Vaccine Development:
Staying Safe at High Speed
Operation Warp Speed (OWS) and the continued Department of Defense (DOD) and Department of Health and Human Services (HHS) partnership set out to develop and make available COVID-19 vaccines at an unprecedented pace. Read on to learn what was, and still is, at stake in the process and why it matters.
Source: Zubada/stock.adobe.com.A range of scientific approaches1
Several methods exist to develop a COVID-19 vaccine. Here we’ll take a look at approaches using the mRNA platform, the replication-defective live-vector platform, and the recombinant-subunit-adjuvanted protein platform.
mRNA
This method uses mRNA, a biological molecule that codes for protein, that can allow vaccinated individuals to make spike proteins that mimic those of the virus. Vaccine companies create virus-specific mRNA enclosed in lipid nanoparticles, which help with delivery. The mRNA is released inside the cells of a vaccinated person, creating an immune response against SARS-CoV-2, the novel coronavirus that causes COVID-19.
Sources: GAO, adapted from GAO-20-583SP; Adaptation of images depicting vaccine technologies with permission from Springer Nature: Nature (“The Race for Coronavirus Vaccines: A Graphical Guide,” Ewen Callaway) © 2020. | GAO-21-319Replication-defective live-vector platform2
This approach uses a non-replicating virus that delivers genetic instructions to produce the spike protein of SARS-CoV-2 in vaccinated individuals.
Sources: GAO, adapted from GAO-20-583SP; Adaptation of images depicting vaccine technologies with permission from Springer Nature: Nature (“The Race for Coronavirus Vaccines: A Graphical Guide,” Ewen Callaway) © 2020. | GAO-21-319Recombinant-subunit-adjuvanted protein
This method uses purified proteins that mimic the SARS-CoV-2 spike proteins. Often, this approach requires an adjuvant, a component of the vaccine which helps the immune system to mount a response.
Sources: GAO, adapted from GAO-20-583SP; Adaptation of images depicting vaccine technologies with permission from Springer Nature: Nature (“The Race for Coronavirus Vaccines: A Graphical Guide,” Ewen Callaway) © 2020. | GAO-21-319Examining the process
Regardless of the approach used, developing a vaccine normally takes approximately 10 years or longer3. During that time, vaccine candidates move through the following stages:
Traditional Vaccine Timeline
Source: GAO, Analysis of Food and Drug Administration (FDA), Pharmaceutical Research and Manufacturers of America, and Operation Warp Speed Information. Reconfiguration of report figure. | GAO-21-319Note: The timelines for vaccine development depicted in this figure are not drawn to scale. This timeline depicts an example, and the specific development steps and timeline for a given vaccine may vary from this example. There may be some overlap among steps.
a. Phase 1 clinical trials generally test the safety of a product with a small group of healthy volunteers (usually fewer than 100). These trials are designed to determine the product’s initial safety profile and the side effects associated with increasing doses, among other things.
Phase 2 clinical trials are designed to evaluate the effectiveness of a product for a particular use and determine the common short-term side effects and risks associated with the product. These trials are conducted with a medium-size population of volunteers (usually a few dozen to hundreds).
Phase 3 clinical trials are performed after preliminary evidence suggesting effectiveness of a product has been obtained, and are intended to gather additional information about safety and effectiveness. These trials usually involve several hundred to thousands of volunteers, including participants who are at increased risk for infection. According to Food and Drug Administration (FDA) officials, these clinical trial phases may overlap.
b. According to FDA, manufacturing processes are reviewed as part of the vaccine licensure process. Thus, even under a traditional vaccine timeline, some initial manufacturing occurs during development, so the manufacturing processes can be adequately validated.
Exploratory phase4
In this initial stage, a vaccine candidate is identified that might cause vaccinated individuals to produce an effective immune response, including the production of antibodies, against a virus.
Preclinical phase5
In the preclinical phase, researchers use cells and animals to assess safety and produce evidence of clinical promise, evaluated by the candidate’s ability to elicit a protective immune response.
Clinical trial phases6
The vaccine candidate generally goes through three phases of clinical trials – also known as human trials – where it is tested on more volunteers at each successive phase. Safety, potential effectiveness, and delivery methods, among other factors, are evaluated in these phases.
Large-scale manufacturing7
Under a traditional vaccine timeline, some initial manufacturing occurs during development, so the manufacturing processes can be reviewed as part of the vaccine licensure process.
FDA review and licensure8
Once clinical trials are complete, the Food and Drug Administration (FDA) reviews the biologics license application (BLA)9, a request for permission to introduce, or deliver for introduction, a biologic product into interstate commerce, and determines whether the vaccine is safe, pure, and potent (i.e. safe and effective) for marketing in the United States. Postmarket studies are required for some products that FDA has licensed.
Potential Operation Warp Speed Timelinec
Source: GAO, Analysis of Food and Drug Administration (FDA), Pharmaceutical Research and Manufacturers of America, and Operation Warp Speed Information. Reconfiguration of report figure. | GAO-21-319Note: The timelines for vaccine development depicted in this figure are not drawn to scale. These timelines depict examples, and the specific development steps and timelines for a given vaccine may vary from this example.
a. Phase 1 clinical trials generally test the safety of a product with a small group of healthy volunteers (usually fewer than 100). These trials are designed to determine the product’s initial safety profile and the side effects associated with increasing doses, among other things.
Phase 2 clinical trials are designed to evaluate the effectiveness of a product for a particular use and determine the common short-term side effects and risks associated with the product. These trials are conducted with a medium-size population of volunteers (usually a few dozen to hundreds).
Phase 3 clinical trials are performed after preliminary evidence suggesting effectiveness of a product has been obtained, and are intended to gather additional information about safety and effectiveness. These trials usually involve several hundred to thousands of volunteers, including participants who are at increased risk for infection. According to Food and Drug Administration (FDA) officials, these clinical trial phases may overlap.
b. According to FDA, manufacturing processes are reviewed as part of the vaccine licensure process. Thus, even under a traditional vaccine timeline, some initial manufacturing occurs during development, so the manufacturing processes can be adequately validated. According to an OWS fact sheet, in some cases, the federal government is taking on the financial risk to enable large-scale manufacturing to start while clinical trials are ongoing, with the goal of having millions of doses available for distribution upon authorization or licensure of a COVID-19 vaccine.
c. The OWS timeline depicts an example of a potential accelerated timeline for COVID-19 vaccine development. However, the development process of any given OWS vaccine candidate may vary from this example. As of November 2020, approximately 10 months have elapsed since exploratory and preclinical research began in January 2020, after the first U.S. cases of COVID-19 were reported. The timing for any remaining steps have yet to be determined as of this report. According to OWS documentation, certain steps may overlap or be shortened to accelerate the development of a COVID-19 vaccine.
d. During an emergency, as declared by the Secretary of Health and Human Services under 21 U.S.C. § 360bbb-3(b), FDA may temporarily authorize unapproved medical products or unapproved uses of approved medical products through an emergency use authorization (EUA), provided certain statutory criteria are met. FDA has indicated that issuance of an EUA for a COVID-19 vaccine for which there is adequate manufacturing information would require the submission of certain clinical trial information from phase 3 clinical trials that demonstrate the safety and effectiveness of the vaccine in a clear and compelling manner, among other things. Any COVID-19 vaccine that initially receives an EUA from FDA is expected to ultimately be reviewed and receive licensure through a biologics license application, according to FDA guidance.
Ready, set, go: What are technology readiness levels?13
To evaluate Operation Warp Speed (OWS) and the continued DOD and HHS partnership's leading vaccine candidates, we applied the same framework we would when assessing cutting-edge technologies. The following descriptions summarize the HHS integrated technology readiness levels (TRL) used to evaluate the maturity of technologies, in this case vaccines, based on tests of dependability and complexity.
Department of Health and Human Services’ Integrated Technology Readiness Level (TRL) Countermeasure Scale and the Traditional Vaccine Development and Manufacturing Processes
Source: GAO presentation of Department of Health and Human Services criteria for Integrated Technology Readiness Levels (Drugs and Biologics) and Food and Drug Administration guidance ("Emergency Use Authorization for Vaccines to Prevent COVID-19" October 2020). | GAO-21-319
These TRLs are intended to help product managers, government entities, and regulatory bodies determine whether a technology, in this case a vaccine, is ready to move to the next stage of development or should be discontinued in favor of a more promising vaccine. These indicators can also help identify the relative readiness of a vaccine, as measured, for example, by its progress through preclinical testing, clinical trials, and manufacturing. To learn more about the TRLs above, see our report.
Footnotes
- Source: GAO-20-583SP
- Source: GAO-21-207
- Source: GAO-21-207
- Source: GAO-20-583SP
- Source: GAO-21-319
- Source: GAO-21-207
- Source: GAO-21-207
- Source: GAO-21-207
- Source: Biologics License Applications (BLA) Process (CBER) (FDA)
- Source: GAO-21-207
- Source: Emergency Use Authorization (FDA)
- Source: GAO-21-207
- Source: GAO-21-319