Vaccine safety: current systems and recent findingsMelinda WhartonIntroductionVaccines are a major public health achievement andwidespread use of vaccines has led to elimination ordramatic reductions in many diseases. The individualand societal benefits of immunization are great, in termsof prevention of morbidity and mortality, and high levelsof vaccine coverage benefit the community, withdecreased circulation of the disease-causing agents (herdor community immunity) and protection of those whocannot be vaccinated. Along with great benefits comegreat responsibilities to ensure that vaccines are as welltolerated as possible. Vaccines are routinely given tomillions of healthy children, and it is critical that systemsbe in place to detect and respond to possible vaccinesafety issues.In 2010, vaccines that prevent 16 diseases are recommendedfor routine use in children and adolescents [1],and additional vaccines are recommended for adults [2].Since 2005, new vaccines for prevention of pertussis inadolescents and adults have been licensed, along withnew rotavirus vaccines, a meningococcal conjugatevaccine, vaccines for prevention of human papillomavirus-related disease, new combination vaccines, and anew vaccine to prevent zoster in persons 60 years of ageand older. Additionally, during that same period, therehave been new recommendations to expand use of othervaccines, and in 2009, new recommendations were madefor the use of new vaccines for prevention of pandemicH1N1 influenza. With new recommendations for use ofso many new vaccines, as well as ongoing parental concernsabout vaccines and developmental disorders, it isimportant that immunization providers understand thesystem that monitors and responds to vaccine safety, aswell as the role they play in assuring the safety of vaccinesand immunization practice.Prelicensure assessment of vaccine safetyBefore vaccines are licensed for use in the United States,they undergo extensive testing and careful review toevaluate both efficacy and safety. Clinical trials are ofvarying size, but are generally not large enough forassessment of the potential for the vaccine to be associatedwith rare adverse events [3,4]. Regulatory authoritiesalso review manufacturing processes and inspect facilitiesto ensure compliance with current good manufacturingpractices.At the time of licensure, data are generally available onconcomitant use of the vaccine with other vaccinesNational Center for Immunization and RespiratoryDiseases, Centers for Disease Control and Prevention,Atlanta, Georgia, USACorrespondence to Melinda Wharton, MD, MPH,Deputy Director, National Center for Immunization andRespiratory Diseases, Centers for Disease Control andPrevention, 1600 Clifton Road, Mailstop E05, Atlanta,GA 30333, USATel: +1 404 639 8206; e-mail: mew2@cdc.govCurrent Opinion in Pediatrics 2010, 22:88–93Purpose of review

An understanding of vaccine safety is important for all immunization providers, who haveresponsibilities to identify, report, and prevent adverse events.Recent findingsNew analytic methods can provide more rapid information on adverse events comparedwith traditional observational studies. Some adverse events following vaccination arepreventable. Syncope is increasingly recognized postvaccination and may beassociated with severe injury or death. Both human and system factors should beaddressed to prevent vaccine administration errors. Ongoing basic science and clinicalresearch is critical to improved understanding of vaccine safety. A recent studysuggests that many cases of encephalopathy following whole-cell pertussis vaccinewere due to severe myoclonic epilepsy of infancy, a severe seizure disorder associatedwith mutations of the sodium channel gene SCN1A.SummaryVaccine safety requires prelicensure evaluation, postlicensure surveillance andinvestigation, addressing preventable adverse events, reconsideration of vaccine policyas understanding of risks and benefits changes, and ongoing research to betterunderstand the response to vaccination and the pathogenesis of adverse events.Keywordsimmunization, pharmacoepidemiology, postlicensure surveillance, vaccine safety,vaccinesCurr Opin Pediatr 22:88–93_ 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins1040-87031040-8703 _ 2010 Wolters Kluwer Health | Lippincott Williams & Wilkins DOI:10.1097/MOP.0b013e3283350425Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.recommended for use at the same age. These studies aredesigned to detect immunological interference betweenthe two vaccines and are of limited size, evaluatingsimultaneous administration of the new product withone specified set of other vaccines that are recommendedfor use at the same age.Postlicensure monitoring of vaccine safetyPrior to licensure, vaccines are used in thousands ofpeople in clinical trials; following licensure and once inroutine use, vaccines are used in millions of people, andadverse events that occur too infrequently to detect inprelicensure studies may be identified. Additionally,clinical trials are generally performed in healthy populationsand at protocol-specified ages and intervals; inactual use, vaccines are used in the general population,including those with underlying conditions and at agesand intervals that were not studied in the clinical trials. Inorder to assess the safety of the vaccine in the generalpopulation under conditions of routine use, postlicensuresurveillance is needed.In the United States, the Vaccine Adverse Event ReportingSystem (VAERS) is jointly managed by the Centersfor Disease Control and Prevention (CDC) and the Foodand Drug Administration (FDA). VAERS receivesreports from physicians, manufacturers, patients or theirfamilies, or anyone else who chooses to report a case.Additionally, the National Childhood Vaccine Injury Actof 1986 requires reporting of certain adverse events byhealthcare providers and manufacturers. Reporting ismandatory for any adverse event listed by the manufactureras a contraindication to further doses of vaccine orany adverse event listed in the Vaccine Injury Table thatoccurs within the specified period after vaccination(www.hrsa.gov/vaccinecompensation/table.htm). Providersand others reporting to VAERS need not be certainthat the adverse event is caused by the vaccine to report

it; one of the primary objectives of VAERS is to detectnew, unusual, or rare adverse events.Reports may be submitted by mail, telephone, fax, oronline (vaers.hhs.gov/esub/index). Once received, thereport is reviewed and the adverse event is classifiedusing the Medical Dictionary for Regulatory Activities(MedDRAs) codes. VAERS staff request medical recordson adverse events that result in hospitalization, disability,or death. Both FDA and CDC staff review VAERSreports, looking for unexpected patterns and specificadverse events of concern. Data-mining methods areused to identify patterns of disproportional reportingfor further investigation [5].Although VAERS provides important information, it isimportant to note that usually it cannot be determinedfrom either individual or groups of VAERS reportswhether or not a specific adverse event is caused by avaccine. There are a few exceptions; local reactions at thesite of vaccine administration or acute responses associatedwith vaccination (e.g., anaphylaxis or syncope) areconsidered vaccine-associated. If an individual developsa specific adverse event multiple times following vaccination(‘challenge–rechallenge’), causation is inferred.Additionally, adverse events associated with live vaccinesare often associated with replication of vaccine strains,and isolation of the vaccine strain can provide supportiveevidence of a causal role for the vaccine (see below).Analysis and interpretation of VAERS reports is complex[6]. Reports may not contain sufficient information, andespecially for complex clinical syndromes, coding may beinconsistent. VAERS only provides information on vaccinatedpersons who developed the adverse event, thuslimiting the ability to identify whether or not there is anassociation. VAERS is a passive surveillance system, andreporting is incomplete [7]. Some adverse events aremore likely to be reported than others – those that aresevere and are temporarily closely linked to vaccinationare more likely to be reported than other events. Reportingis also influenced by publicity and public awareness ofspecific vaccines and adverse events.In spite of these limitations, VAERS data do serve toidentify adverse events that warrant additional investigation.Most diagnoses of concern are not uniquelyassociated with vaccination and occur at some rate inthe population, apart from any additional cases that maybe associated with vaccination. If the rate of a condition inthe population (unrelated to vaccine use) is known (thebackground rate) and the number of doses of vaccineadministered can be estimated, then the number of casesof the condition that are expected to occur amongrecently vaccinated persons due to chance alone canbe calculated; these are cases that are not caused byvaccination but occur in recently vaccinated personsassuming that vaccine neither causes nor prevents thediagnosis. Although the number of doses of vaccineadministered may not be known, it can be estimatedwith the number of doses of vaccine distributed as anupper limit. The degree of underreporting to VAERS isalso unknown for specific diagnoses, and there may be

uncertainty as well about true background rates in differentpopulation groups. However, this approach can stillbe useful to help identify potential vaccine safety issuesthat require additional investigation. This approach wasused in 1999 when intussusception cases were reported toVAERS among recipients of a then recently licensedrotavirus vaccine [8] and more recently in evaluation ofcases of Guillain–Barre´ syndrome reported among recipientsof meningococcal conjugate vaccine [9]. The conceptis particularly important for the current H1N1Vaccine safety: current systems and recent findings Wharton 89Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.influenza vaccine effort, to facilitate interpretation andcommunication regarding adverse events that occur aftervaccination but may or may not be caused by vaccination[10_].Evaluation of potential vaccine safetyconcernsIn order to determine whether or not a specific adverseevent is causally associated with vaccination, almostalways additional information beyond what is reportedto VAERS is required. For some adverse events – thoseassociated with replication of vaccine strain viruses –identification of the vaccine strain in association with aspecific clinical outcome can provide strong evidence ofcausality. Molecular sequencing methods are now routinelyemployed to identify strains as vaccine-derived orwild-type, allowing cases of paralytic poliomyelitis to becharacterized as caused by wild-type or vaccine-derivedvirus [11]. These molecular methods were recently usedto document transmission of vaccine-derived poliovirusin an undervaccinated community in the United States[12]. Similarly, cases of zoster caused by varicella vaccinestrain virus have been documented [13], as have cases ofmeningitis associated with mumps vaccine virus [14]. Incontrast, cases of subacute sclerosing panencephalitisfollowing measles vaccination have been associated withwild-type virus rather than vaccine strain [15].Other approaches are needed to assess the relationshipbetween vaccination and adverse events. Prelicensure,clinical trials are performed, with random allocation ofparticipants to the vaccine group and the comparisongroup; if there are other important factors that influencethe outcome, random assignment usually results inbalanced allocation between the groups. Postlicensure,adverse events are usually evaluated in observationalstudies in which the differences in vaccine exposureamong persons in the study results from variations inclinical practice or choice, and these study approaches –although extremely valuable – are more subject to beinginfluenced by differences between study groups thatmay influence the outcome. Although there are limitationsin observational studies, they can provide powerfulevidence regarding the relationship between vaccineexposure and adverse events.Regardless of the specific study design, vaccine safetystudies require consistent criteria for defining the adverseevent as well as accurate information on vaccine history.

Field investigations may be undertaken by public healthauthorities in response to specific events of high concern,such as clusters of death postvaccination [16] or whenthere is great urgency to address a potential vaccine safetyproblem [17] or when other approaches are not feasible.In 1955, cases of paralytic poliomyelitis among childrenwho had been vaccinated with inactivated polio vaccinewere identified soon after vaccine licensure. A rapid fieldinvestigation was undertaken by CDC, and within days itwas learned that the cases of paralytic disease wereoccurring among recipients of vaccines from a singlemanufacturer, allowing vaccination with vaccines fromother manufacturers to be resumed [18].Comprehensive health record databases, including claimsdata and those from managed care organizations, are nowwidely utilized for vaccine safety studies. Databases thatallow systematic identification of cases of specifiedoutcomes and provide comprehensive immunizationhistories of defined groups of individuals are most useful.The approach using administrative data is especiallyuseful for events with discrete onset for which healthcareis likely to be sought (e.g., seizures). Although theseapproaches are very powerful, there are limitations touse of administrative data, including misclassification(miscoding, diagnoses that were considered but eliminatedas the evaluation proceeded, and diagnoses thatwere made in the past being carried forward in thepatient’s record). Because of these limitations, the availabilityof chart review to confirm potential cases identifiedin administrative data can greatly strengthen studiesdone using large linked databases [19]. In the UnitedStates, CDC works with the Vaccine Safety Datalink, aconsortium of eight large managed care organizations.The participating managed care organizations are geographicallydiverse, with a combined population of over9.2 million persons and a birth cohort of approximately95 000. Healthcare utilization and diagnostic codes areavailable from outpatient, emergency department, andinpatient settings [20]. Similar approaches are used inother countries. Globally, these systems are an importantcomponent of current plans to monitor the safety of newH1N1 influenza vaccines [21_].Completing an observational study, even using a systemlike the Vaccine Safety Datalink, can take several years.In order to identify and confirm potential vaccine safetyissues in a more timely way, new approaches usingsequential analytic methods have been developed. Inthis approach – called rapid cycle analysis by its developers– specific diagnoses of interest are looked for inspecific intervals of time following vaccination in datasetsthat are regularly updated as additional persons are vaccinatedand outcomes of interest are accrued [22]. Thisapproach is now used routinely for safety monitoring inthe United States. Its utility has been demonstrated withearly recognition of an increase in risk of febrile seizuresfollowing receipt of the combination measles, mumps,rubella (MMR), and varicella vaccine [23]. Similar resultswere obtained from a traditional cohort study in a differentmanaged care population [24]. It has also been

applied to evaluate the safety of the adolescent and adult90 Infectious diseases and immunizationCopyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.formulation of tetanus and diphtheria toxoids andacellular pertussis vaccine [25].Vaccine safety and vaccine policyDecisions about use of vaccines are based on an assessmentof the risks associated with vaccine use and thebenefits to be derived from vaccination. Changes ineither the understanding of risks or in the expectedbenefits of vaccination can lead to a reassessment ofimmunization policy. Decreasing risk of exposure tosmallpox led the United States to discontinue routinesmallpox vaccination of children in 1972, prior to globaleradication of naturally occurring disease. Similarly, progressin the global polio program and decreasing risk ofimportation of disease was one factor that led the UnitedStates to discontinue use of oral polio vaccine in 2000. In1999, the first licensed vaccine for prevention of rotavirusgastroenteritis was found to be associated with intussusception,a type of bowel obstruction in infants, leading towithdrawal of the recommendation for use of that vaccine[26]. (Since then, two different rotavirus vaccines havebeen developed and licensed in the United States; prelicensure[27,28] and postlicensure [29] studies havesupported that neither vaccine is associated with a riskof intussusception comparable to the earlier vaccine.) Acombined measles–mumps–rubella–varicella vaccinewas found to have an increased risk of febrile seizures,compared with the use of separate MMR and varicellavaccines. The Advisory Committee on ImmunizationPractices (ACIP) had previously indicated that the combinedvaccine was preferred over administration ofMMRand varicella vaccines separately. Given the evidence foran increase in risk of febrile seizures associated with useof the combination vaccine, in 2008 the preference for thecombination product was withdrawn [23].Prevention of adverse events followingvaccinationAlthough most persons who are vaccinated experience noor only mild adverse events following vaccination, seriousillness or even deaths caused by vaccination do occur.These events are rare, but to the extent that adverseevents are preventable, immunization providers shouldmake every effort to prevent them.Serious allergic reactions to vaccines or vaccine componentsare rare; a large study in the Vaccine SafetyDatalink reported a risk of less than two cases per milliondoses of vaccine [30]. Yellow fever vaccine and currentlyavailable influenza vaccines are produced in eggs andcontain residual egg protein, which can result in hypersensitivityreactions in persons who are allergic to eggs.The components of MMR are not produced in eggs andpersons who are allergic to eggs can safely receive MMR;MMR (and several other vaccines) do contain gelatin as astabilizer, which may produce hypersensitivity reactionsin persons with gelatin allergies. A complete listing ofUS licensed vaccines, and product inserts containing

all vaccine ingredients, is available on the FDA Web site(www.fda.gov/BiologicsBloodVaccines/Vaccines/ApprovedProducts/ucm093830.htm). Clinical guidance for evaluationand subsequent vaccination of persons with hypersensitivityreactions has been published [31].Because of the risk of adverse events, live attenuatedvaccines are generally contraindicated in severely immunocompromisedpersons. Contraindications vary basedon the nature and severity of the immunodeficiency.General guidance is published [32], but consultation withan infectious disease or immunology specialist may berequired.As more vaccines are recommended for use among adolescentsand young adults, reports of syncope followingvaccination havemarkedly increased [33]. Syncope followingvaccination can be associated with serious injury ordeath [34,35,36_]. The ACIP recommends that vaccineproviders strongly consider observing patients for 15 minafter they are vaccinated. If syncope develops, patientsshould be observed untilsymptomsresolve [32]. Personnelshould be aware of the signs and symptoms of presyncopeand take appropriate measures to prevent injury ifweakness, dizziness, or loss of consciousness occurs [37].Another category of adverse events that should be preventableare those due to vaccine administration errors.Although vaccine administration errors rarely result inserious adverse events, administration of a contraindicatedlive vaccine to a severely immunocompromisedperson can result in serious injury or death. A review ofmedical errors reported to VAERS during the periodJanuary 2006 to September 2007 found that the wrongproduct was given in 24% of the reports [38]. Forexample, inadvertent administration of vaccines insteadof tuberculin purified protein derivative (PPD) for tuberculosisskin testing as well as administration of PPDinstead of various vaccines have been reported to VAERSand the FDA’s Adverse Event Reporting System [39,40],and other errors, including unintentional administrationof varicella vaccine instead of varicella zoster immuneglobulin [41], have been reported to other systems. Toprevent such errors, both human and system factorsshould be addressed. Immunization providers shouldalways carefully read labels and record the productname and lot number before each tuberculosis skin testor vaccination. ACIP discourages prefilling of syringesbecause of the risk of vaccine administration errors [32].Improved storage practices, improved packaging andlabeling, and bar code scanning can also help reducesuch errors.Vaccine safety: current systems and recent findings Wharton 91Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.Genetic factors likely contribute to risk of adverse eventsassociated with vaccines, and future research willundoubtedly lead to better understanding of the relationshipamong genomics, the immune response, and adverseevents following vaccination [42–45]. Even if screeningis not feasible, improved understanding of the pathogenesisof adverse events may lead to the development of

safer vaccines.Ongoing basic science and clinical research is critical tobetter understanding of vaccine safety. Soon after thewhole-cell pertussis vaccine (combined with diphtheriaand tetanus toxoids,DTP) began being used in theUnitedStates, there were reports of serious neurological eventsoccurring following immunization, some of which wereassociated with long-term sequelae. Subsequent studiessupported that DTP might rarely produce acute encephalopathy,but a causal relationship between DTP andpermanent brain damage was not demonstrated. Nonetheless,concerns about the reactogenicity of whole-cellpertussis vaccines led to the development of less reactogenicacellular pertussis vaccines, which have replaced thewhole-cell vaccine in the United States. In 2006, researchersin Australia and New Zealand reported that eight of 14patients diagnosed with vaccine encephalopathy followingreceipt of DTP vaccine met clinical criteria for severemyoclonic epilepsy of infancy (SMEI), and an additionalfour patients were classified as borderline SMEI. Of these12 patients, 11were found to have mutations of the sodiumchannel gene SCN1A, an established finding in SMEI thattypically arises as a de-novo mutation [46__].New technologies including systems biology approachesare now being applied to the study of vaccines[47,48,49_]. These and other new methods will no doubtlead to better understanding of the response to vaccinationand the myriad of factors – including vaccines – thatresult in human disease.ConclusionWith newly recommended vaccines come responsibilitiesto assess the safety of these new products and to respondin a timely way to any vaccine safety issues that areidentified. Newer methods, including data-miningapproaches and sequential analytic methods, are nowbeing used to monitor the safety of new vaccines, allowingmore rapid understanding of their safety. Ongoingclinical and basic science research is critical for continuedprogress in development of safer vaccines.