Despite the unprecedented global focus on developing a COVID-19 vaccine, experts are still expecting it to take 18 months to develop it. Amélie Boulais, who works in the vaccine platform of Sartorius’ bioprocessing division at Sartorius talks about the challenges facing companies racing to develop a vaccine, which include bioprocess process management and manufacturing ramp-up, among others.

Sartorius has helped enable biopharmaceutical companies manufacture vaccines during infectious disease outbreaks and pandemics like Ebola, Zika, and H1N1, and now they are supporting companies around the world that are developing COVID-19 vaccines of all varieties.

Back in March, Sartorius supported CanSino Biologics Inc. and the Institute of Bioengineering in China in their development of the first SARS-CoV-2 vaccine candidate to enter clinical trials, leveraging Sartorius’ BIOSTAT STR single-use bioreactor system for the upstream preparation of the recombinant vaccine. –KB
 
Contract Pharma: What are the key challenges vaccine developers face?
 
Amélie Boulais: The main challenge for developing a vaccine is speed. There are many more specific concerns, but many of these tie back to trying to develop a vaccine quickly. The industry knows how to proceed to develop new vaccine, but to make it available for the population in 2021 is a great challenge.
 
Clinical trials are especially lengthy and complex for vaccines, for several reasons. First, the efficacy of a vaccine cannot be determined until Phase III trials. With therapeutics, patients who are sick are given the treatment during Phase II trials, so the efficacy of the treatment can be rapidly evaluated. Vaccines are administered to healthy people as a prophylactic treatment, so it takes longer to understand whether it is actually effective, by monitoring the number of patients who catch the disease over time. The second challenge is that because it is administered to such a large population, side effects that occur in even 0.01 percent of the population are a big deal. That might translate to tens of thousands of people and, because they aren’t sick to begin with, their tolerance for issues will be low. To identify side effects in a small subset of patients, the clinical trial has to enroll a great deal of patients, and this is lengthy and costly. Third, the patient population could encompass almost anyone in the world. This includes patients of all ages and also people with a variety of underlying conditions.
 
Another challenge is that there is no precedent for what vaccine platform will work best for COVID-19. Researchers are almost starting from scratch when deciding on an antigen and platform. As a result, we are seeing many different approaches, from mRNA platforms to viral vaccines to viral vectors and recombinant subunits. Currently, there are more than 135 vaccines in preclinical development, 18 in Phase I, 12 in Phase II, seven in Phase III and one that is approved for limited use. In this sense, it’s a challenge for individual vaccine developers – but for the public, our odds of receiving a successful vaccine soon are high. We have many shots on goal. 
 
Companies must also think through how they plan to ramp up manufacturing to vaccinate entire countries around the world so rapidly. This means it will need to be scaled at unprecedented speed. One way we are tackling this is vaccine developers are working to produce massive quantities of the vaccine before the clinical trials are complete. This approach could mean losing millions of dollars if the vaccine proves ineffective or unsafe, but it’s a necessary strategy for meeting the aggressive timelines set forth.
 
CP: What types of vaccine technology are being explored and which do you think has the most potential?
 
AB: There are a wide range of platforms being used for the development of a SARS-CoV-2 vaccine. At this time, it is hard to say which will be the most successful. Many are promising in theory, but we need strong data to confirm that they are effective for a significant duration of time and that no major side effects will appear. Currently, there are 32 vaccines in human trials, representing a wide range of different technologies. These include:
 
Traditional viral platforms: This type of vaccine has been used for a long time with many notable success stories, such as the measles, influenza and rabies vaccines. The approach centers around the creation of an inactivated or attenuated form of the virus. Phase III candidates include two from Sinopharm (one from Wuhan Institute of Biological Products and one from Beijing Institute of Biological Products) and Sinovac.
 
Recombinant proteins or peptides: To create this vaccine, researchers produce a specific component of the virus, called the antigen, using recombinant DNA technology. The resulting protein/peptide antigens primes the immune system to target a specific feature of the virus. This is how the widely used HPV vaccine works. For SARS-CoV-2, companies have focused on the so-called spike protein, which is how the virus gets into our cells. Some of the more advanced vaccine candidates include Anhui Zhifei Longcom (Phase II), Novavax (Phase I/Phase II) and Finlay Vaccine Institute (Phase I/Phase II).
 
Viral vector: When creating this vaccine, researchers genetically engineer a virus that carries the genetic information for the antigen of the SARS-CoV-2 virus to the patient’s body. Once inside the body, the patient will begin creating the antigen in their own cells. While this platform is relatively new, it has been used to create other successful vaccines, such as the Ebola vaccine. The most advanced candidates include: Oxford University in partnership with AstraZeneca (Phase II/Phase III) and CanSinoBio, which has received limited approval for military use in China. Beyond the military, it is pursuing Phase III clinical trials.   
 
mRNA or DNA: Instead of injecting an antigen into patients, these vaccines introduce genetic material that allows the patient to produce the antigen in their own cells. This streamlines vaccine production by removing the need to generate the antigen in live cells. While no mRNA or DNA vaccine has been brought to the market previously, some of the successful candidates thus far rely on the technology, including Moderna (Phase III) and BioNTech (Phase II/Phase III).
 
CP: What timeline do you anticipate for a Covid-19 vaccine?
 
AB: The original estimate was 12 to 18 months, so we are still looking at possibly another year. That may sound like a long time, but vaccine development typically takes closer to 10 years. Decades on, we still don’t have a vaccine against HIV. For SAR-CoV-2, this is reason to be optimistic. A vaccine seems within reach and companies, non-profits, and governments are all dedicating a huge amount of resources to get them across the line. In the United States, “Operation Warp Speed” has set the goal of delivering 300 million doses of a safe vaccine by January 2021.
 
While speed is a concern, we still have to think about safety. Shortcuts cannot be taken during clinical trials, and these vaccines must be held to our high standards for safety and efficacy – despite the pressure and urgency. The area where we can really ramp up speed is manufacturing. Certain groups have pledged to begin large-scale manufacturing for the most promising candidates prior to their approval. Once the vaccine has been deemed safe and effective, we will already have an initial stockpile ready to go. While this is a huge financial bet, it may expedite the timeline by several months. We will be able to provide more reliable timelines once we see the outcome of the phase III trials for the frontrunner vaccine candidates. 
 
CP: What are the manufacturing challenges once a vaccine is approved? 
 
AB: Now that we are seeing more vaccines in Phase II/III trials, we really have to get serious about how we are going to produce enough doses for the entire population. Aside from ramping up manufacturing prior to approval, there are several tactics the industry is employing to help streamline the process.

With this timeline, it’s not possible to construct entirely new facilities. Fortunately, the bioprocessing industry has a wide network of CDMOs with manufacturing capacity, widely relying on s single-use technologies. They are flexible enough to adjust to the COVID-19 processes being currently developed. These can be implemented and validated faster than a stainless steel facility. They are also more responsive to shifts in demand, which we expect to see as different vaccines hit the market.  



The processes for developing and manufacturing the vaccine must be high-quality to allow for both safety and speed. Small deviations in the process can be captured and proactively addressed using statistical models based on multivariate data analysis and real time multivariate statistical process monitoring and control software. Other solutions, such as process intensification and high-throughput development tools, can expedite the timelines and increase productivity, allowing commercial production out of smaller facilities. 
 
Safety and efficacy should never be compromised for speed. Developers, manufacturers, CDMOs, suppliers and funding organizations must work together to strategically balance risk and speed when scaling up their processes to ensure that these are never compromised.