Safety, tolerability and immunogenicity of a recombinant hepatitis B ...

[Human Vaccines 5:2, 92-97; February 2009]; ©2009 Landes Bioscience

Research Paper

BU TE .

Safety, tolerability and immunogenicity of a recombinant hepatitis B vaccine manufactured by a modified process in healthy young adults

ST RI

Pierre Van Damme,1 Gianmaria Minervini,2 Charles L. Liss,2 Barbara McCarson,2 Timo Vesikari,3 John W. Boslego2 and Prakash K. Bhuyan2,* 1Center for the Evaluation of Vaccination; University of Antwerp; Belgium; 2Merck Research Laboratories; North Wales, Pennsylvania USA; 3University of Tampere Medical School; Tampere, Finland

DI

Abbreviations: AEs, adverse experiences; ANOVA, analysis of variance; anti-HBs, serum antibody to HBsAg; CI, confidence interval; GMTs, geometric mean titers; HBsAg, hepatitis B surface antigen; mpHBV, modified process hepatitis B vaccine; SPRs, seroprotection rates

Introduction

.D

O

Hepatitis B is a preventable disease that has high global prevalence (≥300 million chronic carriers).1 Serious complications and sequelae of hepatitis B virus infection include fulminant hepatic necrosis, cirrhosis of the liver, chronic active hepatitis and hepatocellular carcinoma. Over 600,000 people worldwide are estimated to die each year of hepatitis B-associated acute and chronic liver disease.1,2 Current treatments for chronic hepatitis B are limited; interferon can convert chronically infected people to being hepatitis B surface antigen (HBsAg) negative and oral therapy can suppress viral replication, but viral eradication is infrequently achieved.3 However, prevention through vaccination has been available since 1982.4 RECOMBIVAX HBTM [hepatitis B vaccine (recombinant), Merck & Co., Inc., Whitehouse Station, NJ] is a well-established vaccine against hepatitis B, which has been used worldwide since its initial licensure in 1986.5,6 In the United States, the effectiveness of hepatitis B vaccination is evidenced by the decline of the incidence of reported acute hepatitis B since 1990 by 79% to the current rate of 1.8 cases per 100,000 population.7 Similar trends have been noted in New Zealand, where COMVAXTM [hepatitis B vaccine (recombinant) with haemophilus b conjugate (meningococcal protein conjugate), Merck & Co., Inc., Whitehouse Station, NJ] and RECOMBIVAX HBTM are the sole hepatitis B vaccines used.8 Since 1981, the hepatitis B vaccine has been changed from a plasma-derived vaccine to a recombinant, yeast-derived vaccine and thimerosal, a preservative, was removed from the formulation in 1999. To improve upon older processes and to develop a potentially more immunogenic vaccine, a modified process hepatitis B vaccine (mpHBV), was developed. The antigen component of the mpHBV is not different from the antigen component of currently licensed RECOMBIVAX HBTM; only the composition of the amorphous aluminum hydroxyphosphate sulfate adjuvant has been modified by utilizing a higher phosphate content (relative to the current product, RECOMBIVAX HBTM) during the manufacturing process. The aluminum phosphate component of aluminum adjuvant is thought to potentiate immune responses to certain antigens by making them more available for uptake by dendritic cells.9

09

LA N

DE S

BI

OS

CI

EN CE

Background: Merck has developed a manufacturing process modification for RECOMBIVAX HBTM. Three lots of modified process hepatitis B vaccine (mpHBV) were studied in a randomized, blinded trial to demonstrate similarity of the three lots of mpHBV and noninferiority to RECOMBIVAX HBTM (control vaccine) with regard to immunogenicity. Results: Month 7 SPRs for the mpHBV groups ranged from 97.8 to 98.9% (98.2% for the mpHBV groups combined). The seroprotection rate (SPR) for the control group was 98.5%. The estimated geometric mean titer (GMT) was 1761 mIU/mL for the mpHBV groups combined and 1108 mIU/mL for the control group. The GMT ratio (mpHBV/control) was 1.6 [95% confidence interval (CI): 1.2 to 2.1], indicating superiority of mpHBV compared with control. The percentages of subjects reporting any adverse experience (AE), injection-site AEs, or systemic AEs were similar across the four vaccination groups. There were no serious AEs. Methods: Healthy 20-to 35-year-old subjects (N = 860) received a 1-mL intramuscular dose [10 mcg hepatitis B surface antigen (HBsAg)] of mpHBV from 1 of 3 lots or control at Day 1, and Months 1 and 6. Serum antibody to HBsAg (anti-HBs) was assayed Predose 1 and 1 month Postdose 3 (Month 7) using a quantitative hepatitis B antibody assay (Ortho VITROS ECi assay). Anti-HBs GMTs and SPRs (% of subjects with an anti-HBs titer ≥10 mIU/mL) were compared at Month 7. After each dose, injection-site AEs and oral temperature were recorded for 5 days; systemic AEs were recorded for 15 days. Conclusions: The SPRs for the mpHBV groups and the control group were high; responses were consistent across the mpHBV groups. The mpHBV and control vaccines were generally well tolerated.

NO T

Key words: safety, immunogenicity, hepatitis B, recombivax, seroprotection rate

20

*Correspondence to: Prakash Bhuyan; Merck Research Laboratories; P.O. Box 1000; UG3CD-28; North Wales, Pennsylvania 19454-1099 USA; Tel.: 267.305.6294; Fax: 267.305.6515; Email: [email protected]

©

Submitted: 04/10/08; Revised: 07/07/08; Accepted: 07/14/08 Previously published online as a Human Vaccines E-publication: http://www.landesbioscience.com/journals/vaccines/article/6587

92

Human Vaccines

2009; Vol. 5 Issue 2

NO T

DI

ST RI

BU TE .

Hepatitis B vaccine manufactured by a modified process

.D

Approximately 11% of the subjects were not included in the per-protocol immunogenicity analysis at Month 7; the proportions of subjects excluded from each vaccination group were similar. The most common reasons for exclusion from the per-protocol immunogenicity analysis were: missing postvaccination serology result (4%); discontinuation of the subject due to pregnancy (2.2%); the receipt of a prohibited concomitant vaccination (2%); and subject was initially seropositive (1.6%). Subjects across all four vaccination groups were similar with respect to age, race, gender, weight and tobacco use (Table 1). Approximately 40% of the subjects were male, the mean and median age was approximately 27 years in all four vaccination groups and, as would be expected in a study conducted in Belgium, Finland and Sweden, a large majority (>99%) of the subjects were reported as White (Caucasian). Approximately two-thirds of the study population reported a prestudy medical condition. These proportions were similar across all groups. Slightly more than 20% of the study population reported an immune system disorder (such as seasonal allergies and drug hypersensitivity), nearly 20% had a prior surgical or medical procedure and approximately 16% reported a prior infection. Only five individual prestudy medical conditions were reported prestudy in more than 5% of the study population: seasonal allergy (9.7%), headache (5.9%), drug hypersensitivity (5.7%), asthma (5.7%) and allergic rhinitis (5.0%). The percentage of subjects with any prior therapies was slightly less than 50% and the percentages with any prior therapies were similar across the four vaccination groups. No individual therapies were received by more than 5% of the total study population. The most common prior therapy was sexual hormones such as ethinyl estradiol (+) gestodene (birth control pills), consistent with a young female population. The other common therapies were ibuprofen, antihistamines for chronic respiratory conditions and drugs for obstructive airway diseases. Concomitant analgesic use was similar for the mpHBV group (23.7%) and control (19.2%) over the course of the study. Concomitant acetaminophen was used in

EN CE

The purpose of this study (Protocol 054) was: (1) to demonstrate the consistency of the immunologic response to 3 lots of the mpHBV; and (2) to evaluate the safety, tolerability and immunogenicity of the mpHBV in comparison to the current process vaccine (control; RECOMBIVAX HBTM). The mpHBV was administered for the first time to humans in this study.

O

Figure 1. Subject disposition.

Results

©

20

09

LA N

DE S

BI

OS

CI

Participant accounting and demographics. Overall, 100% (860/860) of subjects randomized received the first vaccination in the 3-dose series (Fig. 1). Approximately 99% of the study population received the second dose of the series, and approximately 97% received all three doses. Of the 860 subjects enrolled in this study, 825 (95.9%) completed the study. The numbers of subjects who discontinued were evenly distributed across the four vaccination groups. A subject completed the study if he or she received all three vaccinations, provided 15 days of safety follow-up after each dose, and had both the baseline (Day 1) and postvaccination (Month 7) serum samples. One subject received two doses of mpHBV from Lot B and 1 dose of RECOMBIVAX HBTM. This subject was included in all subject accounting summaries: however, this subject was excluded from all immunogenicity summaries. Of the 646 subjects who received one of the lots of the mpHBV, 27 subjects (4.2%) discontinued, while 8 of 214 subjects (3.7%) discontinued in the group that received RECOMBIVAX HBTM. The most common reason for discontinuation from the study was for a pregnancy, a protocol deviation occurring in 2.3% of subjects in the mpHBV groups combined and in 1.9% of subjects receiving RECOMBIVAX HBTM. Of the subjects who received the mpHBV, three subjects (0.5%) discontinued due to a clinical adverse experience (AE), while one subject (0.5%) who received RECOMBIVAX HBTM discontinued due to a clinical AE.

www.landesbioscience.com

Human Vaccines

93


study during the 15-day follow-up period (Table 4), all in subjects who received mpHBV; however, none of these resulted in discontinuation. There were two discontinuations due to vaccine-related AEs [headache (moderate intensity; discomfort enough to cause interference with usual activities) and injection-site pain (severe intensity; incapacitating with inability to work or do usual activity)] in subjects who received the mpHBV; both starting within 24 hours after vaccination and lasting 2 and 5 days, respectively. No subjects died in this study. There were no clinically meaningful differences between mpHBV and RECOMBIVAX HB™ and among the consistency lots of mpHBV with respect to injection-site AEs, systemic clinical AEs, serious AEs, discontinuations due to AEs, and temperature elevations. Furthermore, the incidences of injection-site AEs, systemic AEs and temperature elevations did not increase following successive vaccinations with mpHBV or RECOMBIVAX HBTM (data not shown). Less than 3% of the study subjects reported an oral temperature ≥37.8°C (≥100.0°F) in the 5 days following any vaccination. The number of subjects, who reported a maximum temperature above 37.8°C, was 3.1% (20/646) for the combined mpHBV groups and 1.4% (3/214) for the group that received RECOMBIVAX HBTM, which was not a statistically significant difference. Additional safety data for mpHBV will be collected in future and ongoing studies.

.D

O

NO T

DI

ST RI

BU TE .

Table 1 Demographics

Discussion

The determination that anti-HBs at a serum level of ≥10 mIU/mL would be sufficient to provide protection against hepatitis B infection was derived from observations of the serologic responses in acute but resolving hepatitis B infection.10,11 Passive immunization of subjects at high risk of infection with immune serum globulin or high-titer hepatitis B immune globulin verified that a serum level of anti-HBs ≥10 mIU/mL correlated with protection.10,11 This threshold of % anti-HBs ≥10 mIU/mL was, therefore, the key endpoint used in this study. This study met all immunogenicity hypotheses. The three lots of mpHBV were shown to be highly immunogenic and similar with respect to SPR, with an SPR of approximately 98% across the 3 lots; and with high GMTs ranging from 1841 to 1642 mIU/mL at Month 7 (1 month after the third dose). Furthermore, 98.4% of the subjects who received mpHBV had quantifiable anti-HBs (anti-HBs titer ≥5 mIU/mL) by Month 7. Thus, consistency of immunogenicity responses was demonstrated for the 3 lots of mpHBV. The mpHBV was also shown to be superior to RECOMBIVAX HB™ with respect to anti-HBs GMTs. The mpHBV, despite having greater GMTs than RECOMBIVAX HBTM, did not increase the seroconversion rate compared with RECOMBIVAX HBTM. RECOMBIVAX HBTM was also shown to be highly immunogenic. Anti-HBs responses with respect to SPR and GMT were high with an SPR of 98.5% and a GMT of 1140 mIU/mL at Month 7. These immunogenicity findings are consistent with the historic performance of RECOMBIVAX HBTM since licensure.11-13 Furthermore nearly all subjects (99%) had quantifiable anti-HBs (anti-HBs titer ≥5 mIU/mL) at Month 7. The consistency lots of mpHBV and RECOMBIVAX HBTM were generally well tolerated. There were no clinically meaningful differences between mpHBV and RECOMBIVAX HBTM and

©

20

09

LA N

DE S

BI

OS

CI

EN CE

15.9% of mpHBV recipients and 16.8% of control. Concomitant therapies were similar to those noted pre-study. The most common concomitant vaccine was hepatitis A virus vaccine (2.2%). Immunogenicity. As shown in Table 2, the percentage of subjects who were seroprotected at Month 7 ranged from 97.8 to 98.9% for the three lots of mpHBV for a combined seroprotection rate (SPR) of 98.2%. The corresponding SPR for subjects receiving RECOMBIVAX HBTM was 98.5%. None of the bounds of the 90% CIs on the pair-wise difference in lots with respect to the SPR exceeded 4.6 percentage points; therefore, showing consistency of the mpHBV lots. The lower bound of the 95% confidence interval (CI) for the combined lots of mpHBV was 97.1%. Therefore, the second primary hypothesis regarding an adequate response for SPR was successful. The percent of participants who had serum antibody to HBsAg (anti-HBs) titer of ≥100 mIU/mL was 93% (95% CI of 90.8, 95.2) for the combined mpHBV lots and 91.4% (95% CI of 87.2, 95.6) for RECOMBIVAX HBTM. Secondly, the geometric mean titer (GMT) response to the combined lots of mpHBV was compared with the GMT response to RECOMBIVAX HBTM. The GMT response for the combined lots of mpHBV was 1760.9 mIU/mL and the GMT response for RECOMBIVAX HBTM was 1108.2 mIU/mL. The GMT ratio of mpHBV over RECOMBIVAX HBTM was 1.6 (95% CI: 1.2 to 2.1). Therefore, the GMT ratio indicated superiority of the mpHBV compared with RECOMBIVAX HBTM. Results for the initially seronegative subject population (with serology) were similar to those reported above. Adverse experiences. The percentages of subjects reporting any AE, injection-site AEs, or systemic AEs were similar across the four vaccination groups in this study (Table 3). There were no serious vaccine-related AEs in the study. There were four serious AEs in the 94

Human Vaccines



DI

ST RI

BU TE .

Table 2 Summary of anti-HBs responses at month 7 (4 weeks postdose 3) for initially anti-HBs seronegative subjects

OS

CI

EN CE

.D

O

NO T

Table 3 Adverse experience (AE) summary (Days 1 to 15 following any vaccination visit)

©

20

09

LA N

DE S

BI

among the consistency lots of mpHBV with respect to injection-site adverse experiences, systemic clinical adverse experiences, serious adverse experiences, discontinuations due to adverse experiences, and temperature elevations. Furthermore, the incidences of injection-site adverse experiences, systemic adverse experiences and temperature elevations did not increase following successive vaccinations with mpHBV or RECOMBIVAX HBTM. In healthy young adults 20 to 35 years of age who received 3 doses of mpHBV or RECOMBIVAX HBTM at 0, 1 and 6 months, the following conclusions may be drawn: (1) the immune responses to modified process hepatitis B vaccine, as measured by the seroprotection rate, are similar among recipients of all three independent vaccine lots, showing manufacturing consistency; (2) the combined results from the consistency lots of modified process hepatitis B vaccine provide an acceptable seroprotection rate that is comparable to that of RECOMBIVAX HBTM; the modified process hepatitis B vaccine group had a higher GMT than that induced by RECOMBIVAX HBTM; and (3) in general, modified process hepatitis B vaccine has an acceptable safety and tolerability profile that is comparable to that of RECOMBIVAX HBTM. These results support an acceptable safety, immunogenicity and manufacturing profile for this process modification of the licensed hepatitis B vaccine. www.landesbioscience.com

Methods Study design and population. This study evaluated the safety, tolerability and immunogenicity of three doses of RECOMBIVAX HBTM versus mpHBV administered as a 1-mL intramuscular injection at Day 1, Month 1 and Month 6 with a 15-day follow-up period after each dose (date of vaccination considered Day 1). A Month 7 follow-up visit was required for the final serology sample. This randomized, double-blind (subject, investigator, sponsor and laboratory) clinical trial was conducted at 17 sites (10 in Finland, 3 in Belgium and 4 in Sweden) from June 2005 to May 2006. The protocol was approved by the ethical review committee of each country or site and conducted in conformance with applicable country or local requirements. Healthy, young adults 20 to 35 years of age who were hepatitis B-negative according to medical history were eligible for the study. No pre-vaccination testing of HBsAg or anti-HBs was conducted, as this study was conducted in geographic areas that have a low prevalence of hepatitis B.14 Female participants had to have a negative urine pregnancy test. Mandatory criteria for inclusion were: no history of hypersensitivity reaction to any component of the study vaccines; no prior receipt of any hepatitis B vaccination;

Human Vaccines

95


evening temperatures daily for the first 5 days following vaccination using a vaccination report card. Vaccine descriptions. RECOMBIVAX HBTM is a noninfectious, viral subunit vaccine consisting of HBsAg produced in yeast cells. A portion of the hepatitis B virus gene, encoding HBsAg, is cloned into yeast, and the vaccine is produced from cultures of this recombinant yeast strain, according to methods developed in the Merck Research Laboratories. The antigen is harvested and purified from fermentation cultures of a recombinant strain of the yeast Saccharomyces cerevisiae containing the gene for the “adw” subtype of HBsAg. The HBsAg protein is released from yeast cells by cell disruption and purified by physical and chemical methods. RECOMBIVAX HBTM contains ≤1% yeast protein. The purified HBsAg protein in phosphate buffer is treated with formaldehyde and then co-precipitated with alum (potassium aluminum sulfate) to form bulk vaccine adjuvanted with amorphous aluminum hydroxyphosphate sulfate. HBsAg is adsorbed onto approximately 0.5 mg of aluminum (provided as amorphous aluminum hydroxyphosphate sulfate) per mL of vaccine. RECOMBIVAX HBTM is preservative free and free of association with human blood or blood products, and each lot of vaccine is tested for sterility. To produce the mpHBV, the manufacturing process of the adjuvant in the HBsAg bulk intermediate of RECOMBIVAX HB™ was modified by providing additional phosphate during the co-precipitation step, which increases the phosphate to aluminum ratio of the adjuvant. The licensed RECOMBIVAX HBTM and the modified process hepatitis B vaccine (Lot A, Lot B and Lot C) were indistinguishable in appearance. Vaccine supplies were packaged in single-dose glass vials and labeled with a multi-page multilingual booklet label. All subjects received a 3-dose regimen of the assigned vaccine on a 0-, 1- and 6-month schedule, as a 1.0-mL intramuscular injection. The preferable injection site was the deltoid muscle of the upper arm. Clinical material supplied in vials containing 1 mL of vaccine was to be stored at 2 to 8°C. Statistical analysis. Immunogenicity. The primary purpose of this study was to establish similarity among the three lots of mpHBV, and then to compare the mpHBV with RECOMBIVAX HBTM. The statistical criterion for consistency was that the anti-HBs SPR would not differ statistically by more than 10 percentage points between any pair of lots. Six pair-wise comparisons were performed (two one-sided tests at the alpha = 0.05 level, or correspondingly, three two-sided 90% CIs, for each of the three pair-wise comparisons of the three lots) to show the equivalence of each pair of lots. The second primary hypothesis proposed that the combined lots of mpHBV would exhibit an acceptable immune response. The statistical criterion was that the two-sided 95% CI for the SPR has a lower bound that exceeds 90.0%. The primary endpoint for the comparison of mpHBV with RECOMBIVAX HBTM was the Month 7 GMT observed in each group. The primary purpose of the comparison of mpHBV with RECOMBIVAX HBTM was to show that the GMT induced by the mpHBV was at least noninferior to and possibly statistically superior to that induced by RECOMBIVAX HBTM. The statistical criterion for noninferiority required that the lower bound of the two-sided 95% CI for the GMT ratio (mpHBV/ RECOMBIVAX HBTM) exceed 0.67. Confidence intervals were constructed employing an analysis of variance (ANOVA) model with terms for treatment and study center. Conditional on the success of

©

20

09

LA N

DE S

BI

OS

CI

O

.D

EN CE

no recent receipt of immune globulin and/or blood products; no live or inactivated vaccine during the study period; and no known immune dysfunction. Subjects provided written informed consent before they were enrolled. The study was designed to have approximately 860 subjects randomly assigned in a 1:1:1:1 ratio to either one of the three lots of mpHBV or RECOMBIVAX HBTM. Patients were allocated to treatment assignment using a computer-generated randomized allocation schedule generated by the study statistician. All study personnel, including investigators, study site personnel, patients, monitors and central laboratory personnel, remained blinded to treatment allocation throughout the study; the code was revealed to the researchers once recruitment, data collection and laboratory analyses were complete. Based on approximately 215 subjects per vaccination group and with an expected evaluability rate of 80%, the study provided 90% overall experiment-wise power. This includes 91% power to establish lot consistency with regard to the seroprotection rate, greater than 99% power to assess the adequate response for the pooled modified process hepatitis B vaccine lots, and greater than 99% power to establish the noninferiority of the modified process hepatitis B vaccine to RECOMBIVAX HBTM. Study objectives. The primary objectives of this study were to demonstrate, among healthy adults who received vaccine at 0, 1 and 6 months, that: (1) the three lots of mpHBV induce similar anti-HBs responses, as measured by SPR 1 month after the third dose of vaccine; (2) one month after the third dose of vaccine, the combined mpHBV lots will exhibit an acceptable seroprotection rate; and (3) one month after the third dose of vaccine, the anti-HBs GMT for the mpHBV will be noninferior, and possibly superior, when compared with RECOMBIVAX HBTM. The secondary objective was to assess the safety and tolerability of the mpHBV in healthy adults. Measures. Serology samples were obtained on Day 1 prior to the first vaccination and Month 7 (1 month Postdose 3). These samples were tested for anti-HBs by using the VITROS anti-HBs quantitative assay (Ortho-Clinical Diagnostics, Raritan, NJ). Immunogenicity was evaluated at Month 7 with respect to SPR, defined as the percent of subjects with an anti-HBs titer ≥10 mIU/mL and anti-HBs GMT. All subjects were required to record any AEs that occurred within 15 days following vaccination. Subjects were instructed to record oral

NO T

DI

ST RI

BU TE .

Table 4 Serious adverse experience (SAE) listing

96

Human Vaccines



Author contributions

BU TE .

ST RI

DI

CI

EN CE

Van Damme: Subject enrollment, data collection, data analysis and manuscript preparation. Vesakari: Subject enrollment, data collection and manuscript preparation. McCarson: Data analysis/interpretation and manuscript preparation. Boslego: Study concept/design. Minervini, Liss and Bhuyan: Study concept/design, data analysis and manuscript preparation.

NO T

Other than employees of Merck & Co., Inc., (as indicated on the title page), all authors have been investigators for the sponsor. Employees may hold stock and/or stock options in the company.

O

Financial disclosure

References 1. Lee WM. Hepatitis B virus infection. N Engl J Med 1997; 337:1733-45. 2. Goldstein ST, Zhou F, Hadler SC, Bell BP, Mast EE, Margolis HS. A mathematical model to estimate global hepatitis B disease burden and vaccination impact. Int J Epidemiol 2005; 34:1329-39. 3. Loomba R, Liang TJ. Treatment of chronic hepatitis B. Antivir Ther 2007; 12:33-41. 4. WHO Bulletin, Expanded Programme on Immunization, Hepatitis B Vaccine—Making Global Progress. October 1996. 5. U.S. Package Circular: Hepatitis B vaccine (recombinant), RECOMBIVAX HB®: June 2005. 6. Centers for Disease Control. National Immunization Program. Adult Immunization Schedule. Available at: http://www.cdc.gov/nip/recs/adult-schedule.htm. Accessed 2006. 7. Wasley A, Miller JT, Finelli L. Centers for Disease Control and Prevention (CDC). Surveillance for acute viral hepatitis—United States, 2005. MMWR Surveill Summ 2007; 56:1-24. 8. New Zealand Ministry of Health. Immunisation Handbook 2006. Wellington: Ministry of Health. Available at: http://www.moh.govt.nz/moh.nsf/pagesmh/4617/$File/ 200603hepatitis.pdf. Accessed 2007. 9. Romero Mendez IZ, Shi Y, HogenEsch H, Hem SL. Potentiation of the immune response to non-adsorbed antigens by aluminum-containing adjuvants. Vaccine 2007; 25:825-33. 10. Seeff LB, Wright EC, Zimmerman HJ, Alter HJ, Dietz AA, Felsher BF et al. Type B hepatitis after needle-stick exposure: prevention with hepatitis B immune globulin. Final report of the Veterans Administration Cooperative Study. Ann Intern Med 1978; 88:285-93. 11. Cassidy WM, Watson B, Ioli VA, Williams K, Bird S, West DJ. A randomized trial of alternative two-and three-dose hepatitis B vaccination regimens in adolescents: antibody responses, safety and immunologic memory. Pediatrics 2001; 107:626-31. 12. Marsano LS, West DJ, Chan I, Hesley TM, Cox J, Hackworth V et al. A two-dose hepatitis B vaccine regimen: proof of priming and memory responses in young adults. Vaccine 1998; 1:624-9. 13. Hessel L, West DJ. Antibody responses to recombinant hepatitis B vaccines. Vaccine 2002; 20:2164-5. 14. World Health Organization: Department of Communicable Diseases and Response. Epidemic and Pandemic Alert and Response on Hepatitis B. Available at: http://www.who. int/csr/disease/hepatitis/HepatitisB_whocdscsrlyo2002_2.pdf. Accessed 2008.

.D

this hypothesis, the criterion for statistical superiority required the lower bound of the confidence interval for the GMT ratio exceed 1.00. Safety. The AE profile following each vaccination and for the entire 3-dose series was described for each group that received mpHBV and the group that received RECOMBIVAX HBTM. The key safety endpoints were the overall number of subjects reporting injection-site AEs (including erythema, swelling/induration and pain/tenderness/soreness) and the number of subjects reporting elevated temperature during the 5 days following vaccination. A risk difference, a 95% CI on the difference, and a probability value on the difference was calculated for comparisons of the combined lots of mpHBV and RECOMBIVAX HBTM for the data summarized over all three vaccinations for the AEs listed above. Risk differences and a 95% CI on the difference were employed to compare the two groups with respect to all AEs reported by ≥1% of subjects in either group.

Sponsor’s role

OS

This study was funded by Merck & Co., Inc., (sponsor). In conjunction with the external investigators, this study was designed, executed, and analyzed by the sponsor.

BI

Acknowledgements

©

20

09

LA N

DE S

The authors would like to thank: All the subjects who participated in this study. RECOMBIVAX HBTM Protocol 054 Study Group: U. Elonsalo, C.E. Flodmark, K.P.M. Hoppenbrouwers, S. Iwarson, T. Karppa, A. Karvonen, T. Korhonen, P.A. Lagerback, N. Lindblad, A. Malfroot, S. Parry, P. Riikonen, L. Rombo, A. Salomaki, T. Tocklin. Florian Schödel and Sheryl Flores for their overall study and program support. Jon E. Stek for his assistance with the preparation of this manuscript. Data from this manuscript were presented in poster format at the 45th Annual Meeting of the Infectious Diseases Society of America, San Diego, CA, 2007.

www.landesbioscience.com

Human Vaccines

97