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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.

Illustration of medical workers developing a vaccine.
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.

The Process for mRNA Vaccines Generating Antibodies to Protect Individuals from 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-21-319

Replication-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.

The Process for Replication-defective Live-vector Vaccines Generating Antibodies to Protect Individuals from 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-21-319

Recombinant-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.

The Process for Recombinant-subunit-adjuvanted Protein Vaccines Generating Antibodies to Protect Individuals from 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-21-319

Examining 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

Traditional Vaccine Timeline. Duration: Approximately 10 years or longer. Phases include: Exploratory, Preclinical, Clinical Trials (Phase 1, Phase 2, Phase 3), Large-scale Manufacturing, FDA Review and Licensure
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-21-319

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.

Note10: The development process for a vaccine candidate can be terminated at any stage for various reasons including the detection of serious adverse events11. In addition, FDA may allow, in an emergency, the use of unlicensed vaccines through emergency use authorizations (EUA), if there is evidence that the vaccine may be effective and that known and potential benefits outweigh known and potential risks, among other statutory criteria.12

Potential Operation Warp Speed Timelinec

Potential Operation Warp Speed Timeline. Approximately 10 months to Clinical trials and Manufacturing phases (as of November 2020). Phases include: Exploratory & Preclinical (January 2020), Clinical Trials (Phase 1, Phase 2, Phase 3: Potential for FDA Authorization for Emergency Use), Large-scale Manufacturing, FDA Review and Licensure
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-21-319

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

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

  1. Source: GAO-20-583SP
  2. Source: GAO-21-207
  3. Source: GAO-21-207
  4. Source: GAO-20-583SP
  5. Source: GAO-21-319
  6. Source: GAO-21-207
  7. Source: GAO-21-207
  8. Source: GAO-21-207
  9. Source: Biologics License Applications (BLA) Process (CBER) (FDA)
  10. Source: GAO-21-207
  11. Source: Emergency Use Authorization (FDA)
  12. Source: GAO-21-207
  13. Source: GAO-21-319