Elicit: 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.

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.

Records from Elicit search

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: "Zoster Vaccine Recombinant, Adjuvanted AS01B adjuvant innate immune activation"

The search returned 200 total results from Elicit.

Screening

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

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.

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.

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.

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+ T-cell response. Median CD4+ T-cell frequencies increased 24.6-fold at 1 month and remained ≥5.6-fold above baseline in all age groups at 36 months.

Safety Profile and Reactogenicity

Reactogenicity provides indirect evidence of innate immune activation, as local and systemic reactions reflect inflammatory responses to the adjuvant. The most frequent local adverse event was pain, while common systemic adverse events included fatigue and myalgia.

Clinical Efficacy

RZV demonstrated high vaccine efficacy against herpes zoster across diverse populations. In the ZOE trials of immunocompetent adults, efficacy was age-independent with 91% efficacy in individuals aged 80 years or older.

Factors Influencing Adjuvant Response

Age Effects

Most studies found minimal age effects on RZV-induced immune responses.

Immunosuppression Effects

Immunosuppression affected adjuvant responses differentially depending on the mechanism.

Synthesis

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 directly assessed innate immune responses, finding sustained activation of monocytes, dendritic cells, and NK cells for up to 5 years. The mechanistic understanding of AS01B comes primarily from one source describing how MPL and QS-21 synergistically activate innate responses.