Elicit: Innate Immune Activation by Zoster Vaccine AS01B

Zoster Vaccine Recombinant, Adjuvanted AS01B Adjuvant Innate Immune Activation

AS01B induces sustained innate immune activation lasting up to 5 years through TLR4-mediated pathways and generates trained immunity in monocytes and NK cells, but direct measurement of innate responses is severely limited with only one of ten studies directly assessing these mechanisms.

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. More on methods

Screening

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

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

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. 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.

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, remaining high for the 4-year duration of the ZOE-70 trial. Pauksens et al. reported high efficacy with limited waning over 4 years. In the ZOSTER-049 extension study, overall vaccine efficacy was 84.0% (95% CI: 75.9-89.8%) during at least 2 years of follow-up, and 90.9% (95% CI: 88.2-93.2%) from 1 month post-dose 2 until the end of year 2 observation.

In immunocompromised populations, efficacy varied by underlying disease. Dagnew et al. reported 87.2% efficacy in patients with hematologic malignancies who had completed or were undergoing anticancer immunosuppressive therapies. In autologous HSCT recipients, vaccine efficacy against herpes zoster ranged from 42.5% to 82.5% across underlying diseases, with statistically significant efficacy in NHBCL and multiple myeloma patients. Notably, efficacy was high in NHBCL patients despite their lower humoral responses, suggesting that cell-mediated immune responses are the main mechanistic driver for protection against herpes zoster.

References
A. Weinberg, et al. (2017). A comparison of the immunogenicity of a live attenuated herpes zoster vaccine (ZV) and the recombinant gE/AS01B candidate vaccine in older adults. Journal of Immunology
A. Cunningham, et al. (2018). Immune Responses to a Recombinant Glycoprotein E Herpes Zoster Vaccine in Adults Aged 50 Years or Older. Journal of Infectious Diseases
E. Stadtmauer, et al. (2021). Adjuvanted recombinant zoster vaccine in adult autologous stem cell transplant recipients: polyfunctional immune responses and lessons for clinical practice. Human Vaccines & Immunotherapeutics
A. Dagnew, et al. (2018). Immunogenicity, Safety, and Post-hoc Efficacy Assessment of the Adjuvanted Recombinant Zoster Vaccine in Adults with Hematologic Malignancies: A Phase 3, Randomized Clinical Trial. Open Forum Infectious Diseases
Michael J. Johnson, et al. (2024). Trained Immunity Generated by The Recombinant Zoster Vaccine (RZV). Journal of Immunology
A. Bastidas, et al. (2019). Long-term Immunological Persistence of the Adjuvanted Recombinant Zoster Vaccine: Clinical Data and Mathematical Modeling. Open Forum Infectious Diseases
K. Pauksens, et al. (2017). Persistence of Immune Response to an Adjuvanted Varicella‐Zoster Virus Subunit Candidate Vaccine for up to Year 9 in Older Adults. Open Forum Infectious Diseases
Andrew Hastie, et al. (2020). Immunogenicity of the Adjuvanted Recombinant Zoster Vaccine: Persistence and Anamnestic Response to Additional Doses Administered 10 Years After Primary Vaccination. Journal of Infectious Diseases
C. Boutry, et al. (2020). The Adjuvanted Recombinant Zoster Vaccine (RZV) Confers Long-term Protection Against Herpes Zoster: Interim Results of an Extension Study (ZOSTER-049) of Two Clinical Trials (ZOE-50 and ZOE-70). Open Forum Infectious Diseases
L. Oostvogels (2017). Immunogenicity and Safety of an Adjuvanted Herpes Zoster Subunit Candidate Vaccine in Adults with Hematologic Malignancies: A Phase III, Randomized Clinical Trial. Open Forum Infectious Diseases