Vaccination plays an essential role in preventing infectious diseases. It has saved thousands of millions of lives throughout history. But how exactly are vaccines developed?
Vaccines exploit the body’s natural defence mechanisms to build resistance against infections. They are typically biological substances that mimic the natural interaction between the pathogen and the human immune system, training the immune system so that the body can defend itself against subsequent exposure to pathogens. More specifically, vaccines cause the immune system to develop B-lymphocytes and T-lymphocytes, which can kill the pathogen by producing specific antibodies or cytotoxins. Meanwhile, memory B-cells and T-cells are also generated, preserving the repertoire of pathogen-specific antibodies. This is known as immunological memory, which enables the rapid elimination of pathogens in a subsequent exposure to that targeted pathogen.
Similar to drug development, vaccine development can be a challenging process, which typically takes 10 to 15 years and costs up to $500 million. This is because rigorous testing regimes and approval processes are required before bringing a new vaccine to the market. Notably, the safety standards for vaccines are extremely high since vaccines are given to healthy people, instead of targeting a pre-existing condition. There are six crucial steps in the vaccine development process:
1. Early discovery research
2. Preclinical testing
3. Clinical trials
4. Regulatory review and approval
5. Production and distribution
6. Post-market surveillance
Figure 1: Six crucial stages in the vaccine development pipeline. The number of candidate vaccines is gradually filtered down to determine the best vaccine for distribution.
Stage 1: Early discovery research
Vaccines typically contain a key disease-causing component known as the antigen and other components to keep the vaccine safe and effective.
The initial exploratory stage is research-intensive and often lasts 2 to 5 years. It aims to identify the antigen that can safely induce the desired immune response once introduced into the body, conferring protection against the infection on subsequent exposure to the infectious agent.
In order to find the right antigen, the nature of the infection and the infectious agent that causes the disease needs to be identified. Then the antigen can either be derived from the pathogen itself or be generated synthetically from the recombinant DNA. Various forms of antigens give rise to several different types of vaccines, such as live attenuated vaccines, inactivated vaccines, subunit vaccines, toxoid vaccines, nucleic acid vaccines, viral vector vaccines. In some cases, a diverse class of molecules known as adjuvants are also added to the vaccine in order to enhance the immune response in a non-antigen-specific way. Other components that could be involved in the vaccine include stabilizers, preservatives, surfactants, etc.
Typically, several different lead vaccine candidates would be developed to enter the pre-clinical stage, where the candidate vaccines that show the best immune response and evidence of protection will be selected for further testing.
Figure 2: Main types of vaccines against viruses and infectious bacteria. This figure was adapted from Robins & Wosen (2020).
Stage 2: Pre-clinical testing
Pre-clinical studies, which typically take around 2 years, are required before human testing. During the pre-clinical stage, the safety and the immunogenicity of the potential vaccines will be assessed using cell/tissue culture systems and animal models. Immunogenicity refers to the ability to induce the desired immune response.
Early tissue and cell culture testing are indispensable in vaccine development since it allows the proliferation of the target virus in infected cells without the use of live animals. This enables rapid large-scale viral production and provides a high level of control that is not possible in live animals.
Following culture systems, animal models such as mice or monkeys are used to test toxicology and immunogenicity in vivo. At this stage, animal subjects are vaccinated before exposure to the target pathogen. This gives the researchers a better idea of the expected performance of the vaccine in humans.
This stage helps researchers determine the preferred administration route of the vaccine. This could be oral intake, intranasal route, subcutaneous, intradermal or Intramuscular injection. Different methods of delivery could affect the response the vaccine induces, therefore needs to be carefully selected. In addition, preclinical testing provides an indication of the appropriate vaccine dosage and refines the candidate vaccine to make it more effective.
Following the testing, the package of data from pre-clinical testing is submitted for the Investigational New Drug (IND) application to the U.S. Food and Drug Administration (FDA). The IND application needs to include a detailed laboratory report about the formulations, safety, toxicology, immunogenicity and other properties of the candidate vaccine, as well as the production and testing processes. The vaccine is then subjected to clinical trials with human subjects once the IND application has been approved.
Stage 3: Clinical trials
Clinical studies on humans take an average of 6 to 7 years. They are conducted in three phases governed by internationally agreed principles. Generally, a larger number of participants are involved in vaccine studies compared to clinical trials for new drugs, recognizing the fact that vaccines are administered to a healthy population to prevent the disease. Therefore, a large sample is required to fully characterize their effect.
Figure 3: Three phases of clinical trials and the approximate number of participants.
Phase I
In Phase I, only a small group of healthy adult volunteers (usually between 20 – 80 subjects) are involved to evaluate the safety of the candidate vaccine and to assess its ability to elicit an immune response. Tolerance to different doses is also evaluated to determine the right dosage of the vaccine for the next step in the testing process. Phase I studies are often non-blinded where both the researchers and the participants know which treatments are being administered. Candidate vaccines showing promising results in Phase I studies will successfully progress to the next phase.
Phase II
Phase II trials involve a larger number of volunteers (several hundred subjects). The aim of this step is to further consolidate its safety, effective dosage, immunogenicity and administration route. It also helps to determine the requirement for boosters and the appropriate interval between each dose. Many of the participants involved in this stage have the risk of acquiring the disease. In this phase, subjects with similar characteristics, such as physical health condition and age, as well as the intended target population of the vaccine are selected to better model the effect of the vaccine. Not all participants receive the candidate vaccines at this stage; a control group gets the placebo instead of the vaccines. This determines whether the protective effects of the vaccine occur only by chance. Phase II trials are double-blinded where neither the researchers conducting the test nor the participants know which subject had received the vaccine and which had received the placebo. This could reduce or eliminate potential biases during the experiment. Typically, only one or two potential vaccines can pass Phase II testing and enter Phase III trial.
Phase III
In Phase III, the vaccine is tested in thousands of volunteers who are at risk of the targeted disease. This assesses the safety and protective effects in a much larger group of volunteers. Potential side effects and other rare, unexpected problems could also be monitored in this stage. Quite often, Phase III studies are carried out in multiple sites in many countries to ensure the efficacy of the vaccine in different populations. Similar to Phase II trials, Phase III studies are also double-blind tests with a placebo group for control.
Stage 4: Regulatory review and approval
Once Phase III studies are successful, the manufacturer could submit the Biologics License Application (BLA) to the FDA for a license to sell the vaccine. Data from all previous pre-clinical and clinical studies will be reviewed by the authorities, who will decide whether or not to authorize the vaccine for use. The standard for the safety and potency of the vaccine is extremely high since vaccines are given to people who have not been previously affected by the disease. It needs to elicit the appropriate immune response without severe side effects or infection.
Stage 5: Production and distribution
Once approved by the FDA, the manufacturer starts the mass production of the vaccine, which will be distributed across the globe to ensure as many people as possible can access it. The vaccine could either be part of the national immunization program or purchased privately. The manufacturing process will be closely monitored by the FDA, which ensures the safety, efficacy and purity of the vaccine meet the standard.
But this is not the end of the story!
Stage 6: Post-market surveillance
After the vaccine has been introduced to the market, it continues to be monitored. This ongoing surveillance is also known as Phase IV trials, which keeps track of the performance of the vaccine over a long period of time. The side effects after vaccine administration are also tracked and reported by the Vaccine Adverse Event Reporting System (VAERS).
Why should you care?
According to the World Health Organization (WHO), as many as 3 million lives could be saved by vaccines every year. Vaccination is responsible for the eradication of smallpox and the restriction of measles, polio and many other highly contagious diseases. Many diseases responsible for childhood deaths have disappeared as a result of the coverage of vaccines, leading to much lower child mortality. These days, the COVID-19 vaccines are produced to fight against the COVID-19 pandemic. Thanks to the worldwide collaboration and substantial amounts of funding, researchers have managed to develop COVID-19 vaccines within a year, which is no mean feat. So far, nearly half of UK adults have received their first dose of the vaccine, which significantly reduces infection rate and eases the symptoms.
However, there are still a couple of barriers to universal immunization, especially in developing countries. It could be hard for people in underprivileged areas to access vaccines due to their high cost and difficulty in delivery and storage. In addition, some people are reluctant to get vaccinated despite the availability of vaccination services. This is known as vaccine hesitancy, which could be caused by various factors, including complacency and a lack of confidence in the vaccine. Therefore, greater individual awareness and corresponding government measurements are still required to make vaccines more accessible.
Conclusion
Vaccination is one of the most effective and cheapest ways to deal with infectious diseases. Modern vaccine development often involves cooperation between industry, academia, investors, regulatory authorities, etc. Despite technological advances, vaccine development is still a lengthy and complicated process. Remarkably, it only took less than a year to launch the COVID-19 vaccine into the market, which is an extraordinary scientific achievement. More lives could be saved if common vaccine development became faster, and the vaccines became more widely available to the general public.
Author
Helen Luojia Zhang
BSc Biochemistry Imperial College London