Selected Major Issues in Vaccine Safety

Recent examples of the major public health benefits of vaccination include global reductions in measles mortality and record low levels of vaccine-preventable diseases in the United States. Nevertheless, real or perceived vaccine safety issues may adversely impact vaccine programs. Robust postlicensure safety monitoring which combines active and passive surveillance with use of standardized case definitions for adverse events is the scientific basis for assessing safety concerns. Emerging aspects of vaccine safety science include clinical research networks and vaccine risk communication research. Current high-profile safety issues include the introduction of 2 second-generation rotavirus vaccines, for which close monitoring of intussusception is necessary. To date, data from the US do not indicate an elevated risk associated with the licensed Merck vaccine (Rotateq ). An issue of global interest is the use of thimerosal as a preservative in multi-dose vaccine vials. Comprehensive independent reviews as well as recently published research have reaffirmed the lack of association between thimerosal and neurodevelopmental disorders, including autism. Expanded use of annual influenza vaccine and pandemic planning in the developed or developing world should include plans for safety monitoring. As the number of newly licensed vaccines increases, potentially preventable vaccine administration erJohn Iskander, MD, MPH Acting Director, Immunization Safety Office, Office of the Chief Science Officer Centers for Disease Control and Prevention 1600 Clifton Road MS D-26, Atlanta, GA 30333 (USA) Tel. +1 404 639 8889, Fax +1 404 639 8834, E-Mail [email protected] © 2008 Nestec Ltd., Vevey/S. Karger AG, Basel 0517–8606/08/0662–0093$24.50/0 Accessible online at: www.karger.com/ane Iskander /Gidudu /Arboleda /Huang Ann Nestlé [Engl] 2008;66:93–102 94 duction initiative using measles-containing vaccine as a central tool has exceeded its target goals [11] . Vaccination programs may have additional benefits to those not targeted for vaccination as demonstrated by decreased carriage of pneumococcus and subsequent decreased disease levels in age groups not targeted for vaccination [12] . ‘Lifecycle’ of Vaccine Safety Concerns Maximizing the benefits of vaccines requires relatively high and sustained coverage (uptake) levels, so that herd immunity thresholds are achieved and susceptible individuals do not accumulate [13, 14] . Paradoxically, it is just when vaccine benefits are most apparent and vaccine coverage is highest that vaccine safety concerns are most likely to arise in the consciousness of the general public and the media [15] . These concerns may arise partly because patients, parents and health care providers no longer have any first-hand experience with vaccine-preventable diseases. Thus, it is often said that vaccines are the victims of their own success. A pattern that has been observed in several countries, including Japan, the United Kingdom (UK) and Nigeria, where loss of public confidence in vaccines was followed by decreased coverage leading to outbreaks of vaccine-preventable diseases, often with considerable morbidity and mortality [16] . It is only after such first-hand experiences that confidence in vaccination resumes and coverage rebounds. This article describes a proactive strategy to monitor vaccine safety on an ongoing basis in order to maintain both the public and health care provider confidence in the safety of vaccines. Because of the global scope of vaccines and vaccination programs, this review will discuss overall considerations for monitoring vaccine safety and will highlight several key issues as case examples. A comprehensive review of all issues related to vaccine safety methodologies and specific issues under study is beyond the scope of this paper. Similarly, although monitoring of safety within vaccine clinical trials is crucial, this review will not address pre-licensure study of safety in detail. Information resources, including websites, which provide updated information on newly emerging issues in vaccine safety will be highlighted. Post-Licensure Safety Surveillance The primary rationale for closely monitoring the safety of newly licensed vaccines and newly introduced vaccine programs is that clinical trials do not have the power to detect rare vaccine adverse events. Even the very largest trials [17–19] which have enrolled up to 70,000 participants cannot detect vaccine adverse events rarer than 1 in 10,000 vaccinees. Although rare side effects may halt vaccination programs on occasion [20, 21] , providers should understand that some commonly used vaccines have demonstrated rare and potentially serious side effects; in these instances, policymaking bodies have judged that the individual and community benefits of vaccination outweigh the risks. For instance, measles-containing vaccines which have played a key role in measles mortality reduction are associated with thrombocytopenia (which is self-limited and uncomplicated) in approximately 1 in 30,000 vaccinees [22] . As with any medical product, safety considerations for vaccines should be rigorously scientifically assessed; however, policy decisions must take into account both documented benefits and risks. In some instances, adverse reactions to vaccines may be so rare that they only emerge after extensive post-licensure use. The association of myopericarditis with the NYC BOH strain of smallpox vaccine in approximately 1 per 10,000 vaccinees was discovered long after global smallpox eradication was achieved, when the US undertook military and civilian smallpox vaccination programs in 2003 as part of bioterrorism preparedness activities [23] . This was due partly to the rareness of the finding but also because of the much more active safety monitoring measures undertaken in the absence of wild disease [21] . Another key reason for post-licensure monitoring is that trials, regardless of their size, may exclude certain populations [24] such as persons with underlying medical conditions or premature infants. Because vaccination recommendations, particularly for children, are often universal, the public health community has a duty to ensure the safety of new vaccines under actual conditions of everyday use and practice among diverse patient populations. Like other licensed medical products, vaccines may be subject to use outside of FDA-recommended age or risk group indications. This is referred to as ‘off-label’ use; monitoring off-label vaccine usage can be an important aspect of safety monitoring [25] .