Vaccine Development, Testing, and Regulation

Introduction

The development of a vaccine -- from first identifying the causative agent of a disease to delivering a vaccine to the public -- can take anywhere from months to years, with the average time somewhere in the 10- to 15-year range. In the United States, private companies do most vaccine development, but public agencies (e.g. the government) can also be involved in the process. In some parts of the world, the government funds and regulates the entire process.

The process has changed in the modern era of vaccination, with more regulation and oversight from governmental agencies, more involvement from the public in how vaccines are marketed, and more collaboration between once-competing companies is becoming the norm. In this article, we will explore the different steps toward developing a vaccine, as well as regulating its sale and monitoring its safety.

Identifying the Causative Agent

The vaccine was the first vaccine developed. Back in the late 1700s, smallpox was a disease that caused periodic epidemics all over the world, with . While scientists then did not know what caused smallpox, they did know that exposure to a similar disease -- cowpox -- conferred immunity against smallpox. It wouldn’t be until the mid-1800s that . And it wouldn’t be until the 1930s that electron microscopes allowed for the visualization of viruses. (Although the theory of viruses as causative agents of disease was developed in the late 1800s.)

Even when the causative agent (virus, bacteria, fungi, parasite) is identified, much work needs to be done to get to a vaccine. First, the agent needs to be grown in a laboratory so enough of it can be sampled for testing. This is not always easy to do. For example, only grow in buffered charcoal yeast extract (BCYE) media. And most viruses will only grow in tissues they can use to infect and multiply.

Once the agent can be grown in the laboratory, it can be sampled and tested in animal models to understand how immune systems react to it. In doing so, scientists can understand which parts of the agent trigger the immune system, or if they need to use the whole agent in a future vaccine. More recently, with the advent of , scientists only need the genetic code of an infectious agent to develop the mRNA vaccine. But even that could take some time, as they must pinpoint which part of the virus to try and replicate with the mRNA.

Laboratory and Animal Studies

Exploratory Phase

In this phase, which usually lasts 2-4 years, scientists in government and academic labs use basic research to find natural or man-made ingredients that could help stop or treat a disease. These ingredients might be parts of viruses, weakened germs, or other substances from disease-causing organisms.

Pre-Clinical Phase

Before a vaccine can be tested on people, it goes through what are called “preclinical tests.” These tests use lab-grown cells and laboratory animals like mice or monkeys to check if the vaccine is safe and if it works by triggering a defense response in the body. Researchers use these tests to guess how humans might react, and to find a safe amount to start testing on people. They might change the vaccine to make it better, or give it to animals, and then expose those animals to the disease to see if it works. If a vaccine doesn't cause the right defense response in this stage, it usually doesn't go any further. This phase often takes 1-2 years and is mostly done by private companies.

As scientists learn more about how animal immune systems respond, and as computer technology has improved, they use computer models to predict how the laboratory test will go. This helps cut down on the cost of keeping laboratory animals. More importantly, animals don’t face unnecessary risks.

IND Application

Next, a company applies for permission to start testing the vaccine in humans. This is called an Investigational New Drug (IND) application, and it is sent to the U.S. Food and Drug Administration (FDA). The company must explain how they make and test the vaccine, summarize their lab findings, and outline their proposed human study. An ethics committee at the institution where human trials will take place must agree to the study plan. The FDA has 30 days to review and approve this application. Once approved, the vaccine can be tested in three phases on humans.

Clinical Studies with People

Phase I Vaccine Trials

In Phase I, a small group of 20-80 adults tests the vaccine first. If the vaccine is for children, researchers start with adults and then include younger participants until they reach the kids' age group. These trials are often open, meaning everyone knows who gets the vaccine and who gets a placebo (a harmless, inactive substance). The goal of Phase I is to check if the vaccine is safe and how well it prompts the body's defense system to act. Sometimes, researchers might try to expose vaccinated volunteers to the disease under controlled conditions to see how well the vaccine works, especially if the disease is treatable with medication and not known to be deadly.

Phase II Vaccine Trials

Phase II involves several hundred people, including some who might be more likely to catch the disease. These trials are randomized and controlled, with some people getting a placebo while others get the vaccine. In phase II trials, researchers focus on the vaccine's safety, how well it works, the best dose, timing of doses, and the way to give the vaccine. The randomization allows the different groups of people being studied to have as much in common between groups, and little differences from person to person within the groups.

Phase III Vaccine Trials

Successful vaccines from phase II go to phase III, involving thousands to tens of thousands of people. And these trials could be done at different sites around the world. These trials are also randomized and double-blind, meaning neither the participants nor researchers know who gets the real vaccine or placebo.

A key goal of phase III is to identify rare side effects and test how well the vaccine works. For example, if a side effect happens in 1 out of every 10,000 people, the trial needs many participants to spot this rare event. Researchers also check if the vaccine prevents the disease, stops infection, or triggers a defense response in the body.

Approval and Licensure

After a successful phase III trial, the vaccine maker applies for a license from the FDA. The FDA checks the clinical trial data, the need for the vaccine (e.g. is it urgent?), the manufacturing site, and approves the vaccine labeling. Even after the vaccine is licensed, the FDA periodically inspects production facilities and keeps tabs on reported adverse events.

Monitoring After Approval

The CDC works with different groups to make sure vaccines in the U.S. are safe. They work with government agencies like the FDA, which checks vaccines before they are used by people, and the NIH, which studies new vaccines. They also work with non-government groups like the , vaccine manufacturers, academic institutions, and private groups interested in vaccine science and safety.

Phase IV Trials

Phase IV studies are a part of drug testing that happens after a new medicine is already being sold. These studies are really important because they help us understand how safe and effective the medicine is when used by lots of different people in real life, outside of earlier, more controlled tests. This phase helps to find out any rare side effects and how well the drug works for various groups of people, like those with different health conditions. It's like a big, ongoing experiment that continues as long as the drug is sold, to make sure it's safe and works well for everyone.

VAERS

The (VAERS) is like a safety check for vaccines in the USA. After vaccines are approved, VAERS keeps an eye on them to make sure they're safe. Anyone can tell VAERS if they think a vaccine caused a health problem. Remember, just because someone reports a problem doesn't mean the vaccine caused it. VAERS then looks for any patterns or big concerns. If they find something unusual, they'll study it more to keep vaccines safe. VAERS gets many reports every year, but most of them are about mild issues, like a sore arm. They take all reports seriously, but they will need more information to know if a vaccine really caused a problem. And they usually follow-up on reports to confirm their veracity.

Vaccine Safety Datalink

The (VSD) is a special project by the CDC and other health groups in the U.S. It started in 1990 and helps ensure that vaccines are safe. VSD looks at the health records from different places to see what vaccines people get, when they get them, and what other vaccines they get at the same time. They also check if people get sick after getting a vaccine. VSD studies vaccines to answer questions about their safety, especially new ones, or if there are changes in how they're used. Since 1990, VSD has done many studies on vaccine safety. They've looked into whether vaccines with certain ingredients are safe for kids, if vaccines cause certain types of seizures, and if the HPV and COVID-19 vaccines are safe.

Clinical Immunization Safety Assessment (CISA) Project

. They have experts in many areas like infectious diseases and children's health. CISA also looks into vaccine safety problems and gives advice that helps us understand vaccines better. They do research on vaccine safety, especially focusing on COVID-19 and flu vaccines, and vaccines for pregnant women. This research is important because it includes people who are usually not part of the first tests of vaccines. CISA can study common reactions to vaccines, like fever, and also work with special groups, like pregnant women. They are ready to help in emergencies, like a pandemic, and have been helping with COVID-19 vaccine safety since December 2020. Doctors can ask CISA for help with COVID-19 vaccine questions.

V-Safe

V-Safe is , like the flu shot. You sign up using your phone or computer and then get texts or emails asking about your health. This helps the CDC know if the vaccines are safe. V-safe started in 2020 for COVID-19 vaccines and now also checks on vaccines for a virus called Mpox (formerly “monkeypox”) and another one for respiratory syncytial virus (RSV), which is a lung infection. If you get these vaccines, you can sign up for V-safe and answer questions about how you feel. This info helps scientists and doctors learn about the vaccines and make sure they're safe.

Vaccine Safety Coordinators

A vaccine coordinator is a person in a healthcare facility or agency who makes sure vaccines are stored and handled properly. They need to be trained to manage vaccines during regular times and emergencies. Their main jobs are counting vaccine stock, keeping vaccines at the right temperature, and making sure they're used before they expire. They also train other staff members in handling vaccines, and they keep good records of how vaccines are stored and handled.

A Special Case: The COVID-19 Pandemic and Operation Warp Speed

In late 2019, health officials in China found several cases of pneumonia in Wuhan, Hubei Province. , they discovered the cause was a new type of coronavirus, named "SARS CoV-2." Chinese scientists shared the virus's genetic information and samples with the world, helping labs globally start working on a vaccine.

In the U.S., the government gave money to vaccine makers to speed up their research for a fast and effective vaccine against the pandemic. Normally, vaccine development is a step-by-step process: first phase I trials, then phase II, and finally phase III. This method ensures unsuccessful vaccines don't move to more expensive trial stages. But, with government funding as backup, companies could run different trial phases at the same time.

This new approach lets safety and effectiveness tests happen alongside vaccine production. Normally, large-scale vaccine manufacturing waits until after phase III results. With "," large-scale manufacturing began as soon as the vaccines were proven safe in phase I, and while their effectiveness was still being studied. If the vaccines didn't work, the government's funding would cover the costs of any manufactured vaccine that wouldn’t be used.

The three vaccines from Operation Warp Speed (two mRNA and one viral vector) went through all the usual safety and effectiveness checks as other pre-pandemic vaccines. They had the same number of participants and trial phases. The same safety standards and independent reviews were maintained. The only difference was the faster timeline, made possible by government funding to cover risks usually borne by the manufacturers.

Government Oversight

In the United States

At the end of the 19th century, several vaccines for humans were developed. They were smallpox, rabies, plague, cholera, and typhoid vaccines. However, no regulation of vaccine production existed.

On July 1, 1902, the U.S. Congress passed "An act to regulate the sale of viruses, serums, toxins, and analogous products," later referred to as the (even though "biologics" appears nowhere in the law). This was the first modern federal legislation to control the quality of drugs. This act emerged in part as a response to , which involved smallpox vaccine and diphtheria antitoxin.

The Act created the Hygienic Laboratory of the U.S. Public Health Service to oversee the manufacture of biological drugs. The Hygienic Laboratory eventually became the National Institutes of Health. The Act established the government’s right to control the establishments where vaccines were made.

The United States Public Service Act of 1944 mandated that the federal government issue licenses for biological products, including vaccines. After a poliovirus vaccine accident in 1954 (known as the Cutter incident), the Division of Biologics Standards was formed to oversee vaccine safety and regulation. Later, the DBS was renamed the Bureau of Biologics, and became part of the Food and Drug Administration. It is now known as the Center for Biologics Evaluation and Research.

Outside of the United States

In the European Union, the (EMA) supervises regulation of vaccines and other drugs. The EMA’s process is very similar to that of the FDA in the United States. More broadly around the world, a. Many countries have adopted the WHO standards, and others have standards similar to those of the United States. .

Conclusion

In conclusion, the journey from discovering the cause of a disease to creating and distributing a vaccine is a complex and lengthy process, often taking 10 to 15 years. This process involves several critical stages, starting with identifying the causative agent of the disease, which can be a virus, bacteria, or other pathogens. Once identified, extensive laboratory and animal studies are conducted to understand how the immune system reacts and develop a potential vaccine.

The vaccine is then put through a rigorous testing process, including exploratory, pre-clinical, and multiple phases of clinical trials with human participants, to ensure its safety and effectiveness. This includes testing in small groups of adults in Phase I trials, larger groups in Phase II, and thousands of participants in Phase III. After successful trials, the vaccine requires approval and licensure from regulatory bodies like the FDA in the United States.

Post-approval, the vaccine's safety continues to be monitored through various systems such as VAERS, the Vaccine Safety Datalink, and the CISA Project. These systems track adverse events and conduct ongoing studies to ensure long-term safety and effectiveness. The process also involves special initiatives in emergency situations, as seen with the COVID-19 pandemic and Operation Warp Speed, which accelerated vaccine development while maintaining safety standards.

Overall, the development of vaccines is a collaborative effort involving scientists, regulatory agencies, healthcare professionals, and the public. This intricate process ensures that vaccines are not only effective in combating diseases, but also safe for widespread use.

Sources and Further Reading

• VAX. 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.
• U.S Department of Health and Human Services. . U.S. Food and Drug Administration. Updated 01/09/2018. Accessed 01/17/2018.
• U.S. Department of Health and Human Services. . U.S. Food and Drug Administration. Updated 10/05/2017. Accessed 01/17/2018.
• 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.
• Centers for Disease Control and Prevention. Ensuring the Safety of Vaccines in the United States.. Accessed January 2024.
• European Medicines Agency. Safety of COVID-19 vaccines. Available at: . Accessed January 2024.
• Suvarna V. Phase IV of Drug Development. Perspect Clin Res. 2010;1(2):57-60.
• MediProducts. What is a Vaccine Coordinator? [Internet]. Available at: https://www.mediproducts.net/blog/topic/healthcare-management/what-is-a-vaccine-coordinator. Accessed January 2024.
• Salman O, Topf K, Chandler R, Conklin L. Progress in Immunization Safety Monitoring - Worldwide, 2010-2019 [published correction appears in MMWR Morb Mortal Wkly Rep. 2021 Aug 06;70(31):1065]. MMWR Morb Mortal Wkly Rep. 2021;70(15):547-551. Published 2021 Apr 16. doi:10.15585/mmwr.mm7015a2