The Vaccine Industry

VACCINE DEVELOPMENT

Vaccine development is difficult, complex, highly risky, and costly, and includes clinical development, process development, and assay development. The risk is high because most vaccine candidates fail in preclinical or early clinical development and less than 10% of vaccine candidates entering Phase 2 achieve licensure.

The high failure rate is driven by multiple factors:

• 1

  Incomplete understanding of the biology of protection.

• 2

  Lack of good animal models to predict vaccine behavior in humans.

• 3

  Unpredictability of human immune system reactions to antigens.

• 4

  Unpredictability of vaccine safety.

• 5

  Unpredictability of the impact of combining multiple components in a vaccine.

• 6

  Inherent difficulty in conducting meaningful clinical studies.

Vaccine development requires strong project management systems and controls and requisite skill sets among scientists and engineers. A key strategic document that guides the stakeholders in vaccine development is the “target product profile” (TPP). The TPP summarizes the desired characteristics and features of the product under development, the key attributes of the product that provide competitive advantage, and, finally, a topline roadmap of nonclinical and clinical studies required to evaluate the products efficacy and safety in the target population. A well-defined TPP provides all the stakeholders, including research, process development, manufacturing, clinical, regulatory, and senior management, with a clear statement of the desired outcome of the product development program.

Process development involves making preparations of the test vaccine that satisfy regulatory requirements for clinical testing including clinical lots, preclinical toxicology testing, and analytical assessment, and finally scale-up methods that lead to a consistent manufacturing process typically at one-tenth of full scale. Usually three consecutive lots are tested in the clinic for immunogenicity. Assay development involves the definition of specific methods to test the purity of raw materials, stability and potency of the vaccine product, and immunologic and other criteria to predict vaccine efficacy. Go/no-go decisions must be made at each stage of clinical and process development and must be data-driven. Clinical, process, and assay development tasks must be closely integrated. Clinical development involves studies of the effects of vaccines on patients for safety, immunogenicity, and efficacy through a staged process: Phase 1, early safety and immunogenicity in small numbers; Phase 2, safety, dose ranging, and immunogenicity in 200–400 individuals; sometimes Phase 2b, nonlicensure, proof-of-concept trials for efficacy; and Phase 3, safety and efficacy trials that permit licensure, which generally require thousands of subjects. In addition, concomitant studies with existing vaccines have to be conducted prior to licensure.

“Process” can be broadly divided into two categories: bulk manufacturing and finishing operations. Bulk manufacturing includes cell culture or fermentation-based manufacturing or both followed by a variety of separation processes to purify the vaccine. The finishing operations include formulation with adjuvant/stabilizer followed by vial or syringe filling (including lyophilization in the case of live viral vaccines) followed by labeling, packaging, and controlled storage. Process development may be as costly as clinical development and is critically important to the overall success of a vaccine development program. As development proceeds toward licensure, costs escalate as clinical studies become larger, manufacturing scales up, and facilities must be built. Postlicensure studies of safety and efficacy (Phase 4) of vaccines are essential and represent a large additional cost. It is important to note that, unlike pharmaceuticals, vaccines that pass early proof-of-concept studies in humans have a very high probability of achieving licensure.

Clinical activities are more visible than bioprocess development and clearly drive the go/no-go decisions that direct progress. The two are interwoven and each has rate-limiting steps, so they must be done in concert.

The first stage of vaccine development involves acceptance of a candidate from a basic research laboratory and development of a small-scale process and formulation to make material for Phase 1 study, analytical release assays, preclinical toxicology, immunological assays to evaluate clinical responses, an investigational new drug (IND) filing, and well-designed Phase 1/2a studies.

The second step is to complete the definition of product and process prior to initiation of Phase 2 dose-ranging studies, which may take a year or more. Product definition includes methods of synthesis/bioprocess steps, number of components, and stability/formulation. Stability, release, and raw material assays must be in place. Immunologic and other assays must be established to support dose-ranging studies, and a regulatory plan for vaccine process and product submissions must be written.

The third step is to define the clinical dose and arrive at the appropriate manufacturing scale, which may take 2 years or more. It results in the identification, manufacture, filling, and release of clinical-grade vaccine, usually in a pilot plant; demonstration of safety and dose response in a Phase 2 clinical study; validation of critical assays to support Phase 3 clinical studies; consistency of lot manufacture (ability to produce three or more consecutive production-scale lots that meet all product specifications based on validated analytical methods); and completion of technology transfer to final site of manufacture of full-scale lots, including process and analytical procedures. For vaccine targets for which animal studies are not predictive of efficacy in humans, such as human immunodeficiency virus (HIV), malaria, and tuberculosis (TB), small Phase 2b proof-of-concept studies based on adaptive clinical trial designs may be used to gain confidence before committing significant resources for process development, analytic development, and factory construction.

In general, the analytical and release assays are particularly difficult to develop because, in most cases, vaccines are considered “not well-characterized” biologicals by regulatory agencies. The release assays initially involve functional potency assays such as animal immunogenicity prior to acceptance of more robust and precise in vitro assays that correlate with these functional potency assays. In general, variability of biological assays is a major hurdle in achieving process scale-up and manufacturing consistency.

The fourth stage is the completion of Phase 3 pivotal clinical studies and corresponding consistency lot studies, which requires 3–5 years. Keys to successful Phase 3 clinical studies are an accurate estimate of sample size based on disease incidence, low dropout rates, precise clinical endpoint definitions related to future label claims, and rigorous data management to the highest standards. In addition to clinical studies, scale-up and manufacture of consistency lots, including transfer to the facility of all assays, facility validation, demonstration of consistency, and real-time stability are needed to support adequate shelf-life claims.

The final stage is Biologics License Application (BLA) preparation, licensure, and vaccine launch, which requires 1.5–2 years. Accordingly, the total elapsed time for development is 10–15 years, assuming all activities proceed as planned. The new EUA regulations allow the FDA to accelerate approvals of new medical countermeasures and help protect the public more rapidly against emerging biological threats.

Manufacturing plants are very expensive to construct, ranging from $100 million to $500 million depending on the size (dose requirements) and manufacturing complexity, with an additional expenditure of approximately 20% of that cost for validation activities that are now required under the current good manufacturing practices regulations. With few exceptions, each vaccine requires a different plant because of unique manufacturing requirements and the regulatory difficulties associated with changing over to a different product. Some processes are scalable, such as bacterial or yeast fermentation, so that increasing the size of the manufacturing unit (i.e., fermenter) will greatly increase the yield; unit cost will decrease with volume increase. Other manufacturing processes, for example, those dependent on viral growth in embryonated hen eggs or cell lines, are not scalable. Additional plants or modules within plants must be built to increase the throughput, so unit costs do not appreciably decrease with volume increases. Despite the complexity of bulk vaccine manufacturing, 3–5 years postproduct launch, the fully burdened bulk cost of production for most of the older vaccines declines to as little as $0.60–$3.00 per dose, and significant elements of product cost are primarily driven by activities related to filling, vialing, and packaging ( Table 5.2 ). It is likely that that the new vaccine technologies, with simpler bulk manufacturing processes, will significantly reduce capital investment in new facilities, shorten development timelines and reduce product cost, potentially making them a preferred development pathway for future vaccines.

The commitment to build a plant must be made early (4–6 years before expected licensure) including a 6- to 12-month finished goods inventory build-up to expedite product to the market. Otherwise a gap of 1–5 years between licensure and product launch will occur.

Furthermore, it is far better to produce consistency lots in the final vaccine production factory to demonstrate the ability to manufacture the vaccine reliably and to use those lots in the Phase 3 efficacy trials. Otherwise, immune studies will be required for “bridging” the product used in the efficacy trial to material manufactured in the commercial factory. This is especially difficult if immune studies are not highly reproducible, as is the case with most cellular immune assays. Such decisions pose large financial risks if the product in development fails and requires access to large amounts of capital, an attribute usually restricted to large pharmaceutical companies. Estimates for the cost of development of a new drug or vaccine have risen from $231 million in 1991, to $1 billion in 2020. ^{, , ,}

These estimates take into account all costs, including R&D costs of products that fail, postlicensure clinical studies, and improvements in manufacturing processes. These estimates are validated by biotechnology companies that are focused on one vaccine and have successfully brought it to market. For example, Aviron, which was subsequently acquired by Medimmune, spent between $500 million and $700 million on R&D for the development of a live attenuated influenza vaccine. In summary, vaccine development from concept to licensure is typically a lengthy process as illustrated by timelines for some of the currently licensed vaccines, but the new technologies and extraordinary funding during the COVID-19 pandemic demonstrated the ability to significantly shorten these timelines ( Table 5.3 ).

ROLE OF PARTNERS

The predominant players in the development and manufacture of vaccines are the several full-scale vaccine companies. Many other organizations, both public and private, contribute to the process ( Table 5.4 ).

The role of large, full-service vaccine companies ( Table 5.5 ) is predominantly in development. They engage in some limited basic research and significant amounts of targeted research regarding specific organisms, but the preponderance of activity is in clinical and process development and manufacture. Sufficient personnel and expertise in clinical and process development, bioengineering and project management reside almost exclusively in these companies. Clinical development that will meet U.S. Food and Drug Administration (FDA) standards is also managed mostly by the large companies contracting with academic and private research organizations. Personnel and expertise in regulatory affairs, data management, statistics, and all other required disciplines also exist within the large companies. Perhaps most importantly, their management is structured to make rapid go/no-go decisions required to minimize risk and assess efficient vaccine development.

Many smaller organizations, often referred to as biotechnology companies, are engaged in vaccine research. They are often started by university scientists, supported by venture capitalists, and are capable of basic research on a vaccine concept. At this early stage, they usually have limited capacity in process development, manufacturing, and clinical development, and none in distribution, sales, or marketing. If research results are favorable, capacity in process enginee­ring, clinical studies, and manufacturing must be enhanced or obtained by partnering. Because of the large cost of adding new capacities and expertise, many biotech companies in advanced product development will opt to partner with large, full-scale companies.

The number of small companies engaged in vaccine R&D has grown considerably in the last 10 years, latching on to new technologies and developing vaccines for unmet medical needs or targeting opportunities to improve existing vaccines. As a result, renewed interest is focused on developing vaccines for cytomegalovirus (CMV), respiratory syncytial virus (RSV), Staphylococcus aureus , chikungunya virus, and other pathogens, and efforts continue to develop improved vaccines for hepatitis B, influenza, pneumococcus, HPV, and others. We expect these young companies to speed up innovation in the vaccine space in the same way Chiron Corporation and Praxis/Connaught did for hepatitis B and Haemophilus influenzae type b (Hib) vaccines respectively about 35 years ago. The greatest contributions of the biotechnology companies continue to be introducing multiple ideas into early vaccine development, and testing them to determine if they should be rejected or carried forward. These small companies are dependent on several factors for their success:

• 1

  A vibrant basic research environment that allows for creation of new ideas, an environment that exists in well-funded U.S. National Institutes of Health (NIH) academic research programs.

• 2

  A strong venture capital and investment community that views vaccine companies as potentially financially rewarding as other investment opportunities.

• 3

  Strong patent laws providing the intellectual property protection that is essential for commercial success.

Several branches of the U.S. government play major roles in vaccine R&D.

The NIH is the major funding source via intramural and extramural (largely academic) programs of fundamental research, and directed research on pathogens, which may lead to new vaccine candidates. The NIH, through its vaccine trials network, has increased its role in clinical development domestically and internationally. In addition, the Dale and Betty Bumpers Vaccine Research Center at the NIH was established in 1999 primarily to pursue the development of HIV vaccines, and it has contributed to the development of other vaccines including COVID-19 as well.

The U.S. Centers for Disease Control and Prevention (CDC) is the primary government agency responsible for epidemiological monitoring of disease trends. The CDC conducts disease surveillance and epidemiological studies to ascertain the prevalence and incidence of specific diseases; this information provides a rationale for prioritizing vaccine development. Through the Advisory Committee on Immunization Practices (ACIP), the CDC recommends usage of vaccines and is responsible for most of the public purchases through the Vaccines for Children program and other federal, state, and local government purchases for childhood vaccines, thereby playing a major role in determining the demand and potential profit associated with vaccines. Professional organizations such as the American Academy of Pediatrics and the American Academy of Family Physicians also make recommendations for vaccine usage. There is no federal vaccine program for purchase of adult vaccines, although Medicare part B covers COVID-19, influenza, hepatitis B, and pneumococcal conjugate vaccines. Medicare part D and private insurance cover shingles, Tdap, and other vaccines.

The Department of Defense (DOD) conducts vaccine R&D to help it fulfill its mission of protecting deployable personnel and their families against infectious disease threats in the United States and abroad. Thus, the DOD assesses infectious disease risks in specific theaters and establishes prioritization of vaccine targets, especially those not being funded and developed in the private sector.

The U.S. Army Medical Research and Materiel Command (USAMRMC) is a major DOD organization conducting basic and applied medical research programs supporting military operations. The U.S. Army Medical Material Development Activity is its advanced product development agency, which aligns closely with the Walter Reed Army Institute of Research, the U.S. Army Medical Research Institute for Infectious Diseases, and the Naval Medical Research Center in conducting or supporting surveillance studies and vaccine trials.

USAMRMC’s longstanding overseas laboratories (e.g., in Thailand and Kenya) provide opportunities for the United States to partner with host nations in the development and evaluation of vaccines of shared interest. Some of the more recent efforts have focused on vaccines against malaria, dengue, HIV, norovirus, and Ebola.

The Biomedical Advanced Research and Development Authority (BARDA) within the Health and Human Services Department was established in 2006 to facilitate development and purchase of vaccines and other products for public health emergencies such as pandemic influenza or coronavirus. BARDA also manages Project BioShield for the procurement of advanced medical countermeasures for biological warfare threats and has successfully developed medical countermeasures against smallpox, anthrax, and botulinum toxin. In addition, BARDA is funding a variety of early-stage novel vaccine approaches for pandemic influenza, and it played a major role in supporting development and manufacture of several COVID-19 vaccines. BARDA is intended to overlap with and fill the gap that is not being funded by the private sector between NIH-funded preclinical or initial Phase 1 trials and large-scale clinical trials.

The Center for Biologics Evaluation and Research (CBER), a division of the FDA, is responsible for licensing new vaccines. CBER establishes standards for manufacturing processes, facilities, and pre- and postlicensing clinical studies to ensure that licensed vaccines are safe and effective (see Table 5.4 ). These standards have a profound impact on the nature and direction of vaccine development and its costs. In addition, CBER maintains a strong research base internally, so it is better positioned to evaluate data from various studies. CBER remains the premier vaccine regulatory agency in the world.

Nongovernmental organizations (NGOs) are playing an increasing role in vaccine research.

The Bill and Melinda Gates Foundation supports several organizations including the International AIDS Vaccine Initiative, the Malaria Vaccine Initiative, and others with significant funding for development of vaccines that would have the greatest impact on diseases of developing countries. In addition, a related organization, Programs for Appropriate Technology in Health (PATH), is a nonprofit group that forges private sector partnerships to develop vaccine technologies suitable for the developing world. These product development partnerships (PDPs), essentially not-for-profit biotech companies, bring together specialized knowledge, animal models, immunologic assays, and field sites for vaccine testing as well as early capital investment to reduce the scientific technical risks, opportunity costs, and financial risk to their biotech and large pharma industrial partners. They also provide opportunities for validation of novel vaccine technologies and platforms.

RESPONSE TO COVID-19 PANDEMIC

The global biopharmaceutical industry, especially U.S. companies, set a record-breaking pace of innovation to develop effective COVID-19 vaccines by utilizing new technology platforms. In an unprecedented feat, three COVID-19 vaccines were approved under Emergency Use Authorization (EUA) in the United States, and similar approvals were granted in Europe and other parts of the world. About 20 vaccine candidates have received emergency use or full authorization in one or more countries, and more were expected in 2021. The magnitude of this vaccine development is reflected in the fact that more than 100 clinical trials are ongoing and about 200 preclinical programs are still in progress.

In addition to the contributions of the biopharmaceutical industry, in response to the COVID-19 pandemic a number of new public–private partnerships greatly increased their roles in vaccine development so that new vaccines were developed within 11 months of obtaining the gene sequence of the severe acute respiratory syndrome (SARS) coronavirus 2 (SARS-CoV-2), an extraordinary feat and just 8 or 9 months after first human doses were administered.

While remarkable, this timeline does not include basic research which is included for the other vaccines in Table 5.3 . The fundamental discovery that allowed development of mRNA vaccines was made in 2005. In 2020, Operation Warp Speed (OWS), a U.S. government program, was established to facilitate and accelerate the development, manufacture, and distribution of COVID-19 vaccines. OWS chose six companies using three different technologies hoping that at least one would succeed. By providing $12 billion to fund clinical development, process development, manufacturing facilities, and purchase of FDA-approved final product, these funds reduced much of the financial risk to companies and allowed significantly more risk taking. Phase 1 and 2 studies, normally run sequentially, were performed simultaneously; manufacturing facilities were built, and product manufactured in high volume before product approval. For larger companies OWS provided guaranteed purchase of approved product. For smaller companies it provided support for clinical studies, process development, manufacturing facilities, and product purchase.

The Coalition for Epidemic Preparedness Innovations (CEPI), a European organization, launched in 2017, is a global public–private partnership created to accelerate the development of vaccines against emerging infectious diseases, to stop future epidemics, and to ensure equitable access to these vaccines. During 2020, they provided $1.3 billion to support nine vaccine candidates.

The COVID-19 Vaccines Global Access (COVAX) is a global initiative to provide equitable access to COVID-19 vaccines. It is led by the Global Alliance for Vaccines and Immunization (GAVI), the World Health Organization (WHO), and CEPI. They have secured agreements to provide 2 billion doses of COVID-19 vaccines under development to countries with limited means. This guaranteed market encourages vaccine development.