Need for developing case definitions and guidelines for adverse events following exposure to vaccinia virus:
Following a declaration by The World Health Assembly in 1980 on the worldwide eradication of smallpox [1], comprehensive smallpox vaccination programs around the world were stopped. Today, >50% of the world’s population is potentially unprotected against smallpox disease [2]. Recent warnings about the possible threat of using smallpox virus as a biologic weapon [3], [4] prompted a resurgence of public health vaccination programs against smallpox.
In this context, and in the broader context of a need for data comparability, as discussed in the overview paper in this volume, establishing criteria for assessing adverse events following smallpox (vaccinia) vaccination is important for clinicians administering the smallpox vaccine and appropriately treating patients with adverse events following immunization (AEFI), and also for scientists collecting, analyzing, and communicating data on AEFI. Understanding the normal changes and progression of a successful vaccination site is crucial for early recognition of complications. Based on two double-blind studies [5], [6], using different dilutions of smallpox vaccine in previously unimmunized adults, Frey et al. [6] noted the following descriptions about the vaccination sites (p. 1266):
“Success was defined by the presence of a primary vesicle at the inoculation site 7–9 days after scarification. Other signs and symptoms of the replication of vaccinia virus include edema, tenderness, and erythema at the site of vaccination and regional lymphadenopathy. Subsequently, the vesicle evolves into a small ulcer over which a scab forms [2nd week post-vaccination], ultimately leaving a small scar [3rd week post-vaccination]”.
Successful vaccination correlates with the laboratory demonstration of the development of a cytotoxic T cell response, lymphocyte proliferation, neutralizing antibodies, and vaccinia virus-specific interferon-γ production. This combination of clinical and laboratory response to smallpox vaccination provides long term, and perhaps life-long immunity [7].
This paper lists, in sections two and three, respectively, the case definition and guidelines for data collection, analysis, and presentation that the Brighton Collaboration Vaccinia Virus Adverse Events Working Group has developed for the standardized collection and assessment of robust take (RT) following exposure to vaccinia virus, with applicability in study settings with different availability of resources and access to health care. Widespread use of this definition with its guidelines will enable data comparability and lead to a better understanding of this event.
1.2. Methods for the development of the case definition and guidelines for RT following exposure to vaccinia virus
Following the process described in the overview paper in this volume [8], a Brighton Collaboration Vaccinia Virus Adverse Events Working Group was formed in January 2003 with 32 members. Members volunteered for at least one of five different subgroups, each addressing one adverse event following exposure to vaccinia virus. The RT subgroup included eight members with clinical, public health or industry background. The member composition and results of the web-based survey completed by the reference group (discussed in the overview paper in this volume) with subsequent discussions in the working group can be viewed at: http://brightoncollaboration.org/internet/en/index/working_groups.html.
To guide decision-making for the case definition and guidelines, a literature search was performed by the coordinators and team lead for RT following smallpox vaccination using as search terms smallpox vaccine, smallpox, vaccinia, exanthema, adverse event, infection, secondary infection, robust primary and robust take, within Medline and PubMed databases from 1966 to 2003. From this list, relevant articles were reviewed. Relevant citations from the articles above were also obtained. Additionally, multiple general medical, pediatric and infectious disease text books were searched as were case definitions from the Centers for Disease Control and Prevention (CDC) (http://www.bt.cdc.gov/agent/smallpox/vaccination/clinicians.asp#ae) [9] the Advisory Committee on Immunization Practices [10], and reviews [11], [12], [13], [14] and references employed to develop these working definitions. References predating 1966 identified by working group participants were also included. A decision was made to limit the articles to those in the English language when few foreign publications were found. Data (unpublished) from the Department of Defense immunization program and the United States Vaccine Adverse Event Reporting System were also reviewed. We did not initiate additional literature searches through our usual contact at the Cochrane Collaboration, because it was felt that the extensive search conducted by CDC and by this working group, in conjunction with the substantial input of scientists who generated much of the data from the 1960s and 1970s, was sufficiently comprehensive for our task. Few articles dealt specifically with robust takes, although several included discussions of the range of reactions following smallpox vaccination that are expected. Particular attention was paid to recent clinical trials of smallpox vaccine as they contained detailed descriptions of the expected reaction size after vaccination. Each article was summarized to include information on the type of study and a description of the event thought to have been a RT. Because of the scarcity of published literature addressing vaccinia virus AEFI case definitions and guidelines, this working group relied particularly heavily on consultations with experts for selected criteria during the development of the document and for an overall review of the final draft.
