The efficacy, immunogenicity and safety of a recombinant tetrameric gE-Fc fusion protein vaccine for herpes zoster in adults 40 years of age or older：a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial

The efficacy, immunogenicity and safety of a recombinant tetrameric gE-Fc fusion protein vaccine for herpes zoster in adults 40 years of age or older：a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial | Research Square Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Help Center Sign In Submit a Preprint Cite Share Download PDF Article The efficacy, immunogenicity and safety of a recombinant tetrameric gE-Fc fusion protein vaccine for herpes zoster in adults 40 years of age or older：a multicentre, randomised, double-blind, placebo-controlled, phase 3 trial Jingxin Li, Peng-Fei Jin, Ya-Ru Quan, Xuefeng Gao, Mingwei Wei, and 13 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-9064014/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 07 Aug, 2026 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Abstract Abstract A recombinant gE-Fc fusion protein adjuvanted with aluminum hydroxide, LZ901, has elicited favorable cellular immunogenicity in adults, non-inferiority to HZ/su (GSK) in previous study. Here we conducted a randomized, placebo-controlled, phase 3 trial across 14 sites of four provinces in China, to evaluate the efficacy and safety of LZ901 in adults ≥40 years. Participants (1:1) received two intramuscular doses of LZ901 or placebo 30 days apart. The primary objective was to assess the efficacy of LZ901during the first 12 months after vaccination, in reducing the risk of herpes zoster. 26018 participants (13010 in LZ901 group, 13008 in placebo group) were evaluated. Over median 332 days follow-up, herpes zoster was confirmed in 15 LZ901 recipients and in 178 placebo recipients (1.3 versus 15.8 per 1000 person-years) in the pre-protocol cohort. Overall vaccine efficacy against herpes zoster was 91.6% (95% confidence interval [CI], 86.3 to 95.3; p<0.001). Efficacy against in participants between 40 and 69 years of age was 93.9% (95% CI, 89.1 to 97.0; p<0.001), while that in participants who were older than 70 years was 66.9% (95% CI, 14.6 to 89.2; p=0.016). Post-herpetic neuralgia (PHN) was identified in one of 15 cases in LZ901 group and in 24 of 178 cases in placebo group, resulting a vaccine efficacy of 95.9% (95% CI, 63.9 to 99.93; p<0.001) against PHN. LZ901 group had more injection-site and systemic reactions within 7 days than the placebo group, but the occurrences of grade 3 reactions were low and similar in both groups (0.4% versus 0.3%). No serious adverse events or safety concerns associated with LZ901 were noted. LZ901 significantly reduced the risk of herpes zoster in adults who were 40 years of age or older in 12 months, with a favorable safety profile. This study has already completed the trial registration at Chinese Clinical Trial Registry, ChiCTR (ChiCTR2300076253). Health sciences/Medical research/Clinical trial design/Clinical trials/Phase III trials Health sciences/Medical research/Epidemiology Figures Figure 1 Figure 2 Figure 3 Introduction Herpes zoster arises from varicella-zoster virus (VZV) reactivation, which establishes lifelong latency in the dorsal root ganglia following primary infection during childhood 1,2 . Over 95% of adults aged 50 years or older have been infected with VZV, with an estimated lifetime risk of 30% for herpes zoster 3 . Herpes zoster can lead to severe complications 4 , among which post-herpetic neuralgia (PHN), the most common complication, affects 10~18% of herpes zoster patients, causing persistent neuropathic pain that substantially impairs quality of life and increases healthcare utilization 5,6 . Herpes zoster has a high incidence among individuals aged 40 years and older, and the incidence increases with age, reaching 8~12/1000 person-years in adults ≥80 years, driven by age-related decline in VZV-specific T-cell immunity, a critical defense mechanism against viral reactivation 7,8 . With global aging populations, herpes zoster has emerged as an increasingly significant health burden worldwide. Currently, two vaccines have been licensed for herpes zoster: a first-generation live attenuated zoster vaccine and a second-generation recombinant zoster vaccine (HZ/su, GSK) containing VZV glycoprotein E adjuvanted with AS01B. Live attenuated zoster vaccine shows 51% efficacy against herpes zoster in adults ≥50 years, but protection wanes to 18.3% in those ≥80 years 9,10 . While, HZ/su demonstrates >90% efficacy against herpes zoster and PHN across all ages, including those aged 70 years or older, with sustained protection exceeding 70% over 10 years 11-13 . However, despite the high efficacy, immunization of HZ/su is accompanied by high reactogenicity with 10% of recipients experiencing grade 3 reactions 14 . Additionally, the high costs and constrained global supply severely restrict its access in low-and middle-income countries (LMICs). These challenges highlight the need for other equally effective vaccines against herpes zoster, with improved tolerability and affordability. The investigational zoster vaccine LZ901, an aluminum hydroxide adjuvanted recombinant VZV glycoprotein E with human Fc fusion (gE-Fc), represents a promising candidate. Its tetrameric structure of gE-Fc combining four VZV gE domains with dual human IgG1 Fc fragments enhances Fcγ receptor-mediated antigen uptake by dendritic cells, driving robust CD4⁺ and CD8⁺ T-cell responses 15 . In a prior head-to-head trial, LZ901 was non-inferior to HZ/su in cellular immunogenicity at 30 days after immunization, and demonstrated a more favorable reactogenicity profile 16 . However, the efficacy of LZ901 against herpes zoster in adults has not been revealed. Here, we first report the preliminary efficacy, immunogenicity, and safety of LZ901 in adults 40 years of age or older from an ongoing phase 3 trial conducted in China. Results Study populations Between September 28 and December 11, 2023, we screened 29,439 volunteers, of whom 26,039 were enrolled and randomized to the vaccine group (n=13018) or placebo group (n=13021) (Figure 1). Overall, 25,577 participants received two doses of LZ901 (n=12,788) or placebo (n=12,789), and 12,707 and 12,680 participants, respectively, were included in the per-protocol population for the primary efficacy analysis. The safety population comprised 26,019 participants who received at least one dose (LZ901, n=13,011; placebo, n=13,008), while the per-protocol immunogenicity population included 1,475 and 1,462 participants, respectively. In the safety population, 99.2% of the participants were Han Chinese and 59.1% were female, with a mean age of 57.0 years (range, 40 to 90 years). Demographic characteristics were similar between the two study groups (Table 1). Efficacy During the surveillance period from day 1 to month 12 after the second dose, a total of 270 participants reported suspected herpes zoster (Figure S1). By excluding 41 cases occurring within 0-30 days after the first or second dose, a total of 194 confirmed herpes zoster cases occurring more than 30 days after the second dose were included in the primary efficacy analysis. Of the 193 confirmed herpes zoster cases in the per-protocol population, 15 occurred in the LZ901 group and 178 in the placebo group. The overall vaccine efficacy of 91.6% (95% CI, 86.3 to 95.3; p<0.001) among participants who were 40 years of age or older (Table 2, Figure 2). Laboratory-confirmed cases comprised 13 cases (1.1/1000 person-years) with LZ901 versus 164 cases (14.5/1000 person-years) with placebo, corresponding to a vaccine efficacy of 92.1% (95% CI, 86.7 to 95.7) (Table 2). PHN was identified in one of 15 cases in LZ901 group and in 24 of 178 cases in placebo group, resulting a vaccine efficacy of 95.9% (95% CI, 63.9 to 99.9) (Table 2, Figure 2). However, when PHN was defined as pain persisting for at least 90 days after the onset of herpes zoster, PHNs were identified in one of 15 cases in LZ901 group and in 8 of 178 cases in placebo group, resulting a vaccine efficacy of 89.0% (95% CI, 41.3 to 99.4; p < 0.001). For herpes zoster-associated severe acute pain, 12 cases occurred in the LZ901 group and 160 in the placebo group, and vaccine efficacy was 92.6% (95% CI, 87.2 to 96.1) (Table S2). Efficacy against herpes zoster in participants between 40 and 69 years of age was 93.9% (95%CI, 89.1 to 97.0), while that in participants who were older than 70 years was 66.9% (95%CI, 14.6 to 89.2) (Table 2). No significant variation in vaccine efficacy was observed among participants under 70 years of age, with efficacy ranging from 94.0% (95%CI, 80.2 to 99.0) in the 40-49 year age group to 90.8% (95%CI, 80.5 to 96.5) in the 60-69 year age group (Table S1). No difference of vaccine efficacy against  herpes zoster was observed across sex, region and chronic disease subgroups (Table S1). Estimated vaccine efficacy in the modified intention-to-treat population was much the same as that in the per-protocol analysis (Table S1 and S2). A post-hoc analysis revealed that the first dose of the LZ901 vaccine rapidly induced partial protection, with an efficacy of 85.8% (95%CI, 20.1 to 99.2) between days 15 and 30 after the first dose. Moreover, the increase in vaccine efficacy was even more pronounced following the second dose: efficacy reached 83.4% (95% CI: 2.9 to 99.1) within the first 14 days and 100% (95% CI, 54.9 to 100.0) between days 15 and 30 after the second dose (Table S3). Safety Within 30 days after vaccination, 16.4% (2137/13011) of participants in the LZ901 vaccine group reported at least one adverse reaction, which was more frequent than that (9.0%, 1167/13008) reported in the placebo group (p<0.001). Injection-site solicited reactions within 7 days after vaccination were reported in 11.6% (1503/13011) of participants in the LZ901 group and 3.7% (484/13008) in the placebo group (p <0.001). Systemic solicited reactions were reported by 5.2% (681/13011) of LZ901 participants and 4.3% (555/13008) of participants receiving placebo (p<0.001) (Figure 3, Table S4). Although the incidence of adverse reactions was significantly higher in the LZ901 group compared to that in the placebo group, the occurrence of grade 3 reactions did not differ significantly between the groups (0.4% vs 0.3% p=0.672). The most commonly reported reaction in the LZ901 recipients was pain at injection-site (10.3%, 1334/13011) (Figure 3). The occurrences of unsolicited reactions were similar between the two groups, with 2.6% (341/13011) in LZ901 group vs 2.5% (320/13008) in placebo group (p=0.409) (Table S4). The overall numbers of SAEs were similar in the LZ901 group (425 in 13011 participants [3.3%]) and the placebo group (475 in 13008 participants [3.7%]) (Table S5). All the SAEs were unlikely related to LZ901 nor placebo, except for one SAE: a 58-year-old participant had non-infectious gastroenteritis diagnosed two days after receiving the first dose of LZ901 and recovered after 6 days of hospitalization for treatment. The participant did not receive the second dose and was clinically well throughout the study. A total of 31 deaths were recorded, all of which were unrelated to vaccination (18 herpes zoster recipients [0.1%] and 15 placebo recipients [0.1%]) during the whole study period (Table S9). Immunogenicity More than 98% of participants were seropositive for anti-gE antibodies at baseline, with GMCs of 1152.6 (95%CI, 1099.0 to 1208.9) mIU/mL in LZ901 group and 1136.1 (95%CI, 1083.6 to 1191.1) mIU/mL in placebo group, respectively. Two doses of LZ901 elicited a substantial increase of antibody titre, with GMC on day 30 after two doses of 33140.3 (95%CI, 32022.8 to 34296.8) mIU/mL and GMFI of 28.8 (95%CI, 27.4 to 30.1) compared to that at baseline. By 12 months, the GMC of anti-gE antibodies declined to 11169.4 (95%CI, 10743.7 to 11612.0) mIU/mL, with a 3.0-fold decrease from the peak level observed at day 30 (Figure S2, Figure S3, Table S6). A ≥4-fold rise in anti-gE antibody titer was achieved in 98.4% (1451/1475) of LZ901 recipients at 30 days and maintained in 82.4% (1215/1475) at 12 months. While, the 4-fold increase were only noted in 0.8% (12/1462) and 3.2% (47/1462) in the placebo group at day 30 and 12 months, respectively (Table S6). Discussion In this multicenter, phase 3 trial, two doses of the LZ901 vaccine demonstrated an efficacy of 91.6% (95% CI, 86.3 to 95.3) against all diagnosed herpes zoster. In individuals aged 50 years and older, the efficacy against herpes zoster was 91.1% (84.9 to 95.2). LZ901 also significantly reduced the incidence of PHN, with a vaccine efficacy of 89.0% (41.3 to 99.4). These findings indicate that LZ901 effectively prevents herpes zoster and substantially reduces its complications, a crucial outcome given the substantial impact of PHN on quality of life 5,22 . In addition to the robust protection achieved after the two-dose regimen, partial protection emerged rapidly after the first dose. Vaccine efficacy reached 85.8% (20.1 to 99.2) during days 15-30 post-first dose, and increased further to 91.7% (57.9 to 99.5) within 30 days after the second dose. Age-stratified analyses showed consistently high LZ901 efficacy in adults aged 40–69 years (90.8%–96.9%), but reduced efficacy in those aged ≥70 years (66.9%). Compared with the licensed HZ/su vaccine, which maintains >90% efficacy even in older adults 11-13 , LZ901 may have an efficacy gap in this age group, possibly due to differences in adjuvant systems. HZ/su contains the AS01B adjuvant, which elicits strong cellular immune responses and may better overcome immunosenescence 23,24 . In contrast, LZ901 employs aluminum hydroxide, which likely provides a more moderate level of immunostimulation compared to AS01B, particularly in those ≥70 years 23,25,26 . However, LZ901 demonstrated a more favorable safety profile, with predominantly mild to moderate reactions and markedly fewer grade 3 events than HZ/su (0.4% vs. 16.5%), which may improve acceptability among older adults 13 . Unlike previous herpes zoster vaccine trials that enrolled adults aged ≥50 years 10,12 , this study included participants aged ≥40 years. Emerging epidemiological data indicate a rising risk among younger adults, a trend that may be driven by increased awareness, diagnosis and reporting. In our trial, the incidence of herpes zoster in placebo recipients aged 40~49 years was 14.2 per 1000 person-years, underscoring a non-negligible disease burden in this younger demographic. The use of a placebo-controlled design was in the context of the herpes zoster vaccine immunization landscape at the time of study initiation in China, when HZ/su vaccine was expensive and limited in supply, and a domestic live-attenuated herpes zoster vaccine had just been approved but not yet widely accessible. Notably, besides of this efficacy trial of LZ901 vaccine, we did a head-to-head comparison on immunogenicity of LZ901 and HZ/su previously, which showed that LZ901 was non-inferior to HZ/su in eliciting both CD4+ and CD8+ T-cell responses 16 . Several limitations should be acknowledged. First, the small number of participants and herpes zoster cases among those ≥70 years limited the precision of our efficacy estimate in this high-risk group. Further studies with larger sample sizes of the people ≥70 years are needed to get a robust estimation of the LZ901 vaccine efficacy in older adults. Second, the reported efficacy reflects protection within 12 months after vaccination, longer-term durability of protection remains unknown. This trial is ongoing, and the follow-up study over three years will help clarify the persistence of immune protection and the potential need for booster immunisation. Third, immunocompromised individuals, such as those with HIV, malignancies, or receiving dialysis, were excluded from this trial. Although HZ/su has shown efficacy in certain immunocompromised subgroups 27,28 , the efficacy and safety of LZ901 in those immunocompromised populations remain to be evaluated. Finally, the study population was predominantly Han Chinese, limiting the generalizability of the findings to other ethnic groups. In conclusion, the LZ901 vaccine significantly reduced the risk of herpes zoster and PHN in adults aged between 40 and 69 years of age in the first 12 months after vaccination. Methods Study design This is a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial conducted at 14 sites of four provinces in China. Eligible participants were healthy adults aged 40 years or older with no self-reported history of varicella or herpes zoster vaccination and no diagnosis of herpes zoster within the 5 years prior to enrollment. Detailed inclusion and exclusion criteria are included in full protocol in Supplementary Appendix. The protocol and informed consent were approved by the institutional review board of the Jiangsu Provincial Center of Disease Control and Prevention. Written informed consent from each participant was obtained before screening. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice guidelines. This report presents the pre-specified 12-month analysis, at which point the primary efficacy endpoint was met, demonstrating the primary efficacy of LZ901. The study remains ongoing to assess the persistence of protection and immune responses. At this stage, the authors remain blinded to participant-level data. Randomisation and masking Participants were stratified according to sites and age (40~49, 50~59, 60 ~69, and ≥70 years) before randomization. And then, participants were randomly assigned in a 1:1 ratio to receive either two-dose of LZ901 vaccine or placebo using an online centralized randomization system. Randomization lists were generated by an independent statistician using SAS (version 9.4). The packaging and appearance of vaccine and placebo were identical, with the randomization code labeled as the only identifier. The investigators, participants, and those who were responsible for the evaluation of any study end point were masked to the group assignment. Primary and secondary endpoints The primary objective of the study was to evaluate the efficacy of the LZ901 vaccine in reducing the risk of herpes zoster, as compare with placebo. The primary endpoint was herpes zoster occurring ≥30 days after the second dose, including laboratory-confirmed cases and clinically confirmed cases in whom-laboratory results were unavailable or inconclusive. The secondary efficacy endpoint was the laboratory-confirmed herpes zoster cases occurring at least 30 days after the second dose. Safety endpoints include the incidence of participants with solicited injection-site or systemic reactions, unsolicited adverse events, and serious adverse events (SAEs). Secondary immunological endpoints included seroconversion rates, geometric mean concentrations (GMCs) and geometric mean fold increase (GMFI) at day 30 after the second dose. Seropositivity of gE-specific IgG antibodies in serum is defined as concentration ≥100 milli-International Units (mIU)/mL. Exploratory efficacy outcomes were the incidence of PHN and herpes zoster-associated severe acute pain (ZBPI>3). PHN was defined as pain in the area of herpes zoster rash with a “worst pain in the last 24 hours” score of 0 or greater according to the Zoster Brief Pain Inventory, which persisted or appeared 28 days or more after rash recovery 17 . Besides, a post-hoc analysis for vaccine efficacy against PHN using an alternative, more stringent definition of pain persisting for ≥90 days after rash onset, which was following the European consensus-based (S2k) guideline was performed 18 . Exploratory immunological endpoints included GMCs and GMFI of antibodies at month 12, 24 and 36 following the second dose, and the 24-month and 36-month persistence data are not yet available due to ongoing follow-up and will be reported in future publications. Procedure The investigational vaccine LZ901 were developed by Beijing Luzhu Biotechnology Co., Ltd., China. LZ901 vaccine contains 100 μg of tetrameric recombinant VZV gE-Fc protein and 0.25mg aluminum hydroxide adjuvant per 0.5ml/vial in each dose. The placebo contains only aluminum hydroxide adjuvant without the recombinant gE protein. Both the vaccine and placebo were used in liquid form and stored at 2~8℃. Vaccine or placebo was administered intramuscularly into the deltoid muscle at day 0 and day 30, following a two-dose regimen. Participants were observed at the clinic for 30 minutes after vaccination and used paper diary cards to record solicited adverse events within 7 days. Unsolicited adverse events within 30 days after each dose and all serious adverse events up to 12 months after the second dose were recorded. Adverse events were graded according to the China State Food and Drug Administration (2019) 19 , and their causal relationship to vaccination was assessed by investigators using the WHO-UMC system 20 . Immunogenicity subgroup involving 3000 participants were recruited from Guanyun, Jiangsu Province. Participants in the immunogenicity subgroup donated blood samples for immunogenicity measurements at baseline before the first dose, and 30 days, 12 months after the second dose. Details of anti-gE antibody concentrations assay methods are provided in Supplementary Appendix. Suspected cases of herpes zoster Suspected herpes zoster was defined as the occurrence of new unilateral rash with or without pain after vaccination. Herpes zoster onset was confirmed by real-time polymerase chain reaction (PCR) assay (positive or negative); if confirmation by PCR was unavailable, it was verified by the Clinical Event Committee (CEC) (Figure S1). Pain associated with herpes zoster, including symptoms such as allodynia and pruritus, was assessed using the Zoster Brief Pain Inventory. The detailed criteria for the diagnosis of herpes zoster cases and pain associated with herpes zoster are provided in the Supplementary Appendix. Statistical analysis Sample size was calculated assuming 65% vaccine efficacy against herpes zoster and an incidence of 8 cases per 1,000 person-years in the placebo group 21 . Allowing for a 15% dropout rate over 12 months, 13,000 participants per group provided 95% power to demonstrate vaccine efficacy, with the lower bound of the 95% confidence interval exceeding 25% at a one-sided alpha of 0.025, and ensured accrual of at least 103 confirmed cases required by the case-driven design. Calculations were performed using PASS software (version 13). Vaccine efficacy was defined as 100×(1- incidence rate ratio), where the incidence rate ratio was the ratio of the incidence density in LZ901 group to that in the placebo group. A Poisson regression model was used to estimate the incidence rate ratio and its 95% confidence interval. Herpes zoster-free survival was analyzed using Kaplan-Meier curves, with group differences assessed by the log-rank test. Follow-up ended at the first confirmed herpes zoster episode, 12 months post-vaccination, or the last contact date, whichever occurred first. Fisher’s exact test or the chi-square test was used for categorical data, and the Clopper-Pearson method was employed to calculate the 95% CIs for rates. Meanwhile, the Student’s t-test was utilized to compare log-transformed antibody concentrations between the LZ901 group and the placebo group, while a paired t-test was applied to compare log-transformed antibody concentrations pre- and post-vaccination. All tests were two-tailed, with p values ≤0.05 considered statistically significant. Statistical analyses were performed using SAS software (version 9.4; SAS Institute). Declarations Data availability Individual participant data are available under restricted access for the requirements imposed by the Chinese Human Genetic Resources Administration concerning the public disclosure of clinical trial data. Researchers who provide a scientifically sound proposal will be are allowed to access to the de-identified individual participant data. Individual participant data can be obtained with a request to the corresponding author ( [email protected] ). All data generated in this study and the study protocol are provided in the Supplementary Information file. Acknowledgments This work was supported by National Key Research and Development Program of China (grant number 2023YFC2307601), National Natural Science Foundation of China (grant number 82222062), and Beijing Luzhu Biotechnology Co. We thank the participants in the trial and the members of the LZ901-300 trial team for their dedication and the contributions to the trial, and the members of the data and safety monitoring board (Chen Yao, Ph.D. [chair], Peking University First Hospital, Beijing; Jianhong Li, Ph.D., Dongzhimen Hosptial, Beijing University of Chinese Medicine, Beijing; Xuanyi Wan, Ph.D., Institutes of Biomedical SciencesFudan University, Shanghai; Huaqing Wang, Ph.D., Chinese Center for Disease Control and Prevention, Beijing) for their hard work, support, and guidance of the trial; and the adjudication committee (Wenhui Lun, Ph.D. [chair], Beijing Ditan Hospital, Capital Medical University, Beijing; Wenfei Li, Ph.D., Shandong First Medical University & Shandong Academy of Medical Sciences, Jinan; Ying Su, Ph.D., Qilu Hospital of Shandong University, Jinan) for their critical and timely review of the trial data. Author contributions J.L., L.Z. and Y.T. are the principal investigators of this trial. J.L., S.X., L.Z., Y.T., P.J. and X.G. designed the trials and the study protocol. P. J. and X. C. drafted of the manuscript. J.L. and P.J. contributed to critical review and revising of the report. P. J. and J. L. contributed to the data interpretation and revising of this manuscript. M.W., L.Z., Z.W, X.L. and the LZ901-300 Study Group led and participated in the site work, including the recruitment, follow-up and data collection. X.G., H.P., H.S., and Q.X. contributed to study supervision. S.X., Y.Q., K.X. and W.W. led the laboratory tests and analyses. J.X. and X.C. was responsible for statistical analysis. P.J. and X. C. contributed to literature search. Competing interests The authors declare no competing interests. References Cohen JI. Herpes zoster. N Engl J Med 2013; 369 (18): 1766-7. Gershon AA, Breuer J, Cohen JI, et al. Varicella zoster virus infection. Nat Rev Dis Primers 2015; 1 : 15016. Harpaz R, Ortega-Sanchez IR, Seward JF. Prevention of herpes zoster: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2008; 57 (Rr-5): 1-30; quiz CE2-4. Johnson RW, Alvarez-Pasquin MJ, Bijl M, et al. Herpes zoster epidemiology, management, and disease and economic burden in Europe: a multidisciplinary perspective. Ther Adv Vaccines 2015; 3 (4): 109-20. Johnson RW, Rice AS. Clinical practice. Postherpetic neuralgia. N Engl J Med 2014; 371 (16): 1526-33. Drolet M, Brisson M, Schmader KE, et al. The impact of herpes zoster and postherpetic neuralgia on health-related quality of life: a prospective study. Cmaj 2010; 182 (16): 1731-6. Kawai K, Gebremeskel BG, Acosta CJ. Systematic review of incidence and complications of herpes zoster: towards a global perspective. BMJ Open 2014; 4 (6): e004833. Valladales-Restrepo LF, Velasquez-Quimara S, Machado-Alba JE. Pharmacological Treatment of Herpes Zoster and Factors Associated with Its Recurrence. Antibiotics (Basel) 2023; 12 (4). Tricco AC, Zarin W, Cardoso R, et al. Efficacy, effectiveness, and safety of herpes zoster vaccines in adults aged 50 and older: systematic review and network meta-analysis. Bmj 2018; 363 : k4029. Oxman MN, Levin MJ, Johnson GR, et al. A vaccine to prevent herpes zoster and postherpetic neuralgia in older adults. N Engl J Med 2005; 352 (22): 2271-84. Strezova A, Díez Domingo J, Cunningham AL, et al. Final analysis of the ZOE-LTFU trial to 11 years post-vaccination: efficacy of the adjuvanted recombinant zoster vaccine against herpes zoster and related complications. EClinicalMedicine 2025; 83 : 103241. Lal H, Cunningham AL, Godeaux O, et al. Efficacy of an adjuvanted herpes zoster subunit vaccine in older adults. N Engl J Med 2015; 372 (22): 2087-96. Cunningham AL, Lal H, Kovac M, et al. Efficacy of the Herpes Zoster Subunit Vaccine in Adults 70 Years of Age or Older. N Engl J Med 2016; 375 (11): 1019-32. ACoIP A. Grading of Recommendations, Assessment, Development, and Evaluation (GRADE): Recombinant Zoster Vaccine (RZV) and Herpes Zoster Live-Attenuated Vaccine (ZVL). 2024. https://www.cdc.gov/acip/grade/herpes-zoster.html. Quan Y, Liu C, Lu X, et al. Comparison of the Immunogenicity of the LZ901 Vaccine and HZ/su Vaccine in a Mouse Model. Vaccines (Basel) 2024; 12 (7). Jin PF, Quan YR, Xiu SX, et al. Immunogenicity and safety of a recombinant gE-Fc fusion protein subunit vaccine for herpes zoster in adults ≥50 years of age: a randomised, active-controlled, non-inferiority trial. Nat Commun 2025; 16 (1): 7590. Chinese Expert Consensus on the Diagnosis and Treatment of Postherpetic Neuralgia. Chinese Journal of Pain Medicine 2016; 22 (3): 161-7. Gross GE, Eisert L, Doerr HW, et al. S2k guidelines for the diagnosis and treatment of herpes zoster and postherpetic neuralgia. J Dtsch Dermatol Ges 2020; 18 (1): 55-78. NMPA. Standard guidelines for grading adverse events in clinical trials of prophylactic vaccines. 2019. https://www.nmpa.gov.cn/xxgk/ggtg/ypggtg/ypqtggtg/ 20191231111901460.html. WHO. The use of the WHO-UMC system for standardised case causality assessment. 2013. https://www.who.int/publications/m/item/WHO-causality assessment. van Oorschot D, Vroling H, Bunge E, Diaz-Decaro J, Curran D, Yawn B. A systematic literature review of herpes zoster incidence worldwide. Hum Vaccin Immunother 2021; 17 (6): 1714-32. Johnson RW, Bouhassira D, Kassianos G, Leplège A, Schmader KE, Weinke T. The impact of herpes zoster and post-herpetic neuralgia on quality-of-life. BMC Med 2010; 8 : 37. Didierlaurent AM, Morel S, Lockman L, et al. AS04, an aluminum salt- and TLR4 agonist-based adjuvant system, induces a transient localized innate immune response leading to enhanced adaptive immunity. J Immunol 2009; 183 (10): 6186-97. Didierlaurent AM, Laupèze B, Di Pasquale A, Hergli N, Collignon C, Garçon N. Adjuvant system AS01: helping to overcome the challenges of modern vaccines. Expert Rev Vaccines 2017; 16 (1): 55-63. Reed SG, Bertholet S, Coler RN, Friede M. New horizons in adjuvants for vaccine development. Trends Immunol 2009; 30 (1): 23-32. Marrack P, McKee AS, Munks MW. Towards an understanding of the adjuvant action of aluminium. Nat Rev Immunol 2009; 9 (4): 287-93. Bastidas A, de la Serna J, El Idrissi M, et al. Effect of Recombinant Zoster Vaccine on Incidence of Herpes Zoster After Autologous Stem Cell Transplantation: A Randomized Clinical Trial. Jama 2019; 322 (2): 123-33. Mullane KM, Morrison VA, Camacho LH, et al. Safety and efficacy of inactivated varicella zoster virus vaccine in immunocompromised patients with malignancies: a two-arm, randomised, double-blind, phase 3 trial. Lancet Infect Dis 2019; 19 (9): 1001-12. Tables Table 1. Baseline characteristics of participants Characteristic Safety Population Per-protocol efficacy population Per-protocol immunogenicity population LZ901 group (N=13010) Placebo group (N=13008) LZ901  group (N=12707) Placebo group (N=12680) LZ901 group (N=1475) Placebo group (N=1462) Age(years), Mean (SD) 57.0 (9.0) 57.0 (8.9) 57.0 (9.0) 57.0 (8.9) 57.3 (9.3) 57.3 (9.2) Age group-no. of participants (%) 40-49 years 3001 (23.1) 3001 (23.1) 2947 (23.2) 2935 (23.1) 351 (23.8) 355 (24.3) 50-59 years 4505 (34.6) 4506 (34.6) 4398 (34.6) 4391 （34.6） 493 (33.4) 484 (33.1) 60-69 years 4501 (34.6) 4500 (34.6) 4384 (34.5) 4382 (34.6) 491 (33.3) 487 (33.3) ≥70 years 1003 (7.7) 1001 (7.7) 978 (7.7) 972 (7.7) 140 (9.5) 136 (9.3) Sex-no. of participants (%) Male 5324 (40.9) 5307 (40.8) 5199 (40.9) 5197 (41.0) 661 (44.8) 635 (43.4) Female 7686 (59.1) 7701 (59.2) 7508 (59.1) 7483 (59.0) 814 (55.2) 827 (56.6) Ethnicity-no. of participants (%) Han ethnic 12912 (99.2) 12905 (99.2) 12610 (99.2) 12577 (99.2) 1474 (99.9) 1461 (99.9) Others 98 (0.8) 103 (0.8) 97 (0.8) 103 (0.8) 1 (0.1) 1 (0.1) BMI(kg/m 2 ), Mean (SD) 25.5 (3.4) 25.5 (3.4) 25.5 (3.4) 25.5 (3.4) 26.3 (3.4) 26.2 (3.4) Comorbidities diseases-no. of participants (%) Hypertension 2565 (19.7) 2639 (20.3) 2492 (19.6) 2562 (20.0) 260 (17.6) 245 (16.8) Diabetes 706 (5.4) 790 (6.1) 686 (5.4) 763 (6.0) 72 (4.9) 53 (3.6) Cardiovascular disease other than hypertension 226 (1.7) 233 (1.8) 218 (1.7) 221 (1.7) 11 (0.7) 6 (0.4) Chronic respiratory disease 183 (1.4) 207 (1.6) 180 (1.4) 196 (1.6) 6 (0.4) 3 (0.2) Table 2. Vaccine efficacy against the herpes zoster and post-herpetic neuralgia in the per-protocol efficacy population* LZ901 group Placebo group Vaccine Efficacy % (95% CI) † No. of participants No. of cases Cumulative follow-up person-years‡ Incidence per 1000 person-years No. of participants No. of Cases Cumulative follow-up person-years‡ Incidence per 1000 person-years Herpes zoster Overall 12707 15 11376.9 1.3 12680 178 11292.8 15.8 91.6 (86.3-95.3) <70 years 11729 10 10504.9 1.0 11708 163 10427.2 15.6 93.9 (89.1-97.0) ≥50 years 9760 13 8735.5 1.5 9745 145 8673.3 16.7 91.1 (84.9-95.2) ≥70 years 978 5 872.1 5.7 972 15 865.6 17.3 66.9 (14.6-89.2) Laboratory-confirmed herpes zoster Overall 12707 13 11376.9 1.1 12680 164 11292.8 14.5 92.1 (86.7-95.7) <70 years 11729 9 10504.9 0.9 11708 149 10427.2 14.3 94.0 (88.9-97.2) ≥50 years 9760 11 8735.5 1.3 9745 134 8673.3 15.4 91.8 (85.6-95.8) ≥70 years 978 4 872.1 4.6 972 15 865.6 17.3 73.5 (27.1-92.5) Post-herpetic neuralgia ¶ Overall 12707 1 11376.9 0.09 12680 24 11292.8 2.1 95.9(63.9-99.9) <70 years 11729 1 10504.9 0.1 11708 23 10427.2 2.2 95.7 (61.9-99.9) ≥50 years 9760 1 8735.5 0.1 9745 22 8673.3 2.5 95.5 (78.5-99.7) ≥70 years 978 0 872.1 0 972 1 865.6 1.1 100.0 (-94.5-100) *The per-protocol efficacy population excluded participants who did not receive the second dose of vaccine or who received a confirmed diagnosis of herpes zoster within 1 month after the second dose. †Efficacy was calculated by means of the Poisson method. For the comparison of efficacy against herpes zoster and laboratory-confirmed herpes zoster of the vaccine versus placebo, P<0.001 in both the ≥40 and <70 years age groups, and P=0.016, 0.009 in the ≥70 years age group, respectively. For the efficacy against postherpetic neuralgia comparisons as placebo, P<0.001 in the ≥40 years age group, P=0.001 in the <70 years age group, the numbers of cases in the placebo group were not sufficient to obtain a significant result in the ≥70 years age group. ‡ Data were censored at the time of the first confirmed diagnosis of herpes zoster or postherpetic neuralgia ¶ Post-herpetic neuralgia was defined by pain persisting for ≥28 days after rash recovery. Additional Declarations There is NO Competing Interest. Supplementary Files 3SupplementaryAppendix.docx Supplementary Appendix 5LZ901PhaseIIIProtocol1.docx Protocol 6LZ901PhaseIIIStatisticalAnalysisPlan1.docx Protocol CONSORT2025editablechecklist.docx CONSORT checklist ReportingsummaryNCOMMS26020161.pdf Reporting summary SourcedataTicketID11060643.xlsx Cite Share Download PDF Status: Published Journal Publication published 07 Aug, 2026 Read the published version in Nature Communications → Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. 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