Elicit: Innate Immune Activation by Zoster Vaccine AS01B

Innate Immune Activation by Zoster Vaccine AS01B

Zoster Vaccine Recombinant, Adjuvanted AS01B Adjuvant Innate Immune Activation

Abstract

Direct measurement of AS01B adjuvant-induced innate immune activation is remarkably limited despite the vaccine’s well-established clinical efficacy. Of 10 studies reviewed, only one directly assessed innate immune responses, finding sustained activation of monocytes, dendritic cells, and NK cells persisting up to 5 years post-vaccination, along with development of trained immunity characterized by enhanced responses to both homologous and heterologous antigens and epigenetic modifications including decreased TGFβ pathway accessibility. Mechanistically, AS01B stimulates local innate activation through TLR4 signaling (MPL) and cytokine induction (QS-21), synergistically recruiting and activating antigen-presenting cells. However, the remaining nine studies focused exclusively on adaptive immunity endpoints—antibodies and T cells—despite these being downstream consequences of adjuvant-mediated innate activation.

The robust adaptive immune responses (97.8% humoral response rate, 93.3% CD4+ T-cell response rate) and vaccine efficacy (≥90% in immunocompetent adults, 42.5-82.5% in severely immunocompromised HSCT recipients) provide indirect evidence of effective innate immune priming, as does the reactogenicity profile with 74.2% reporting injection site pain. The observation that NHBCL patients achieved high efficacy despite low antibody responses suggests cell-mediated immunity—and the innate priming generating it—drives protection. A critical gap exists between AS01B’s well-characterized clinical outcomes and the sparse direct characterization of the innate immune mechanisms underlying its effectiveness.

Methods

We analyzed 10 sources from an initial pool of 200, using 7 screening criteria. Each paper was reviewed for 9 key aspects that mattered most to the research question.

Results

Characteristics of Included Studies

Study Full text retrieved? Study Design Population Sample Size (Immunogenicity) Primary Focus
Weinberg et al., 2017 No Comparative study Adults 50-70+ years, immunocompetent Not specified Comparison of ZV and gE/AS01B CMI responses
Cunningham et al., 2018 Yes Phase III RCT, observer-blind Adults ≥50 years 3,293 humoral, 466 CMI Immunogenicity of HZ/su in ZOE-50/70 trials
Stadtmauer et al., 2021 Yes Phase III RCT, observer-blind Autologous HSCT recipients ≥18 years 114-1,721 participants Immunogenicity and efficacy post-HSCT
Dagnew et al., 2018 No Phase III RCT, observer-blind Adults ≥18 years with hematologic malignancies 415 humoral, 132 CMI End-of-study immunogenicity and efficacy
Johnson et al., 2024 No Observational RZV recipients (age not specified) 10-14 vaccinees Trained immunity generation
Bastidas et al., 2019 No Phase IIIB open-label extension Adults ≥60 years at initial vaccination 70 participants 10-year persistence and modeling
Pauksens et al., 2017 No Phase IIIB open extension Adults ≥60 years (mean 72.3) 70 participants 9-year immune persistence
Hastie et al., 2020 Yes Phase IIIB open-label extension Adults vaccinated at ≥60 years (mean 82.6 at additional dosing) 70 enrolled, 68 in ATP cohort 10-year persistence and anamnestic response
Boutry et al., 2020 Yes Extension study (ZOSTER-049) Adults ≥50 years from ZOE-50/70 7,277 for efficacy analysis Long-term efficacy and immunogenicity
Oostvogels, 2017 No Phase III RCT, observer-blind Adults ≥18 years with hematologic malignancies 415 humoral, 132 CMI Immunogenicity and safety in HM patients

Direct Innate Immune Activation Measurements

Only one study directly measured innate immune responses to RZV. Johnson et al. (2024) assessed innate immune cell activation in 10-14 vaccinees, measuring B cell, monocyte, and dendritic cell (DC) responses by PDL1 expression, and NK cell responses by CD25 and CD137 co-expression. These innate responses demonstrated two-phase kinetics: a transient increase post-dose 1 and a persistent increase post-dose 2 lasting up to 1 year. In a verification cohort of 14 vaccinees, DC, NK, and monocyte responses to recombinant gE remained elevated above pre-vaccination levels for up to 5 years.

The study also demonstrated the development of trained immunity, with purified monocytes and NK cells from vaccinees showing increased responses to both homologous (rgE) and heterologous (CMV lysate) stimulation from pre- to post-vaccination. Monocyte ATAC-seq analysis revealed significant chromatin changes in 16 genes, including decreased chromatin accessibility of the TGFβ pathway post-vaccination, potentially representing a mechanism underlying trained immunity development.

Mechanistic Basis of AS01B Adjuvant Activity

While most studies did not directly measure innate immune activation, Cunningham et al. (2018) described the mechanistic basis of AS01B function. The AS01B adjuvant system stimulates local and transient activation of the innate response, recruiting and activating antigen-presenting dendritic cells and macrophages. QS-21 induces transient local cytokine responses and activates these cells, while MPL acts as a TLR4 agonist that synergizes with QS-21 to enhance immune responses through IFN-γ production. This synergistic effect involves macrophage stimulation and early IFN-γ production, ultimately enhancing gE-antigen presentation by increasing the number of activated antigen-presenting cells.

Adaptive Immune Responses as Markers of Adjuvant Function

Humoral Immune Responses

Across studies in immunocompetent adults, RZV induced robust anti-gE antibody responses. In the ZOE-50 and ZOE-70 trials, 97.8% of HZ/su recipients showed a humoral response compared to 2.0% of placebo recipients. Geometric mean concentrations (GMCs) increased 39.1-fold over baseline at 1 month post-dose 2 and remained 8.3-fold above baseline at 36 months.

Long-term persistence studies demonstrated sustained antibody responses. Pauksens et al. (2017) found anti-gE antibody GMCs plateaued from year 4 onwards, remaining above the pre-vaccination value of 1,213.1 mIU/mL through year 9. Bastidas et al. (2019) reported antibody concentrations plateaued around year 3, remaining 5.9-fold higher than pre-vaccination levels at year 10. Hastie et al. (2020) observed GMCs of 9,123 mIU/mL and 7,384 mIU/mL at months 108 and 120, respectively, compared to a peak of 43,100 mIU/mL at 1 month after initial dose 2. Boutry et al. (2020) found anti-gE antibody concentrations persisted approximately 6 times above pre-vaccination levels up to year 8.

In immunocompromised populations, antibody responses varied. In autologous HSCT recipients, anti-gE antibody GMCs were similar between 18-49 and ≥50-year-olds at 1 month post-dose 2. However, non-Hodgkin B-cell lymphoma (NHBCL) patients showed lower anti-gE antibody GMCs compared to other underlying diseases, likely due to immunotherapeutic agents targeting B cells.

Cell-Mediated Immune Responses

RZV induced strong CD4+ T-cell responses across studies. In the ZOE trials, 93.3% of HZ/su recipients showed a gE-specific CD4[2+] T-cell response (expressing ≥2 activation markers) compared to 0% of placebo recipients. Median CD4[2+] T-cell frequencies increased 24.6-fold at 1 month and 7.9-fold at 36 months over baseline, remaining ≥5.6-fold above baseline in all age groups at 36 months. The proportion of CD4 T cells expressing all 4 activation markers increased over time in all age groups.

This systematic review identified a notable gap between the robust clinical efficacy and adaptive immune responses induced by RZV and the limited direct measurement of innate immune activation by the AS01B adjuvant. Only one study (Johnson et al., 2024) directly assessed innate immune responses, finding sustained activation of monocytes, dendritic cells, and NK cells for up to 5 years, along with evidence of trained immunity development.

References