The response of the biomedical community and biopharmaceutical industry to the COVID-19 pandemic has been rapid and far-reaching. In less than five months, the global R&D community has identified more than 115 vaccine candidates, with 73 in pre-clinical stages and eight actively engaged in Phase I clinical testing.
While this type of a response is proof of the strong, international biomedical infrastructure that has been built over the past century, many people across the globe are anxiously awaiting a return to normalcy. One of the only feasible paths towards that is nations achieving widespread immunity – hopefully through a vaccine. Despite this critical need, many experts anticipate that vaccine development will likely take at least 18 months, which is already an ambitious target.
This seems like a long time to wait, but vaccine development has historically taken much longer than 18 months. Even though HIV was first identified in 1981, there is still no approved vaccine. There are also no approved vaccines for SARS or MERS; outbreaks that began in 2003 and 2012, respectively. And while Ebola broke out in 2014, a vaccine was just approved by the U.S. Food and Drug Administration at the end of 2019.
So, why the long wait? There are inherent complexities with vaccine development that slow down timelines. Clearly the stakes are high: Without adequate testing of candidate efficacy and safety, vaccination could end up doing more harm than good. Once proven, manufacturing enough doses to meet the global need will introduce myriad other challenges.
One Size Does Not Fit All
Vaccination is a controlled, mock exposure of the human immune system to a foreign pathogen, a virus, bacteria, fungus, or other microbe. This can be done through injection of an inactivated or attenuated pathogen or a purified antigen distinct to the disease-causing pathogen. By administering a vaccine to a person, the immune system learns and remembers the distinguishing features of a pathogen. In so doing, future exposure to the pathogen results in a rapid and forceful immune response and rapid clearance before it can cause severe disease.
Emerging infectious diseases are a threat in the word we are currently living in: an increasing and globalized population confronted by ecological change. The emergence of a pandemic was a question of when, not if. Some pathogens have been clearly identified as threats, like Influenza. The industry is better equipped for an influenza pandemic, as vaccines like those available for seasonal influenza iterate each year, so the developer has a template to build upon. This was not an option with SARSCoV-2: There were no vaccines in development before 2020 and no precedent for what works best. SARS-CoV-2 is the disease X that the World Health Organization was expecting.
There are several distinct platforms that have emerged as leading strategies for developing a vaccine against SARS-CoV-2.
- Traditional viral platforms: This strategy uses inactive or live-attenuated forms of the virus and has a long, track record of success for vaccine development. The polio vaccine, for example can be administered with an inactivated or attenuated form of the virus. SARS-CoV-2 was only recently identified and isolated in culture, so it will take a long time to develop the right process to obtain an attenuated or inactivated form that is safe for clinical testing.
- Recombinant protein or peptides: Researchers identify the antigen of interest and produce it using a recombinant approach. Most of the teams working on a recombinant protein vaccine are focusing on the SARS-CoV-2 Spike protein or a part of it called the receptor-binding-domain. Recombinant proteins can be produced using a number of different expression systems, being microbial such as E.coli, insect cells or mammalian cells like CHO among others. This is a traditional platform with a long track record of success for prevention of a number of diseases.
- Viral vector: Genetically engineered viruses, such as adenoviruses or measles, are used to carry the genetic information coding for the SARS-Cov-2 antigen in the body. Once injected, the coronavirus antigen will be produced in the body. This is a highly productive manufacturing platform that can be used to develop and produce vaccines against different indications. This is a relatively new strategy that was successfully used for development of the Ebola vaccine. Currently, an adenovirus vector that expresses a SARS-CoV-2 antigen is being investigated in a Phase I trial.
- mRNA or DNA: This uses nucleic acids, either RNA or DNA, that encode for the specific viral antigens. Once injected into the patient’s body, the cells will take up the DNA or mRNA and start producing the antigen. One major advantage of RNA- and DNA-based vaccines is that they are, relative to other vaccine platforms, simple, flexible, and can be rapidly engineered. Thus, a few vaccine candidates, like mRNA-1273 and INO-4800, have already entered Phase I testing for SARS-CoV-2. However, this strategy is unproven: no mRNA nor DNA vaccine has been licensed yet.
Each platform and vaccination strategy has its own list of advantages and disadvantages, and no one can predict the winner yet.
For all vaccine candidates, questions remain about dosing, stability, and the degree to which they induce immunological memory. The addition of adjuvants – additional vaccine components that enhance immune response – or stabilizers to prolong shelf-life may address some of these hurdles, but they require more chemical, biochemical, biophysical, and clinical testing.
The Complexity of Clinical Trials
For a variety of reasons, vaccine clinical trials are often more convoluted than diagnostic or therapeutic studies.
The first complication has to do with the patient population. Vaccines must be made for everyone in the global population. This includes patients of every age, sex, and underlying condition. Developing a vaccine that is efficacious in each of these unique demographics can be a challenge.
Vaccine trials are lengthy because efficacy is not known during clinical Phase III. Typically, in Phase II and III trials of other biopharmaceuticals, patients who are sick are given the treatment and monitored to see if they get better. In this case, vaccines are being administered to healthy people whereas with vaccine trials, people that are monitored to ensure they do not contract the disease. Vaccine developers are working closely with regulatory bodies, such as the U.S. Food and Drug Administration and the European Medicines Agency to accelerate clinical trials without compromising patient safety.
To ensure vaccine safety and identify potential adverse events, a large population must be studied. For example, to identify a side effect that occurs in 0.01 percent of the population, tens of thousands of patients will need to be tested. Identifying and enrolling that many patients in a short period of time can be difficult and time-consuming. Not doing so though, could lead to a vaccination that will eventually need to be withdrawn because of the side effects. For example, after a previous rotavirus vaccine, RotaShield, was administered for a year, it was suspended and ultimately withdrawn because it caused intussusception in some patients. Tolerance for even minor side effects may also be low. Vaccines are prophylactic, so there is no immediate gain or improvement in health that individuals can latch onto as a tradeoff for the side effect.
Ramping Up Manufacturing
Once a vaccine has gone through clinical testing, companies must scale small manufacturing operations up to serve the global population. Some, such as the Gates Foundation, are proposing producing large doses of the most promising vaccines before they complete clinical trials, to get a head start on the massive doses that will need to be produced. This is a huge financial risk, but it is steps like this that would have to be taken to ensure developers can meet the 18-month timeline. Successfully scaling up production will require cooperation between developers, manufacturers, CDMOs, suppliers and funding organizations. It will also require vaccine developers and manufacturers to strategically balance risk and speed when scaling-up their processes.
Given the speed at which the vaccine must be produced, manufacturers will heavily rely on single-use technologies. Single-use platforms can be implemented and validated much faster than traditional stainless steel facilities and offer the flexibility needed to keep up with the changing demand associated with vaccines. The strategies based on manufacturing platforms such as recombinant proteins, viral vectors and nucleic acid offer the opportunity to adjust existing platforms to the COVID-19 vaccine demand. Of course, vaccine producers will have to rely on bioprocessing partners able to ensure a quality supply.
An experienced bioprocessing partner can help ensure process safety through various ranges of services, such as biosafety testing, cell banking, or product testing, as well as delivery of high-quality technologies. For example, multi-level controls from single-use solutions suppliers ensure the highest level of assurance of integrity for patient and operator safety, preventing leaks or microbial ingress.
To ensure process robustness needed during scale-up, tech transfer and to mitigate the risk of failure, advanced sensors and process analytical technologies can be used. This can also be combined with multivariate data analysis and real time multivariate statistical process monitoring and control software’s. Monitoring and control of manufacturing processes are essential to deliver high quality vaccines.
In the rapidly evolving world of COVID-19, the tools and technologies used must also be flexible. This will require both upstream and downstream products that allow the developer to rapidly scale-up, scale-down or scale-out.
A Challenging Process
While vaccine developers and manufacturers are working as quickly as possible to develop a vaccine against the SARS-CoV-2 virus, there are many necessary hurdles in the process that prevent companies from moving too quickly. Much of this is to ensure adequate testing and for the safety of the general public. By optimizing antigen and platform selection, clinical trials, and manufacturing, vaccine developers and bioprocessing partners can ensure that, on their side, the clinical testing and scale up is as efficient as possible. As an industry, we are operating with unprecedented speed, but we need to maintain our safety and efficacy standards.
Author Biography
Amélie Boulais is Marketing Manager within the Vaccine Segment at Sartorius Stedim Biotech. In her position, she analyzes the trends of the vaccine industry in order to define best-in-class solutions with the required associated process development support and related services for vaccine applications.