Skip to main content

Main menu

  • Home
  • Content
    • Current
    • Archive
    • Upcoming Scientific Articles
  • Info for
    • Authors
    • Reviewers
    • Advertisers
    • Subscribers
  • About Us
    • About the North Carolina Medical Journal
    • Editorial Board
  • More
    • Alerts
    • Feedback
    • Help
    • RSS
  • Other Publications
    • North Carolina Medical Journal

User menu

  • My alerts
  • Log in

Search

  • Advanced search
North Carolina Medical Journal
  • Other Publications
    • North Carolina Medical Journal
  • My alerts
  • Log in
North Carolina Medical Journal

Advanced Search

  • Home
  • Content
    • Current
    • Archive
    • Upcoming Scientific Articles
  • Info for
    • Authors
    • Reviewers
    • Advertisers
    • Subscribers
  • About Us
    • About the North Carolina Medical Journal
    • Editorial Board
  • More
    • Alerts
    • Feedback
    • Help
    • RSS
  • Follow ncmj on Twitter
  • Visit ncmj on Facebook
Research ArticleINVITED COMMENTARIES AND SIDEBARS

Vaccine Development: Steps to Approval of an Investigational Vaccine

Emmanuel B. Walter and M. Anthony Moody
North Carolina Medical Journal March 2021, 82 (2) 141-144; DOI: https://doi.org/10.18043/ncm.82.2.141
Emmanuel B. Walter
Professor, Department of Pediatrics and chief medical officer, Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • For correspondence: chip.walter@duke.edu
M. Anthony Moody
Associate professor, Department of Pediatrics and research quality officer, Duke Human Vaccine Institute, Duke University School of Medicine, Durham, North Carolina.
  • Find this author on Google Scholar
  • Find this author on PubMed
  • Search for this author on this site
  • Article
  • Figures & Data
  • References
  • Info & Metrics
  • PDF
Loading

Development and licensure of a vaccine is a complex and highly regulated process starting with preclinical development and continuing with three phases of clinical investigation. Ensuring a safe, potent, and effective vaccine is of paramount importance. Following approval, vaccine safety is ensured through multiple well-established mechanisms.

Introduction

During the last century, vaccines were declared among the 10 great public health achievements, highlighted by the eradication of smallpox, elimination of the central nervous system virus poliomyelitis in the Americas, and improved control of other infectious diseases such as measles [1]. The first decades of the current century saw the development of new vaccines to combat rotavirus, human papillomavirus, and herpes zoster. Improved polysaccharide-protein conjugate vaccines for Streptococcus pneumoniae and Neisseria meningitidis were also produced. Novel adjuvants were added to some vaccines with the goal of enhancing the body’s immune response. To reduce the “shot burden” on children, numerous combination vaccines were developed, facilitating administration of multiple vaccine antigens in a single syringe. In addition, vaccines to combat influenza were further advanced, including a live attenuated intranasal vaccine, a high-dose vaccine for older adults, and influenza vaccines manufactured using novel technologies. During their development, each new vaccine underwent rigorous testing, and on average took 8 to 17 years from the time of conceptualization to approval [2]. Herein, we describe steps in the development of a vaccine.

Vaccine Candidate Development

Vaccine candidate development begins with the recognition of an infectious disease burden and the opportunity to prevent it through immunization. This can be facilitated by the identification of a protective response, usually found in persons who were infected, recovered, and were subsequently protected against reinfection. Basic science research takes this firm rationale for a new vaccine through the identification of antigens that can stimulate an immune response and leads to the development of a vaccine manufacture approach. These approaches include inactivated, live attenuated, subunit, viral vectored, and nucleic acid vaccine platforms. The approach used depends on a number of factors including the experience of the developer and the prospects for making a safe and effective vaccine for use in the target population.

In the United States, the development and approval process for a vaccine candidate is monitored by the Centers for Biologics Evaluation and Research (CBER) of the US Food and Drug Administration (FDA). Vaccines are unique as they are regulated as both a drug and as a biological product, or biologic. The FDA defines a drug as an article intended for use in the diagnosis, cure, mitigation, treatment, or prevention of disease [3]. Unlike drugs that are synthesized with a known chemical structure, biologics are complex mixtures composed of sugars, proteins, nucleic acids, or complex combinations of these substances, or they may be living entities such as cells and tissues [4]. Furthermore, as compared to drugs typically used to treat patients with diagnosed medical conditions, vaccines are given to large populations of healthy children and adults. Hence, to ensure safety, the development, approval, and post-approval process for vaccines is closely monitored and regulated.

Vaccine Candidate Approval Process

As required by Title 21 of the Code of Federal Regulations, approved and licensed vaccines must meet standards to ensure they are safe, pure, potent, and effective. In the state of North Carolina, per Chapter 130A of North Carolina’s General Statutes, only vaccine preparations that meet the standards of the FDA or its successor in licensing vaccines and are approved for use by the North Carolina Commission for Public Health may be used [5]. The initial step toward approval for a candidate vaccine is rigorous preclinical testing (Figure 1). Studies are conducted in animals to assess if there are any vaccine-induced toxicities that might preclude the vaccine from being administered to humans [6]. In particular, animal testing assesses reactions at the site of administration, as well as systemic reactions or laboratory abnormalities. Animal studies also evaluate whether a candidate vaccine induces an immune response and, if animal models for disease exist, test how well vaccinated animals resist disease when challenged with the offending pathogen. Results from animal studies are used to predict a safe starting dose for the first-in-human trials. In addition, reproductive and developmental toxicity studies are performed if the vaccine is targeted for use in pregnant women.

FIGURE 1.
  • Download figure
  • Open in new tab
  • Download powerpoint
FIGURE 1.

Steps from Concept through Approval of an Investigational Vaccine

If animal testing results are promising and a human clinical trial is planned, the vaccine developer and/or the sponsor must submit an investigational new drug (IND) application to the FDA. The IND describes the vaccine, its method of manufacture, and quality control tests for release [6]. Also included are preclinical data about the vaccine’s safety and ability to elicit a protective immune response in animal testing, as well as the proposed investigational plan, including a clinical protocol for human studies. The plan must clearly outline study endpoints for evaluation of the vaccine candidate.

Phased Testing

With FDA concurrence, a promising vaccine candidate generally proceeds through three successive phases of human trials (Table 1) [7]. Study phases may overlap, or in some cases multiple earlier phase trials may be needed, depending upon trial results. In each phase of investigation, human subject safety is considered of paramount importance. If at any time a vaccine is deemed unsafe, the pathway toward development is either terminated or the developmental course is significantly altered. Early phase vaccine investigations are commonly sponsored by academic investigators, small biotech companies, or the pharmaceutical industry. As investigations move along the developmental pathway, studies are more likely to be sponsored by larger pharmaceutical companies.

View this table:
  • View inline
  • View popup
TABLE 1.

Phases of Clinical Evaluation of an Investigational Vaccine

First-in-human testing of an investigational vaccine occurs in a Phase 1 study designed to assess whether it is safe, tolerable to the subject, and induces a satisfactory immune response. Phase 1 studies are small, including fewer than 100 subjects. Most Phase 1 studies are conducted in healthy adults even if adults are not the intended target population for the vaccine. These investigations frequently include a dose escalation study design in which the vaccine is tested at successively higher dosage levels, but only after the vaccine is deemed safe at the preceding lower doses. These studies provide early data on the side effect profile and immune response at different dose levels. Vaccine safety and tolerability are closely monitored in study participants and efforts are specifically targeted at identifying local and systemic side effects, monitoring clinical safety laboratory parameters, and following subjects for the occurrence of any unsolicited adverse events, serious adverse events, and adverse events of clinical interest.

Phase 2 investigations are typically larger and include several hundred participants from the target population for the vaccine. Phase 2 investigations further refine the optimal dosage and vaccination schedule. Like Phase 1 studies, these investigations assess both vaccine safety and immune response and may provide evidence of efficacy. In addition, the larger number of participants allows for better estimates of the proportions of individuals with common short-term side effects.

The last stage in the clinical development of a vaccine is a Phase 3 trial. These pivotal trials are used to make a final determination of the benefit versus risk of the vaccine upon which approval rests. These studies are designed to determine vaccine efficacy by measuring the occurrence of the disease of interest in persons randomized to either receive the vaccine or not. For diseases with which infection is infrequent and measuring vaccine efficacy is impractical, surrogate markers of vaccine efficacy may used. A surrogate marker is a measure of an immune response that from prior investigations has been established to correlate with protection [8]. Phase 3 investigations include several hundreds to tens of thousands of subjects. Like earlier-phase investigations, Phase 3 studies also monitor subject safety. Very large Phase 3 studies frequently include detailed assessments of vaccine side effects and immune response in defined substudy populations.

Late Phase 3 investigations also include evaluations of the consistency of investigational vaccine manufacture by comparing vaccine safety and immunogenicity (ability of an antigen to provoke an immune response) in subjects receiving the vaccine from different manufacturing lots. Frequently, studies are also designed to evaluate the effects of coadministrating the investigational vaccine with other approved vaccines that are likely to be given at the same time in clinical practice. These studies assess the safety of vaccine coadministration as well as the effect on the immune response of both the investigational and coadministered vaccine antigens.

Ultimately, sponsors may request permission to introduce a biologic product into interstate commerce by filing a Biologics License Application (BLA) with the FDA. A BLA includes applicant information, product and manufacturing information, preclinical and clinical study data, and proposed product labeling information [9]. The efficacy and safety data from the trials provide information for the FDA review team to make a risk/benefit assessment. The product label includes information to assist health care providers with understanding the vaccine’s proper use, including its potential benefits and risks. Simultaneously, the vaccine manufacturing plant undergoes a detailed inspection by the FDA to review the manufacturing process. After reviewing the BLA, the sponsor and the FDA may present their respective findings to the FDA’s Vaccines and Related Biological Products Advisory Committee (VRBPAC). This non-FDA expert committee provides advice regarding the safety and efficacy of the vaccine for the proposed indication and assists the FDA with its determination for approval of the vaccine. Under section 564 of the Federal Food, Drug, and Cosmetic Act, the FDA may also authorize unapproved use of a vaccine in the event of a public health emergency.

Distribution and Continued Evaluation

Once licensed by the FDA, the Centers for Disease Control and Prevention (CDC) Advisory Committee on Immunization Practices (ACIP) provides advice as to how a vaccine is to be used in the civilian US population [10]. The committee advises the CDC on population groups and/or circumstances in which a vaccine is indicated in addition to making recommendations on contraindications and precautions for use of the vaccine. When making recommendations, ACIP considers several factors, including the safety, immunogenicity, and effectiveness of the vaccine at different ages; the severity of the disease; the number of people who get the disease if there is no vaccine; and the feasibility of implementing potential recommendations. ACIP frequently initiates discussions regarding potential vaccine recommendations for new vaccines during the FDA approval process so that recommendations for use occur in a timely manner.

After approval and distribution in the population, vaccine safety continues to be monitored. Through the vaccine approval process, the FDA may require the sponsor to conduct post-marketing Phase 4 studies to continue to evaluate the vaccine’s safety, efficacy, or optimal use [11]. Additional commitments to maintain pharmacovigilence programs to assess the occurrence of adverse events of special interest, or to maintain a registry of women who receive the vaccine during pregnancy, may also be required. Vaccine manufacturers are also required to test each lot of a vaccine they produce to make sure it is safe, pure, and potent. Vaccine lots cannot be distributed until released by the FDA. Furthermore, the FDA continues to inspect manufacturing facilities every other year, and every year for those manufacturing influenza vaccines.

The safety of approved vaccine products is also monitored and studied through several well-established federally sponsored mechanisms [12]. The CDC and FDA co-manage the Vaccine Adverse Event Reporting System (VAERS), a passive reporting system for persons who experience adverse events following immunization (AEFI). VAERS is useful for detecting signals that might indicate a possible safety problem with a vaccine but is not useful for determining if a vaccine is causally related to an adverse event. In addition, the CDC’s Vaccine Safety Datalink (VSD) uses electronic health data from nine health care organizations throughout the United States to both monitor vaccine safety and conduct studies about rare and serious adverse events following immunization. These studies are able to determine whether side effects are related to vaccination. Similarly, the FDA’s Post-Licensure Rapid Immunization Safety Monitoring (PRISM) system links data from health plans with data from state and city immunization registries to identify and analyze rare health outcomes that would otherwise be difficult to assess. Lastly, the CDC’s Clinical Immunization Safety Assessment (CISA) project provides consultation on clinical vaccine safety issues in addition to conducting studies to identify risk factors and preventive strategies for AEFI, particularly in special populations.

In summary, the steps to FDA approval of a vaccine involve a regulated preclinical and clinical developmental process to assure its safety and efficacy. Once approved, numerous mechanisms are in place to ensure that a vaccine product remains safe, pure, and potent. Health care providers and the public should take comfort in the rigorous manner in which vaccine integrity is ensured.

Acknowledgments

Potential conflicts of interest. E.B.W. has served as an investigator for clinical trials funded by Moderna and Pfizer. M.A.M. reports no relevant conflicts of interest.

  • ©2021 by the North Carolina Institute of Medicine and The Duke Endowment. All rights reserved.

References

  1. 1.↵
    1. Centers for Disease Control and Prevention (CDC)
    . Ten great public health achievements—United States, 1900-1999. MMWR Morb Mortal Wkly Rep. 1999;48(12):241-243.
    OpenUrlPubMed
  2. 2.↵
    1. Kanesa-thasan N,
    2. Shaw A,
    3. Stoddard JJ,
    4. Vernon TM.
    Ensuring the optimal safety of licensed vaccines: A perspective of the vaccine research, development, and manufacturing companies. Pediatrics. 2011;127(suppl 1):S16-S22. doi: 10.1542/peds.2010-1722D
    OpenUrlAbstract/FREE Full Text
  3. 3.↵
    1. US Food and Drug Administration
    . Classification of Products as Drugs and Devices and Additional Product Classification Issues. FDA website. https://www.fda.gov/regulatory-information/search-fda-guidance-documents/classification-products-drugs-and-devices-and-additional-product-classification-issues#drug. Published September 2017. Accessed October 22, 2020.
  4. 4.↵
    1. US Food and Drug Administration
    . What Are “Biologics” Questions and Answers. https://www.fda.gov/about-fda/center-biologics-evaluation-and-research-cber/what-are-biologics-questions-and-answers. Published February 6, 2018. Accessed October 22, 2020.
  5. 5.↵
    Public Health: Immunization required, § 130A-152 (1957, 2007).
  6. 6.↵
    1. Marshall V,
    2. Baylor NW.
    Food and Drug Administration regulation and evaluation of vaccines. Pediatrics. 2011;127(suppl 1):S23-S30. doi: 10.1542/peds.2010-1722E
    OpenUrlAbstract/FREE Full Text
  7. 7.↵
    1. Preiss S,
    2. Garçon N,
    3. Cunningham AL,
    4. Strugnell R,
    5. Friedland LR.
    Vaccine provision: Delivering sustained & widespread use. Vaccine. 2016;34(52):6665-6671. doi: 10.1016/j.vaccine.2016.10.079
    OpenUrlCrossRef
  8. 8.↵
    1. Plotkin SA.
    Correlates of protection induced by vaccination. Clin Vaccine Immunol. 2010;17(7):1055-1065. doi: 10.1128/CVI.00131-10
    OpenUrlAbstract/FREE Full Text
  9. 9.↵
    1. US Food and Drug Administration
    . Biologics License Applications (BLA) Process (CBER). https://www.fda.gov/vaccines-blood-biologics/development-approval-process-cber/biologics-license-applications-bla-process-cber. Updated November 20, 2020. Accessed October 22, 2020.
  10. 10.↵
    1. Pickering LK,
    2. Meissner HC,
    3. Orenstein WA,
    4. Cohn AC.
    Principles of vaccine licensure, approval, and recommendations for use. Mayo Clin Proc. 2020;95(3):600-608. doi: 10.1016/j.mayocp.2019.11.002
    OpenUrlCrossRef
  11. 11.↵
    1. US Food and Drug Administration
    . Postmarketing Requirements and Commitments: Introduction. https://www.fda.gov/drugs/guidance-compliance-regulatory-information/postmarket-requirements-and-commitments. Published January 12, 2016. Accessed October 22, 2020.
  12. 12.↵
    1. US Department of Health & Human Services: Vaccines
    . Vaccine Safety. Vaccines.gov website. https://www.vaccines.gov/basics/safety. Updated February 2020. Accessed October 22, 2020.
PreviousNext
Back to top

In this issue

North Carolina Medical Journal: 82 (2)
North Carolina Medical Journal
Vol. 82, Issue 2
March-April 2021
  • Table of Contents
  • Index by author
Print
Download PDF
Email Article

Thank you for your interest in spreading the word on North Carolina Medical Journal.

NOTE: We only request your email address so that the person you are recommending the page to knows that you wanted them to see it, and that it is not junk mail. We do not capture any email address.

Enter multiple addresses on separate lines or separate them with commas.
Vaccine Development: Steps to Approval of an Investigational Vaccine
(Your Name) has sent you a message from North Carolina Medical Journal
(Your Name) thought you would like to see the North Carolina Medical Journal web site.
CAPTCHA
This question is for testing whether or not you are a human visitor and to prevent automated spam submissions.
4 + 5 =
Solve this simple math problem and enter the result. E.g. for 1+3, enter 4.
Citation Tools
Vaccine Development: Steps to Approval of an Investigational Vaccine
Emmanuel B. Walter, M. Anthony Moody
North Carolina Medical Journal Mar 2021, 82 (2) 141-144; DOI: 10.18043/ncm.82.2.141

Citation Manager Formats

  • BibTeX
  • Bookends
  • EasyBib
  • EndNote (tagged)
  • EndNote 8 (xml)
  • Medlars
  • Mendeley
  • Papers
  • RefWorks Tagged
  • Ref Manager
  • RIS
  • Zotero
Share
Vaccine Development: Steps to Approval of an Investigational Vaccine
Emmanuel B. Walter, M. Anthony Moody
North Carolina Medical Journal Mar 2021, 82 (2) 141-144; DOI: 10.18043/ncm.82.2.141
del.icio.us logo Digg logo Reddit logo Twitter logo Facebook logo Google logo Mendeley logo
  • Tweet Widget
  • Facebook Like
  • Google Plus One

Jump to section

  • Article
    • Introduction
    • Vaccine Candidate Development
    • Vaccine Candidate Approval Process
    • Phased Testing
    • Distribution and Continued Evaluation
    • Acknowledgments
    • References
  • Figures & Data
  • Info & Metrics
  • References
  • PDF

Related Articles

  • No related articles found.
  • PubMed
  • Google Scholar

Cited By...

  • Immunizing North Carolina
  • Google Scholar

More in this TOC Section

  • Sidebar: Community-driven Approaches to Preventing Overdoses Among American Indians
  • Sidebar: History Shaping the Future: How History Influences Health in North Carolina Native American Communities
  • Sidebar: Impact of Racial Misclassification of Health Data on American Indians in North Carolina
Show more INVITED COMMENTARIES AND SIDEBARS

Similar Articles

About & Contact

  • About the NCMJ
  • Editorial Board
  • Feedback

Info for

  • Advertisers
  • Authors
  • Reviewers
  • Subscribers

Articles & Alerts

  • Archive
  • Current Issue
  • Get Alerts
  • Upcoming Articles

Additional Content

  • Current NCIOM Task Forces
  • NC Health Data & Resources
  • NCIOM Blog
North Carolina Medical Journal

ISSN: 0029-2559

© 2022 North Carolina Medical Journal

Powered by HighWire