Immunogenicity and Safety of an Adjuvanted Herpes Zoster Subunit Vaccine Coadministered With Seasonal Influenza Vaccine in Adults Aged 50 Years or Older

Abstract

Background: The immunogenicity and safety of an adjuvanted herpes zoster subunit (HZ/su) vaccine when coadministered with a quadrivalent seasonal inactivated influenza vaccine (IIV4) was investigated in a phase 3, open-label, randomized clinical trial in adults aged ≥50 years.

Methods: Subjects were randomized 1:1 to receive either HZ/su (varicella zoster virus glycoprotein E; AS01B Adjuvant System) and IIV4 at day 0 followed by a second HZ/su dose at month 2 (coadministration group), or IIV4 at month 0 and HZ/su at months 2 and 4 (control group). The primary objectives were the HZ/su vaccine response rate in the coadministration group and the noninferiority of the antibody responses to HZ/su and IIV4 in the coadministration compared with the control group. Safety information was collected throughout the duration of the study.

Results: A total of 413 subjects were vaccinated in the coadministration group and 415 in the control group. The HZ/su vaccine response rate in the coadministration group was 95.8% (95% confidence interval, 93.3%-97.6%) and the anti-glycoprotein E GMCControl/Coadmin ratio was 1.08 (.97-1.20). The primary noninferiority objectives were met. No safety concerns were observed.

Conclusions: No interference in the immune responses to either vaccine was observed when the vaccines were coadministered, and no safety concerns were identified.

Clinical trials registration: NCT01954251.

Keywords: adjuvant; coadministration; herpes zoster; influenza; subunit vaccine.

Figure 1.

Subject disposition. A total of 828 subjects aged ≥50 years were randomized to the 2 treatment groups. Subjects in the coadministration group received the first herpes zoster subunit (HZ/su) vaccination (HZ/su-1) and the quadrivalent seasonal inactivated influenza vaccine (IIV4) vaccination in different arms on day 0 (d 0) and the second HZ/su vaccination (HZ/su-2) at month 2 (mo 2). Subjects in the control group received the IIV4 vaccination on day 0, HZ/su-1 at month 2, and HZ/su-2 at month 4. Blood samples for immunogenicity analyses were collected on day 0, day 21, and month 3 for the coadministration group, and on day 0, day 21, month 2, and month 5 for the control group. The final study follow-up was a phone call to collect final safety data 1 year after the HZ/su-2 vaccination. Subjects were withdrawn from the study owing to a serious adverse event (SAE) or potential immune-mediated disease (pIMD) (9 subjects), a nonserious adverse event (AE; 3 subjects), withdrawn consent (w/d; 8 subjects), or loss to follow-up (LFU; 12 subjects).

Figure 2.

Seroconversion rates (SCRs) for the quadrivalent seasonal inactivated influenza vaccine (IIV4) according to age group and Center for Biologics Evaluation and Research (CBER) criteria. SCRs at postvaccination day 21 are presented for each age group in the coadministration (Coadmin) and control treatment groups in the according-to-protocol immunogenicity cohort for each influenza strain in IIV4. Seroconversion was defined as a postvaccination hemagglutination inhibition antibody titer of either ≥40 1/dilution for initially seronegative subjects or ≥4-fold the prevaccination antibody titer for initially seropositive subjects. Dotted lines represent minimum CBER-specified requirements for the lower limit of the 95% confidence interval (CI) of the SCR in each age group: 40% for subjects aged 50–64 years and 30% for those aged ≥65 years. Asterisks denote SCRs that met these criteria, and error bars represent 95% CIs.

Figure 3.

Seroprotection rates (SPRs) according to age group and Center for Biologics Evaluation and Research (CBER) criteria. SPRs at prevaccination (Pre) and postvaccination day 21 (d 21) are presented for subjects aged 50–64 or ≥65 years in the coadministration (Coadmin) and control treatment groups in the according-to-protocol immunogenicity cohort for each influenza strain in the quadrivalent seasonal inactivated influenza (IIV4) vaccine. Seroprotection was defined as a hemagglutination inhibition antibody titer ≥40 1/dilution. Dotted lines represent minimum CBER-specified requirements for the lower limit of the 95% confidence interval (CI) of the SPR in each age group: 70% for subjects aged 50–64 and 60% for those aged ≥65 years. All SPRs at day 21 met the age-specific CBER criteria. Error bars represent 95% CIs.

Figure 4.

Reactogenicity of the herpes zoster subunit (HZ/su) and quadrivalent seasonal inactivated influenza (IIV4) immunizations. Solicited local and general reactions are presented for the total vaccinated cohort. The coadministration (Coadmin) group received the first dose of HZ/su and the IIV4 vaccine on day 0 and the second dose of HZ/su at month 2. The control group received the IIV4 vaccine on day 0, the first dose of HZ/su at month 2, and the second dose of HZ/su dose at month 4. A, Local reactions occurring in the coadministration group within 7 days after coadministration of the first dose of HZ/su (HZ) and IIV4 or in the control group within 7 days after each vaccine was administered separately are shown for each arm. Reactions for the coadministration group were recorded concurrently for 7 days after day 0; reactions for the control group were recorded for 7 days after day 0 for IIV4 and 7 days after the first dose of HZ/su was administered at month 2. B, General reactions occurring within 7 days after the first dose of HZ/su and IIV4 coadministration in the coadministration group or within 7 days after each vaccine was administered separately in the control group. General reactions for the coadministration group were recorded for 7 days after day 0 and were attributable to both vaccines given at the same time; reactions for the control group were recorded for 7 days after day 0 for IIV4 and 7 days after the first dose of HZ/su was administered at month 2, and so were attributable to each vaccine given separately. GI, gastrointestinal symptoms. C, General reactions occurring within 7 days after administration of the second dose of HZ/su in each group. Reactions were recorded in month 2 for the coadministration group and in month 4 for the control group. A local reaction for redness or swelling was recorded if the diameter was ≥20 mm; it was recorded as grade 3 intensity if the diameter was >100 mm. Fever was recorded if the oral temperature was ≥37.5°C; it was recorded as grade 3 intensity if it was >39.0°C. Other general reactions were recorded if they were mild or easily tolerated (no interference in normal daily activity), moderate (discomfort that interfered with normal daily activity), or severe (grade 3; significant discomfort that prevented normal daily activity). Error bars represent 95% confidence intervals.