Evaluation of anthrax vaccine safety in 18 to 20 year olds: A first step towards age de-escalation studies in adolescents☆
Introduction
Bioterrorist attacks using spores derived from Bacillus anthracis have been identified as a high priority threat by the United States (US) Department of Homeland Security [1]. This issue was highlighted by bioterrorism-related cases of anthrax illnesses after envelopes containing spores of this organism were sent through the US mail [2]. Accordingly, the US Department of Health and Human Services (HHS) has been charged to address preparedness for such attacks. This preparedness includes providing guidance on the use of post-exposure prophylaxis (PEP) using anthrax vaccine and antibiotics [2]. Anthrax Vaccine Adsorbed (AVA, BioThrax®) manufactured by Emergent BioSolutions Incorporated, was licensed in the US in 1970 for prevention of anthrax in adults aged 18 to 65 years. However, children and pregnant women are special populations for its use [3], [4]. AVA is prepared from sterile culture filtrates of the toxigenic, nonencapsulated B. anthracis V770-NP1-R grown in a protein-free medium. The final product formulation contains aluminum hydroxide, sodium chloride, benzethonium chloride and formaldehyde [3]. The primary immunogen in AVA is anthrax toxin protective antigen (PA). Anti-PA IgG antibodies are considered to protect against anthrax by neutralizing the B. anthracis toxins, inhibiting spore germination, and enhancing phagocytosis and killing of spores by macrophages [5], [6], [7], [8], [9], [10], [11], [12], [13].
The current US Advisory Committee on Immunization Practices recommendation for PEP use of AVA is subcutaneous (SC) administration of three doses at 0, 2 and 4 weeks to be initiated within 10 days following an anthrax event [14]. The safety profile of AVA in adults 18–65 years of age is well established [15], [16], [17], [18], [19], [20], [21], [22]. There is however, a paucity of data on AVA safety and immunogenicity in special populations, and none in children [23].
In 2011, a HHS interagency tabletop exercise, designated Dark Zephyr, was conducted to simulate an anthrax emergency [24]. During this exercise, it was estimated that up to 7.6 million people, of which approximately 25% would be children, could be exposed to B. anthracis spores [24]. If such a large-scale event actually happened, the absence of safety and immunogenicity data of AVA in pediatrics may result in concerns about the administration of this vaccine to individuals less than 18 years of age, a situation that could possibly deny children a potentially life-saving prophylactic countermeasure.
During the fall of 2011, the National Biodefense Science Board, now known as the National Preparedness and Response Science Board (NPRSB) was charged with assessing challenges in the use of AVA in the pediatric population in case of a large-scale anthrax emergency [24]. The NPRSB recognized that, in case of mass exposure of a population to B. anthracis spores, a FDA approved research investigational new drug protocol would allow the administration of AVA to children using a PEP regimen. However, this effort would require a research team to collect safety and immunogenicity data from these children after each AVA dose during this mass vaccination event. Consequently, the NPRSB noted that this type of post-event evaluation would pose major challenges to first responders, parents and research personnel in terms of mass vaccination of children during a large-scale anthrax spore exposure. Therefore, the NPRSB panel concluded that “HHS should develop a plan for and conduct a pre-event study of AVA in children, to include a research IND. HHS should submit a study protocol to one or more institutional review boards, and comply with the 21 CFR 50.54/45, CFR 46.407 federal review process.” [24].
In response to the NPRSB report, the Secretary of HHS requested that the Chair of the Presidential Commission for the Study of Bioethical Issues convene a panel to review the ethical considerations of conducting clinical research studies of medical countermeasures in children. The Secretary went further to ask this panel to specifically include the ethics of conducting a pre-event AVA study in children. The Commission held four public forum meetings that addressed this issue directly and a summary report was issued on March of 2013 [25]. In that report, the Presidential Commission referred to the Code of Federal Regulations (CFR) regarding protections for children involved in research [26].
First, the Commission indicated that pre-event AVA studies could not be conducted in children in the US under 45 CFR 46.405, which specifies that studies above minimal risk require the possibility of direct benefit to the participating child. Second, pediatric studies may be possible using 45 CFR 46.407, which stipulates that a rarely utilized Presidential waiver could be sought if the information gained could possibly benefit children in general even if the study might not benefit the individual child. Finally, the Commission suggested a unique approach that would render a pre-event AVA study to “no more than a minor increase over minimum risk” by using a stepwise, age de-escalation approach. Specifically, the Commission suggested that a pre-event study of individuals 18 to 20 years of age might provide information to substantiate that such a study in 16 to 17 year-olds would involve no more than minimal risk. Consequently, the Commission indicated, with important caveats, that an age de-escalation pathway might be considered under the 45 CFR 46.404, as it poses no more than minimal risk.
In light of this Presidential Commission's unique alternative pathway suggestion, we implemented a retrospective study with an exploratory objective to describe and compare safety and immunogenicity data from healthy individuals aged 18 to 20 years to the same type of data in individuals aged 21 to 29 years who participated in several HHS-sponsored AVA clinical trials. For this study the ‘older’ age group of 21 to 29 years, albeit somewhat arbitrary, was chosen as the most appropriate age group to compare safety and immunogenicity data to the 18 to 20 year old group for several reasons. First, including data from subjects up to age 65 years would result in a markedly larger and very unbalanced sample size compared to the 18 to 20 year old group. Also, previous data has shown a decrease in antibody responses to AVA as age increases in ten year increments from 18 to 65 year olds [27]. Finally, injection site reactions to AVA significantly decrease with advancing age [20].
Section snippets
Retrospective studies utilized
This investigation consisted of an exploratory summary reanalysis of existing electronically stored databases from final clinical study reports from four previous HHS-funded studies involving AVA conducted by the US Centers for Disease Control and Prevention (CDC) or funded by Biomedical Advanced Research and Development Authority (BARDA) that took place since the year 2000. Study AVA000, sponsored by CDC, had study arms that involved different AVA intramuscular (IM) or subcutaneous (SC) dosing
Results
For all four studies combined there were 74 subjects 18 to 20 years of age and 243 subjects 21 through 29 years of age (Table 1). Table 1 also illustrates the demographics of subjects enrolled in each of the studies. When all study groups were combined, there were no significant differences in demographic characteristics of age, race or gender between the two age categories.
Table 2 shows the proportion of subjects in each age group who experienced any grade 1 to 3, or any maximum grade 3
Discussion
AVA appeared tolerable in both age groups in the present study, with few maximum grade 3 elicited AEs and no SAEs attributable to AVA observed in subjects that received AVA at 0, 2 or 4 weeks. Overall, the 18 to 20 year olds had similar rates of local and systemic AEs compared to the 21 to 29 year age group.
It is important to note that the overall proportions of elicited local and systemic AEs were similar to those reported for other vaccines, including diphtheria-tetanus-acellular pertussis
Funding sources
Studies utilized in this Special Article were funded by:
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Centers for Disease Control and Prevention.
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Health and Human Services contract number: HHS100200700037C.
Financial disclosure
The authors have indicated they have no financial relationships relevant to this article to disclose
Contributors’ statement
Drs. James King and Eric Espeland conceptualized and designed the study, drafted the initial manuscript and approved the final manuscript as submitted.
Dr. Yonghong Gao created and wrote the statistical analyses plan at the inception, performed the analyses reported in the manuscript, reviewed and revised the manuscript and approved the final manuscript as submitted.
Drs. Conrad P. Quinn and Thomas M. Dreier were the primary subject matter experts on anthrax and anthrax vaccines, provided
Conflict of interest statement
The authors also do not have any conflict of interest to disclose.
Acknowledgements
We appreciate the input of Drs. Robin Robinson, Richard Hatchett, Gary Disbrow, Jo Ellen Schweinle, and Carol Linden from BARDA as well as Drs. Leonard Mayer, Stephen Hadler, Michael McNeil, Charles E. Rose and Ms. Stacey Martin, MSc and Jarad Schiffer, MS from the CDC for their assistance and review of the manuscript.
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The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Health and Human Services/Assistant Secretary for Preparedness and Response/Biomedical Advanced Research and Development Authority or the Centers for Disease Control and Prevention. None of the authors had any conflicts of interest with this manuscript or the topic therein.