FDA has the right to conduct its own testing of manufacturers’ vaccines [2, 4].

Post-Licensure Monitoring of Vaccines A variety of systems such as Phase IV trials, the Vaccine Adverse Event Reporting System (VAERS), and the Vaccine Safety Datalink (VSD) used in the monitoring the vaccines after they have been approved.

Phase IV Trials Phase IV trial 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.

VAERS It is a voluntary reporting system, established in 1990 by CDC and FDA. The main objective of VAERS were “to detect possible signals of adverse events associated with vaccines.” Adverse vaccine effects are a major health problem when approximately about 30,000 cases were reported each year to VAERS. Between 10% and 15% of these reports describe serious medical events that result in hospitalization, life-threatening illness, disability, or death. For example, VAERS has successfully identified several rare adverse events related to vaccination. Among them are an intestinal problem after the first vaccine for rotavirus was introduced in 1999 and neurologic and gastrointestinal diseases related to yellow fever vaccine [2, 4].

VSD VSD was established by CDC in 1990. It 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.

Rapid Cycle Analysis (RCA), a program under VSD was launched in 2005 with the objective to monitoring a real-time data to compare rates of adverse events in recently vaccinated people with rates among unvaccinated people. RCA has been used mainly to monitor new vaccines such as the conjugated meningococcal vaccine, rotavirus vaccine, MMR vaccine and the HPV vaccine. Data obtained allows more detail investigation that might possibly associated with adverse events and vaccination studied further [3].

In Conclusion

Vaccines are developed, tested, and regulated in a very similar manner to other drugs. In general, vaccines are even more thoroughly tested than non-vaccine drugs because the number of human subjects in vaccine clinical trials is usually greater. In addition, post-licensure monitoring of vaccines is closely examined by the Centers for Disease Control and the FDA.

References

1. VAX. Understanding vaccine trials: How are AIDS vaccines tested? IAVI Report. Volume 1, no. 1. August 2003. Accessed 01/17/2018.Plotkin, S.A., Orenstein, W.A., Offit, P.A., eds. Vaccines, 5th ed. Philadelphia: Saunders, 2008. Chapters 3 and 73. 2. U.S Department of Health and Human Services. Vaccine product approval process. U.S. Food and Drug Administration. Updated 01/09/2018. Accessed 01/17/2018. 3. U.S. Department of Health and Human Services. Investigational New Drug (IND) Application. U.S. Food and Drug Administration. Updated 10/05/2017. Accessed 01/17/2018. 4. Lilienfeld, D.E. The first pharmacoepidemiologic investigations: national drug safety policy in the United States, 1901-1902. Perspectives in Biology and Medicine. 51.2 (2008): 192-96.