A short introduction to vaccines
Vaccines are top-of-mind for most people these days. This pandemic has forced us all to become armchair epidemiologists and scientists. We’re all hoping that a vaccine becomes available soon, but most of us don’t know how they get made and out to consumers. Let’s take a look at the process of vaccine production with some help from our friends at Klick Health.
First, we need to understand what a vaccine is. It’s typically made up of an agent that resembles a disease-causing bacteria or virus, which can be made from a weakened or deactivated form of the microbe, or an antigen. An antigen is a substance or molecule that’s capable of evoking an immune response. The goal of a vaccine is to trigger an immune response from your body, but without giving you enough of the bacteria or virus to actually get sick (for example, using one of the pathogen’s toxins or surface proteins to trigger a safe immune response without causing disease).
The immune response that results after vaccination is what sets up our bodies to better respond when we encounter the pathogen naturally. When we do, because our immune system has already encountered this threat, it responds faster and stronger than it would without vaccination. Much like the immunity we develop after getting sick, we’re better able to fight off the virus or bacteria. Symptoms are also often not as strong after vaccination, with the added bonus of not having to be sick in order to develop immunity.
There are four main processes used to develop a vaccine:
- Live attenuated – the virus is weakened in a laboratory, so that it can still cause an infection, albeit a significantly weaker one. Because these vaccines are so similar to a natural infection, they tend to create a strong and long-lasting immune response. Some examples of live attenuated vaccines: MMR, smallpox, chickenpox.
- Inactivated vaccines – the virus is killed, but the antigens are still present and provide an immune response. This response may be weaker, so booster shots may be needed and, over time, these repeated exposures will create a strong immune response. Some examples of inactivated vaccines: hepatitis A, rabies, influenza.
- Subunit/conjugate – these vaccines use only a small part of the microbe—like a protein, a toxin it produces, or the “casing” around the germ—to generate an immune response. An adjuvant may also be added to boost the immune response (aluminum salt adjuvants are most common in vaccines). Some examples of subunit/conjugate vaccines: Hepatitis B, Shingles, HPV.
- DNA/RNA-based vaccines – these vaccines use viral RNA or DNA (genetic material) to create an antigen, which then induces an immune response. No vaccines of this kind have been approved; however, this novel technology is being used in some of the proposed and ongoing COVID-19 vaccine trials.
The clinical trial phases [FDA] are designed to research a vaccine’s efficacy and safety.
There are typically four phases:
Phase I is the first time a vaccine is tested in humans, where it’s given to a small group of 20 to 100 healthy volunteers, who are generally considered to be at low risk for complications from the disease for which the vaccine is being developed. The main purpose of this phase is to identify any major safety issues and to confirm a safe dosage. Safety is scrutinized in terms of how the vaccine and its dosage affect the body.
If phase 1 is successful, then the vaccine is tested on a larger group of individuals—usually several hundred — in phase II clinical trials. This phase continues to test for safety and includes study participants matching the profiles of individuals in whom the vaccine is intended to be used. Study participants are divided into at least two groups, one that receives the potential new vaccine and one that receives a placebo, which looks the same as the vaccine but has no active ingredients. In a double-blind, placebo-controlled study, neither the patients nor the researchers have any idea which volunteers receive the vaccine and which receive the placebo, to ensure there is no bias when interpreting the results. Phase II trials also allow investigators to fine-tune research questions and methods ahead of designing phase III protocols.
After passing phase II trials, the vaccine can enter phase III, where it is studied in a much larger group, often involving thousands, possibly tens of thousands of participants. Phase III aims to demonstrate the safety and efficacy (sometimes including an optimized dosage) in participants at a large enough scale to confirm results with statistical tools and compare the new therapy or vaccine to the current standard of care, if one exists. The large number of study participants helps identify any side effects not identified in the smaller phase I and II trials.
After a vaccine completes phase III with positive results, the manufacturer applies for regulatory approval to make the vaccine available in a range of countries or regions. Marketing authorization requirements may vary from country to country and are determined by individual regulatory agencies.
Accelerating research and development
Vaccine development and trials typically take several years. Previously, the most rapidly developed vaccines have been the Mumps vaccine (about four years: 1963-1967) and the Ebola vaccine (about five years: 2014-2019). Under the current pandemic, measures are being taken to accelerate development while maintaining safety procedures. To do this, the vaccine manufacturers and governments have formed unprecedented coalitions to share their discoveries and data, and to fund vaccine creation and distribution [WHO]. Many trials are condensing the timeline by overlapping research and clinical trial phases. Regulatory bodies are also accelerating their process by collecting and analyzing continuous data and prioritizing reviews and approvals.
Coordinating across all of the research teams within one company is difficult enough, but coordinating the world’s COVID-19 response is a much more massive challenge. Solutions like Conductor can help orchestrate that work at task, project, and workstream levels and provide visibility into progress, by tracking KPIs shared between teams and geographies.
Aside from developing the vaccine itself, successfully delivering a vaccine depends on managing many other items as well: syringes, vials, or tubes to store and deliver the vaccine; additives to preserve and stabilize liquid vaccines or diluents to reconstitute vaccines in powdered form; and packaging and refrigerated containers to store and transport the vaccine. The Pfizer/BioNTech vaccine candidate, for example, requires ultra-cold -70°C freezers that currently aren’t widely available and will mean rethinking the storage and distribution supply chain [Quartz].
All these items need to be produced or sourced and be readily available when the vaccine is manufactured. Manufacturing enough doses to supply the world’s nearly eight billion people is a huge undertaking that goes far beyond just the manufacturing facilities, themselves. Global production of glass vials and syringes to store and administer the vaccines, for example, has to ramp up 5 to 10% in just two years to be able to produce enough to meet the demand. Accordingly, the Gates Foundation is investing billions of dollars in manufacturing facilities to ramp up in advance of the COVID-19 vaccine candidates even being approved.
Meanwhile, the approved vaccine must be produced in large quantities, grown in a lab under tightly controlled conditions, and purified to remove any components that aren’t needed for the final vaccine formulation. At this point, it may be inactivated or formulated, depending on which type of vaccine preparation is being made. Immune response-boosting adjuvants may also be added.
Packaging, delivery, and distribution
Syringes, vials, or tubes are then filled with the vaccine. Visual inspection is performed by a combination of technicians and technology to assure the quality of the contents. In large quantities, the filling process may go on for several months.
Vaccines are then packaged according to the specific requirements of the country in which they’ll be used. Samples are tested by both the manufacturer and by external health authorities to ensure quality is maintained.
Once a batch has passed all the required quality criteria, it can be released for distribution to pharmacies, health systems, healthcare providers, etc. Vaccines typically need to be transported and stored in cold rooms and temperature-controlled shipping solutions. Supplying the world with enough vaccine doses will require transportation solutions that have never really been considered before. According to the International Air Transport Association (IATA), providing a single dose of the vaccine to 7.8 billion people will require the use of 8,000 Boeing 747 cargo aircraft!
Accelerating packaging, delivery, and distribution
Packaging and distribution are highly repeatable processes that can be accelerated by creating structure to standardize and automate these tasks. Because they also have a high need for accurate data/KPI tracking, tools like Conductor’s Playbooks can help to codify these processes, making them easy to scale and adapt to the various regional requirements where the vaccine will be distributed. Conductor can help plan the approach, track work at the global and regional levels, manage the people involved, and provide real-time reporting on progress.
Finally, the vaccine reaches us, the consumer! The World Health Organization estimates that immunization currently prevents 2-3 million deaths worldwide each year. Safely accelerating their production and delivery could have a significant impact on the health of the world and our collective recovery from the current pandemic situation.
Special thanks to our friends from Klick Health, Rachael Harrison, PhD, VP, Science & Regulatory and Whitney Winter, PhD, Medical Strategist for lending their guidance and expertise to this article!