A grading system for local skin reactions developed for clinical trials of an intradermal and transcutaneous ETEC vaccine
Introduction
Early-phase clinical trials of vaccine candidates focus on safety and immunogenicity evaluation, and are an essential step in the evaluation, refinement, and regulatory review of novel vaccine components prior to expanded clinical development. Of utmost importance at early-stage vaccine development is a detailed assessment of product safety and reactogenicity, which are commonly assessed based on the objective documentation of local and systemic adverse events. Specifically, vaccine routes which exploit the unique immune mediators present in superficial skin layers are increasingly being tested but are commonly associated with cutaneous vaccine site reactions. In recent years, various skin-vaccination approaches have been utilized, to include microneedles, topical application with and without skin pre-treatment, investigator-injection into the subcutaneous or intra-dermal space, and others. Local cutaneous vaccine site reactions have been commonly reported with these vaccine approaches. Herein, we describe a grading scale developed to objectively evaluate local cutaneous reactions. The scale was crafted ahead of early-phase evaluation of prototype enterotoxigenic Escherichia coli (ETEC) vaccines based on the adhesin antigen CfaE, administered with and without mutant heat-labile toxin LTR192G (mLT).
Intradermal (ID) vaccination presents vaccine antigens to tissues densely populated by dendritic cells, macrophages, and other antigen presenting cells, and in some instances have demonstrated dose-sparing effects [1], [2], [3]. Several existing vaccines have been, or are now being evaluated by the ID route while selected vaccines in development are being preferentially evaluated for use by the route. Vaccines now considered candidates for intradermal administration include rabies, viral hepatitis and influenza among others [2], [4], [5], [6], [7], [8], [9].
The transcutaneous vaccine route also takes advantage of similar cutaneous immune effector pathways and has been evaluated as a potentially viable option for delivery of enteric vaccines. Some antigens, such as the ETEC heat-labile toxin (LT) and its derivatives, when delivered at mucosal sites via nasal or enteric approaches, are limited due to concerns over neurologic or gastrointestinal toxicity and reactogenicity whereas the transcutaneous route has been found to be a tolerable and effective means to induce immune responses with these antigens [10], [11], [12].
Both the transcutaneous and the intradermal vaccination routes commonly result in a visible range of local vaccine site reactions, sometimes at higher rates than with other common routes (i.e.- intramuscular) [4]. Current regulatory requirements mandate the characterization of the severity of vaccine-related (and unrelated) adverse events using a grading system based on degree of impact of functional activity, (1: Mild; 2: Moderate; 3: Severe; 4: Life-threatening). However, sole use of such disability grading fail to fully characterize the full spectrum of vaccine site cutaneous reactions commonly observed and may limit comparison of safety and acceptability profiles across products, doses and routes. In 2005, the US Food and Drug Administration (FDA) issued general guidelines for the characterization and severity grading of cutaneous and other adverse reactions in vaccine trials but these are limited by only a narrow scope of cutaneous signs and symptoms (erythema and swelling) and use arbitrary dimensions to assign a severity grade [13]. The FDA guidance, while adequate for the assessment of intramuscular vaccinations, may lack the necessary specificity to describe the range local cutaneous adverse reactions seen after cutaneous vaccination.
Skin and toxicity grading scales also have been developed for the evaluation of external beam radiation therapy as well as drugs with recognized skin toxicity (epidermal growth factors and tyrosine kinase inhibitors); however, scales developed for assessing reactogenicity in vaccine clinical trials remain limited [14], [15], [16], [17]. A wide variety of skin reactions to vaccines have been described [18]. Although there have been efforts to develop standardized criteria to classify and report on local vaccine reactions, they remain complex [19].
In order to develop a simpler method, and one tailored to the common vaccine site reaction types we would be likely to have to evaluate, we formed a working group of clinicians, vaccinologists and dermatologists to develop and refine a more comprehensive Vaccine Site Appearance Grading Scale (VSAGS) to be used in the characterization of local cutaneous vaccine site reactions associated with transcutaneous and intradermal vaccine administration. The resulting scale was incorporated into the clinical assessment of the reactogenicity of ongoing candidate ETEC vaccines, was low-cost, and easy to implement during clinical trial activites.
The work described herein was conducted at the Naval Medical Research Center (NMRC) in Silver Spring, MD. The primary mission for NMRC is the Research and Development of medical countermeasures and diagnostics to support Department of Defense operational requirements. One of NMRCs infectious disease efforts has been discovery, development, and collaboration towards vaccine candidates against diarrheagenic ETEC disease, and in recent years culminated development of on a fimbrial-adhesin subunit approach [20]. The fimbrial approach relies on prototype vaccines which combine an LT-toxin component (in the form of a single-mutant modified LT; mLT) with selected colonization factor antigens (CFs) to attain broad coverage of circulating ETEC strains [21].
In terms of ETEC antigens, the cutaneous vaccination route has been demonstrated to be immunogenic and protective against enteric disease; in a single large field trial of a heat-labile toxin (LT) based patch vaccine, vaccination was protective against travelers’ diarrhea due to ETEC strains expressing LT toxin without ST (heat-stable toxin) [22].To date, trials of these antigens have demonstrated immunogenicity in animals when administered by mucosal and parenteral routes, as well as in humans by the transcutaneous and transdermal route [21], [23], [24], [25], [26]. Concurrent with the start of human clinical evaluation of the fimbrial antigens, the need to standardize the description and characterization of local cutaneous site reactions after transcutaneous and intradermal vaccination led to the development of a methodology to systematically categorize vaccine site reactions.
Section snippets
Methods
Ahead of protocol development for the planned human trials in 2012, we reviewed the published literature describing the range of common local adverse events associated, transcutaneous, intradermal and other skin vaccination approaches. Searches of MEDLINE and EMBASE were conducted for early-phase human clinical trials among healthy adults published through 2012. MEDLINE searches utilized major medical subject headings (MeSH) as well. Manual review of the bibliographies of available articles was
Cutaneous adverse events after transcutaneous and intradermal vaccination
Methodology for transcutaneous vaccination varied across studies reviewed (Table 1) and included patch techniques with different skin preparations (i.e. - abrasion, shaving and/or the use of specialized patch devices). Skin preparation in itself has been associated with various degrees of local cutaneous adverse events independent of the vaccine product and been described [27]. For example, a hydrogel patch, not containing vaccine product, was noted to be associated with mild erythema which the
Design and use of a vaccine site reaction grading scale (VSAGS)
The grading scale was developed for use on a series of human trials of ETEC subunit vaccines administered with and without mLT, in order to compare rates of cutaneous adverse events and their appearance/acceptability, across a variety of dose levels and administration techniques. Clinicians were trained to approach the characterization of each local vaccine site adverse event in a two-step fashion. Our proposed methodology entails a two-step evaluation of cutaneous adverse events. Firstly,
Conclusions
Transcutaneous and intradermal vaccination strategies are associated with adverse event profiles including a variety of cutaneous manifestations. Existing adverse event grading systems are insufficient in differentiating subtle distinctions of skin reactogenicity needed for detailed characterization. Standardized systems for grading and scoring the full range of local signs and symptoms are needed in order to make adequate comparisons between vaccine candidates, routes of administration, and
Disclaimer
The opinions and assertions herein should not be construed as official or representing the views of the Department of the Navy, Department of the Army, Department of Defense, or the US Government. This is a US Government work. There are no restrictions on its use. There were no financial conflicts of interests among any of the authors.
Copyright Statement
The authors are either employees of the U.S. Government or military service members. This work was prepared as part of official duties. Title 17 U.S.C. §105 provides that ‘Copyright protection under this title is not available for any work of the United States Government.’ Title 17 U.S.C. §101 defines a U.S. Government work as a work prepared by a military service member or employee of the U.S. Government as part of that person’s official duties.
CRediT authorship contribution statement
Ramiro L. Gutiérrez: Conceptualization, Methodology, Writing - original draft, Visualization, Investigation, Writing - review & editing. Chad K. Porter: Conceptualization, Methodology, Writing - original draft, Visualization, Investigation, Writing - review & editing. Abel Jarell: Conceptualization, Methodology, Visualization, Investigation, Writing - review & editing. Ashley Alcala: Conceptualization, Methodology, Visualization, Investigation, Writing - review & editing. Mark S. Riddle:
Declaration of Competing Interest
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
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Proposing a standardized assessment of COVID-19 vaccine-associated cutaneous reactions
2023, Journal of the American Academy of DermatologyA first in human clinical trial assessing the safety and immunogenicity of transcutaneously delivered enterotoxigenic Escherichia coli fimbrial tip adhesin with heat-labile enterotoxin with mutation R192G
2020, VaccineCitation Excerpt :The severity of self-reported symptoms (adverse events) was recorded according to the following grading scale: absent, mild (does not interfere with routine activities, moderate (interferes with daily activities), severe (prevents routine activities) and serious (potentially life-threatening). In addition to subject self-report of site reactions, standardized physical examinations with visualization of the vaccine site were conducted by trained physicians using a standardized vaccine site assessment grading scale [19]. Examinations included an assessment for Tegaderm® reaction, erythema, papules, dyspigmentation, edema, ulceration, and erosion and dimensions were recorded and graded with a specific six point scale ranging from absent to marked.
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