Twinrix

Immunogenicity: Standard 0-, 1-, and 6-Month Dosing Schedule

In 11 clinical trials, sera from 1,551 healthy adults aged 17–70 years, were assessed following administration of 3 doses of Twinrix on a 0-, 1-, and 6-month schedule. Seroconversion (defined as equal to or greater than assay cut-off depending on assay used: either HAVAB Test [≥20 mIU/mL] or ENZYMUN-Test [≥33 mIU/mL]) for antibodies against HAV was elicited in 99.9% of recipients, and protective antibodies (defined as ≥10 mIU/mL: AUSAB Test) against HBV surface antigen were detected in 98.5% of recipients, 1 month after completion of the 3-dose series.

One of the 11 trials was a comparative trial conducted in a US population given either Twinrix (on a 0-, 1-, and 6-month schedule) or Havrix (0- and 6-month schedule) and Engerix-B (0-, 1-, and 6-month schedule). The monovalent vaccines were given concurrently in opposite arms. An immunogenicity analysis was performed in 533 participants who completed the study according to protocol. Seroconversion rates against HAV and seroprotection rates against HBV were the following:

• Twinrix (n=264):
  
  • Month 1:  91.6% (HAV); 17.9% (HBV)
  • Month 2:  97.7% (HAV);  61.2% (HBV)
  • Month 7:  99.6% (95% CI, 97.9-100.0) (HAV); 95.1% (95% CI, 91.7-97.4) (HBV)
• Havrix and Engerix-B (n=269):
  
  • Month 1:  98.1% (HAV); 7.5% (HBV)
  • Month 2:  98.9% (HAV); 50.4% (HBV)
  • Month 7:  99.3% (95% CI, 97.3-99.9) (HAV); 92.2% (95% CI, 88.3-95.1) (HBV)
• The absolute difference in anti-HAV seropositivity rates between groups was 0.36% (90% CI: -1.8, 3.1). Non-inferiority in terms of anti-HAV response was demonstrated (lower limit of the 90% CI was higher than the pre-specified non-inferiority criterion of -4.3%). 
• The absolute difference in anti-HBsAg seroprotection rates between groups was 2.8% (90% CI: -1.3, 7.7). Non-inferiority in terms of anti-HBV response was demonstrated (lower limit of the 90% CI was higher than the pre-specified non-inferiority criterion of -9.4%).

Since the immune responses to hepatitis A and hepatitis B induced by Twinrix were non-inferior to the monovalent vaccines, efficacy is expected to be similar to the efficacy for each of the monovalent vaccines.

Immunogenicity: Accelerated Dosing Schedule (Day 0, 7, and 21 to 30, Month 12)

In 496 healthy adults, the safety and immunogenicity of Twinrix given on a 0-, 7-, and 21- to 30-day schedule followed by a booster dose at 12 months (n=250), was compared with separate vaccinations with monovalent hepatitis A vaccine (Havrix at 0 and 12 months) and hepatitis B vaccine (Engerix-B at 0, 1, 2, and 12 months) as a control group (n=246).

After a booster dose at Month 12, seroprotection rates for hepatitis B and seroconversion rates for hepatitis A at Month 13 following Twinrix were non-inferior to the control group. Results were the following:

• Twinrix (n=194-204): 
  
  • Month 13: 100% (95% CI, 98.1-100.0) (HAV); 96.4% (95% CI, 92.7-98.5) (HBV)
• Havrix + Engerix-B (n=197-207):
  
  • Month 13: 100% (95% CI, 98.1-100.0) (HAV); 93.4% (95% CI, 89.0-96.4) (HBV)
• The absolute difference in anti-HBs seroprotection rates between groups (Havrix + Engerix-B minus Twinrix) was -2.99 (95% CI, -7.80, 1.49). Non-inferiority was demonstrated as the upper limit of the 95% CI was lower than the pre-defined limit of 7%. 
• The absolute difference in anti-HAV seropositivity rates between groups (Havrix + Engerix-B minus Twinrix) was 0 (95% CI, -1.91, 1.94). Non-inferiority was demonstrated as the upper limit of the 95% CI was lower than the pre-defined limit of 7%. 

Immunogenicity in Adults Older than 40 Years

The effect of age on immune response to Twinrix was studied in 2 trials.

• The first trial evaluated participants aged 41–63 years (N=72; mean age: 50). All participants were seropositive for anti-HAV antibodies following the third dose of Twinrix. For the hepatitis B response, 94% of participants were seroprotected after the third dose of Twinrix.
• The second trial included participants aged 19 years and older with a comparison between those older than 40 years (n=183, aged 41–70 years; mean age: 48) and those aged 40 years or younger (n=191; aged 19–40 years; mean age: 33). More than 99% of participants in both age groups achieved a seropositive response for anti-HAV antibodies, and GMTs were comparable between the age groups. In the older adults who received Twinrix, 92.9% (95% CI, 88.2-96.2) achieved seroprotection against hepatitis B compared with 96.9% (95% CI, 93.3-98.8) of the younger adults. The GMT was 1,890 mIU/mL in the older group compared with 2,285 mIU/mL in the younger group.

Duration of Immunity

In two clinical trials, participants (n=129) demonstrated that antibodies to both HAV and HBV surface antigen persisted for at least 4 years after the first vaccine dose in a 3-dose series of Twinrix, given on a 0-, 1-, and 6-month schedule. For comparison, after the recommended immunization regimens for Havrix and Engerix-B, respectively, similar studies of 114 participants have shown that seropositivity to HAV and HBV also persists for at least 4 years.