Shingrix glycoprotein E antigen antibody response duration of protection

Shingrix anti-glycoprotein E antibody responses plateau at 5-7 fold above baseline levels by year 3 and persist for at least 10-11 years post-vaccination.

Abstract

Shingrix (adjuvanted recombinant zoster vaccine, RZV) elicits anti-glycoprotein E antibody responses that persist for at least 10-11 years post-vaccination. Across 10 studies with follow-up ranging from 12 months to 11 years, anti-gE antibody concentrations demonstrated a consistent pattern: an initial peak at one month post-dose 2 (17,000-19,000 mIU/mL), followed by a decline that plateaued around year 3 at 5- to 7-fold above pre-vaccination baseline levels. This plateau persisted through at least 12 years of follow-up, with antibody levels never returning to baseline. Vaccine efficacy against herpes zoster remained above 84% annually through year 8, with overall efficacy estimates of 81.6-90.9% across studies with 4-10 years of follow-up. The 11-year final analysis showed overall efficacy of 87.7% (95% CI: 84.9-90.1%) from vaccination through end of follow-up, though efficacy was lower in adults ≥70 years (73.2%) compared to younger age groups (86.7-87.1%). Cell-mediated immune responses paralleled humoral immunity, plateauing at 3.3-7-fold above baseline and persisting through 10-11 years. Similar antibody response patterns were observed in general populations, Asian populations, and immunocompromised renal transplant recipients, indicating robust protection across diverse host contexts for at least a decade following vaccination.

Methods

We analyzed 10 sources from an initial pool of 200, using 8 screening criteria. Each paper was reviewed for 5 key aspects that mattered most to the research question.

Records from Elicit search

• n = 200

• Papers screened using: Shingrix Vaccine, Relevant Outcomes, Follow-up Duration, Study Design, Study Population, Quantitative Data, Shingrix Focus, Human Studies

• n = 200

• Papers screened out

• n = 190

• Papers included for extraction

• n = 10

Paper search

We performed a semantic search across over 138 million academic papers from the Elicit search engine, which includes all of Semantic Scholar and OpenAlex.

We ran this query: "Shingrix glycoprotein E antigen antibody response duration of protection"

The search returned 200 total results from Elicit.

We retrieved 200 papers most relevant to the query for screening.

Screening

We screened in sources based on their abstracts that met these criteria:

• Shingrix Vaccine: Does this study involve participants who received Shingrix (recombinant zoster vaccine)?
• Relevant Outcomes: Does this study measure glycoprotein E-specific antibody responses and/or clinical protection against herpes zoster?
• Follow-up Duration: Does this study have a follow-up duration of at least 12 months post-vaccination?
• Study Design: Is this study a randomized controlled trial, cohort study, case-control study, systematic review, or meta-analysis?
• Study Population: Does this study include adults aged 18 years and older?
• Quantitative Data: Does this study report quantitative measures of antibody levels, antibody persistence, vaccine efficacy, or effectiveness over time?
• Shingrix Focus: Does this study include Shingrix data (rather than focusing solely on live zoster vaccine/Zostavax without Shingrix comparison)?
• Human Studies: Is this a human study (not an in vitro or animal study)?

We considered all screening questions together and made a holistic judgement about whether to screen in each paper.

Data extraction

We asked a large language model to extract each data column below from each paper.

• Study Duration: Extract the total follow-up duration for assessing Shingrix antibody response and protection, including:

  • Maximum follow-up time post-vaccination (in years/months)
  • Specific time points when measurements were taken (e.g., Y1, Y2, Y4, Y6, Y10)
  • Whether this was an extension study or primary study period
  • Any interim analysis time points reported

• Anti-gE Antibody Levels: Extract all quantitative data on glycoprotein E antibody concentrations from Shingrix vaccination, including:

  • Measurement method (ELISA, etc.)
  • Antibody concentration values at each time point
  • Units of measurement
  • Geometric mean concentrations (GMCs) or other summary statistics
  • Fold-increase compared to pre-vaccination levels
  • Any thresholds or cut-offs used to define protective levels

• Vaccine Efficacy: Extract vaccine efficacy data against herpes zoster specifically for Shingrix over time, including:

  • Overall vaccine efficacy percentages with 95% confidence intervals
  • Annual vaccine efficacy estimates by year post-vaccination
  • Efficacy by age groups if stratified
  • Time period over which efficacy was calculated
  • Any decline or stability patterns in efficacy over time

• Antibody Persistence: Extract data on the persistence and durability of anti-gE antibody responses, including:

  • Description of antibody level changes over time (decline, plateau, stability)
  • Comparison to pre-vaccination baseline levels at latest time points
  • Whether antibody levels remained above specific thresholds
  • Any description of waning or maintenance of immune response
  • Time to return to baseline levels (if applicable)

• Sample Characteristics: Extract key sample characteristics relevant to assessing antibody response duration, including:

  • Total number of participants in antibody analysis
  • Age range and mean age at vaccination
  • Any exclusions or dropouts affecting long-term follow-up
  • Geographic location or population characteristics that might affect generalizability of duration data

Results

Characteristics of included studies

The review included 10 studies evaluating the duration of protection from Shingrix (adjuvanted recombinant zoster vaccine, RZV) through anti-glycoprotein E (gE) antibody responses and vaccine efficacy. Studies varied in design, duration, and population characteristics.

Most studies were extension trials following participants from the pivotal ZOE-50 and ZOE-70 trials, with the longest follow-up reaching 11 years post-vaccination. Three studies specifically examined the ZOSTER-049 extension cohort at different interim time points. Sample sizes ranged from 70 participants in smaller extension cohorts to over 15,000 in the primary ZOE-50 trial. The majority of participants were of European ancestry (76%), though one study specifically examined Asian populations and another focused on immunocompromised renal transplant recipients.

Anti-glycoprotein E antibody concentrations over time

Studies consistently measured anti-gE antibody concentrations using enzyme-linked immunosorbent assay (ELISA), with a technical cutoff of 97 mIU/mL for seropositivity. Antibody levels were reported in milli-international units per milliliter (mIU/mL).

Anti-gE antibody concentrations demonstrated a consistent pattern across studies. Following an initial peak at approximately one month post-second dose (range 17,296.9-19,163.8 mIU/mL), antibody levels declined but plateaued at sustained elevations above baseline. The plateau phase typically began around year 3 post-vaccination and persisted through the longest follow-up periods. At 6 years post-vaccination, antibodies remained 7.3-fold above pre-vaccination levels (8159.0 vs. 1121.3 mIU/mL). The longest follow-up data showed antibody concentrations sustained at 5- to 7-fold above baseline through 10-12 years.

A modest decline in geometric mean concentrations (GMCs) was observed in the 6-year follow-up study, where antibody levels decreased by 20-25% between months 36 and 72, yet remained substantially elevated compared to pre-vaccination (8159.0 vs. 1121.3 mIU/mL at month 72). The 11-year follow-up showed stable GMCs from year 5 to year 8, a modest decrease at year 9, and then stabilization through year 12 at 6844.3 mIU/mL. Despite these fluctuations, antibody levels never returned to baseline during any study period.

In the immunocompromised renal transplant population, antibody responses followed a similar pattern with peak GMCs of 19,163.8 mIU/mL at one month post-dose 2, declining to 8545.1 mIU/mL by 12 months post-dose 2 but remaining 6.3-fold above baseline.

Vaccine efficacy against herpes zoster over time

Vaccine efficacy data demonstrated sustained protection across multiple years of follow-up, with annual estimates and age-stratified analyses available from several studies.

The primary ZOE-50 trial demonstrated exceptionally high initial vaccine efficacy of 97.2% (95% CI: 93.7-99.0) over a mean follow-up of 3.2 years, with efficacy ranging from 96.6% to 97.9% across age groups (50-59, 60-69, ≥70 years). This high level of protection was maintained in the Asian sub-analysis, which showed 95.6% efficacy in adults ≥50 years and 94.7% in adults ≥70 years over 4 years, with no significant decline during the follow-up period.

Extended follow-up through the ZOSTER-049 study showed vaccine efficacy remained above 84% annually from years 4 through 6, and overall efficacy of 84.0% (95% CI: 75.9-89.8%) during at least 2 years of follow-up in the interim analysis. When calculated from 1 month post-dose 2 through the year 2 interim analysis, overall efficacy was 90.9% (95% CI: 88.2-93.2%). The 10-year interim analysis reported vaccine efficacy of 81.6% (95% CI: 75.2-86.6%) during the ZOSTER-049 study period and 89.0% (95% CI: 85.6-91.3%) from 1 month post-dose 2 through year 10.

The final 11-year analysis revealed more detailed temporal patterns. Annual vaccine efficacy remained stable between 83.9% and 82.8% during years 6-8, decreased to 73.7% during year 9 and 71.7% during year 10, but rebounded to 82.0% during year 11. Overall vaccine efficacy during the ZOE-LTFU study was 79.8% (95% CI: 73.7-84.6%) for participants ≥50 years and 73.2% (95% CI: 62.9-80.9%) for participants ≥70 years. When calculated from 1 month post-dose 2 through the end of the 11-year follow-up, overall efficacy was 87.7% (95% CI: 84.9-90.1%). Age-stratified analysis at 11 years showed efficacy of 86.7% in the 50-59 year age group, 87.1% in the 60-69 year age group, and 73.2% in the ≥70 year age group.

Cell-mediated immune responses

While antibody levels provide one measure of immunologic persistence, cell-mediated immunity (CMI) also contributed to sustained protection. Studies measured gE-specific CD4[2+] T-cells expressing ≥2 activation markers using intracellular cytokine staining.

The frequency of gE-specific CD4[2+] T-cells remained above baseline from year 6 to year 8 post-vaccination. By 6 years post-vaccination, the gE-specific cell-mediated immune response was 3.8 times higher than pre-vaccination values (477.3 vs. 119.4 activated gE-specific CD4+ T cells per 10^6 cells). This cellular response plateaued at approximately 3.3-fold above pre-vaccination levels starting around year 4 and persisting through year 10. The 11-year follow-up showed that cell-mediated immune responses plateaued at approximately 7-fold above pre-vaccination levels.

In the comparative study examining RZV versus live zoster vaccine, RZV recipients demonstrated significantly higher gE-specific responses measured by interferon-γ (IFN-γ) and interleukin 2 (IL-2) at all time points post-immunization. Only RZV recipients maintained higher post-vaccination gE-specific IL-2+ and IFN-γ+ responses for 5 years, suggesting that the 5-year persistence of VZV-specific memory and gE-specific Th1 immunity may underlie superior RZV efficacy.

Protection in immunocompromised populations

The renal transplant study provided critical data on RZV immunogenicity in chronically immunosuppressed individuals receiving daily immunosuppressive therapy. In this population, anti-gE antibody GMCs were 1354.4 mIU/mL pre-vaccination, peaked at 19,163.8 mIU/mL (95% CI: 15,041.5-24,416.0) at 1 month post-dose 2, and remained elevated at 8545.1 mIU/mL (95% CI: 6,753.7-10,811.5) at 12 months post-dose 2. This represented a 14.1-fold increase at peak and a sustained 6.3-fold increase at 12 months post-dose 2. Both humoral and cell-mediated immune responses were higher in RZV recipients compared to placebo across all post-vaccination time points and persisted above pre-vaccination baseline at 12 months post-dose 2. No safety concerns arose, and overall occurrences of renal function changes, rejections, serious adverse events, and potential immune-mediated diseases were similar between RZV and placebo groups.

Synthesis

The data demonstrate remarkably consistent immunologic and clinical protection across diverse populations and extended follow-up periods, though with some nuanced temporal patterns that warrant interpretation.

Antibody dynamics and plateau phase: All studies converge on a characteristic antibody response pattern: an initial peak at 1 month post-dose 2 (17,000-19,000 mIU/mL), followed by a decline that stabilizes into a plateau phase beginning around year 3. This plateau represents a 5- to 7-fold elevation above baseline that persists through at least 10-12 years. The 20-25% decline observed between months 36 and 72 in one study and the modest decrease at year 9 in another appear to represent normal antibody homeostasis rather than immunologic waning, as levels remained substantially above the 97 mIU/mL seropositivity cutoff and stabilized rather than continuing to decline.

Vaccine efficacy stability with late fluctuation: Vaccine efficacy remained remarkably stable at >84% annually through year 8, with overall estimates ranging from 81.6% to 90.9% across studies with 4-10 years of follow-up. The decrease to 73.7% during year 9 and 71.7% during year 10, followed by a rebound to 82.0% during year 11, likely reflects statistical variation in small numbers of breakthrough cases in the aging cohort rather than a true immunologic decline. This interpretation is supported by the maintained antibody plateau during this same period and the subsequent rebound in efficacy.

Age-related heterogeneity: The lower efficacy observed in participants ≥70 years (73.2%) compared to younger age groups (86.7-87.1%) likely reflects both the increased herpes zoster risk with advancing age and potentially reduced immune responses in the oldest participants. However, the 73.2% efficacy in this oldest cohort still represents substantial clinical benefit, particularly given that these participants were 72.5 years old on average at the start of the long-term follow-up study and reached ages in the early 80s by the end of follow-up. The initial ZOE-50 trial showed similar high efficacy (96.6-97.9%) across all age groups, suggesting that aging during the follow-up period may contribute to the observed differences.

Consistency across populations: The similar antibody response patterns in general populations, Asian populations, and immunocompromised renal transplant recipients suggests that the fundamental mechanism of RZV-induced immunity is robust across diverse host contexts. The 6.3-fold sustained elevation at 12 months in renal transplant recipients is comparable to the 5-7-fold plateau observed in immunocompetent populations at later time points.

Integration of humoral and cellular immunity: The dual persistence of both antibody responses (5-7-fold above baseline) and cell-mediated responses (3.3-7-fold above baseline) through 10-11 years suggests that RZV induces coordinated and durable immune memory. The finding that only RZV (not live zoster vaccine) maintained gE-specific memory responses through 5 years provides mechanistic support for the superior long-term efficacy observed in clinical trials.

The preponderance of evidence indicates that RZV induces sustained immunologic protection lasting at least 10-11 years post-vaccination, with antibody levels plateauing at 5-7-fold above baseline, cell-mediated responses maintained at similar elevations, and vaccine efficacy consistently exceeding 80% in most age groups. While minor fluctuations occur, particularly in years 9-10, the overall trajectory demonstrates stability rather than progressive waning.

References

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