Yellow Fever 17D Vaccine Safety and Immunogenicity in the Elderly

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617.761.4310; Fax: 617.494.0924; Email: ... The incidence of serious and severe multisystem adverse events (AEs) following yellow fever (YF) 17D vaccine is higher .... In this paper, we analyze clinical trial and post-marketing safety data and ...
[Human Vaccines 1:5, 207-214, September/October 2005]; ©2005 Landes Bioscience

Yellow Fever 17D Vaccine Safety and Immunogenicity in the Elderly Research Paper

ABSTRACT The incidence of serious and severe multisystem adverse events (AEs) following yellow fever (YF) 17D vaccine is higher in persons of advanced age. One hypothesis for the occurrence of these AEs in the elderly is immunological senescence and a reduced ability to clear the vaccine virus infection. We determined age-specific rates of serious and nonserious AEs in two large clinical trials of two YF 17D vaccines from different manufacturers. In addition, we analyzed AEs reported in a large general practice data base in the United Kingdom. Neutralizing antibody responses were compared in young and elderly subjects. In the clinical trials, involving a total of 4,532 subjects, there were no neurological and viscerotropic AEs; interestingly, the incidence of common injection site and systemic AEs was significantly lower in elderly than in younger subjects. The neutralizing antibody categorical and quantitative responses were equivalent across younger and elderly subjects. In contrast, the larger retrospective analysis of 43,555 persons receiving YF 17D in the UK general practice database revealed a higher incidence of significant neurologic and multisystem AEs with advancing age. The age-specific reporting rate ratio (RRR) was approximately twice that in the 25–44 year-old reference group for subjects in the 45–64 year age group (RRR 1.82; 95% CI 0.88,3.77) and 3-fold higher for the 65–74 year-old age group (RRR 2.82; 95% CI 0.81, 9.81). These results are consistent with previous reports on YF vaccine safety in the US (Martin M, et al. Emerg Infect Dis 2001;6:945-51; Khromova et al., Vaccine 2005;23:3256-63). In elderly persons, YF 17D vaccine is associated with a higher frequency of significant AEs in the elderly but a lower incidence of common nonserious side-effects. The neutralizing antibody response, which is the mediator of protective immunity to YF, is not diminished in healthy, elderly persons.

of Global Migration and Quarantine; Centers for Disease Control and Prevention; Atlanta, Georgia USA

3Virtu Stat, Ltd.; North Wales, Pennsylvania USA

*Correspondence to: Thomas P. Monath; Acambis; 38 Sidney Street; Cambridge, Massachusetts 02139 USA; Tel.: 617.761.4310; Fax: 617.494.0924; Email: [email protected]

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Received 10/1/05; Accepted 10/2/05

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Previously published online as a Human Vaccines E-publication: http://www.landesbioscience.com/journals/vaccines/abstract.php?id=2221

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1Acambis; Cambridge, Massachusetts USA and Cambridge UK

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Thomas P. Monath1,* Martin S. Cetron2 Karen McCarthy1 Richard Nichols1 W. Tad Archambault3 Leisa Weld2 Philip Bedford1

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yellow fever 17D vaccine, elderly, adverse events, immunogenicity

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ACKNOWLEDGEMENTS

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The authors thank Drs. Michael Martin (DGMQ, CDC), Gina Mootrey (Vaccine Safety and Development Activity, National Immunization Program, CDC) who evaluated CIOMS reports and Manette Niu (CBER/FDA) who assisted in the statistical analysis of the retrospective study. Chris Murphy and Robert Schrader, Acambis, performed serological studies.

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Yellow fever (YF) 17D is a live, attenuated vaccine developed nearly 70 years ago by empirical passage in tissue culture. Following subcutaneous inoculation, the vaccine induces neutralizing antibodies—the mediator of protective immunity—in nearly 100% of individuals. Immunity following a single dose is probably life-long.1 The vaccine is indicated for the prevention of yellow fever in travelers to and residents of endemic areas of tropical South America and Africa. For decades, YF 17D vaccine had a virtually unblemished safety record, except for rare cases of post-vaccinal encephalitis (now called yellow fever vaccine-associated neurotropic adverse events, YEL-AND), which occurred principally in very young infants and led to a widely-accepted contraindication for use in infants less than nine months of age. However, in the last decade a second type of rare, serious adverse event, YF vaccine associated viscerotropic adverse events (YEL-AVD) has been recognized.2 YEL-AVD closely resembles the disease caused by wild-type strains of YF virus, and appears to be the result of an overwhelming 17D virus infection of extraneural vital organs, including the liver.3-5 In contrast to neurotropic adverse events, YEL-AVD has occurred principally in persons of advanced age. Of 29 such cases that have been recorded, the age is known for 26, of whom 13 (50%) were persons over 60 years, despite (as shown in this paper and elsewhere6) the fact that proportionately fewer elderly than young persons receive YF vaccinations. The median age of YEL-AVD cases is 58 years (range 4–79).7 In addition to the predilection for YEL-AVD in elderly persons, retrospective analyses of large vaccine safety data bases in the US6,6a and Australia8 have shown that the incidence of severe or serious systemic adverse events is higher in persons ≥ 60 years, with a relative risk ranging from 5.9 to 16.2 compared to younger persons.6,6a,8 Human Vaccines

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Yellow Fever 17D Vaccine Safety and Immunogenicity in the Elderly

Although these reports indicate that elderly persons undergoing primary vaccination may be at greater risk of certain adverse events (AEs), there are few published data on the safety and tolerability of YF vaccines in clinical trials involving persons of advanced age who are closely followed-up. Moreover, there are no data in elderly subjects on neutralizing antibody responses. The latter might shed light on the underlying reasons for systemic adverse events, and in any case is important in the assessment of efficacy of the vaccine in persons of advanced age. We previously reported the results of a Phase 3 clinical trial in healthy adult subjects of two yellow fever 17D vaccines, YF-VAX® (sanofi-pasteur, Swiftwater PA) and ARILVAX™ (Chiron, Speke, UK).9 There was no upper age limit on enrolment in this study. Accordingly, there was an opportunity to retrospectively evaluate safety, tolerability and neutralizing antibody responses in older subjects and to compare them with young subjects in the study. Safety in elderly subjects was also evaluated in two other studies: (1) an open-label prospective study of travelers who received ARILVAX™ in the United Kingdom (UK), and (2) a retrospective analysis of AE reports made to the ARILVAX™ manufacturer and the UK regulatory control agency. This analysis, which assessed large numbers of subjects, was designed similarly to the first US study of age-related risk.6 In this paper, we analyze clinical trial and post-marketing safety data and compare the incidence of AEs in older versus young adults. Antibody responses by age group are also reported.

MATERIALS AND METHODS

Vaccines. YF-VAX® is a 17D vaccine approved for use in the US. ARILVAX™ is also a 17D vaccine licensed in the UK and other countries in Europe and Asia. Both vaccines were derived from a common ancestor (Colombia 88) in the 17D-204 lineage and are virtually identical at the sequence level.10 Vaccines used in clinical studies were obtained from the manufacturers and were used prior to their respective expiration date. Double-blind study (Acambis Protocol H-070-005). The design of this trial and safety and immunogenicity results for the entire study population have been previously published.9 Briefly, a randomized, double-blind out-patient study was conducted in 1,440 healthy subjects ≥18 years of age, approximately half of whom received the YF-VAX® and half ARILVAX™. A randomly selected subset of ~310 subjects in each treatment group was tested for YF neutralizing antibodies 30 days after vaccination. The primary efficacy endpoint was the proportion of subjects who developed a log10 neutralization index (LNI) of ≥0.7. The LNI is the log10 difference in virus titer of a mixture of serum and virus between the Day 1 and Day 31 samples; cut-off for a positive LNI is 0.7.9 The antibody responses (seroconversion rates and geometric mean antibody titers) were compared across age groups in 10-year intervals. Reverse cumulative antibody titer distribution curves were generated for young (subjects 18–44 years) versus elderly (≥60 years) and the age-specific responses compared by logrank test. To evaluate differences between older and younger subjects, we reanalyzed the incidence of AEs for subjects between subjects 18 and 44 years and older subjects ≥65 years of age. All subjects, regardless of age were in good general health and had no precaution or contraindication to YF vaccination. Inclusion and exclusion criteria and study procedures were previously published.9 AEs were summarized by body system and preferred term [Coding Symbols for Thesaurus of Adverse Reaction Terms (COSTART)], with each subject counted once for each body system and once for each AE within each body system. P-values for differences between treatment groups were determined by chi-square (or Fisher’s exact test for values near 0 or 100%). Open-label study (Acambis Protocol H-070-007). An open-label, multi-center safety study was conducted in 2000-2001 in the UK to evaluate actively monitored adverse events following vaccination of travelers with

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ARILVAX™. Subjects met the following inclusion/exclusion criteria in order to be eligible: (1) need YF vaccination for travel to a YF-endemic area; (2) no previous history of YF vaccination, travel to, or residence in a YF endemic area; (3) age: >9 months of age; and (4) no history of egg allergy, HIV infection, immunosuppression or on immunosuppressive medication, pregnancy, or lactation. All aspects of the protocol were explained and written informed consent obtained (including parent/legal guardian if subject is a child). A medical history and examination were performed prior to vaccination. We determined the incidence of AEs within the 30-day period following administration of ARILVAX™. In total, 3000 volunteers (≥9 months of age) who required ARILVAX™ for travel were to be evaluated. The sample size establishes an upper bound of 0.001 for the 95% confidence interval for the incidence of an AE in the case that the event is not observed. The AEs were recorded on a symptom diary card by the subject and documented through scripted telephone interview by study staff on Day 14 and Day 35 after vaccine administration. AEs were summarized as described above (Protocol H-070-005). Frequencies of AEs by maximum severity were provided by event within each body system. The most severe occurrence of an AE was counted for each subject. Retrospective analysis. The objective of this study was to determine the age-specific incidence of AEs following administration of ARILVAX™ using methodology previously applied by Martin et al6 to the analysis of Vaccine Adverse Event Reporting System (VAERS ) data on YF-VAX®. Data on the number of doses of ARILVAX™ sold during the period 1995–1999 were obtained from the manufacturer. The number of doses of ARILVAX™ in 1999 was decreased by 1/3 to reflect that reporting was still incomplete for that year. The number of ARILVAX™ doses administered by age group in the UK was extrapolated from a separate General Practice Research Database (GPRD) provided by Dr. Herschel Jick, Boston Collaborative Drug Surveillance Program, Boston University School of Medicine, Lexington, MA. Since 1987, over 4 million residents in the UK have been enrolled with selected general practitioners (GPs) who use office computers to provide data for research purposes to the GPRD.11 The information recorded includes patient characteristics, drugs dispensed, clinical diagnoses, and notation of adverse events. The number of ARILVAX™ doses administered by age to patients in the GPRD was determined between 1987–1998. The proportion of vaccinees by age group in the GPRD was used to extrapolate the number of doses of ARILVAX™ administered by age group in the UK between 1995 and 1999. The interval used to determine age distribution (utilizing all available data on over 12000 yellow fever vaccine prescriptions from the GPRD database) overlapped by differed from the interval for the safety database on vaccine doses distributed by the manufacturer; however it was considered unlikely that the age distribution would differ significantly across the two time intervals. Adverse event reports were received by the ARILVAX™ manufacturer’s Safety Department from health providers and/or the UK Medicines and Healthcare Products Regulatory Agency (MHRA) and information was recorded on standard forms (Council for International Organization of Medical Sciences, CIOMS). The CIOMS forms were transferred to one of the authors (MC) at the Centers for Disease Control, where they were blinded for age, after which they were given to three study investigators for classification of adverse events. The only change in this methodology from the previous VAERS study6 was that one of the three original investigators (Dr. Tsai) was replaced; the other two medical reviewers (Drs. Martin and Mootrey) had previously conducted the VAERS analysis of YF-VAX®. The three reviewers independently analyzed the reports, classifying AEs as previously done for the VAERS analysis. Where more than one category was applicable, the most serious category was used. Events were excluded if an alternative explanation/diagnosis was evident. After completing their independent review, the investigators collectively discussed reports that were classified differently and reached a consensus. Inadvertent administration of YF vaccine during pregnancy was excluded from the analysis unless there was an associated AE. Adverse events reported from patients outside the UK

Human Vaccines

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Yellow Fever 17D Vaccine Safety and Immunogenicity in the Elderly

were excluded because there were no denominator information. Systemic AEs (SyAEs) were defined as neurologic or multisystemic reactions; some, but not all met the criteria as serious adverse events as defined by the International Conference on Harmonization (ICH) and the U.S. Food and Drug Administration (FDA). SyAEs were distinguished from other AEs (OAEs), which included other reactions (hypersensitivity; local reactions; nonspecific events without other focal finding such as dizziness, headache, or nausea; and neurologic or multisystemic events that had a full and rapid clinical recovery in