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.

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.

Characteristics of Included Studies

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.

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.

Safety Profile and Reactogenicity

Reactogenicity provides indirect evidence of innate immune activation, as local and systemic reactions reflect inflammatory responses to the adjuvant.

In hematologic malignancy patients, pain was the most frequent local solicited adverse event, reported by 48.2% of participants, while fatigue was reported by 47.8%. RZV was more reactogenic than placebo in this population, though the occurrence of unsolicited adverse events, serious adverse events (SAEs), and potential immune-mediated diseases (pIMDs) was similar between study groups. No safety concerns were identified.

Across studies, the safety profile was consistently described as clinically acceptable.

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. 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.

Factors Influencing Adjuvant Response

Age Effects

Most studies found minimal age effects on RZV-induced immune responses. Weinberg et al. reported that gE/AS01B efficacy does not vary with age of the vaccinee, unlike the live attenuated zoster vaccine whose efficacy decreases with age.

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. The clinical outcomes provide the ultimate validation of AS01B’s effectiveness: ≥90% efficacy in immunocompetent adults and 42.5-82.5% efficacy even in severely immunocompromised HSCT recipients.