How Vaccines Are Developed

According to the World Health Organization, as of 11 April 2020, three COVID-19 vaccine candidates were in clinical evaluation and another 67 candidates were in preclinical development.1 Just a few weeks later, the Milken Institute reported that more than 120 coronavirus vaccine candidates were in development.2Although the final number of vaccine candidates that will be investigated for COVID-19 specifically can’t be predicted, Dennis M. Gross, MS, PhD, SSYB, SFC, CEO, and Professor of Pharmacology, Pennsylvania Drug Discovery Institute, Doylestown, Pennsylvania, anticipates that the current surge in demand for vaccine development will continue long after COVID-19 vaccines come to market.

“There will be an increased need for many types of vaccines as the number of infectious diseases continues to rise,” said Gross in an interview with Pharmaceutical Engineering® following his 22 April 2020 webinar presentation, “Vaccines 101,” sponsored by the ISPE Delaware Valley Chapter. The webinar was part of a three-lecture lunch-and-learn series: “Immunology 101,” “Vaccines 101,” and “Anti-Virals.” Information from the presentation on vaccines is shared in this article. He explained that one reason to expect more types of infectious diseases to emerge is the growing risk of zoonotic transmission. Though the origins of COVID-19 remain unclear, the novel coronavirus may have initially been transmitted from animals. Gross noted that contact between animals and humans becomes more likely as the unprecedented deforestation in regions such as the Amazon and sub-Saharan Africa uproots wild animals from their habitats.

Types of Vaccines

In his presentation, Gross classified vaccines in four general categories: whole pathogen vaccines, subunit vaccines, toxoid vaccines, and nucleic acid vaccines. Each type is uniquely formulated to “train” the immune system to respond when exposed to a particular pathogen to ward off disease. The techniques used to create vaccines and their specific formulations affect the products’ safety and stability profiles.

Whole Pathogen Vaccines

Two types of vaccines are classified in the whole pathogen category: live attenuated vaccines (LAVs) and inactivated whole-cell vaccines. As the name indicates, an LAV contains a pathogen that has been “attenuated,” or weakened, but is still alive. LAVs generate an immune response that is similar to the immune response a person’s body would launch when infected with the wild-type pathogen;4 however, the weakened pathogen in the vaccine typically causes only mild disease or no disease at all. As a result, the vaccinated person can usually gain immunity without serious illness. There is some risk that an attenuated pathogen could change back to its original form and cause disease, and LAVs may not be effective or safe for immunocompromised individuals or pregnant women.3^,4

Inactivated whole-cell vaccines use pathogens whose living properties have been chemically or physically destroyed. These types of vaccines tend to be more stable than LAVs. Also, because they contain no live components, inactivated whole-cell vaccines cannot cause disease. However, these vaccines may not cause an immediate immune response, or the initial vaccine response may not confer lasting immunity. Therefore, individuals may require multiple vaccine doses or periodic boosters.4

Subunit Vaccines

Subunit vaccines contain only the portion of the pathogen that produces an antigenic response. Because these vaccines do not contain live pathogens, they are safer than LAVs. However, they are especially difficult to develop due to the challenges of determining which parts of the pathogen are needed to create lasting immunoprotection. Also, multiple vaccine doses or boosters may be required because subunit vaccines use inactivated pathogens.4

One of the biggest pitfalls in vaccine supply chain management relates to the predictability and reliability of output.

Toxoid Vaccines

Manufacturers have used weakened toxins (i.e., toxoids) produced by certain bacteria such as diphtheria or tetanus to formulate vaccines against the infections caused by those bacteria.3^, 4 Toxoid vaccines cannot cause disease or revert to a virulent pathogen, so they are considered safer than LAVs. They are also relatively stable products because they are resistant to environmental changes in temperature, humidity, or light.4

Nucleic Acid Vaccines

Types of nucleic acid vaccines under investigation for use in humans and animals include DNA plasmid vaccines, recombinant vector vaccines, and mRNA vaccines.5^, 6

• DNA plasmid vaccines introduce plasmids containing genes from the pathogen that causes the infection into the host tissues to spur an immune response that leads to immunity.
• Recombinant vector vaccines are created by inserting a pathogen’s DNA into a different, deactivated pathogen. Gross explained in his presentation that these vaccines rely on the DNA’s instruction-giving behaviors to direct cells to make proteins that resemble those of the infectious pathogen, causing the body to respond by producing antibodies.
• mRNA vaccines use messenger RNA to instruct cells to build antigenic proteins that the immune system will recognize, triggering it to create antibodies against the pathogen.

Vaccine Development Strategies

The strategies manufacturers select to develop vaccines are dictated by a range of factors, including which microorganism strains are available for investigation as well as the company’s previous experiences and areas of expertise, according to Gross. Organizations tend to gravitate toward strategies where they have had some success, he said. For example, Merck has past experience with recombinant vector vaccines, whereas Moderna was already focusing on recombinant mRNA encapsulated in nanoparticles prior to the emergence of COVID-19.

Preclinical Research

In the initial preclinical stages of vaccine development, researchers undertake a series of exploratory steps to select the type of vaccine they want to develop, identify and cultivate potential antigens, assess the immune response desired from the vaccine, and begin planning a manufacturing process that will create a safe and consistent product that can be used in clinical trials and eventually released to the market.7^, 8

Preclinical investigations also involve experimentation with adjuvants—substances that amplify the antigen’s immune response—as well as stabilizers to improve shelf life, preservatives to prevent microbial growth, and other vaccine elements [4]. In his interview with Pharmaceutical Engineering, Gross explained that adjuvant selection has limited room for innovation because manufacturers want to minimize the potential for unknown variables, such as the possibility that the adjuvant could be an irritant that causes adverse reactions.

After researchers derive a formulation for a vaccine candidate, that candidate undergoes rigorous preclinical testing to begin the evaluation of its safety and efficacy, Gross said. A key priority at this stage is to determine a plausible dosing regimen to generate an immune response. This step includes in vitro and in vivo analysis

If the candidate shows promise, researchers use animal models to help estimate the appropriate approach to human dosing.8 However, sponsors may struggle to find a suitable animal model for testing the vaccine candidate.

“You want to try to get the same immunity response in the animal model as you would in a human to determine the appropriate dose for humans,” Gross explained. “Animal modeling in vaccine development is not the same as using animal models in drug development because you’re dealing with the immune system, which is harder to model than other human systems, such as the endocrine or cardiovascular system.”

Clinical Trials

If preclinical studies of the vaccine candidate successfully meet scientific standards and produce sufficient evidence that the candidate seems safe for human use and could provide immunoprotection, researchers can begin clinical trials. Vaccines usually must undergo three phases of clinical trials be-fore regulators will consider them for market approval9^, 10^,11

Phase 1 trials evaluate the safety of the vaccine in a small number of low-risk subjects (typically, 10–100 healthy adults), Gross explained. This phase also provides information about how dose-response properties contribute to side effects, as well as immunogenic data useful for evaluating the efficacy of the vaccine.9^, 10^, 11

A vaccine candidate that is well tolerated and has enough evidence of safety and efficacy in Phase 1 can advance to Phase 2 trials, in which the product is tested in several hundred participants who represent the target population to further evaluate its safety profile and appropriate dosages.9^, 10^, 11

If the vaccine candidate passes Phase 2 trials, testing can progress to Phase 3 randomized controlled trials. To help investigators more fully understand the protective efficacy of the candidate, the number of participants tested tends to be quite large (e.g., in the tens of thousands), the populations studied are more heterogeneous than those studied in Phases 1 and 2, and the trial duration is longer than in the earlier phases.9^, 10^, 11Testing continues to focus on the candidate’s immunogenicity, protective efficacy against the target disease, and safety. The use of a control group is important to evaluate the candidate’s protective efficacy, which may be calculated as follows12^, 13 ^{(p. 24)}

Assessment for immunogenicity involves measuring the amount of protective antibodies a vaccine candidate produces in the test participants. This may indicate the degree of protection the candidate offers.12 In addition to evaluating the efficacy of the vaccine candidate, investigators use Phase 3 trials to continue to monitor the candidate for adverse effects as well as its behavior in specific populations.

Assuming the clinical trial evidence supporting the candidate is strong, the sponsoring manufacturer applies for market approval of the candidate. In the US, vaccine manufacturers submit a Biologics License Application (BLA) to the FDA.10

Postapproval Surveillance

If regulators grant a license for a vaccine, the vaccine enters the postapproval stage.10 At this point, the manufacturer may conduct Phase 4 trials and other forms of postmarketing surveillance to collect and analyze data on the long-term risks and effectiveness of the vaccine, associated health outcomes, and a range of pharmacoeconomic parameters, Gross noted in his presentation.

In some cases, the manufacturer may conduct large postmarketing studies with thousands of participants. Known as “megatrials,” these studies can potentially help the manufacturer identify concerns about the vaccine or additional indications for the product. National regulatory authorities also have surveillance apparatus to help track the effectiveness and safety of licensed vaccines.10

Supply Chain Hurdles

Vaccine manufacturing and distribution is an intricate process, and whatever is produced can expire relatively quickly. However, perhaps no obstacles are more challenging than those involving supply chain management.

“One of the biggest pitfalls in vaccine supply chain management relates to the predictability and reliability of output from your manufacturing organization,” said Nitin Goel, MBA, Senior Manager, Early Portfolio Commercial Strategy (Global Vaccines) at GSK in Washington, D.C., in an interview with Pharmaceutical Engineering.

Goel explained that vaccines often require long manufacturing times and can have high batch-failure rates and brief shelf lives. These issues limit the amount of product manufacturers can make and distribute. “It takes a long time to manufacture product, and whatever you produce can go bad pretty quickly,” he said.

The challenges of manufacturing stable and reliable vaccine batches constrain the flexibility and adaptability of the supply chain and can have deleterious downstream effects. Historically, manufacturers have sometimes struggled to respond promptly to changes in vaccine demand. Although manufacturers may have good information to reliably predict short-term demand for routine vaccinations, they cannot fully anticipate how stochastic incidents such as large disease outbreaks or large batch failures might dramatically alter the balance between supply and demand.

Manufacturers may try to forecast the long-term demand for vaccines based on information from various national immunization schedules. However, because vaccine manufacturing capacity requires a significant amount of capital and time to develop, such investment decisions come at great risk. If the forecast is off, the manufacturer might over- or underproduce the vaccine, leading to a surplus or deficit of millions of doses.

Moreover, the lack of globally standardized product specification requirements (e.g., for quality control or labeling) can impair a manufacturer’s ability to shift already-produced doses from one country to another. In such situations, manufacturers may require many months to adapt the supply chain. Until vaccine supply chain issues are resolved, populations are more vulnerable to communicable diseases and the company’s reputation may be damaged.

Goel noted that one way to help ease supply chain headaches is to maintain significant stock at every step of the supply chain to maximize the manufacturers’ flexibility to respond to unexpected events. Another important strategy for vaccine manufacturers is sustaining good relations and transparency with key external partners such as public health authorities in countries where the manufacturer supplies vaccines. When manufacturers and external partners have a shared understanding of the facts regarding production capabilities and the supply chain, they can better cooperate to lessen the risks posed to patient health and well-being.

Looking Ahead

Vaccine development is usually a lengthy process. According to Gross, successful vaccines have typically taken 10 to 15 years to move from preclinical research to market approval, and some have taken even longer—for example, Merck’s Varivax vaccine for varicella infection (chickenpox) took 23 years to be brought to market.

Sponsors of COVID-19 vaccine candidates hope they can dramatically shorten the typical development timeline. However, Gross warned, “You can’t neglect safety by going too far too fast.” Even if some vaccine candidates, such as those using mRNA, are developed quickly, scalability will present a challenge. It is uncertain what would be required to scale a vaccine created for research to mass production sufficient for an entire country—or the world. Access to an approved vaccine is very likely going to become another issue in the pandemic.