An Open Randomized Study of Inactivated Hepatitis A Vaccine Administered Concomitantly with Typhoid Fever and Yellow Fever Vaccines

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1 An Open Randomized Study of Inactivated Hepatitis A Vaccine Administered Concomitantly with Typhoid Fever and Yellow Fever Vaccines Elaine C. Jong, Karen M. Kaplan, Karen A. Eves, Colleen A.Taddeo, Hassan D. Lakkis, and Barbara J. Kuter Background: Concomitant administration of several vaccines is a common practice when travel clinics prepare persons for international travel. The purpose of the study was to compare the immunogenicity and safety of hepatitis A, typhoid fever, and yellow fever vaccines administered concomitantly with hepatitis A vaccine administered alone and typhoid fever and yellow fever vaccines administered alone. Methods: Healthy adults 18 to 55 years of age were randomized to receive either VAQTA, TyphimVi, and YF-VAX on day 0 and VAQTA at week 24 (Group 1); TyphimVi and YF-VAX on day 0 and an optional dose of VAQTA 1 month later (Group 2); or VAQTA at day 0 and week 24 (Group 3). Results: From March to December 1997, a total of 240 subjects were enrolled, 80 in each treatment group. Most were female and Caucasian, and the mean age was 29.4 years. Four weeks after vaccine dose 1, seroconversion to protective antibody levels against hepatitis A was 95.9% in Group 1 and 100% in Group 3. In Group 1, 93.4% of subjects demonstrated at least a 4-fold rise in neutralizing antibody levels against typhoid, compared with 90% in Group 2. Serum neutralizing antibody against yellow fever developed in 98.6% of subjects in Group 1 compared with 100% in Group 2. Conclusions:These findings were consistent with similarity in the immune responses between treatment groups as defined a priori. The adverse experience (AE) profile did not appear to be substantially affected by concomitant administration of all three vaccines. Providing these three vaccines concomitantly can simplify the process of obtaining pretravel prophylaxis and may help ensure that all needed vaccines are administered. Epidemiologic studies suggest that hepatitis A virus (HAV) infection is the leading cause of vaccine-preventable infection among travelers. 1 3 Vaccination against hepatitis A is recommended for susceptible persons traveling to or working in countries that have an elevated risk of HAV infection. 4,5 Although travel accounts for only approximately 5% of hepatitis A cases in the United Elaine C. Jong, MD: Clinical Professor, University of Washington School of Medicine, Seattle, Washington; Karen M. Kaplan, MD, Karen A. Eves, BS, Colleen A. Taddeo, BS, Hassan D. Lakkis, PhD, and Barbara J. Kuter, PhD, MPH: Merck Research Laboratories, Merck and Co., Inc., West Point, Pennsylvania. Presented, in part, at the 47th Annual Meeting of the American Society of Tropical Medicine and Hygiene, October 18-22, 1998, San Juan, Puerto Rico. [Abstract #79] This study was supported by a grant from Merck & Co., Inc. Dr. Jong is on the Speakers Bureau list for Aventis Pasteur, makers of the typhoid fever vaccine (Typhim Vi) and yellow fever vaccine (YF Vax) studied. Drs. Kaplan, Lakkis, and Kuter and Ms. Tadeo are all employees of Merck and Co. Inc. Reprint requests: Karen M. Kaplan, MD, Merck & Co., Inc., PO Box 4 BL1-7, West Point, PA J Travel Med 2002; 9: States, % of cases in some northern European countries may be attributable to travel. 6 For many of these same travelers, vaccination against typhoid fever and yellow fever also is recommended. 5 Providing these vaccines concomitantly can simplify the process of obtaining pretravel prophylaxis and may help ensure that all needed vaccines are administered. The purpose of this study was to evaluate the immunogenicity and safety of hepatitis A vaccine administered concomitantly with typhoid and yellow fever vaccines. The concomitant administration of inactivated hepatitis A vaccine (VAQTA, Merck, West Point, PA), Vi polysaccharide typhoid vaccine (TyphimVi, Aventis Pasteur, Swiftwater, PA, formerly Pasteur Merieux Connaught), and live attenuated 17D yellow fever vaccine (YF-VAX, Aventis Pasteur, formerly Pasteur Merieux Connaught) was compared with hepatitis A vaccine administered alone, as well as to typhoid and yellow fever vaccines administered concomitantly without hepatitis A vaccine. Methods Subjects This study was approved by the Institutional Review Board of the participating center, and written informed consent was obtained from all subjects prior to enroll- 66

2 Jong et al., Hepatitis A Vaccine with Typhoid Fever and Yellow Fever Vaccines 67 ment. Healthy adults, 18 to 55 years of age with no history of clinical HAV infection, were eligible for participation at the study site in Seattle, Washington. Potential subjects were excluded if they were pregnant; nursing or expecting to conceive during the study period; were unwilling to use an acceptable method of birth control during the study period (women of childbearing potential); were allergic to any vaccine component (including alum, formaldehyde, neomycin, egg or chicken embryo protein); were experiencing a moderate or severe febrile illness (temperature 100 F oral or 38 C oral); had received any other hepatitis A, typhoid, or yellow fever vaccines in the past; had received immune globulin or blood-derived products within the previous 6 months or planned to receive such products in the 7 months thereafter; were receiving immunosuppressive treatment; had severe thrombocytopenia or any coagulation disorder that would contraindicate intramuscular injection; or had any condition that in the opinion of the investigator might interfere with the study objectives. Vaccine and Randomization Subjects were randomized by age to one of three treatment groups. Subjects in Group 1 received VAQTA, TyphimVi and YF-VAX on day 0 and VAQTA at week 24. Two active control groups were implemented in this study. Subjects in Group 2 received TyphimVi and YF-VAX on day 0 and were offered an optional dose of VAQTA 1 month later. Subjects in Group 3 received VAQTA at day 0 and week 24. Planned enrollment was 50 to 80 subjects in each of the three groups. Randomization stratified subjects such that, subjects 18 to 30 years of age were assigned the lowest available case numbers and subjects 31 to 55 years of age were assigned the highest available case numbers. VAQTA as a 50-U dose was injected intramuscularly in the deltoid region of the arm. TyphimVi as a 0.5-mL dose was injected intramuscularly and YF-VAX as a 0.5-mL dose was injected subcutaneously, both in the deltoid region of the opposite arm. Safety Surveillance Subjects were asked to record on a vaccination report card their oral temperature and any injection-site or systemic complaints 4 hours after each injection and daily for the 4 days following the vaccine administration date. Any systemic complaint that occurred on the day of vaccination or within the subsequent 14 calendar days also was recorded. Subjects also were asked to notify the study center personnel immediately of any unexpected or severe reaction. All local and systemic reactions, regardless of severity, as well as reasons for premature withdrawal from the study were recorded. Any elevated temperature ( 101 F, oral equivalent) was reported as an adverse experience (AE). A temperature was classified as febrile if no numeric temperature was obtained for a subject,but there was an indication that the subject had a fever (e.g., felt warm). Serology A 10 to 15 ml blood sample was collected from each subject immediately prior to the first vaccination and 4 weeks following each vaccination. To determine hepatitis A antibody levels, serum samples were tested at Merck Research Laboratories (MRL) using the modified HAVAB assay (Abbott Laboratories, North Chicago, IL). Samples 10 miu/ml were considered seropositive. Levels of typhoid Vi antibody were measured using a radioimmunoassay (RIA). Titers were expressed as g antibody/ml of serum using RIA. Seroconversion for Vi antibody was defined by a 4-fold rise in antibody titer between the pre- and postvaccination serum samples. Levels of the 17D virus neutralizing yellow fever antibody were measured in a plaque reduction test in pig kidney cells. Seroconversion for the 17D virus neutralizing antibody was defined by the presence of a titer > 0.27 IU/mL. All typhoid and yellow fever tests were performed by Pasteur Merieux Serums and Vaccins, Val de Reuil, France. The seropositivity rates (SPRs) for hepatitis A vaccine, the percent of subjects with 4-fold rise in antibody titer for typhoid vaccine, and the seroconversion rates (SCRs) for yellow fever vaccine were evaluated 4 weeks following the first vaccination(s) for each treatment group. For hepatitis A vaccine, the SPR was defined as the proportion of subjects who were seronegative prevaccination by the modified HAVAB with a titer < 10 miu/ml and seropositive postvaccination by the modified HAVAB with a titer 10 miu/ml.for typhoid vaccine, the percent 4-fold rise in antibody titer was defined as the proportion of subjects having a 4-fold rise in antibody titer from the prevaccination blood sample to the 4 weeks postvaccination blood sample. For yellow fever vaccine, the SCR was defined as the proportion of subjects having a neutralizing antibody titer 0.27 IU/mL prevaccination and a neutralizing antibody titer > 0.27 IU/mL postvaccination. Statistical Methods The immunogenicity analyses were based on a perprotocol approach. The primary immunogenicity hypotheses, that the response rates 4 weeks following dose 1 for each vaccine in the investigational group (Group 1) were noninferior to the corresponding response rates in the control groups (Group 2 or Group 3) by 20 percentage points were tested based on Farrington and Manning 7 expanded to a stratified setting (age categories of 18 to 30 and 31 to 55 years of age), at the onesided.025 level. This corresponds to a lower bound of the 2-sided 95% confidence interval (CI) on the dif-

3 68 Journal of Travel Medicine, Volume 9, Number 2 ference in response rates excluding a decrease of 20 percentage points. Requiring all three tests to be significant for the study to be successful controls the overall alpha at.025, one-sided. Based on simulations, assuming 70 subjects in each treatment group for the primary analyses, 90% response rates, and independence of the three comparisons, the probability of success of the three tests simultaneously is 91%. For safety, Fisher s exact test was used to compare Group 1 to Group 2 to assess the impact of adding VAQTA to the travelers vaccine regimen and Group 1 to Group 3 to assess the impact of the travelers vaccines on the safety profile of VAQTA (2-sided,.05 level). Because of the multiple statistical tests being performed on the safety data,each at =.05,the overall significance level for safety was in fact greater than =.05. All subjects with safety follow-up after dose 1 were included in the safety analyses and summaries. Results Subjects From March to December 1997, 240 subjects were enrolled in the study with 80 subjects in each treatment group. No apparent differences were observed among the three groups with respect to gender, age, or race/ethnicity. The majority of subjects enrolled were female, and the mean age was 29.4 years; 78.3% were identified as Caucasian and 14.2% as Asian. Safety Table 1 displays the summary of adverse experiences by treatment group following the first vaccination visit. No serious vaccine-related AEs (life-threatening, requiring hospitalization, or death) were reported in any treatment group. One subject in Group 1 was diagnosed with a malignant neoplasm, unrelated to vaccination, 105 days following dose 1.There were no significant (p >.05) differences between Group 1 and Group 3 with respect to the proportion of subjects with one or more injection-site AEs for VAQTA. Furthermore, for typhoid and yellow fever vaccines, there were no significant (p >.05) differences between Group 1 and Group 2 with respect to the proportion of subjects with one or more injection-site AEs (see Table 1). The proportion of subjects in Groups 1 and 2 with any systemic AEs was 48.8% and 45.0%, respectively, a difference that was not statistically significant. Table 1 VAQTA Administered Concomitantly versus Nonconcomitantly with Other Travelers Vaccines. Summary of Adverse Experiences Percent of Subjects with Adverse Experience(s) Treatment Groups Typhim Vi,YF-VAX, and VAQTA Typhim Vi and YF-VAX VAQTA (Group 1) (Group 2) (Group 3) (n=80) (n=80) (n=80) Common Systemic Adverse Experiences (day 0 to day 14 following vaccination visit 1) Subjects with any systemic adverse experiences Headache Asthenia/fatigue Nausea Myalgia Pharyngitis Infection, respiratory, upper Fever* Injection-Site Adverse Experiences (day 0 to day 4 following Typhim Vi YF-VAX VAQTA Typhim Vi YF-VAX VAQTA vaccination visit 1) Subjects with any injection-site adverse experiences Tenderness Pain Warmth Erythema Swelling *Fever is defined as 101 F (38.3 C), oral equivalent.

4 Jong et al., Hepatitis A Vaccine with Typhoid Fever and Yellow Fever Vaccines 69 The most frequently reported specific injectionsite AEs were pain, tenderness, warmth, swelling, and erythema. There were no significant differences in the incidence of specific injection-site AEs for VAQTA between Groups 1 and 3 (p >.05) nor between Groups 1 and 2 for yellow fever vaccine. The difference in reported swelling between Groups 1 and 2 following typhoid vaccine injection was statistically significant (11.3% compared with 25.0%, p =.039). No other statistically significant differences in rates of injection-site AEs for typhoid vaccine between Group 1 and Group 2 were found, nor were any statistically significant differences in the rates of specific systemic AEs between Groups 1 and 2 noted. Immunogenicity One month following dose 1, SPRs and geometric mean titers (GMTs) for hepatitis A in Groups 1 and 3 were 95.9% and 35.0 miu/ml and 100% and 49.2 miu/ml respectively (Table 2). The proportions of subjects with 4-fold rises in typhoid antibody titers and GMTs in Groups 1 and 2 were 93.4% and 2.9 miu/ml and 89.7% and 2.3 miu/ml, respectively. The SCRs and GMTs for yellow fever in Groups 1 and 2 were 98.6% and 21.6 miu/ml and 100% and 20.2 miu/ml, respectively. Based on an analyses stratified for age category (18 to 30 and 31 to 55 years of age), the difference in SPRs for hepatitis A between Groups 1 and 3 was 4.2 (95% confidence interval [CI] , p <.001), the difference in proportions of subjects with 4-fold rise for typhoid between Groups 1 and 2 was 3.7 (95% CI , p <.001), and the difference in SCRs for yellow fever between Groups 1 and 2 was 1.4 (95% CI , p <.001). In each case the 95% CI excluded a decrease of 20 percentage points or more and the corresponding p-value was.025; therefore the differences were statistically significantly less than 20 percentage points. Discussion This study demonstrated that hepatitis A seropositivity rates were generally similar when inactivated hepatitis A vaccine was administered with and without Vi polysaccharide typhoid vaccine and live attenuated 17D yellow fever vaccine. Likewise, when these typhoid and yellow fever vaccines were administered concomitantly with or without hepatitis A vaccine, the immune responses for typhoid and yellow fever vaccines were generally similar. The hepatitis A seropositivity responses of 95.9% and 100% when all three vaccines were administered concomitantly (Group 1) and when hepatitis A vaccine was administered alone (Group 3), respectively, were Table 2 Immunogenicity for Hepatitis A, Typhoid, and Yellow Fever Vaccines 4 Weeks Post Dose 1 by Treatment Group Treatment Group VAQTA, Typhim Vi, and Typhim Vi, and YF-VAX YF-VAX VAQTA Concomitantly Concomitantly Alone Vaccine Response Rate (Group 1) (Group 2) (Group 3) Hepatitis A Typhoid Yellow fever Observed SPR (Positive/tested) 95.9% (70/73) 100% (72/72) (95% CI) (88.5% 99.1%) (95.9% 100%) GMT (95% CI) ( ) ( ) Observed percent 4-fold rise in antibody titer (Positive/tested) 93.4% (71/76) 89.7% (70/78) (95% CI) (85.3% 97.8%) (80.8% 95.5%) GMT (95% CI) ( ) ( ) Observed SCRs (Positive/tested) 98.6% (70/71) 100% (73/73) (95% CI) (92.4% 100%) (96.0% 100%) GMT (95% CI) ( ) ( ) SPR = seropositivity rate; tested = number of subjects in each treatment group with serology evaluated; CI = confidence interval; GMT = geometric mean titer. GMTs and their 95% CIs were computed from the analysis of variance model; SCR = seroconversion rate.

5 70 Journal of Travel Medicine, Volume 9, Number 2 consistent with responses observed in previous clinical trials. 8 Although the GMTs for the typhoid and yellow fever vaccines were similar when administered concomitantly with and without hepatitis A vaccine, the GMTs for hepatitis A vaccine decreased slightly when the vaccine was administered concomitantly with typhoid and yellow fever vaccines. The slight decrease in GMTs is not likely to be clinically significant since the GMTs were at least 3-fold higher than the seropositivity cutoff of 10 miu/ml for hepatitis A. No differences in immunogenicity in each of the three treatment groups by age category were observed, and the overall safety profile of the three vaccines did not appear to be adversely affected by concomitant administration. The findings in this study of 240 healthy subjects provide objective evidence to support the common clinical practice of administering hepatitis A, typhoid fever, and yellow fever vaccine concomitantly. Such same day scheduling of vaccine doses allows travelers to make fewer visits to travel clinics or to other health care providers in order to receive recommended vaccines prior to travel. The finding that concomitant injection of vaccines did not significantly increase either injection site or systemic adverse experiences may improve compliance in receiving all recommended vaccines among international travelers, and allay fears that such concomitant administration might potentiate adverse experiences. Acknowledgments We thank Julie Valley, Benita Sharp, Jeff Altman, and John Martines of the Hall Health Primary Care Center, Seattle, Washington for their invaluable assistance during the conduct of this study. References 1. Steffen R, Gyurech D. Advances in hepatitis A prevention in travellers. J Med Virol 1994; 44: Steffen R, Kane MA, Shapiro CN, et al. Epidemiology and prevention of hepatitis A in travellers. JAMA 1994; 272: Steffen R. Risk of hepatitis A in travelers. Vaccine 1992; 10 (Suppl 1):S Centers for Disease Control and Prevention. Prevention of hepatitis A through active or passive immunization: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR 1999; 48: Centers for Disease Control and Prevention. Health information for international travel, Atlanta: Department of Health and Human Services, Loscher T, Keystone JS, Steffen R. Vaccination of travelers against hepatitis A and B. J Travel Med 1999; 6: Farrington CP, Manning G. Test statistics and sample size formulae for comparative binomial trials with null hypothesis of non-zero risk difference or non-unity relative risk. Stat Med 1990; 9: VAQTA [package insert]. West Point, PA: Merck & Co., Inc., Urban gardening in Strasbourg, France. Submitted by Charles D. Ericsson, MD.