GRADING OF RECOMMENDATIONS, ASSESSMENT, DEVELOPMENT, AND EVALUATION (GRADE) FOR ACAM2000: A LICENSED SMALLPOX VACCINE FOR PERSONS AT RISK FOR ORTHOPOXVIRUS DISEASE Open Access

Abstract

Despite smallpox eradication, orthopoxviruses still remain at the forefront of public health concern, as the potential for acquiring orthopoxvirus disease still exists; whether naturally, through inadvertent laboratory exposure, or intentional release. Protection is best achieved through vaccination with a vaccinia virus vaccine. In the United States (U.S.), the Advisory Committee on Immunization Practices (ACIP) is tasked with developing and providing expert written guidance on the use of vaccines and vaccine-related agents, approved by the Food and Drug Administration (FDA), for control of vaccine-preventable diseases in the U.S. civilian population. In 2008, ACAM2000 replaced Dryvax as the only FDA licensed and approved smallpox vaccine available for use in the U.S. for protection against orthopoxvirus disease. Despite ACAM2000 having been widely used since 2008, ACIP smallpox vaccination recommendations have not been updated since 2003. As the current recommendations are out of date, the need for development of new ACIP smallpox vaccination recommendations is paramount.

The purpose of this study was to utilize the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) approach to determine the evidence type (quality) for ACAM2000 within the context of the policy question considered by the ACIP Smallpox Vaccine Workgroup: "Should ACAM2000 be recommended routinely for persons at risk for Orthopoxvirus disease?" Critical outcomes were determined through a modified Delphi analysis, and a systematic review of literature was conducted. Data from five randomized controlled trials were pooled using meta-analysis. Pooled risk ratios for cutaneous response and mild adverse events (MAE) outcomes indicated there was no difference in these outcomes occurring in individuals vaccinated with ACAM2000 or Dryvax. Serious adverse events (SAE) and myo/pericarditis resolved with sequelae were each less likely to occur in those vaccinated with ACAM2000, while myo/pericarditis resolved without sequelae was more likely to occur among individuals vaccinated with ACAM2000. Using GRADE, the overall evidence quality across all critical outcomes was determined to be of moderate quality. The results of this study will be made available to ACIP for final consideration, and will aid in forming U.S. policy regarding smallpox vaccinations for persons at risk for orthopoxvirus disease.

Table of Contents

CHAPTER 1: INTRODUCTION
Introduction and Rationale......................................................................1
Problem Statement.............................................................................. 2
Study Framework................................................................................ 3
Purpose Statement.............................................................................. 4
Significance Statement......................................................................... 4
Definition of Terms...............................................................................6

CHAPTER 2: REVIEW OF LITERATURE
Introduction.........................................................................................8
Review of Literature..............................................................................8
Summary of Current Problem and Study Relevance...................................14

CHAPTER 3: METHODOLOGY
Introduction........................................................................................16
Methods.............................................................................................16
Data Analysis......................................................................................20
Study Limitations and Delimitations.........................................................21

CHAPTER 4: RESULTS
Introduction.........................................................................................22
Findings............................................................................................. 22
Summary........................................................................................... 33

CHAPTER 5: CONCLUSIONS, IMPLICATIONS, AND RECOMMENDATIONS
Introduction.........................................................................................35
Summary of Study................................................................................35
Conclusions..........................................................................................37
Implications and Recommendations..........................................................38

REFERENCES.......................................................................................42

APPENDICES
Appendix A: Rating of Outcome Measures..................................................44
Appendix B: Literature Review Search Criteria............................................45
Appendix C: Assessment of Risk of Bias for Randomized Controlled Trials.......46
Appendix D: Determining Evidence Type....................................................47
Appendix E: Reported Rates of Serious Adverse Events................................48
Appendix F: Estimate Effects - Forest Plots.................................................49

LIST OF FIGURES AND TABLES
Figure 1: Systematic Review Approach......................................................18
Table 1: Rating of Outcome Measures........................................................23
Table 2: Characteristics of Selected Studies................................................25
Table 3: Evidence Table for Critical Outcomes: Benefits................................27
Table 4: Evidence Table for Critical Outcomes: Harms..................................29
Table 5: Summary of Findings Table: Evidence Type (Quality) for ACAM2000....32

About this Master's Thesis

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School	Rollins School of Public Health
Department	Career Masters of Public Health
Degree	MPH
Submission	Master's Thesis
Language	English
Research Field	Health Sciences, Public Health Biology, Virology
Keyword	ACAM2000 GRADE Smallpox Vaccination ACIP
Committee Chair / Thesis Advisor	O'Connor, Jean, Emory University
Committee Members	Petersen, Brett W. , Centers for Disease Control and Prevention
Partnering Agencies	CDC

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