Learn about developing a vaccine and the challenges that come along with it.
Because of the COVID-19 pandemic, there have been various statements released by people in positions of power regarding a timely vaccine. President Trump believed a couple of months to a year would be sufficient time for the release of a vaccine. Dr. Fauci stated he believed a vaccine could be ready by early 2021. For context, as of June 5th, 2020 there were about 2 million coronavirus vaccine doses “ready to go” once scientists figure out whether it is safe and effective. The reality is, most vaccines never even make it to the market. If they do, it can take up to 10 years to complete. This is quite a contrast from what Dr. Fauci and President Trump have expressed. This article will cover challenges to vaccine development, as well as legal ways to fast track their manufacturing. If you want to learn about the ways that COVID-19 has affected the medical device industry, check out this article.
Vaccines can take a long time to develop for many reasons, mainly because there are so many obstacles in a vaccine's path to legal licensing in the US. A few of these obstacles include:
There are many things standing in the way of a quick and timely vaccine release. See this list of vaccines approved for use in the US, which is quite short if you think about all of the possible types of diseases out there! This article will be mainly about vaccines for viruses, not bacterial infections. If you want more information on vaccines for bacterial infections, see this list.
Vaccine development is a complex and intricate process, with 6 definitive phases:
The preclinical phase mostly involves animals and in vitro systems. There will be experiments determining the toxicity and immunogenicity, as well as effort to combine antigens or viruses for a combination vaccine. This phase is also used to begin developing the vaccines’ manufacturing strategy. All of these will culminate into filing for an Investigational New Drug (IND). If you want to learn more about partnering with big pharma, and possibly receiving funding for your trials, check out this article.
Phase I begins after one obtains an IND filing. It often involves 10-40 volunteers, where the primary concern is their safety. A vaccine developer will ask themselves: is this safe for use on humans? This is also the time to experiment and fine tune the dose size and best route of administration.
If Phase I is completed correctly, the vaccine will move on to Phase II. Phase II will involve 50-500 volunteers, and can last from several months to several years. Phase II will be more focused on adverse events, and the volunteers' response to them. Vaccine developers will also look for immune responses in specific target groups.
Phase III can take anywhere from 2-5 years. Phase III will involve several thousand volunteers, anywhere from 20,000 to 50,000. This phase also involves a placebo to make results even more accurate. Vaccine developers typically have their final manufacturing procedures ready at this stage as well.
BLA filing deserves its own stage because it can take anywhere from 1-2 years. BLA stands for Biologics License Application. According to the Food and Drug Administration's (FDA) website:
“To be considered, the license application must provide the multidisciplinary FDA reviewer team (medical officers, microbiologists, chemists, biostatisticians, etc.) with the efficacy and safety information necessary to make a risk/benefit assessment and to recommend or oppose the approval of a vaccine.”
In many cases, back and forth between the FDA and the filing team can elongate the process to beyond a year.
Even after the developers obtain BLA approval and introduce the product to the market, their work is not finished. There is monitoring of the safety and efficacy of the vaccine as long as it is still on the market. In addition to monitoring, the FDA will stay up to date with any new indications or findings related to the vaccine to ensure its safety beyond the initial release.
Viral vaccines are used to treat viruses. There are various types of viral vaccines, including:
This article will cover a few of these examples in more depth later on. Each type is used to treat a different disease, and the type of vaccine will be different depending on the particular disease.
DNA/RNA vaccines have not been approved for use in the US. DNA/RNA vaccines have many positives, like the fact that they are non-infectious and that they can produce T and B-cell immune responses. However, both DNA and RNA vaccines have their shortcomings. For RNA vaccines, there are concerns regarding its stability and how it can lead to low immunogenicity. There also seems to be poor immunogenicity for DNA vaccines, as well as a concern that DNA vaccines could potentially integrate into the human genome.
Virus-like particles (VLPs) are commercially available and licensed in the US. There are many positives of a virus-like particle, including the fact that they are non-infectious. They are non-infectious because they do not contain any viral genetic material, instead they are a subassembly of viral structural proteins. This allows the immune system to process the virus-like particle in a similar manner to the parent virus itself.
The challenges to VLPs mainly come from the question of stability. For example, the commercial HPV vaccine, Gardasil (Merck), must be refrigerated at a very low temperature and protected from light. This can make mass manufacturing and transport more complicated and expensive.
Immunity to most human viral diseases is best achieved through the use of a live viral vaccine. Historically, the most effective vaccines have been types of live viruses, like the polio vaccine. But, the use of these vaccines can cause an infection, unlike the VLP or RNA vaccines. Live virus vaccines interact directly with the immune system. After entering the body, the vaccine is recognized as a possible antigen and the immune system will take over.
Recombinant vaccines are made from recombinant DNA technology. This technology involves inserting encoded DNA strands into bacterial or mammalian cells. CHO cells are the most important part of this process, as they have become the most effective way of producing recombinant vaccines.
These are the 4 critical parameters for a recombinant vaccine:
There is no question vaccines have revolutionized our world. There is also no question that their development should not be rushed. However, in some circumstances (like with the COVID-19 pandemic) a timely vaccine is required. The makers of each individual vaccine need to question what attributes are needed for each individual virus. Testing multiple theories or routes is essential to ensuring maximum efficacy and safety.
A correlate of protection is a measurable sign that an individual has developed sufficient immune response to a particular disease. This finding takes a long time to develop and state as fact, and there are many obstacles to surpass before developers can claim a correlation of protection. Issues mainly arise when using animals as a model before testing on humans. This can lead to gaps of efficacy between animal and human trials. Oftentimes, a trial will work in mouse and rodent models, but not in humans and this is an obstacle vaccine developers must be aware of.
The most important thing is to make sure developers have an immune response that is responsible and statistically correlated with protection from the particular virus. And remember, an immune response does not guarantee immunity or full protection from a particular virus.
Once a vaccine is developed and producers ensure its safety and efficacy, they are now responsible for its manufacturing. This includes making sure potency and protection is the same (and correct) in each large scale batch of the vaccine. In order to streamline this process, vaccine developers should create a DOE. DOE stands for Design of Experiments. If they do not have a DOE, they might just be using trial and error as a strategy, which is not proven to be efficient.
In terms of physical manufacturing, single-use bioreactors are best chosen over stainless steel tanks. This is because the single-use bioreactors offer lower initial investment costs and an increased reliability.
As stated earlier, manufacturing should be on a vaccine developer's mind throughout the entire development process of a vaccine. Feasibility and efficiency of manufacturing are an integral part of a vaccine’s development.
In 1992, the FDA instituted the Accelerated Approval regulations. These regulations allowed developmental drugs for serious conditions to be approved based on a surrogate endpoint (as opposed to a fixed endpoint). Additionally, in 2012, the FDA passed the Food and Drug Administration Safety Innovations Act (FDASIA). This allows the FDA to expedite approval of drugs to fill an unmet medical need. In short, these laws allow faster approval and implementation of drugs if there is a dire (and time sensitive) medical need, like the COVID-19 pandemic has brought.
Here are the 4 most basic ways for a drug or vaccine to be fast tracked by the FDA screening process. Click the links to get a more detailed look at their meanings.
This article only skims the surface of the field of vaccine manufacturing. Long trials and many failures are in store for vaccine developers. But, it is important to understand the end goal, to reduce disease and medical problems for the betterment of our society and the individuals within it. Ensuring the complete safety and efficacy of a new vaccine is essential before beginning to administer it to the world community.
As an academic researcher, Dr. Jacobson studied the molecular basis of autoimmunity and the use of cDNA vaccines as a means to break peripheral tolerance. In early-stage biotech, he led initiatives on IND enabling studies for therapeutic cancer vaccines and oversaw relationships with contract manufacturing organizations (CMO).
If you want to learn more about pitching an idea (whether it be for a vaccine or not), check out this article.