|
1
|
Huang S, Zhang X, Su Y, Zhuang C, Tang Z, Huang X, Chen Q, Zhu K, Hu X, Ying D, Liu X, Jiang H, Zang X, Wang Z, Yang C, Liu D, Wang Y, Tang Q, Shen W, Cao H, Pan H, Ge S, Huang Y, Wu T, Zheng Z, Zhu F, Zhang J, Xia N. Long-term efficacy of a recombinant hepatitis E vaccine in adults: 10-year results from a randomised, double-blind, placebo-controlled, phase 3 trial. Lancet 2024; 403:813-823. [PMID: 38387470 DOI: 10.1016/s0140-6736(23)02234-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 09/27/2023] [Accepted: 10/04/2023] [Indexed: 02/24/2024]
Abstract
BACKGROUND Hepatitis E virus (HEV) is a frequently overlooked causative agent of acute hepatitis. Evaluating the long-term durability of hepatitis E vaccine efficacy holds crucial importance. METHODS This study was an extension to a randomised, double-blind, placebo-controlled, phase-3 clinical trial of the hepatitis E vaccine conducted in Dontai County, Jiangsu, China. Participants were recruited from 11 townships in Dongtai County. In the initial trial, a total of 112 604 healthy adults aged 16-65 years were enrolled, stratified according to age and sex, and randomly assigned in a 1:1 ratio to receive three doses of hepatitis E vaccine or placebo intramuscularly at month 0, month 1, and month 6. A sensitive hepatitis E surveillance system including 205 clinical sentinels, covering the entire study region, was established and maintained for 10 years after vaccination. The primary outcome was the per-protocol efficacy of hepatitis E virus vaccine to prevent confirmed hepatitis E occurring at least 30 days after administration of the third dose. Throughout the study, the participants, site investigators, and laboratory staff remained blinded to the treatment assignments. This study is registered with ClinicalTrials.gov (NCT01014845). FINDINGS During the 10-year study period from Aug 22, 2007, to Oct 31, 2017, 90 people with hepatitis E were identified; 13 in the vaccine group (0·2 per 10 000 person-years) and 77 in the placebo group (1·4 per 10 000 person-years), corresponding to a vaccine efficacy of 83·1% (95% CI 69·4-91·4) in the modified intention-to-treat analysis and 86·6% (73·0 to 94·1) in the per-protocol analysis. In the subsets of participants assessed for immunogenicity persistence, of those who were seronegative at baseline and received three doses of hepatitis E vaccine, 254 (87·3%) of 291 vaccinees in Qindong at the 8·5-year mark and 1270 (73·0%) of 1740 vaccinees in Anfeng at the 7·5-year mark maintained detectable concentrations of antibodies. INTERPRETATION Immunisation with this hepatitis E vaccine offers durable protection against hepatitis E for up to 10 years, with vaccine-induced antibodies against HEV persisting for at least 8·5 years. FUNDING National Natural Science Foundation of China, Fujian Provincial Natural Science Foundation, Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences, and the Fundamental Research Funds for the Central Universities.
Collapse
Affiliation(s)
- Shoujie Huang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen, China
| | - Xuefeng Zhang
- Jiangsu Provincial Centre for Disease Control and Prevention, Nanjing, China
| | - Yingying Su
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen, China
| | - Chunlan Zhuang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen, China
| | - Zimin Tang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen, China
| | - Xingcheng Huang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen, China
| | - Qi Chen
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen, China
| | - Kongxin Zhu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen, China
| | - Xiaowen Hu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen, China
| | - Dong Ying
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen, China
| | - Xiaohui Liu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen, China
| | - Hanmin Jiang
- Dongtai Centre for Disease Control and Prevention, Yancheng, Jiangsu, China
| | - Xia Zang
- Dongtai Centre for Disease Control and Prevention, Yancheng, Jiangsu, China
| | - Zhongze Wang
- Dongtai Centre for Disease Control and Prevention, Yancheng, Jiangsu, China
| | - Changlin Yang
- Dongtai Centre for Disease Control and Prevention, Yancheng, Jiangsu, China
| | - Donglin Liu
- Dongtai Centre for Disease Control and Prevention, Yancheng, Jiangsu, China
| | - Yijun Wang
- Dongtai Centre for Disease Control and Prevention, Yancheng, Jiangsu, China
| | - Quan Tang
- Yancheng Centre for Disease Control and Prevention, Yancheng, Jiangsu, China
| | | | | | - Huirong Pan
- Xiamen Innovax Biotech Company, Xiamen, China
| | - Shengxiang Ge
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen, China
| | - Yue Huang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen, China
| | - Ting Wu
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen, China
| | - Zizheng Zheng
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen, China
| | - Fengcai Zhu
- Jiangsu Provincial Centre for Disease Control and Prevention, Nanjing, China
| | - Jun Zhang
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen, China.
| | - Ningshao Xia
- State Key Laboratory of Vaccines for Infectious Diseases, Xiang An Biomedicine Laboratory, School of Public Health and National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Innovation Platform for Industry-Education Integration in Vaccine Research, NMPA Key Laboratory for Research and Evaluation of Infectious Disease Diagnostic Technology, the Research Unit of Frontier Technology of Structural Vaccinology of Chinese Academy of Medical Sciences, Xiamen University, Xiamen, China.
| |
Collapse
|
|
2
|
Cui T, Zhang X, Wang Q, Yue N, Bao C, Jiang R, Xu S, Yuan Z, Qian Y, Chen L, Hang H, Zhang Z, Sun H, Jin H. Cost-effectiveness analysis of hepatitis E vaccination strategies among patients with chronic hepatitis B in China. Hepatol Res 2024; 54:142-150. [PMID: 37706554 DOI: 10.1111/hepr.13967] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2023] [Revised: 08/16/2023] [Accepted: 09/05/2023] [Indexed: 09/15/2023]
Abstract
AIM This study aimed to evaluate the cost-effectiveness of hepatitis E vaccination strategies in chronic hepatitis B (CHB) patients. METHODS Based on the societal perspective, the cost-effectiveness of three hepatitis E vaccination strategies-vaccination without screening, screening-based vaccination, and no vaccination-among CHB patients was evaluated using a decision tree-Markov model, and incremental cost-effectiveness ratios (ICERs) were calculated. Values for treatment costs and health utilities were estimated from a prior investigation on disease burden, and values for transition probabilities and vaccination-related costs were obtained from previous studies and government agencies. Sensitivity analyses were undertaken for assessing model uncertainties. RESULTS It was estimated that CHB patients superinfected with hepatitis E virus (HEV) incurred significantly longer disease course, higher economic burden, and more health loss compared to those with HEV infection alone (all p < 0.05). The ICERs of vaccination without screening and screening-based vaccination compared to no vaccination were 41,843.01 yuan/quality-adjusted life year (QALY) and 29,147.32 yuan/QALY, respectively, both lower than China's per-capita gross domestic product (GDP) in 2018. The screening-based vaccination reduced the cost and gained more QALYs than vaccination without screening. One-way sensitivity analyses revealed that vaccine price, vaccine protection rate, and decay rate of vaccine protection had the greatest impact on the cost-effectiveness analysis. Probabilistic sensitivity analyses confirmed the base-case results, and if the willingness-to-pay value reached per-capita GDP, the probability that screening-based vaccination would be cost-effective was approaching 100%. CONCLUSIONS The disease burden in CHB patients superinfected with HEV is relatively heavy in China, and the screening-based hepatitis E vaccination strategy for CHB patients is the most cost-effective option.
Collapse
Affiliation(s)
- Tingting Cui
- Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, China
| | - Xuefeng Zhang
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China
| | - Qiang Wang
- Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, China
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
| | - Na Yue
- Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, China
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
| | - Changjun Bao
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China
| | - Renjie Jiang
- Yancheng Center for Disease Control and Prevention, Yancheng, China
| | - Shilin Xu
- Yancheng Center for Disease Control and Prevention, Yancheng, China
| | - Zhaohu Yuan
- Zhenjiang Center for Disease Control and Prevention, Zhenjiang, China
| | - Yunke Qian
- Zhenjiang Center for Disease Control and Prevention, Zhenjiang, China
| | - Liling Chen
- Suzhou Center for Disease Control and Prevention, Suzhou, China
| | - Hui Hang
- Suzhou Center for Disease Control and Prevention, Suzhou, China
| | - Zhong Zhang
- Nanjing Center for Disease Control and Prevention, Nanjing, China
| | - Hongmin Sun
- Nanjing Center for Disease Control and Prevention, Nanjing, China
| | - Hui Jin
- Department of Epidemiology and Health Statistics, School of Public Health, Southeast University, Nanjing, China
- Key Laboratory of Environmental Medicine Engineering, Ministry of Education, School of Public Health, Southeast University, Nanjing, China
| |
Collapse
|
|
3
|
Cai B, Peyrani P, Beeslaar J, Burman C, Balmer P. Modeling persistence of hSBA titers over time following a primary series and a booster dose of MenB-FHbp. Vaccine 2023; 41:2729-2733. [PMID: 37024411 DOI: 10.1016/j.vaccine.2023.02.078] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/29/2022] [Accepted: 02/25/2023] [Indexed: 04/07/2023]
Abstract
MenB-FHbp is a meningococcal serogroup B vaccine. Persistence of hSBA titers against 4 diverse test strains ≤ 4 years after a 2-dose MenB-FHbp primary series and ≤ 26 months after a booster dose administered 4 years post-primary has been demonstrated. Here, we developed a power law model (PLM) to estimate the persistence of hSBA titers up to 5 years after a MenB-FHbp primary series and a booster dose using hSBA data from previous MenB-FHbp clinical trials in healthy adolescents. The PLM-predicted hSBA titers closely followed observed values after a 0, 6 month MenB-FHbp primary series and a booster dose 4 years later. At 5 years post-primary and 5 years post-booster, the PLM predicted that 15.2 %-50.0 % and 51.2 %-70.9 % of individuals, respectively, would have hSBA titers ≥ 1:8 or 1:16. The PLM supports that the persistence of hSBA titers is maintained for at least 5 years post-primary MenB-FHbp vaccination and post-booster.
Collapse
|
|
4
|
Zhang J, Zheng Z, Xia N. Prophylactic Hepatitis E Vaccine. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1417:227-245. [PMID: 37223870 DOI: 10.1007/978-981-99-1304-6_16] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
The hepatitis E has been increasingly recognized as an underestimated global disease burden in recent years. Subpopulations with more serious infection associated damage or death include pregnant women, patients with basic liver diseases, and elderly persons. Vaccine would be the most effective means for prevention of HEV infection. The lack of an efficient cell culture system for HEV makes the development of classic inactive or attenuated vaccine infeasible. Hence, the recombinant vaccine approaches are explored deeply. The neutralizing sites are located almost exclusively in the capsid protein, pORF2, of the virion. Based on pORF2, many vaccine candidates showed potential of protecting primate animals, two of them were tested in human and evidenced to be well-tolerated in adults and highly efficacious in preventing hepatitis E. The world's first hepatitis E vaccine, Hecolin® (HEV 239 vaccine), was licensed in China and launched in 2012.
Collapse
Affiliation(s)
- Jun Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China.
| | - Zizheng Zheng
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - Ningshao Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| |
Collapse
|
|
5
|
Zhou YH, Zhao H. Immunobiology and Host Response to HEV. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1417:93-118. [PMID: 37223861 DOI: 10.1007/978-981-99-1304-6_7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Subscribe] [Scholar Register] [Indexed: 05/25/2023]
Abstract
Hepatitis E virus (HEV) usually causes acute self-limiting hepatitis but sometimes leads to chronic infection in immunocompromised persons. HEV is not directly cytopathic. Immunologically mediated events after HEV infection are believed to play important roles in the pathogenesis and clearance of infection. The anti-HEV antibody responses have been largely clarified since the determination of major antigenic determinant of HEV, which is located in the C-terminal portion of ORF2. This major antigenic determinant also forms the conformational neutralization epitopes. Robust anti-HEV immunoglobulin M (IgM) and IgG responses usually develop 3-4 weeks after infection in experimentally infected nonhuman primates. In humans, potent specific IgM and IgG responses occur in the very early phase of the disease and are critical in eliminating the virus, in concert with the innate and adaptive T-cell immune responses. Testing anti-HEV IgM is valuable in the diagnosis of acute hepatitis E. The long-term persistence and protection of anti-HEV IgG provide the basis for estimating the prevalence of HEV infection and for the development of a hepatitis E vaccine. Although human HEV has four genotypes, all the viral strains are considered to belong to a single serotype. It is becoming increasingly clear that the innate and adaptive T-cell immune responses play critical roles in the clearance of the virus. Potent and multispecific CD4+ and CD8+ T cell responses to the ORF2 protein occur in patients with acute hepatitis E, and weaker HEV-specific CD4+ and CD8+ T cell responses appear to be associated with chronic hepatitis E in immunocompromised individuals.
Collapse
Affiliation(s)
- Yi-Hua Zhou
- Departments of Experimental Medicine and Infectious Diseases, Nanjing Drum Tower Hospital, Nanjing University Medical School, Nanjing, China
| | - Hong Zhao
- Department of Infectious Diseases, Second Hospital of Nanjing, Southeast University School of Medicine, Nanjing, China
| |
Collapse
|
|
6
|
Modelling SARS-CoV-2 Binding Antibody Waning 8 Months after BNT162b2 Vaccination. Vaccines (Basel) 2022; 10:vaccines10020285. [PMID: 35214743 PMCID: PMC8876471 DOI: 10.3390/vaccines10020285] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/07/2022] [Revised: 02/08/2022] [Accepted: 02/09/2022] [Indexed: 02/01/2023] Open
Abstract
Several lines of evidence suggest that binding SARS-CoV-2 antibodies such as anti-SARS-CoV-2 RBD IgG (anti-RBD) and neutralising antibodies (NA) are correlates of protection against SARS-CoV-2, and the correlation of anti-RBD and NA is very high. The effectiveness (VE) of BNT162b2 in preventing SARS-CoV-2 infection wanes over time, and this reduction is mainly associated with waning immunity, suggesting that the kinetics of antibodies reduction might be of interest to predict VE. In a study of 97 health care workers (HCWs) vaccinated with the BNT162b2 vaccine, we assessed the kinetics of anti-RBD 30–250 days after vaccination using 388 individually matched plasma samples. Anti-RBD levels declined by 85%, 92%, and 95% at the 4th, 6th, and 8th month from the peak, respectively. The kinetics were estimated using the trajectories of anti-RBD by various models. The restricted cubic splines model had a better fit to the observed data. The trajectories of anti-RBD declines were statistically significantly lower for risk factors of severe COVID-19 and the absence of vaccination side effects. Moreover, previous SARS-CoV-2 infection was associated with divergent trajectories consistent with a slower anti-RBD decline over time. These results suggest that anti-RBD may serve as a harbinger for vaccine effectiveness (VE), and it should be explored as a predictor of breakthrough infections and VE.
Collapse
|
|
7
|
Behrendt P, Wedemeyer H. [Vaccines against hepatitis E virus: state of development]. Bundesgesundheitsblatt Gesundheitsforschung Gesundheitsschutz 2022; 65:192-201. [PMID: 35099576 PMCID: PMC8802100 DOI: 10.1007/s00103-022-03487-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2021] [Accepted: 12/22/2021] [Indexed: 11/30/2022]
Abstract
In Europa ist aktuell kein Impfstoff gegen das Hepatitis-E-Virus (HEV) zugelassen. Demgegenüber steht in China bereits seit 10 Jahren mit HEV-239 (Hecolin®, Xiamen Innovax Biotech Co., Xiamen, China) ein Vakzin gegen den HEV-Genotyp 4 zur Verfügung. Herausforderungen für die Entwicklung von Impfstoffen ergeben sich v. a. aus den Unterschieden zwischen den Genotypen bezüglich Verbreitung, Übertragungswege und Risikogruppen. Weitere Hindernisse sind die Umhüllung von HEV im Blut durch Wirtsmembranen, die Replikation in verschiedenen Organen außerhalb der Leber sowie schwächere Immunantworten in vulnerablen Gruppen. In diesem Artikel wird der aktuelle Stand der verfügbaren und in fortgeschrittener präklinischer Evaluation befindlichen Vakzine gegen HEV mit Fokus auf Strategien der Impfstoffentwicklung dargestellt. Herausforderungen und Limitationen werden beschrieben. Aktuelle Impfkandidaten fokussieren auf proteinbasierte Immunisierungen mit dem Ziel der Induktion von schützenden, neutralisierenden Antikörperantworten. Das Ziel der HEV-239-Zulassungsstudie mit mehr als 100.000 Studienteilnehmern war die Verhinderung von akuten symptomatischen Infektionen. Es ist jedoch unklar, inwieweit asymptomatische Infektionen durch das Vakzin verhindert wurden und ob es in Risikopatienten für einen komplizierten Verlauf, wie Patienten mit Leberzirrhose, Immunsupprimierten und Schwangeren, effektiv genug wirkt. Effiziente In-vitro-Modelle ermöglichen zunehmend die Entwicklung von monoklonalen neutralisierenden Antikörpern zur passiven Immunisierung oder Therapie. Zukünftige Vakzine sollten neben einem sehr guten Sicherheitsprofil eine eindeutige Protektion gegenüber allen Genotypen demonstrieren. Die Entwicklung einer effizienten passiven Immunisierungsstrategie, insbesondere für immunsupprimierte Personen, ist wünschenswert.
Collapse
Affiliation(s)
- Patrick Behrendt
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Deutschland
| | - Heiner Wedemeyer
- Klinik für Gastroenterologie, Hepatologie und Endokrinologie, Medizinische Hochschule Hannover, Carl-Neuberg-Str. 1, 30625, Hannover, Deutschland.
| |
Collapse
|
|
8
|
Azman AS, Paul KK, Bhuiyan TR, Koyuncu A, Salje H, Qadri F, Gurley ES. Hepatitis E in Bangladesh: Insights from a National Serosurvey. J Infect Dis 2021; 224:S805-S812. [PMID: 34549775 PMCID: PMC8687073 DOI: 10.1093/infdis/jiab446] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Background Hepatitis E virus (HEV) genotypes 1 and 2 are a major cause of avoidable morbidity and mortality in South Asia. Despite the high risk of death among infected pregnant women, scarce incidence data has been a contributing factor to global policy recommendations against the introduction of licensed hepatitis E vaccines, one of the only effective prevention tools. Methods We tested serum from a nationally representative serosurvey in Bangladesh for anti-HEV immunoglobulin G and estimated seroprevalence. We used Bayesian geostatistical models to generate high-resolution maps of seropositivity and examined variability in seropositivity by individual-level, household-level, and community-level risk factors using spatial logistic regression. Results We tested serum samples from 2924 individuals from 70 communities representing all divisions of Bangladesh and estimated a national seroprevalence of 20% (95% confidence interval [CI], 17%–24%). Seropositivity increased with age and male sex (odds ratio, 2.2 male vs female; 95% CI, 1.8–2.8). Community-level seroprevalence ranged widely (0–78%) with higher seroprevalence in urban areas, including Dhaka, with a 3.0-fold (95% credible interval, 2.3–3.7) higher seroprevalence than the rest of the country. Conclusions Hepatitis E infections are common throughout Bangladesh. Strengthening surveillance for hepatitis E, especially in urban areas, can provide additional evidence to appropriately target interventions.
Collapse
Affiliation(s)
- Andrew S Azman
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, USA.,Institute of Global Health, Faculty of Medicine, University of Geneva, Geneva, Switzerland
| | | | | | - Aybüke Koyuncu
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, USA
| | - Henrik Salje
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, USA.,University of Cambridge, Cambridge, UK
| | | | - Emily S Gurley
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, USA
| |
Collapse
|
|
9
|
Xia R, Sun S, Shen M, Zhang L, Zhuang G. Targeted hepatitis E vaccination for women of childbearing age is cost-effective in China. Vaccine 2019; 37:5868-5876. [PMID: 31443991 DOI: 10.1016/j.vaccine.2019.08.003] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 07/13/2019] [Accepted: 08/02/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND Hepatitis E virus (HEV) infection is hyper-endemic in China, it is characterized with a high morbidity of fulminant hepatitis and mortality in pregnant women. The first hepatitis E vaccine, HEV 239, was licensed in China in 2011 which provides an effective preventive measure. OBJECTIVE To evaluate the cost-effectiveness of vaccination with HEV 239 in women of childbearing age in China and whether HEV antibody screening should be considered before vaccination. METHODS A decision tree-Markov model was constructed to simulate HEV infection in a closed female cohort with an average first-marriage age of 25 years and evaluate health and economic outcomes of two potential vaccination strategies, direct vaccination and combined screening and vaccination, from a societal perspective. An incremental cost-effectiveness ratio (ICER, additional costs per disability-adjusted life-year (DALY) averted) was calculated for each vaccination strategy versus no vaccination and between two vaccination strategies. Univariate and probabilistic sensitivity analyses were conducted to assess the robustness of the model findings. RESULTS ICERs of direct vaccination and combined screening and vaccination versus no vaccination were $4040 and $3114 per DALY averted, respectively, much lower than 1-time Chinese per-capita GDP ($8127). Direct vaccination would need additional $45,455 for each DALY averted compared with combined screening and vaccination, far more than the 3-time per-capita GDP. Probabilistic sensitivity analyses confirmed our findings that two vaccination strategies would be cost-effective if the willingness-to-pay reached the 1-time per-capita GDP, and that combined screening and vaccination would be more cost-effective than direct vaccination strategy. CONCLUSION Vaccinating women of childbearing age with HEV 239 would cost less than the 1-time per-capita GDP for each DALY averted in China, and the vaccination with a prior screening would be the optimal option.
Collapse
Affiliation(s)
- Ruyi Xia
- Department of Epidemiology and Biostatistics, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China.
| | - Shuliu Sun
- Department of Obstetrics, Northwest Women's and Children's Hospital, Xi'an, Shaanxi 710061, China.
| | - Mingwang Shen
- Department of Epidemiology and Biostatistics, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China.
| | - Lei Zhang
- Department of Epidemiology and Biostatistics, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China; Melbourne Sexual Health Centre, Alfred Health, Melbourne, Australia; Central Clinical School, Faculty of Medicine, Monash University, Melbourne, Australia; School of Public Health and Preventive Medicine, Faculty of Medicine, Monash University, Melbourne, Australia.
| | - Guihua Zhuang
- Department of Epidemiology and Biostatistics, School of Public Health, Xi'an Jiaotong University Health Science Center, Xi'an, Shaanxi 710061, China.
| |
Collapse
|
|
10
|
Kmush BL, Yu H, Huang S, Zhang X, Wu T, Nelson KE, Labrique AB. Long-term Antibody Persistence After Hepatitis E Virus Infection and Vaccination in Dongtai, China. Open Forum Infect Dis 2019; 6:ofz144. [PMID: 31024978 PMCID: PMC6475590 DOI: 10.1093/ofid/ofz144] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2018] [Accepted: 03/25/2019] [Indexed: 01/25/2023] Open
Abstract
Background Hepatitis E virus (HEV) is of global significance. HEV is a common cause of acute hepatitis in China. One of the major unanswered questions about HEV is the persistence of antibodies after infection and vaccination. Methods We examined antibody persistence 6.5 years after HEV exposures through natural infection and vaccination. Ninety-seven vaccine recipients and 70 individuals asymptomatically infected with HEV enrolled in the phase III HEV239 vaccine trial in Dongtai, China, were revisited. Results Antibody loss was 23.4% (95% confidence interval [CI], 17.1%-30.5%), with a nonsignificantly higher percentage of loss among those naturally infected (30.0%; 95% CI, 19.6%-42.1%) than those vaccinated (18.6%; 95% CI, 11.4%-27.7%; P = .085). Age and gender were not associated with antibody persistence. Only 2 people (1.2%) self-reported medically diagnosed jaundice or hepatitis-like illness in the last 10 years, both of whom had persistent antibodies. Contact with a jaundice patient and injectable contraceptive use were marginally associated with loss of detectable anti-HEV antibodies (P = .047 and .082, respectively), whereas transfusion was marginally associated with antibody persistence (P = .075). Conclusions Antibody loss was more common among those naturally infected compared with those vaccinated. However, none of the characteristics examined were strongly associated with antibody loss, suggesting that factors not yet identified may play a more important role in antibody loss. Long-term postvaccination antibody persistence is currently unknown and will be an important consideration in the development of policies for the use of the highly efficacious HEV vaccine. ClinicalTrials.gov registration. NCT01014845.
Collapse
Affiliation(s)
- Brittany L Kmush
- Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Huan Yu
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
| | - Shoujie Huang
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
| | - Xuefang Zhang
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China
| | - Ting Wu
- National Institute of Diagnostics and Vaccine Development in Infectious Diseases, State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, School of Public Health, Xiamen University, Xiamen, China
| | - Kenrad E Nelson
- Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.,Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| | - Alain B Labrique
- Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland.,Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
| |
Collapse
|
|
11
|
Abstract
Soon after the 1991 molecular cloning of hepatitis E virus (HEV), recombinant viral capsid antigens were expressed and tested in nonhuman primates for protection against liver disease and infection. Two genotype 1 subunit vaccine candidates entered clinical development: a 56 kDA vaccine expressed in insect cells and HEV 239 vaccine expressed in Escherichia coli Both were highly protective against hepatitis E and acceptably safe. The HEV 239 vaccine was approved in China in 2011, but it is not yet prequalified by the World Health Organization, a necessary step for introduction into those low- and middle-income countries where the disease burden is highest. Nevertheless, the stage is set for the final act in the hepatitis E vaccine story-policymaking, advocacy, and pilot introduction of vaccine in at-risk populations, in which it is expected to be cost-effective.
Collapse
Affiliation(s)
- Bruce L Innis
- Center for Vaccine Innovation and Access, PATH, Washington, D.C. 20001
| | - Julia A Lynch
- International Vaccine Institute, SNU Research Park, Gwanak-gu, Seoul 08826, Korea
| |
Collapse
|
|
12
|
Hakim MS, Ikram A, Zhou J, Wang W, Peppelenbosch MP, Pan Q. Immunity against hepatitis E virus infection: Implications for therapy and vaccine development. Rev Med Virol 2017; 28. [PMID: 29272060 DOI: 10.1002/rmv.1964] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/10/2017] [Revised: 11/10/2017] [Accepted: 11/14/2017] [Indexed: 12/20/2022]
Abstract
Hepatitis E virus (HEV) is the leading cause of acute viral hepatitis worldwide and an emerging cause of chronic infection in immunocompromised patients. As with viral infections in general, immune responses are critical to determine the outcome of HEV infection. Accumulating studies in cell culture, animal models and patients have improved our understanding of HEV immunopathogenesis and informed the development of new antiviral therapies and effective vaccines. In this review, we discuss the recent progress on innate and adaptive immunity in HEV infection, and the implications for the devolopment of effective vaccines and immune-based therapies.
Collapse
Affiliation(s)
- Mohamad S Hakim
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.,Department of Microbiology, Faculty of Medicine, Universitas Gadjah Mada, Yogyakarta, Indonesia
| | - Aqsa Ikram
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.,Atta-Ur-Rahman School of Applied Biosciences, National University of Science and Technology, Islamabad, Pakistan
| | - Jianhua Zhou
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands.,State Key Laboratory of Veterinary Etiological Biology, National Foot-and-Mouth Disease Reference Laboratory, Lanzhou Veterinary Research Institute, Chinese Academy of Agricultural Sciences, Lanzhou, Gansu, PR China
| | - Wenshi Wang
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands
| | - Maikel P Peppelenbosch
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands
| | - Qiuwei Pan
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center and Postgraduate School Molecular Medicine, Rotterdam, The Netherlands
| |
Collapse
|
|
13
|
Abstract
PURPOSE OF REVIEW Infection with the hepatitis E virus (HEV) is very common worldwide. The epidemiology, viral genotypes, and transmission routes differ between low-resource countries and economically developed countries. These differences have resulted in the design of diverse prevention and treatment strategies to combat HEV. RECENT FINDINGS The population seroprevalence of HEV immunoglobulin G varies between 5 and 50%. However, the diagnosis of acute hepatitis from HEV has not been common in the United States or Western Europe. Chronic progressive HEV infections have been reported among patients who are immunocompromised. Successful treatment of patients with chronic hepatitis from HEV infection with antiviral agents, such as ribavirin or interferon-α, has been reported. Extrahepatic manifestations of HEV infection are common. Large epidemics of hundreds or thousands of cases continue to be reported among populations in Asia and Africa. A subunit peptide HEV vaccine has been found to be highly efficacious in a large clinical trial. However, the vaccine has not been evaluated in populations of pregnant women or other risk groups and is only available in China. SUMMARY Although HEV infections are increasingly recognized as a global public health problem, there are few methods for prevention and treatment that are widely available.
Collapse
|
|
14
|
Zhang J, Zhao Q, Xia N. Prophylactic Hepatitis E Vaccine. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 948:223-246. [PMID: 27738988 DOI: 10.1007/978-94-024-0942-0_13] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Hepatitis E has been increasingly recognized as an underestimated global disease burden in recent years. Subpopulations with more serious infection-associated damage or death include pregnant women, patients with basic liver diseases, and elderly persons. Vaccine would be the most effective means for prevention of HEV infection. The lack of an efficient cell culture system for HEV makes the development of classic inactive or attenuated vaccine infeasible. Hence, the recombinant vaccine approaches are explored deeply. The neutralizing sites are located almost exclusively in the capsid protein, pORF2, of the virion. Based on pORF2, many vaccine candidates showed potential of protecting primate animals; two of them were tested in human and evidenced to be well tolerated in adults and highly efficacious in preventing hepatitis E. The world's first hepatitis E vaccine, Hecolin® (HEV 239 vaccine), was licensed in China and launched in 2012.
Collapse
Affiliation(s)
- Jun Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China.
| | - Qinjian Zhao
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - Ningshao Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| |
Collapse
|
|
15
|
Immunobiology and Host Response to HEV. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2017; 948:113-141. [PMID: 27738982 DOI: 10.1007/978-94-024-0942-0_7] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
Hepatitis E virus (HEV) causes acute self-limiting hepatitis in most cases and chronic infection in rare circumstances. It is believed to be noncytopathic, so immunologically mediated events should play important roles in its pathogenesis and infection outcomes. The anti-HEV antibody response was clarified when the major antigenic determinants on the ORF2 polypeptide were determined, which are located in its C-terminal portion. This subregion also forms the conformational neutralization epitopes. Robust anti-HEV immunoglobulin M (IgM) and IgG responses usually develop 3-4 weeks after infection in experimentally infected nonhuman primates. In humans, potent specific IgM and IgG responses occur in the very early phase of the disease and are critical in eliminating the virus, in concert with the innate and adaptive T-cell immune responses. They are also very valuable in the diagnosis of acute hepatitis E, when patients are tested for both anti-HEV IgM and IgG. The long-term persistence and protection of anti-HEV IgG provide the basis for estimating the prevalence of HEV infection and for the development of a hepatitis E vaccine. Although HEV has four genotypes, all the viral strains are considered to belong to a single serotype. It is becoming increasingly clear that the innate and adaptive T-cell immune responses play critical roles in the clearance of the virus. Potent and multispecific CD4+ and CD8+ T-cell responses to the ORF2 protein occur in patients with acute hepatitis E, and weaker HEV-specific CD4+ and CD8+ T-cell responses appear to be associated with chronic hepatitis E in immunocompromised individuals.
Collapse
|
|
16
|
Su YY, Huang SJ, Guo M, Zhao J, Yu H, He WG, Jiang HM, Wang YJ, Zhang XF, Cai JP, Yang CL, Wang ZZ, Zhu FC, Wu T, Zhang J, Xia NS. Persistence of antibodies acquired by natural hepatitis E virus infection and effects of vaccination. Clin Microbiol Infect 2016; 23:336.e1-336.e4. [PMID: 27836809 DOI: 10.1016/j.cmi.2016.10.029] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2016] [Revised: 10/15/2016] [Accepted: 10/28/2016] [Indexed: 11/30/2022]
Abstract
OBJECTIVE Naturally acquired anti-hepatitis E virus (HEV) immunity can protect against new HEV infections. The aim of this study was to analyse the persistence of naturally acquired anti-HEV immunoglobulin (Ig) G and anti-HEV IgG concentrations after vaccination. METHODS We examined the seropositivity rates of participants included in a phase 3 clinical efficacy trial (67 months' follow-up) for a HEV vaccine (Hecolin; Xiamen Innovax Biotech, China) and predicted long-term persistence using mixed-effect models. RESULTS The analysis focused on 2242 baseline seropositive participants in a control group (placebo recipients) and 2031 baseline seropositive participants in an vaccine group (vaccine recipients) who received 1 to 3 doses of Hecolin. Naturally acquired anti-HEV IgG levels decreased steadily independent of the initial antibody level; 50% of the placebo recipients were expected to have undetectable antibody concentrations after 14.5 years. After immunization with Hecolin, the power-law model and the modified power-law model predicted that 82.1 and 99.4% of the participants, respectively, would remain seropositive for anti-HEV IgG for 30 years after vaccination. CONCLUSIONS Whereas naturally acquired anti-HEV IgG levels decrease steadily, HEV vaccination induces long-lasting, high-level anti-HEV IgG concentrations.
Collapse
Affiliation(s)
- Y-Y Su
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - S-J Huang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - M Guo
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - J Zhao
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - H Yu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - W-G He
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| | - H-M Jiang
- Dongtai Centre for Disease Control and Prevention, Dongtai, China
| | - Y-J Wang
- Dongtai Centre for Disease Control and Prevention, Dongtai, China
| | - X-F Zhang
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China
| | - J-P Cai
- Dongtai Centre for Disease Control and Prevention, Dongtai, China
| | - C-L Yang
- Dongtai Centre for Disease Control and Prevention, Dongtai, China
| | - Z-Z Wang
- Dongtai Centre for Disease Control and Prevention, Dongtai, China
| | - F-C Zhu
- Jiangsu Provincial Center for Disease Control and Prevention, Nanjing, China
| | - T Wu
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China.
| | - J Zhang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China.
| | - N-S Xia
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Public Health, Xiamen University, Xiamen, China
| |
Collapse
|
|
17
|
Kulkarni SP, Thanapati S, Arankalle VA, Tripathy AS. Specific memory B cell response and participation of CD4 + central and effector memory T cells in mice immunized with liposome encapsulated recombinant NE protein based Hepatitis E vaccine candidate. Vaccine 2016; 34:5895-5902. [PMID: 27997340 DOI: 10.1016/j.vaccine.2016.10.046] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2016] [Revised: 10/14/2016] [Accepted: 10/16/2016] [Indexed: 11/20/2022]
Abstract
BACKGROUND Liposome encapsulated neutralizing epitope protein of Hepatitis E virus (HEV), rNEp, our Hepatitis E vaccine candidate, was shown to be immunogenic and safe in pregnant and non-pregnant mice and yielded sterilizing immunity in rhesus monkeys. METHODS The current study in Balb/c mice assessed the levels and persistence of anti-HEV IgG antibodies by ELISA, frequencies of B, memory B, T and memory T cells by flow cytometry and HEV-specific IgG secreting memory B cells by ELISPOT till 420days post immunization (PI) with 5?g rNEp encapsulated in liposome based adjuvant (2 doses, 4weeks apart). Mice immunized with a lower dose (1?g) were assessed only for anamnestic response post booster dose. RESULTS Vaccine candidate immunized mice (5?g dose) elicited strong anti-HEV IgG response that was estimated to persist for lifetime. At day 120 PI, frequency of memory B cells was higher in immunized mice than those receiving adjuvant alone. Anti-HEV IgG titers were lower in mice immunized with 1?g dose. A booster dose yielded a heightened antibody response in mice with both high (>800GMT, 5?g) and low (?100GMT, 1?g) anti-HEV IgG titers. At day 6th post booster dose, HEV-specific antibody secreting plasma cells (ASCs) were detected in 100% and 50% of mice with high and low anti-HEV IgG titers, respectively, whereas the frequencies of CD4+ central and effector memory T cells were high in mice with high anti-HEV IgG titers only. CONCLUSIONS Taken together, the vaccine candidate effectively generates persistent and anamnestic antibody response, elicits participation of CD4+ memory T cells and triggers memory B cells to differentiate into ASCs upon boosting. This approach of assessing the immunogenicity of vaccine candidate could be useful to explore the longevity of HEV-specific memory response in future HEV vaccine trials in human.
Collapse
Affiliation(s)
- Shruti P Kulkarni
- Hepatitis Group, National Institute of Virology, Pune, 130/1, Sus Road, Pashan, Pune 411021, Maharashtra, India
| | - Subrat Thanapati
- Hepatitis Group, National Institute of Virology, Pune, 130/1, Sus Road, Pashan, Pune 411021, Maharashtra, India
| | - Vidya A Arankalle
- Interactive Research School in Health Affairs (IRSHA), Bharati Vidyapeeth Deemed University, Pune-Satara Road, Katraj-Dhankawadi, Pune 411043, Maharashtra, India.
| | - Anuradha S Tripathy
- Hepatitis Group, National Institute of Virology, Pune, 130/1, Sus Road, Pashan, Pune 411021, Maharashtra, India.
| |
Collapse
|
|
18
|
Joshi SS, Arankalle VA. Differential Immune Responses in Mice Immunized with Recombinant Neutralizing Epitope Protein of Hepatitis E Virus Formulated with Liposome and Alum Adjuvants. Viral Immunol 2016; 29:350-60. [PMID: 27285290 DOI: 10.1089/vim.2016.0024] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023] Open
Abstract
In the developing countries, Hepatitis E virus (HEV) is a predominant cause of sporadic acute hepatitis in adults and waterborne epidemics leading to high mortality in pregnant women. Vaccine development mainly focuses on the structural capsid protein open-reading-frame-2 (ORF-2) of the virus. We successfully evaluated liposome-adjuvanted recombinant neutralizing epitope protein (rNEp), a part of ORF-2, 458-607aa, in mice and rhesus macaques. We compared immune response to adjuvants alone, rNEp alone, or adjuvanted with liposome (lipo-rNEp)/alum (al-rNEp) in mice following intramuscular administration of two doses of 5 μg each. IgG anti-HEV titers (enzyme-linked immunosorbent assay), immunophenotyping (flow cytometry, CD3(+)CD4(+), CD3(+)CD8(+), CD11c(+), CD11b(+), CD19(+) cells; costimulatory markers CD80, CD86, MHC-I, MHC-II, and early activation marker CD69), and levels of Th1/Th2 cytokines (IL-2/IFN-γ/IL-4/IL-5 and additionally IL-1β/IL-6/IL-10/TNF for early time points) were determined at early (4/12/24-h postdose-1) and later time points (2 weeks post-both doses). IgG anti-HEV titers were higher in the lipo-rNEp group than al-rNEp post-both doses (p < 0.05). At early time points, cell type proportions were comparable at the site of injection; IL-Iβ levels increased in lipo-rNEp, 24 h, while IL-6 levels rose in lipo-rNEp/al-rNEp/alum-alone groups, 4 h, compared to controls. In the draining lymph nodes (DLNs), CD11c(+)CD86(+) cells increased at 24 h in liposome-alone/lipo-rNEp groups. A rise in the CD11c(+)CD69(+) cells was noted in the lipo-rNEp group compared to other groups (p < 0.05). Cytokine levels in the spleen/sera remained unchanged in all the groups (p > 0.05). At 2 weeks postdose-2, CD11c(+)MHC-II(+)/CD11b(+)MHC-II(+) cells increased in the spleen in the lipo-rNEp and al-rNEp groups, respectively. In the DLNs, CD19(+)MHC-II(+) cells increased in rNEp/al-rNEp/lipo-rNEp groups post-both doses and CD11c(+)CD86(+) cells in the lipo-rNEp group. A balanced Th1/Th2 response was evident in the lipo-rNEp, while a Th2 bias was noted in al-rNEp. Different immune response gene clustering patterns were noted in uncultured spleens from immunized mice and cultured-stimulated splenocytes. In conclusion, lipo-rNEp is a better immunogen, works through dendritic cells, and elicits a balanced Th1/Th2 response, while alum functions through macrophages and induces a Th2 response.
Collapse
|
|
19
|
Ogholikhan S, Schwarz KB. Hepatitis Vaccines. Vaccines (Basel) 2016; 4:E6. [PMID: 26978406 PMCID: PMC4810058 DOI: 10.3390/vaccines4010006] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2015] [Revised: 01/11/2016] [Accepted: 01/14/2016] [Indexed: 12/22/2022] Open
Abstract
Viral hepatitis is a serious health problem all over the world. However, the reduction of the morbidity and mortality due to vaccinations against hepatitis A and hepatitis B has been a major component in the overall reduction in vaccine preventable diseases. We will discuss the epidemiology, vaccine development, and post-vaccination effects of the hepatitis A and B virus. In addition, we discuss attempts to provide hepatitis D vaccine for the 350 million individuals infected with hepatitis B globally. Given the lack of a hepatitis C vaccine, the many challenges facing the production of a hepatitis C vaccine will be shown, along with current and former vaccination trials. As there is no current FDA-approved hepatitis E vaccine, we will present vaccination data that is available in the rest of the world. Finally, we will discuss the existing challenges and questions facing future endeavors for each of the hepatitis viruses, with efforts continuing to focus on dramatically reducing the morbidity and mortality associated with these serious infections of the liver.
Collapse
Affiliation(s)
- Sina Ogholikhan
- Division of Pediatric Gastroenterology and Nutrition, Pediatric Liver Center, Johns Hopkins Medical Institutions, CMSC 2-125, 600 North Wolfe Street, Baltimore, MD 21287, USA.
| | - Kathleen B Schwarz
- Division of Pediatric Gastroenterology and Nutrition, Pediatric Liver Center, Johns Hopkins Medical Institutions, CMSC 2-125, 600 North Wolfe Street, Baltimore, MD 21287, USA.
| |
Collapse
|
|
20
|
Wang X, Li M, Li S, Wu T, Zhang J, Xia N, Zhao Q. Prophylaxis against hepatitis E: at risk populations and human vaccines. Expert Rev Vaccines 2016; 15:815-27. [PMID: 26775537 DOI: 10.1586/14760584.2016.1143365] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Hepatitis E is an emerging global disease caused by hepatitis E virus (HEV) infection. While in developing countries the infection was primarily due to poor sanitary conditions through intake of contaminated water or undercooked meats of infected animals, increasing cases of chronic hepatitis E resulting in rapidly progressive liver cirrhosis and end-stage liver disease have been reported in organ transplant patients or in immune compromised patients in developed countries. Fortunately, hepatitis E is now a vaccine preventable disease with a HEV239 based vaccine licensed for human use. Much work is needed to enable its use outside China. This review recounted the development process of the vaccine, outlined the critical quality attributes of the vaccine antigen and, most importantly, listed the populations at risk for HEV infection and the subsequent disease. These at risk populations could benefit the most from the vaccination if the vaccine is widely adopted.
Collapse
Affiliation(s)
- Xin Wang
- a State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases , Xiamen University , Xiamen , PR China.,b School of Public Health , Xiamen University , Xiamen , PR China
| | - Min Li
- a State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases , Xiamen University , Xiamen , PR China.,b School of Public Health , Xiamen University , Xiamen , PR China
| | - Shaowei Li
- a State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases , Xiamen University , Xiamen , PR China.,b School of Public Health , Xiamen University , Xiamen , PR China.,c School of Life Science , Xiamen University , Xiamen , PR China
| | - Ting Wu
- a State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases , Xiamen University , Xiamen , PR China.,b School of Public Health , Xiamen University , Xiamen , PR China.,c School of Life Science , Xiamen University , Xiamen , PR China
| | - Jun Zhang
- a State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases , Xiamen University , Xiamen , PR China.,b School of Public Health , Xiamen University , Xiamen , PR China.,c School of Life Science , Xiamen University , Xiamen , PR China
| | - Ningshao Xia
- a State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases , Xiamen University , Xiamen , PR China.,b School of Public Health , Xiamen University , Xiamen , PR China.,c School of Life Science , Xiamen University , Xiamen , PR China
| | - Qinjian Zhao
- a State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases , Xiamen University , Xiamen , PR China.,b School of Public Health , Xiamen University , Xiamen , PR China
| |
Collapse
|
|
21
|
Lee GY, Poovorawan K, Intharasongkroh D, Sa-nguanmoo P, Vongpunsawad S, Chirathaworn C, Poovorawan Y. Hepatitis E virus infection: Epidemiology and treatment implications. World J Virol 2015; 4:343-355. [PMID: 26568916 PMCID: PMC4641226 DOI: 10.5501/wjv.v4.i4.343] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/25/2015] [Revised: 08/06/2015] [Accepted: 09/16/2015] [Indexed: 02/05/2023] Open
Abstract
Hepatitis E virus (HEV) infection is now established as an emerging enteric viral hepatitis. Standard treatments in acute and chronic hepatitis E remain to be established. This study undertakes a review of the epidemiology, treatment implication and vaccine prevention from published literature. HEV infection is a worldwide public health problem and can cause acute and chronic hepatitis E. HEV genotypes 1 and 2 are primarily found in developing countries due to waterborne transmission, while the zoonotic potential of genotypes 3 and 4 affects mostly industrialized countries. An awareness of HEV transmission through blood donation, especially in the immunocompromised and solid organ transplant patients, merits an effective anti-viral therapy. There are currently no clear indications for the treatment of acute hepatitis E. Despite concerns for side effects, ribavirin monotherapy or in combination with pegylated interferon alpha for at least 3 mo appeared to show significant efficacy in the treatment of chronic hepatitis E. However, there are no available treatment options for specific patient population groups, such as women who are pregnant. Vaccination and screening of HEV in blood donors are currently a global priority in managing infection. New strategies for the treatment and control of hepatitis E are required for both acute and chronic infections, such as prophylactic use of medications, controlling large outbreaks, and finding acceptable antiviral therapy for pregnant women and other patient groups for whom the current options of treatment are not viable.
Collapse
|