How Vaccines Are Brought Into the Marketplace
Carlos A. Arango, MD
Department of Pediatrics, University of Florida College of Medicine, Jacksonville, Florida
Arango CA. How vaccines are brought into the marketplace. Consultant. 2021;61(6):e1-e4. doi:10.25270/con.2021.02.00007
Received December 17, 2020. Accepted December 28, 2021. Published online February 12, 2021.
The authors report no relevant financial relationships.
Carlos A. Arango, MD, Department of Pediatrics, Baymeadows Pediatrics, 8399 Bayberry Road, Jacksonville, FL 32256 (email@example.com)
The development of vaccines has been one of the most important accomplishments for the human race due to one of the oldest foes to humanity: infectious diseases.1 The business of vaccines is very expensive, as it requires a large investment in manufacturing assets, facilities, and scientists in order to fulfill all of the regulatory requirements needed to bring a vaccine to the marketplace.2 Over the past 20 years, most of the approved vaccines used worldwide were developed in the United States.2,3 Between 1995 and 2014, about 15 vaccines were approved in the United States.2,3
The Phases of Vaccine Development
Developing vaccines is a risky business, because most of the candidates fail in either preclinical trials or in early clinical development. Only 1 in 15 vaccine candidates entering phase 2 of development achieve licensure.2 Three components are crucial for vaccine development: a clinical component, processing component, and assay development.
The clinical component serves to determine whether there is an animal model that can predict the vaccine’s effect in humans, the response of the human immune system, the antigenic response, and the vaccine’s safety. Moreover, if there is an immune response, the animal model can predict the duration of response.
Process development involves preparation of a test vaccine. Toxicology testing and statistical analysis are initially undertaken, thus ensuring that all pertinent information is complete. This process is performed in a facility at one-tenth of a full scale. Three lots are tested and evaluated for immunogenicity. Assay development includes specific methodology to test the purity, potency, and effectiveness of the vaccine.
Clinical development initially includes 3 phases. In phase 1 trials, investigators evaluate the effect of the vaccine on patients for safety, immunogenicity, and efficacy. This phase requires a small number of participants. Phase 2 trials are conducted to determine safety, dose ranges, and immunogenicity in 200 to 400 participants. Phase 3 trials require similar findings as phase 2 but now require several thousand participants in order to seek permission from regulatory agencies to bring the vaccine to the public.
Post-licensure studies of safety and efficacy (phase 4 trials) are essential to determine whether the candidate vaccine remains in the marketplace (Figure). The Vaccine Adverse Event Reporting System (VAERS) is a national vaccine safety surveillance program cosponsored by the US Food and Drug Administration (FDA) and the Centers for Disease Control (CDC). VAERS collects and analyzes information from reports of adverse events that occur after the administration of US-licensed vaccines. Reports are welcome from all concerned individuals: patients, parents, health care providers, pharmacists, and vaccine manufacturers.4,5,6
Figure. Typical Process of Vaccine Development. Source: Vaccine Development – 101. US Food and Drug Administration. Reviewed: December 14, 2020. Accessed: February 2, 2021. https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/vaccine-development-101
Basic research is usually conducted in a research facility. A small-scale process is then set up where data is gathered from the facility, and the availability of relevant animal models, high-quality reagents, and standardized assays to measure immune responses are developed. Preclinical Immunogenicity and toxicology are analyzed. All of this information is gathered, and a determination is made if an adequate clinical response was obtained or not.
Once this data is obtained, an application is sent to the FDA for an investigational new drug (IND). The federal agency reviews the data and provides technical support, if it is requested by the manufacturing company, thus setting up the new drug for a phase 1 trial.
Phase 2 trials usually take 1 year to complete. The process includes materials, components, lyophilizes, and adjuvant medications. Formulation is examined for purity and stability. Immunological tests are performed with dose-escalation to determine the effectiveness of the vaccine and possible adverse effects. Once this data is available, the information is submitted to a regulatory agency for evaluation and approval.
Once the optimal dose is achieved, the process moves to a larger manufacturing facility for production of the vaccine. This usually takes another 2 years. This pilot plant provides the information about manufacturing, purity, testing, packaging, and production of a clinically viable vaccine. This facility proves that standardization has been achieved after testing 3 or more consecutive batches and obtaining identical results to the desired final product. Once this step is complete, the manufacturing process moves to a full-production manufacturing facility. This facility is where the phase 3 trial occurs. Patient enrollment, vaccine administration, and immunogenicity are established. Clinical end points are reviewed. This process usually takes 3 to 5 years.
The last process is a biological license application that usually takes 1 to 2 years. The total time from concept to full production and arrival to markets is about 10 years.
The Cost of Vaccine Development
In 1991, the cost of developing a vaccine was $231 million and increased to 1 billion in 2010.7 This includes the cost of research and development of the products that failed in initial phases, as well as in pre- and post-licensure clinical studies.8,9
Manufacturing companies around the world conduct research and produce vaccines. The Serum Institute of India is the largest producer of vaccines by doses. It has the capacity of producing 1.3 billion doses a year. China is the world’s largest vaccine manufacturing and consuming country in the world, with an output of 1 billion vaccines. There were 6 government-owned regional biological institutes, but they are now part of the China National Biotec Group Company.9 They are currently focused on providing their own domestic supply of vaccines for their citizens.
Brazil has 4 large manufacturing companies. They provide vaccination supplies for their citizens, as well as form associations with other biopharmaceutical companies for producing vaccines for dengue (GlaxoSmithKline), Bacille Calmette-Guérin (Ataulfo de Paiva Foundation), and meningococcus (Novartis). Currently, the Butantan Institute is working with China’s Sinovac to produce CoronaVac for COVID-19. The Oswaldo Cruz Foundation, known as Fiocruz, and its Bio-Manguinhos Immunology Institute will be providing the vaccine developed by Oxford University and AstraZeneca. In India, there are 9 COVID-19 trials in place right now. The Serum Institute of India is manufacturing Covishield in partnership with Oxford University and Astra Zeneca. In Germany, BioNTech and Pfizer have developed and started manufacturing a COVID-19 vaccine as well.
COVID-19 and Vaccine Production
The COVID-19 pandemic has changed the entire landscape of how vaccines are brought to the marketplace. An urgency is needed worldwide, but a number of questions have arisen about the different COVID-19 vaccines, their effectiveness, and safety.
Nucleic acid therapeutics have emerged as promising alternatives to conventional vaccine approaches, in part due to the long process needed to bring a vaccine to the marketplace. As mentioned earlier, the process usually takes 10 years from start to finish. A messenger RNA (mRNA) vaccine for COVID-19 has been developed in less than 1 year, and administration of a COVID vaccine has already started.
At present, 2 mRNA vaccines are being rolled out in the US market: Pfizer and Moderna COVID-19 vaccines. In the United Kingdom, the AztraZeneca/Oxford vaccine started to roll out in January 2021; this vaccine uses a viral vector, ChAdOX. A fourth vaccine, the JNJ-78436725 vaccine by Janssen and Johnson and Johnson, finished phase 3 clinical trials with positive results. Johnson and Johnson is seeking emergency approval with the FDA and is anticipated to be administered very soon; this vaccine uses a viral vector, Ad.26.COV2.S.
It is natural that there is some skepticism about how “rushed” this process was when compared with historical vaccine development. It is true that this is a “new” technology for vaccine manufacturing, but this technology is not really new. The first described use of mRNA was reported in 1990 with a direct gene transfer into mouse muscle in vivo.10 Vaccination with nonviral-delivered, nucleic acid-based vaccines mimics the infection or immunization with live microorganisms and stimulates potent T-helper-cell and B-cell immune responses. Furthermore, nonviral-delivered, nucleic acid-based vaccine manufacturing is safe and timesaving, without the growth of highly pathogenic organisms at a large scale and fewer risks from contamination with live infectious reagents and the release of dangerous pathogens.11 A testament of this is the Ebola virus vaccine.14
As for safety, some COVID-19 vaccines contain mRNA that is a noninfectious, nonintegrating platform, so there is no potential risk for infection or insertional mutagenesis. Additionally, mRNA is degraded by normal cellular processes, and its in-vivo half-life can be regulated through the use of various modifications and delivery methods.12,13
This novel technology contrasts with a more conventional one. For most emerging virus vaccines, the main obstacle is not the effectiveness of conventional approaches but the need for more rapid development and large-scale deployment. The development of more potent and versatile vaccine platforms is, therefore, urgently needed.
There is a standard process in place for vaccines, from phase 1 to 3, and after marketing, phase 4. The United States, Europe, India, Brazil, Japan, and other countries have regulatory bodies that review safety data and related information provided by the pharmaceutical companies. Scientists verify this information and provide approval for the vaccines.
At the time of this writing, several countries have approved several COVID-19 vaccines (Table). It should reassure us that several governing bodies have, independently from each other, looked at the data provided by the manufacturers and deemed the vaccines safe. Now is the time to do our part and promote the use of the vaccines.
There are several unknowns ahead of us: How long the immunity last? Does it require a yearly vaccine like the influenza vaccine? Are there any long-term effects? This information will be forthcoming with phase 4 trials and, in the United States, with the VAERS reporting system.
- Warren KS. New scientific opportunities and old obstacles in vaccine development. Proc Natl Acad Sci USA. 1986;83(24):9275-9277. https://doi.org/10.1073/pnas.83.24.9275
- Douglas RG, Samant VB. The vaccine industry. Plotkin’s Vaccines. 2018;7:41-50.e1. https://doi.org/10.1016/B978-0-323-35761-6.00004-3
- Peter G, des Vignes-Kendrick M, Eickhoff TC, et al; National Vaccine Advisory Committee. Lessons learned from a review of the development of selected vaccines. Pediatrics. 1999;104(4 Pt 1):942-950. https://doi.org/10.1542/peds.104.4.942
- Vaccine testing and the approval process. Centers for Disease Control and Prevention. Reviewed: May 1, 2004. Accessed: February 2, 2021. https://www.cdc.gov/vaccines/basics/test-approve.html
- Vaccine Development – 101. US Food and Drug Administration. Updated: December 14, 2020. Accessed: February 2, 2021. https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/vaccine-development-101
- Vaccines. US Food and Drug Administration. Updated: January 27, 2021. Accessed: February 2, 2021. https://www.fda.gov/vaccines-blood-biologics/vaccines
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- Wolff JA, Malone RW, Williams P, et al. Direct gene transfer into mouse muscle in vivo. Science. 1990; 247(4949 Pt 1):1465-1468. https://doi.org/10.1126/science.1690918
- Zhang C, Maruggi G, Shan H, Li J. Advances in mRNA vaccines for infectious diseases. Front Immunol. 2019; 10:594. https://doi.org/10.3389/fimmu.2019.00594
- Iavarone C, O'Hagan DT, Yu D, Delahaye NF, Ulmer JB. Mechanism of action of mRNA-based vaccines. Expert Rev Vaccines. 2017; 16(9):871-881. https://doi.org/10.1080/14760584.2017.1355245
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- Matz KM, Marzi A, Feldmann H. Ebola vaccine trials: progress in vaccine safety and immunogenicity. Expert Rev Vaccines. 2019;18(12):1229-1242. https://doi.org/10.1080/14760584.2019.1698952