Did you know that immunization prevents two to three million deaths per year? And if global vaccination coverage improved, another 1.5 million deaths could be avoided? And the global vaccines market is projected to reach $58.4 billion by 2024, up from $41.7 billion in 2019. There is a case to be made for vaccines and understanding the production and regulation of them. In this article, we’ll take a closer look at vaccine development history, production, method of action, testing, and regulation in order to help you better understand the market and immunization as a whole.
A Brief History of Vaccines and Their Development
Vaccine development is an extensive and complex process that takes anywhere from 10 to 15 years; it also relies on both public and private involvement. The current system in the United States has in place for developing, testing, and regulating vaccines began at the end of the 19th century. Since then, we have developed vaccinations for rabies (Louis Pasteur developed the rabies vaccine in the 19th century), smallpox, cholera, typhoid, and the plague. However, at the time of their development and production, there were no actual vaccine regulations. Regulations were introduced much later.
Inoculation history dates back as early as the 1500s and early China. Several accounts from the 1500s describe smallpox vaccinations practiced in India and China. The vaccine involved grinding up smallpox scabs and blowing the matter into a nostril. Vaccination had also been practiced by scratching material from a smallpox spore into the skin. Though it is difficult to determine when this specific practice began, some sources claim dates as early as 200 BC. Edward Jenner would later develop the smallpox vaccine in the 18th century after it had been weaponized.
In the 20th century, the study of bacteriology eventually surfaced, focused solely on studying bacteria. From the research that emerged out of bacteriology, we treated diphtheria, anthrax, plague, cholera, typhoid fever, and tuberculosis.
In July of 1902, Congress passed an act to regulate the sale of viruses, serums, toxins, and analogous products, which later became known as the Biological Control Act. It was the first modern federal regulatory law to control the quality of drugs.
The Biological Control Act then created the hygienic laboratory of the United States Public Health Service, which soon became what’s known as the National Institute of Health. This entity has the responsibility of overseeing the manufacturing of biological drugs; the law later established the government’s right to control the establishment where our vaccines are produced.
The United States Public Service Act of 1944 then mandated the federal government to issue licenses for any biological products; this included vaccines. After the Cutter incident, a polio vaccine accident around the mid-1950s, the Division of Biologic Standards emerged to oversee the safety and regulation of vaccines. Later, this division was renamed the Bureau of Biologics and became part of the U.S. Food and Drug Administration (FDA). Now, we may know this as the Center for Biological Evaluation and Research.
Today, because of the amount of research and technology we have available, disease rates are declining. Vaccinations for tetanus, diphtheria, chickenpox, and a number of other diseases are required for school-age children in the United States. Sometimes required for school or travel, vaccines have become a standard part of most lives.
How Are Vaccines Produced?
Vaccines are produced by taking viruses or bacteria and weakening them to prevent replication. Children who receive vaccines are exposed to enough of the virus or bacteria to develop immunity, but not so much of it that they actually become sick. There are a number of different approaches that can be used. The first step to produce vaccines involves generating the antigen to provoke the body’s immune response. Let’s review vaccine production in more detail.
Weakening the Virus
With this approach, viruses are weakened so that they reproduce poorly once inside the body. Vaccinations for measles, mumps, rubella, polio, chickenpox, and influenza are made this way. The advantage of this approach is that one to two doses generally provide lifelong immunity. The limitation of this method is that these vaccines are not to be given to people who have weakened or compromised immune systems.
Inactivating the Virus
Using this strategy, viruses are killed with a chemical. By killing the virus, it will no longer be able to reproduce itself or cause any further disease. Rabies, the flu shot, inactivated polio, and hepatitis A vaccines are made with this approach. The body still sees the virus so the immune system generates cells to protect against that disease. With this approach, the vaccine can’t create even a mild form of the condition it’s meant to prevent and the vaccine is safe for those with a weakened immune system. However, this approach generally requires multiple doses for a person to achieve immunity.
Using Part of the Virus
With this approach, a single part of the virus is removed and used to create a vaccine. The shingles, HPV, and hepatitis B vaccines are made this way. The vaccine is made with a protein that resides on the surface of the virus. This approach is used when an immune response to one part of the bacteria or virus is responsible for protecting against the disease. This kind of vaccine can be given to people with weakened immunity and appears to induce long-lived immunity after receiving just two doses.
Using Part of the Bacteria
Some bacteria cause disease by producing a harmful protein known as a toxin. Several vaccines are made by using toxins and activating them with a chemical. Once it’s been activated, it can no longer cause disease. Tetanus, diphtheria, and pertussis vaccines are made this way.
Providing the Genetic Code for Part of the Virus
A newer approach to vaccine creation uses the genetic code as part of the virus. With this approach, the person who is vaccinated makes part of the virus. The vaccine consists of messenger RNA (mRNA), which is the code for the spike protein of the virus. The vaccinated person’s muscle cells then use this blueprint to make the spike protein from the surface of the virus. This is the approach used in the coronavirus (Covid) vaccine and looks to be one of the new approaches modern science is moving toward.
After the immune system realizes the protein is foreign, it develops an immune response against it which includes immunologic memory so that the next time the person is exposed to the virus, the immune system is ready to respond. This is like other vaccination strategies, but specifically injects parts of the virus directly so it can be leveraged when an immune response to the virus is able to protect against disease. This vaccine can be given to those who are immune-compromised but it may require two doses to be protective.
After the antigen is generated, it must be released from the cells and isolated from the materials used in its growth. From there, the antigen has to be purified. Vaccines that are made from recombinant proteins may involve chromatography. Inactivation may occur.
In the fourth step, an adjuvant may be added to enhance the immune response. Stabilizers or preservatives may be added to prolong shelf-life and allow multi-dose vials to be used safely. Influenza vaccines, for instance, include proteins from chicken eggs. People with egg allergies have to avoid those vaccines.
In the final stages of any vaccine manufacturing, all the components are mixed into a single vessel. From there, it is distributed into vials or syringes, then sealed, and labeled for large-scale distribution. Some vaccines are freeze-dried, then rehydrated at administration.
How Vaccines Work and Prevent Diseases
Vaccines work to protect the body by mimicking disease and stimulating the immune system to build defenses against them. The immune system provides the body with protection from pathogens or the agents that cause disease. Vaccines look like pathogens to the immune system but don’t make the body sick.
Pathogens are covered with molecules known as antigens that trigger a specific immune response. Vaccination exposes the body to antigens that are similar to the antigens found on a pathogen. By posing as a specific pathogen, the vaccine trains the immune system to respond quickly if the body encounters that pathogen in the future.
Antigen-presenting cells roam the body looking for invaders. When an APC finds the vaccine antigen, it ingests the invader, breaks it apart, and displays a piece of the antigen on the surface. APCs displaying the antigen then travel to areas where the immune cells cluster, such as your lymph nodes. Naive T cells specific to the antigen, recognize it as foreign and then activate. T helper cells alert nearby cells to the presence of the Invader.
Naive B cells react to the vaccine antigen when it enters the body. They can recognize the antigens displayed by the APCs as well as antigens that are traveling freely in the body. Active B cells undergo cell division to produce more B cells so that they are specific to the vaccine antigen. Some of these mature into plasma B cells while others develop into memory B cells.
After the activation of the vaccine antigen and receipt of the signals from the T helper cells, B cells transform into the plasma cells which are the immune system’s antibody factories. The B plasma cells produce antibodies specific to the vaccine antigen. Each antibody attaches to a specific target antigen to prevent the antigen from entering a cell.
If the vaccine contains accentuated viruses, the vaccine virus enters the cells. Natural killer T cells activate to find and destroy those cells. Naive T cells require an APC to display an antigen piece before they’re activated.
Vaccines program the immune system to remember particular diseases. The immune system practices on a weakened or killed version of the pathogen, in a primary response. If the pathogen invades the body again in full strength, the immune system is ready to respond with a specific defense. Secondary responses happen faster and at a greater magnitude than primary responses, so the body creates more antibodies to fight the pathogen and more memory cells to fight it again in the future.
Vaccine Production, Testing, and Regulation
When a vaccine is being developed, it must follow a very specific and standard set of steps and testing. As one would guess, the first stages are very exploratory in nature but as the vaccine moves through the process, regulation and oversight increases and becomes a bigger focus. Here is a quick overview of the steps when producing, testing, and regulating a vaccine:
- The exploratory stage
- The preclinical stage
- IND application
- Phase I Vaccine Trials
- Phase II Trials
- Phase III Trials
- Post-Licensure Monitoring
- Phase IV Trials
Now let’s dive a little deeper into each step.
At this stage, the focus is on basic laboratory research. This phase generally lasts two to four years with federally funded academic and governmental scientists identifying natural or synthetic antigens that may help treat or prevent disease.
At the preclinical stage, studies use tissue culture or cell culture systems. In addition to these assays, there will likely be some animal testing to assess the level of safety of the candidate vaccine. Animal testing can also reveal the candidate vaccine’s ability to incite an immune response. The studies often use mice and monkeys to give researchers an idea of the cellular response that may be expected in humans.
They may also suggest a starting dose for the next phase of research as well as a safe method to administer the vaccine. Researchers may adapt the vaccine during this stage to try to make it more effective, which may mean testing multiple formulations. Many vaccines never go beyond this stage because they fail to produce the desired immune response. The preclinical stages generally last one to two years.
A sponsor, generally a private company like drugmakers Pfizer, BioNTech, or Moderna, submits an application for an investigational new drug (IND) to the FDA. The sponsor is required to describe the manufacturing and testing processes in detail, summarize the lab reports, and provide an in-depth summary of the proposed study. A review board that represents an institution where the clinical trial will be conducted has to then give approval of the clinical protocol. The FDA must then approve or deny the application within 30 days. If the IND application has been approved, the vaccine undergoes three phases of testing.
Phase I Vaccine Trials
Phase I is the very first attempt to assess the vaccine in humans by conducting trials through a small group of adults. If the vaccine that’s being developed is actually intended for children, researchers will first test adults. They will then gradually decrease the age of test subjects until they eventually reach the target age group. Phase one trials may be open-label, meaning researchers and subjects know whether they receive a vaccine or a placebo.
The primary goal of Phase I is to assess the safety of the candidate vaccine and establish the type and extent of the immune response the vaccine causes. If there are promising results in Phase I, the vaccine candidate progresses to the next stage.
Phase II Trials
In Phase II, a larger group of several hundred individuals participate. Some of them may belong to the group at risk of developing the disease. These trials are well-controlled, randomized, and include a placebo group. The goal of Phase II is to study vaccine safety, proposed doses, schedule of immunization, and method of delivery. Successful vaccines in this phase move onto longer trials but involve thousands to tens of thousands of people.
Phase III Trials
Successful Phase II vaccines move on to larger trials which are randomized and double-blind. They involve the experimental vaccine being tested against the placebo. Certain rare side effects may not surface in smaller groups of subjects that are tested in earlier phases. The vaccine efficacy is tested as well. At this point, vaccine production can scale up to allow for more widespread distribution.
Post-Licensure Monitoring of Vaccines
Once Phase III has proven to be a success, the vaccine developer will then submit a biologics license application to the FDA. The FDA then inspects the factory where the vaccine will be made and approves the labeling of the vaccine. After licensure, the FDA continues to monitor the production of the vaccine, including inspecting facilities and reviewing manufacturers’ lots for safety, purity, and potency. Additionally, the FDA reserves the right to conduct its own testing of the vaccines.
Beyond that is a number of different systems to monitor vaccines even after they’ve been fully approved. This includes an additional Phase IV for more trials, the Vaccine Safety Datalink, and the Vaccine Adverse Event Reporting System (VAERS).
Phase IV Trials
Phase IV trials are not required, but optional studies. Drug or pharmaceutical companies can choose to proceed to Phase IV after a vaccine has already been released to the public. Some reasons for a Phase IV may include wanting to further test the vaccine for efficacy, safety, and other potential uses.
The VAERS was established by the Centers for Disease Control and Prevention and the FDA in 1990. It is a voluntary reporting with the goal of detecting possible signals of adverse events associated with the vaccine.
Anyone, including parents, healthcare providers, or friends of the patient, can make a report if they suspect an association between a vaccine and an adverse event. The CDC investigates the event and tries to determine whether the event was, in fact, caused by the vaccination.
Vaccines are a crucial part of health and wellness and work to prevent infectious diseases from reaching pandemic levels. With safe production and vigilant regulation, vaccines are an integral part of everyday life for many humans. There are several methods of actually producing a vaccine, but they all have one common goal: to protect and prevent widespread disease. Without laboratory research and the thorough phases, many of us wouldn’t be protected from fatal diseases. At Excedr, we empower research labs with the tools and equipment they need to complete their studies. Contact us today to learn more about how we can help you.