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Voellmy R, Bloom DC, Vilaboa N. Regulated microbe vaccines: from concept to (pre-clinical) reduction to practice. Expert Rev Vaccines 2025; 24:146-156. [PMID: 39873306 DOI: 10.1080/14760584.2025.2459751] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2024] [Revised: 12/08/2024] [Accepted: 01/24/2025] [Indexed: 01/30/2025]
Abstract
INTRODUCTION Vaccines to prevent important infections involving, e.g. influenza viruses, severe acute respiratory syndrome-causing coronaviruses (e.g. SARS-CoV-2), respiratory syncytial viruses (RSV), and human immunodeficiency viruses (HIV) have remained insufficiently effective or are not available at all. Regulated microbes constitute novel vaccine platforms that may be employed for the development of more potent and/or more broadly effective vaccines. AREAS COVERED We review the development and characterization of the vaccine potential of replication-competent controlled herpesviruses (RCCVs) which represent the first examples of regulated microbes used as vaccines. EXPERT OPINION The RCCVs developed to date are suitable for application to the skin and can be activated deliberately to replicate efficiently, but only transiently, in the administration site. Without activation, the RCCVs are incapable of replicating in the nervous system and elsewhere. The RCCVs were found to induce potent anti-herpetic immune responses in mice. Vaccination with RCCVs expressing an influenza virus hemagglutinin broadly protected animals against lethal influenza virus challenges. This protection appeared to be at least in part antibody-mediated. These findings support a rational expectation that RCCVs may be developed into universal, non-seasonal vaccines against influenza and, possibly, against other rapidly evolving pathogens.
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Affiliation(s)
| | - David C Bloom
- Department of Molecular Genetics and Microbiology, University of Florida College of Medicine, Gainesville, FL, USA
| | - Nuria Vilaboa
- Hospital Universitario La Paz-IdiPAZ, Madrid, Spain
- CIBER de Bioingenieria, Biomateriales y Nanomedicina, CIBER-BBN, Madrid, Spain
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Luan N, Cao H, Wang Y, Cunbao Liu KL. LNP-CpG ODN-adjuvanted varicella-zoster virus glycoprotein E induced comparable levels of immunity with Shingrix TM in VZV-primed mice. Virol Sin 2022; 37:731-739. [PMID: 35671982 PMCID: PMC9167804 DOI: 10.1016/j.virs.2022.06.002] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Accepted: 06/01/2022] [Indexed: 11/26/2022] Open
Abstract
Latent varicella-zoster virus (VZV) may be reactivated to cause herpes zoster, which affects one in three people during their lifetime. The currently available subunit vaccine ShingrixTM is superior to the attenuated vaccine Zostavax® in terms of both safety and efficacy, but the supply of its key adjuvant component QS21 is limited. With Ionizable lipid nanoparticles (LNPs) that were recently approved by the FDA for COVID-19 mRNA vaccines as carriers, and oligodeoxynucleotides containing CpG motifs (CpG ODNs) approved by the FDA for a subunit hepatitis B vaccine as immunostimulators, we developed a LNP vaccine encapsulating VZV-glycoprotein E (gE) and CpG ODN, and compared its immunogenicity with ShingrixTM in C57BL/6J mice. The results showed that the LNP vaccine induced comparable levels of gE-specific IgG antibodies to ShingrixTM as determined by enzyme-linked immunosorbent assay (ELISA). Most importantly, the LNP vaccine induced comparable levels of cell-mediated immunity (CMI) that plays decisive roles in the efficacy of zoster vaccines to ShingrixTM in a VZV-primed mouse model that was adopted for preclinical studies of ShingrixTM. Number of IL-2 and IFN-γ secreting splenocytes and proportion of T helper 1 (Th1) cytokine-expressing CD4+ T cells in LNP-CpG-adjuvanted VZV-gE vaccinated mice were similar to that of ShingrixTM boosted mice. All of the components in this LNP vaccine can be artificially and economically synthesized in large quantities, indicating the potential of LNP-CpG-adjuvanted VZV-gE as a more cost-effective zoster vaccine.
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Affiliation(s)
- Ning Luan
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650118, China
| | - Han Cao
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650118, China
| | - Yunfei Wang
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650118, China
| | - Kangyang Lin Cunbao Liu
- Institute of Medical Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Kunming 650118, China.
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Wang W, Pan D, Cheng T, Zhu H. Rational Design of a Skin- and Neuro-Attenuated Live Varicella Vaccine: A Review and Future Perspectives. Viruses 2022; 14:848. [PMID: 35632591 PMCID: PMC9144592 DOI: 10.3390/v14050848] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2022] [Revised: 04/18/2022] [Accepted: 04/18/2022] [Indexed: 11/21/2022] Open
Abstract
Primary varicella-zoster virus (VZV) infection causes varicella, which remains a prominent public health concern in children. Current varicella vaccines adopt the live-attenuated Oka strain, vOka, which retains the ability to infect neurons, establish latency and reactivate, leading to vaccine-associated zoster in some vaccinees. Therefore, it is necessary to develop a safer next-generation varicella vaccine to help reduce vaccine hesitancy. This paper reviews the discovery and identification of the skin- and neuro-tropic factor, the open reading frame 7 (ORF7) of VZV, as well as the development of a skin- and neuro-attenuated live varicella vaccine comprising an ORF7-deficient mutant, v7D. This work could provide insights into the research of novel virus vaccines based on functional genomics and reverse genetics.
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Affiliation(s)
- Wei Wang
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen 361102, China; (W.W.); (D.P.)
| | - Dequan Pan
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen 361102, China; (W.W.); (D.P.)
| | - Tong Cheng
- State Key Laboratory of Molecular Vaccinology and Molecular Diagnostics, National Institute of Diagnostics and Vaccine Development in Infectious Diseases, School of Life Sciences, School of Public Health, Xiamen University, Xiamen 361102, China; (W.W.); (D.P.)
| | - Hua Zhu
- Department of Microbiology and Molecular Genetics, New Jersey Medical School, Rutgers University, Newark, NJ 070101, USA
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Cao H, Wang Y, Luan N, Lin K, Liu C. Effects of Varicella-Zoster Virus Glycoprotein E Carboxyl-Terminal Mutation on mRNA Vaccine Efficacy. Vaccines (Basel) 2021; 9:vaccines9121440. [PMID: 34960186 PMCID: PMC8704662 DOI: 10.3390/vaccines9121440] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2021] [Revised: 11/25/2021] [Accepted: 12/03/2021] [Indexed: 12/30/2022] Open
Abstract
Glycoprotein E (gE) is one of the most abundant glycoproteins in varicella-zoster virus and plays pivotal roles in virus replication and transmission between ganglia cells. Its extracellular domain has been successfully used as an antigen in subunit zoster vaccines. The intracellular C-terminal domain was reported to be decisive for gE trafficking between the endoplasmic reticulum, trans-Golgi network and endosomes and could influence virus spread and virus titers. Considering that the trafficking and distribution of mRNA vaccine-translated gE may be different from those of gE translated against the background of the viral genome (e.g., most gE in virus-infected cells exists as heterodimers with another glycoprotein, gI,), which may influence the immunogenicity of gE-based mRNA vaccines, we compared the humoral and cellular immunity induced by LNP-encapsulated mRNA sequences encoding the whole length of gE, the extracellular domain of gE and a C-terminal double mutant of gE (mutant Y569A with original motif AYRV, which targets gE to TGN, and mutants S593A, S595A, T596A and T598A with the original motif SSTT) that were reported to enhance virus spread and elevate virus titers. The results showed that while the humoral and cellular immunity induced by all of the mRNA vaccines was comparable to or better than that induced by the AS01B-adjuvanted subunit vaccines, the C-terminal double mutant of gE showed stable advantages in all of the indicators tested, including gE-specific IgG titers and T cell responses, and could be adopted as a candidate for both safer varicella vaccines and effective zoster vaccines.
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Ramachandran PS, Wilson MR, Catho G, Blanchard-Rohner G, Schiess N, Cohrs RJ, Boutolleau D, Burrel S, Yoshikawa T, Wapniarski A, Heusel EH, Carpenter JE, Jackson W, Ford BA, Grose C. Meningitis Caused by the Live Varicella Vaccine Virus: Metagenomic Next Generation Sequencing, Immunology Exome Sequencing and Cytokine Multiplex Profiling. Viruses 2021; 13:2286. [PMID: 34835092 PMCID: PMC8620440 DOI: 10.3390/v13112286] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Revised: 11/04/2021] [Accepted: 11/05/2021] [Indexed: 11/21/2022] Open
Abstract
Varicella vaccine meningitis is an uncommon delayed adverse event of vaccination. Varicella vaccine meningitis has been diagnosed in 12 children, of whom 3 were immunocompromised. We now report two additional cases of vaccine meningitis in twice-immunized immunocompetent children and we perform further testing on a prior third case. We used three methods to diagnose or investigate cases of varicella vaccine meningitis, none of which have been used previously on this disease. These include metagenomic next-generation sequencing and cytokine multiplex profiling of cerebrospinal fluid and immunology exome analysis of white blood cells. In one new case, the diagnosis was confirmed by metagenomic next-generation sequencing of cerebrospinal fluid. Both varicella vaccine virus and human herpesvirus 7 DNA were detected. We performed cytokine multiplex profiling on the cerebrospinal fluid of two cases and found ten elevated biomarkers: interferon gamma, interleukins IL-1RA, IL-6, IL-8, IL-10, IL-17F, chemokines CXCL-9, CXCL-10, CCL-2, and G-CSF. In a second new case, we performed immunology exome sequencing on a panel of 356 genes, but no errors were found. After a review of all 14 cases, we concluded that (i) there is no common explanation for this adverse event, but (ii) ingestion of an oral corticosteroid burst 3-4 weeks before onset of vaccine meningitis may be a risk factor in some cases.
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Affiliation(s)
- Prashanth S. Ramachandran
- Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA 94110, USA; (P.S.R.); (M.R.W.); (A.W.)
| | - Michael R. Wilson
- Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA 94110, USA; (P.S.R.); (M.R.W.); (A.W.)
| | - Gaud Catho
- Division of Pediatric Infectious Diseases, Geneva University Hospitals, Faculty of Medicine, University of Geneva, 1205 Geneva, Switzerland;
| | - Geraldine Blanchard-Rohner
- Pediatric Immunology and Vaccinology Unit, Division of General Pediatrics, Department of Pediatrics, Gynecology and Obstetrics, Geneva University Hospitals, University of Geneva, 1205 Geneva, Switzerland;
| | - Nicoline Schiess
- Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD 21205, USA;
| | - Randall J. Cohrs
- Department of Neurology, University of Colorado School of Medicine, Aurora, CO 80045, USA;
| | - David Boutolleau
- Virology Department, National Reference Center for Herpesviruses, Pitie-Salpetriere Hospital, Sorbonne University, 75013 Paris, France; (D.B.); (S.B.)
| | - Sonia Burrel
- Virology Department, National Reference Center for Herpesviruses, Pitie-Salpetriere Hospital, Sorbonne University, 75013 Paris, France; (D.B.); (S.B.)
| | - Tetsushi Yoshikawa
- Department of Pediatrics, Fujita Health University School of Medicine, Aichi, Toyoake 470-1192, Japan;
| | - Anne Wapniarski
- Department of Neurology, Weill Institute for Neurosciences, University of California San Francisco, San Francisco, CA 94110, USA; (P.S.R.); (M.R.W.); (A.W.)
| | - Ethan H. Heusel
- Division of Infectious Diseases/Virology, Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA; (E.H.H.); (J.E.C.); (W.J.)
| | - John E. Carpenter
- Division of Infectious Diseases/Virology, Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA; (E.H.H.); (J.E.C.); (W.J.)
| | - Wallen Jackson
- Division of Infectious Diseases/Virology, Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA; (E.H.H.); (J.E.C.); (W.J.)
| | - Bradley A. Ford
- Department of Pathology, University of Iowa, Iowa City, IA 52242, USA;
| | - Charles Grose
- Division of Infectious Diseases/Virology, Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA; (E.H.H.); (J.E.C.); (W.J.)
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Immunogenicity of Varicella-Zoster Virus Glycoprotein E Formulated with Lipid Nanoparticles and Nucleic Immunostimulators in Mice. Vaccines (Basel) 2021; 9:vaccines9040310. [PMID: 33805880 PMCID: PMC8064366 DOI: 10.3390/vaccines9040310] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2021] [Revised: 03/18/2021] [Accepted: 03/23/2021] [Indexed: 12/21/2022] Open
Abstract
Theoretically, the subunit herpes zoster vaccine ShingrixTM could be used as a varicella vaccine that avoids the risk of developing shingles from vaccination, but bedside mixing strategies and the limited supply of the adjuvant component QS21 have made its application economically impracticable. With lipid nanoparticles (LNPs) that were approved by the FDA as vectors for severe acute respiratory syndrome coronavirus 2 vaccines, we designed a series of vaccines efficiently encapsulated with varicella-zoster virus glycoprotein E (VZV-gE) and nucleic acids including polyinosinic-polycytidylic acid (Poly I:C) and the natural phosphodiester CpG oligodeoxynucleotide (CpG ODN), which was approved by the FDA as an immunostimulator in a hepatitis B vaccine. Preclinical trial in mice showed that these LNP vaccines could induce VZV-gE IgG titers more than 16 times those induced by an alum adjuvant, and immunized serum could block in vitro infection completely at a dilution of 1:80, which indicated potential as a varicella vaccine. The magnitude of the cell-mediated immunity induced was generally more than 10 times that induced by the alum adjuvant, indicating potential as a zoster vaccine. These results showed that immunostimulatory nucleic acids together with LNPs have promise as safe and economical varicella and zoster vaccine candidates.
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Corticosteroids Contribute to Serious Adverse Events Following Live Attenuated Varicella Vaccination and Live Attenuated Zoster Vaccination. Vaccines (Basel) 2021; 9:vaccines9010023. [PMID: 33418856 PMCID: PMC7825138 DOI: 10.3390/vaccines9010023] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/03/2020] [Revised: 12/28/2020] [Accepted: 01/01/2021] [Indexed: 12/28/2022] Open
Abstract
Corticosteroids, when given in high dosages, have long been recognized as a risk factor for severe infection with wild-type varicella-zoster virus in both children and adults. The goal of this review is to assess the degree to which both low-dosage and high-dosage corticosteroids contribute to serious adverse events (SAEs) following live varicella vaccination and live zoster vaccination. To this end, we examined multiple published reports of SAEs following varicella vaccination (VarivaxTM) and zoster vaccination (ZostavaxTM). We observed that five of eight viral SAEs following varicella vaccination, including two deaths, occurred in children receiving corticosteroids, while one of three fatal viral SAEs following live zoster vaccination occurred in an adult being treated with low-dosage prednisone. The latter death after live zoster vaccination occurred in a 70 year-old man with rheumatoid arthritis, being treated with prednisone 10 mg daily. Thus, corticosteroids contributed to more severe infectious complications in subjects immunized with each of the two live virus vaccines. Further, when we surveyed the rheumatology literature as well as individual case reports, we documented examples where daily dosages of 7.5–20 mg prednisone were associated with increased rates of severe wild-type varicella-zoster virus infections in children and adults.
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Abstract
Prophylactic and therapeutic vaccines for the alphaherpesviruses including varicella zoster virus (VZV) and herpes simplex virus types 1 and 2 have been the focus of enormous preclinical and clinical research. A live viral vaccine for prevention of chickenpox and a subunit therapeutic vaccine to prevent zoster are highly successful. In contrast, progress towards the development of effective prophylactic or therapeutic vaccines against HSV-1 and HSV-2 has met with limited success. This review provides an overview of the successes and failures, the different types of immune responses elicited by various vaccine modalities, and the need to reconsider the preclinical models and immune correlates of protection against HSV.
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Affiliation(s)
- Clare Burn Aschner
- Department of Microbiology-Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
| | - Betsy C. Herald
- Department of Microbiology-Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
- Pediatrics, Albert Einstein College of Medicine, Bronx, NY, USA
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Immune Responses to Varicella-Zoster Virus Glycoprotein E Formulated with Poly(Lactic-co-Glycolic Acid) Nanoparticles and Nucleic Acid Adjuvants in Mice. Virol Sin 2020; 36:122-132. [PMID: 32757147 DOI: 10.1007/s12250-020-00261-y] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2020] [Accepted: 06/01/2020] [Indexed: 12/15/2022] Open
Abstract
The subunit herpes zoster vaccine Shingrix is superior to attenuated vaccine Zostavax in both safety and efficacy, yet its unlyophilizable liposome delivery system and the limited supply of naturally sourced immunological adjuvant QS-21 still need to be improved. Based on poly(lactic-co-glycolic acid) (PLGA) delivery systems that are stable during the lyophilization and rehydration process and using a double-emulsion (w/o/w) solvent evaporation method, we designed a series of nanoparticles with varicella-zoster virus antigen glycoprotein E (VZV-gE) as an antigen and nucleic acids including polyinosinic-polycytidylic acid (Poly I:C) and phosphodiester CpG oligodeoxynucleotide (CpG ODN), encapsulated as immune stimulators. While cationic lipids (DOTAP) have more potential than neutral lipids (DOPC) for activating gE-specific cell-mediated immunity (CMI) in immunized mice, especially when gE is encapsulated in and presented on the surface of nanoparticles, PLGA particles without lipids have the greatest potential to induce not only the highest gE-specific IgG titers but also the strongest gE-specific CMI responses, including the highest proportions of interferon-γ (IFN-γ)- and interleukin-2 (IL-2)-producing CD4+/CD8+ T cells according to a flow cytometry assay and the greatest numbers of IFN-γ- and IL-2-producing splenocytes according to an enzyme-linked immunospot (ELISPOT) assay. These results showed that immune-stimulating nucleic acids together with the PLGA delivery system showed promise as a safe and economical varicella and zoster vaccine candidate.
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Tourtelot E, Quataert S, Glantz JC, Perlis L, Muthukrishnan G, Mosmann T. Women who received varicella vaccine versus natural infection have different long-term T cell immunity but similar antibody levels. Vaccine 2020; 38:1581-1585. [PMID: 31959424 DOI: 10.1016/j.vaccine.2019.12.067] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 12/24/2019] [Accepted: 12/31/2019] [Indexed: 12/13/2022]
Abstract
BACKGROUND Varicella-zoster virus (VZV) infection during pregnancy is associated with serious fetal anomalies. The live-attenuated VZV vaccine was approved in 1995, so many vaccinated women are now of childbearing age. The question of long-term immunity to varicella is critical because breakthrough chickenpox can occur after vaccination. OBJECTIVE To compare humoral and T cell immunity between women of childbearing age who were immunized by vaccination or chickenpox disease. STUDY DESIGN Non-pregnant females between 18 and 36 years old with a history of VZV immunization (n = 20) or prior chickenpox disease (n = 20) were recruited. IgG antibody titers and T cell responses were measured by flow cytometry-based methods in serum and peripheral blood, respectively. RESULTS There were no significant differences in median antibody titers between vaccinated and chickenpox groups (p = 0.34). The chickenpox group had significantly higher levels of VZV antigen-specific CD4 T cells (p = 0.004). CONCLUSION Natural infection induced higher VZV-specific T cell immune responses than vaccination.
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Affiliation(s)
- Ellen Tourtelot
- University of Rochester, Strong Memorial Hospital, Department of Obstetrics and Gynecology, United States.
| | - Sally Quataert
- University of Rochester, Strong Memorial Hospital, Department of Vaccine Biology & Immunology, United States
| | - J Christopher Glantz
- University of Rochester, Strong Memorial Hospital, Department of Obstetrics and Gynecology, United States
| | - Lauren Perlis
- University of Rochester, Strong Memorial Hospital, Department of Obstetrics and Gynecology, United States
| | - Gowrishankar Muthukrishnan
- University of Rochester, Strong Memorial Hospital, Department of Vaccine Biology & Immunology, United States
| | - Tim Mosmann
- University of Rochester, Strong Memorial Hospital, Department of Vaccine Biology & Immunology, United States
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The changing epidemiology of varicella and herpes zoster in Hong Kong before universal varicella vaccination in 2014. Epidemiol Infect 2018. [PMID: 29526171 PMCID: PMC6533643 DOI: 10.1017/s0950268818000444] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022] Open
Abstract
In Hong Kong, universal varicella vaccination started in July 2014. Before this, children could receive varicella vaccine via the private market. We analysed the epidemiology of varicella and zoster before universal vaccination. We estimated varicella vaccination coverage through surveys in preschool children. We estimated the burden of varicella and zoster with varicella notifications from 1999/00 to 2013/14, Accident and Emergency Department (A&E) attendance and inpatient admissions to public hospitals from 2004/05 to 2013/14. We fitted a catalytic model to serological data on antibodies against varicella-zoster virus to estimate the force of infection. We found that varicella vaccination coverage gradually increased to about 50% before programme inception. In children younger than 5 years, the annual rate of varicella notifications, varicella admission and zoster A&E attendance generally declined. The annual notification, A&E attendance and hospitalisation rate of varicella and zoster generally increased for individuals between 10 and 59 years old. Varicella serology indicated an age shift during the study period towards a higher proportion of infections in slightly older individuals, but the change was most notable before vaccine licensure. In conclusion, we observed a shift in the burden of varicella to slightly older age groups with a corresponding increase in incidence but it cannot necessarily be attributed to private market vaccine coverage alone. Increasing varicella vaccination uptake in the private market might affect varicella transmission and epidemiology, but not to the level of interrupting transmission.
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Perciani CT, Jaoko W, Walmsley S, Farah B, Mahmud SM, Ostrowski M, Anzala O, Team KI, MacDonald KS. Protocol of a randomised controlled trial characterising the immune responses induced by varicella-zoster virus (VZV) vaccination in healthy Kenyan women: setting the stage for a potential VZV-based HIV vaccine. BMJ Open 2017; 7:e017391. [PMID: 28939581 PMCID: PMC5623463 DOI: 10.1136/bmjopen-2017-017391] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
INTRODUCTION A protective HIV vaccine would be expected to induce durable effector immune responses at the mucosa, restricting HIV infection at its portal of entry. We hypothesise that use of varicella-zoster virus (VZV) as an HIV delivery vector could generate sustained and robust tissue-based immunity against HIV antigens to provide long-term protection against HIV. Given that HIV uniquely targets immune-activated T cells, the development of human vaccines against HIV must also involve a specific examination of the safety of the vector. Thus, we aim to evaluate the effects of VZV vaccination on the recipients' immune activation state, and on VZV-specific circulating humoral and cellular responses in addition to those at the cervical and rectal mucosa. METHODS AND ANALYSIS This open-label, randomised, longitudinal crossover study includes healthy Kenyan VZV-seropositive women at low risk for HIV infection. Participants receive a single dose of a commercial live-attenuated VZVOka vaccine at either week 0 (n=22) or at week 12 (n=22) of the study and are followed for 48 and 36 weeks postvaccination, respectively. The primary outcome is the change on cervical CD4+ T-cell immune activation measured by the coexpression of CD38 and HLA-DR 12 weeks postvaccination compared with the baseline (prevaccination). Secondary analyses include postvaccination changes in VZV-specific mucosal and systemic humoral and cellular immune responses, changes in cytokine and chemokine measures, study acceptability and feasibility of mucosal sampling and a longitudinal assessment of the bacterial community composition of the mucosa. ETHICS AND DISSEMINATION The study has ethical approval from Kenyatta National Hospital/University of Nairobi Ethics and Research Committee, the University of Toronto Research Ethics Board and by Kenyan Pharmacy and Poisons Board. Results will be presented at conferences, disseminated to participants and stakeholders as well as published in peer-reviewed journals. TRIAL REGISTRATION NUMBER NCT02514018. Pre-results.
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Affiliation(s)
- Catia T Perciani
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
| | - Walter Jaoko
- Kenyan AIDS Vaccine Initiative-Institute of Clinical Research (KAVI-ICR), Nairobi, Kenya
- Department of Medical Microbiology, University of Nairobi, Nairobi, Kenya
| | - Sharon Walmsley
- Toronto General Research Institute, University Health Network, Toronto, Ontario, Canada
| | - Bashir Farah
- Kenyan AIDS Vaccine Initiative-Institute of Clinical Research (KAVI-ICR), Nairobi, Kenya
| | - Salaheddin M Mahmud
- Community Health Sciences, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
| | - Mario Ostrowski
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
- Keenan Research Centre for Biomedical Science, St. Michael's Hospital, Toronto, Ontario, Canada
| | - Omu Anzala
- Kenyan AIDS Vaccine Initiative-Institute of Clinical Research (KAVI-ICR), Nairobi, Kenya
- Department of Medical Microbiology, University of Nairobi, Nairobi, Kenya
| | - Kavi-Icr Team
- Kenyan AIDS Vaccine Initiative-Institute of Clinical Research (KAVI-ICR), Nairobi, Kenya
| | - Kelly S MacDonald
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
- Section of Infectious Diseases, Department of Internal Medicine, Max Rady College of Medicine, Rady Faculty of Health Sciences, University of Manitoba, Winnipeg, Manitoba, Canada
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Rueda J, Feito-Rodríguez M, Nieto D, de Lucas-Laguna R. Herpes zóster diseminado posvacunal en un niño sano. ACTAS DERMO-SIFILIOGRAFICAS 2017; 108:587-588. [DOI: 10.1016/j.ad.2016.12.013] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Revised: 12/15/2016] [Accepted: 12/18/2016] [Indexed: 10/20/2022] Open
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Rueda J, Feito-Rodríguez M, Nieto D, de Lucas-Laguna R. Disseminated Herpes Zoster After Varicella Vaccination in a Healthy Boy. ACTAS DERMO-SIFILIOGRAFICAS 2017. [DOI: 10.1016/j.adengl.2017.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/19/2022] Open
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15
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Gershon AA. Is chickenpox so bad, what do we know about immunity to varicella zoster virus, and what does it tell us about the future? J Infect 2017; 74 Suppl 1:S27-S33. [PMID: 28646959 PMCID: PMC5726865 DOI: 10.1016/s0163-4453(17)30188-3] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Varicella and zoster continue to cause significant morbidity and even mortality in children and adults. Complications include bacterial superinfection, central nervous system manifestations such as meningitis, encephalitis, and cerebellar ataxia, and pain syndromes especially post herpetic neuralgia. Many developed countries but not all, are now administering live attenuated varicella vaccine routinely, with a decrease in the incidence of disease, providing personal and herd immunity. There is some controversy, however, in some countries concerning whether a decrease in the circulation of wild type virus will result in loss of immunity to VZV in persons who have already had varicella. This manuscript reviews the complications of varicella and zoster in detail, the reasons for development of vaccines against these diseases, complications of vaccinations, and mechanisms by which immunity to this virus develops and is maintained. There are strong indications that the best way to control disease and spread of this virus is by vaccination against both.
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Affiliation(s)
- Anne A Gershon
- Columbia University College of Physicians and Surgeons, 630 West 168th Street, New York, NY 10032, USA.
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16
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Dysregulated Glycoprotein B-Mediated Cell-Cell Fusion Disrupts Varicella-Zoster Virus and Host Gene Transcription during Infection. J Virol 2016; 91:JVI.01613-16. [PMID: 27795423 DOI: 10.1128/jvi.01613-16] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2016] [Accepted: 10/14/2016] [Indexed: 12/19/2022] Open
Abstract
The highly conserved herpesvirus glycoprotein complex gB/gH-gL mediates membrane fusion during virion entry and cell-cell fusion. Varicella-zoster virus (VZV) characteristically forms multinucleated cells, or syncytia, during the infection of human tissues, but little is known about this process. The cytoplasmic domain of VZV gB (gBcyt) has been implicated in cell-cell fusion regulation because a gB[Y881F] substitution causes hyperfusion. gBcyt regulation is necessary for VZV pathogenesis, as the hyperfusogenic mutant gB[Y881F] is severely attenuated in human skin xenografts. In this study, gBcyt-regulated fusion was investigated by comparing melanoma cells infected with wild-type-like VZV or hyperfusogenic mutants. The gB[Y881F] mutant exhibited dramatically accelerated syncytium formation in melanoma cells caused by fusion of infected cells with many uninfected cells, increased cytoskeleton reorganization, and rapid displacement of nuclei to dense central structures compared to pOka using live-cell confocal microscopy. VZV and human transcriptomes were concurrently investigated using whole transcriptome sequencing (RNA-seq) to identify viral and cellular responses induced when gBcyt regulation was disrupted by the gB[Y881F] substitution. The expression of four vital VZV genes, ORF61 and the genes for glycoproteins gC, gE, and gI, was significantly reduced at 36 h postinfection for the hyperfusogenic mutants. Importantly, hierarchical clustering demonstrated an association of differential gene expression with dysregulated gBcyt-mediated fusion. A subset of Ras GTPase genes linked to membrane remodeling were upregulated in cells infected with the hyperfusogenic mutants. These data implicate gBcyt in the regulation of gB fusion function that, if unmodulated, triggers cellular processes leading to hyperfusion that attenuates VZV infection. IMPORTANCE The highly infectious, human-restricted pathogen varicella-zoster virus (VZV) causes chickenpox and shingles. Postherpetic neuralgia (PHN) is a common complication of shingles that manifests as prolonged excruciating pain, which has proven difficult to treat. The formation of fused multinucleated cells in ganglia might be associated with this condition. An effective vaccine against VZV is available but not recommended for immunocompromised individuals, highlighting the need for new therapies. This study investigated the viral and cellular responses to hyperfusion, a condition where the usual constraints of cell membranes are overcome and cells form multinucleated cells. This process hinders VZV and is regulated by a viral glycoprotein, gB. A combination of live-cell imaging and next-generation genomics revealed an alteration in viral and cellular responses during hyperfusion that was caused by the loss of gB regulation. These studies reveal mechanisms central to VZV pathogenesis, potentially leading to improved therapies.
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De Paschale M, Clerici P. Microbiology laboratory and the management of mother-child varicella-zoster virus infection. World J Virol 2016; 5:97-124. [PMID: 27563537 PMCID: PMC4981827 DOI: 10.5501/wjv.v5.i3.97] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Revised: 07/08/2016] [Accepted: 07/22/2016] [Indexed: 02/05/2023] Open
Abstract
Varicella-zoster virus, which is responsible for varicella (chickenpox) and herpes zoster (shingles), is ubiquitous and causes an acute infection among children, especially those aged less than six years. As 90% of adults have had varicella in childhood, it is unusual to encounter an infected pregnant woman but, if the disease does appear, it can lead to complications for both the mother and fetus or newborn. The major maternal complications include pneumonia, which can lead to death if not treated. If the virus passes to the fetus, congenital varicella syndrome, neonatal varicella (particularly serious if maternal rash appears in the days immediately before or after childbirth) or herpes zoster in the early years of life may occur depending on the time of infection. A Microbiology laboratory can help in the diagnosis and management of mother-child infection at four main times: (1) when a pregnant woman has been exposed to varicella or herpes zoster, a prompt search for specific antibodies can determine whether she is susceptible to, or protected against infection; (2) when a pregnant woman develops clinical symptoms consistent with varicella, the diagnosis is usually clinical, but a laboratory can be crucial if the symptoms are doubtful or otherwise unclear (atypical patterns in immunocompromised subjects, patients with post-vaccination varicella, or subjects who have received immunoglobulins), or if there is a need for a differential diagnosis between varicella and other types of dermatoses with vesicle formation; (3) when a prenatal diagnosis of uterine infection is required in order to detect cases of congenital varicella syndrome after the onset of varicella in the mother; and (4) when the baby is born and it is necessary to confirm a diagnosis of varicella (and its complications), make a differential diagnosis between varicella and other diseases with similar symptoms, or confirm a causal relationship between maternal varicella and malformations in a newborn.
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Wang L, Zhu L, Zhu H. Efficacy of varicella (VZV) vaccination: an update for the clinician. THERAPEUTIC ADVANCES IN VACCINES 2016; 4:20-31. [PMID: 27551429 DOI: 10.1177/2051013616655980] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
Varicella-zoster virus (VZV) infection causes two distinct clinical conditions. Primary varicella infection results in chickenpox, a contagious rash illness typically seen among children. VZV can reactivate years after the initial infection to cause herpes zoster (HZ) and lead to post-herpetic neuralgia, a common complication resulting in persistent pain that may last for years after the zoster rash resolves. A person's risk of having longer lasting and more severe pain associated with HZ increases with age. Since the introduction of VZV vaccines, the rates of infection, hospitalizations, and mortality have declined. In this review, we discuss in detail current VZV vaccines available for the prevention of VZV and HZ infections. Varilrix (GSK Biologicals, UK), Varivax (Merck, USA) and the combined measles, mumps, rubella, and varicella (MMRV) vaccine contain the live attenuated Oka strain of VZV for routine varicella vaccination. While Zostavax is the only HZ vaccine currently approved for use in the United States and the European Union [EMEA, 2011], a subunit vaccine candidate called HZ/su has recently shown improved efficacy for zoster prevention in two clinical trial phase III studies. VariZIG, a post-exposure prophylactic, uses zoster immune globulin to prevent VZV infection in those who have recently been in contact with VZV but lack evidence of varicella immunity and are contraindicated to receive the varicella vaccine. Further, we discuss the skin tropic and neurotropic factor VZV ORF7 gene and its involvement in varicella infection, reactivation and latency in ganglia. Ultimately, these studies can contribute to the development of a neuroattenuated vaccine candidate against varicella or a vector for delivery of other virus antigens.
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Affiliation(s)
- Lili Wang
- Rutgers-New Jersey Medical School, Newark, NJ, USA
| | - Lucy Zhu
- University of California, Berkeley, USA
| | - Hua Zhu
- 225 Warren Street,NJ 07103 Rutgers-New Jersey Medical School, Newark, NJ, 07103-2714, USA
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Herpes zóster en niños vacunados contra el virus varicela zóster: experiencia en nuestro hospital. ACTAS DERMO-SIFILIOGRAFICAS 2015; 106:329-31. [DOI: 10.1016/j.ad.2014.07.007] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2014] [Revised: 07/07/2014] [Accepted: 07/14/2014] [Indexed: 11/22/2022] Open
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Herpes Zoster in Children Vaccinated Against Varicella-Zoster Virus: Experience in our Hospital. ACTAS DERMO-SIFILIOGRAFICAS 2015. [DOI: 10.1016/j.adengl.2015.03.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
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Abstract
The successful human papillomavirus and hepatitis B virus subunit vaccines contain single viral proteins that represent 22 and 12%, respectively, of the antigens encoded by these tiny viruses. The herpes simplex virus 2 (HSV-2) genome is >20 times larger. Thus, a single protein subunit represents 1% of HSV-2's total antigenic breadth. Antigenic breadth may explain why HSV-2 glycoprotein subunit vaccines have failed in clinical trials, and why live HSV-2 vaccines that express 99% of HSV-2's proteome may be more effective. I review the mounting evidence that live HSV-2 vaccines offer a greater opportunity to stop the spread of genital herpes, and I consider the unfounded 'safety concerns' that have kept live HSV-2 vaccines out of U.S. clinical trials for 25 years.
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Affiliation(s)
- William P Halford
- Department of Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, IL 62702, USA
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Varicella-zoster virus and virus DNA in the blood and oropharynx of people with latent or active varicella-zoster virus infections. J Clin Virol 2014; 61:487-95. [PMID: 25453570 DOI: 10.1016/j.jcv.2014.09.012] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2014] [Revised: 09/04/2014] [Accepted: 09/14/2014] [Indexed: 12/28/2022]
Abstract
Varicella-zoster virus (VZV) can be detected in the blood from approximately 5 days before to 4 days after varicella. VZV DNA, primarily in T-lymphocytes, is detected as early as 8-10 days prior to rash and can persist for a week. The duration and magnitude of VZV DNAemia correlates with immune status and the efficacy of antiviral therapy. VZV DNA is also readily detected in the oropharynx just prior to rash and for 1-2 weeks thereafter. Detection of VZV DNA in blood and saliva has been useful for diagnosis and prognosis in atypical cases of varicella. Herpes zoster (HZ) is also characterized by VZV DNAemia at onset and for many weeks thereafter, and VZV DNA is present in the oropharynx shortly after HZ onset. Detection of VZV DNA in blood and saliva facilitates the diagnosis of zoster sine herpete and other atypical manifestations of VZV reactivation, such as neurologic syndromes when cerebrospinal fluid is not available, Bell's palsy, and atypical pain syndromes. VZV DNA is sometimes present in the blood and saliva of asymptomatic individuals. In total these observations extend understanding of the pathophysiology and epidemiology of VZV, and increasingly contribute to the clinical management of VZV infections.
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Watson B. Varicella-zoster vaccine in the USA: success for control of disease severity, but what next? Expert Rev Anti Infect Ther 2014; 3:105-15. [PMID: 15757461 DOI: 10.1586/14787210.3.1.105] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
In the period from 1990 to 1994, before the introduction of a varicella vaccine to the USA, approximately 100 deaths in otherwise healthy individuals, children and adolescents under 20 years of age, were attributable to varicella complications. The administration of a single-dose vaccine has now been widespread in the USA for nearly 10 years; however, since the effectiveness of a single dose in children under 13 years of age in an outbreak situation is approximately 80%, consideration of a second booster dose is in progress although not yet recommended. Licensure of a measles-mumps-rubella-varicella vaccine may hasten the recommendation.
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Affiliation(s)
- Barbara Watson
- Jefferson Medical College, Medical Specialist, Immunization Program, Division of Disease Control, The Philadelphia Department of Public Health, 500S Broad Street, Philadelphia, PA 19146, USA.
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Fadrowski JJ, Furth SL. Varicella zoster virus: vaccination and implications in children with renal failure. Expert Rev Vaccines 2014; 3:291-8. [PMID: 15176945 DOI: 10.1586/14760584.3.3.291] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The varicella zoster virus is associated with significant disease in those with chronic kidney disease, both pre- and postrenal transplantation. With the advent of the varicella vaccine, the opportunity to prevent significant morbidity and mortality exists. Despite the secondary immune defects associated with renal failure, the varicella vaccine has been demonstrated to be immunogenic, safe and efficacious in pediatric patients with kidney disease.
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Affiliation(s)
- Jeffrey J Fadrowski
- Division of Pediatric Nephrology, Welch Center for Prevention, Epidemiology and Clinical Research, Johns Hopkins University School of Medicine, Park 335, 600 N. Wolfe Street, Baltimore, MD 21287, USA.
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Prelog M, Schönlaub J, Jeller V, Almanzar G, Höfner K, Gruber S, Eiwegger T, Würzner R. Reduced varicella-zoster-virus (VZV)-specific lymphocytes and IgG antibody avidity in solid organ transplant recipients. Vaccine 2013; 31:2420-6. [PMID: 23583889 DOI: 10.1016/j.vaccine.2013.03.058] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2012] [Revised: 02/04/2013] [Accepted: 03/28/2013] [Indexed: 02/01/2023]
Abstract
BACKGROUND Varicella-zoster-virus (VZV) infection may cause significant morbidity and mortality in immunocompromised patients. So far, only IgG-anti-VZV antibody concentrations were used to estimate immunity against VZV, but the antibody binding strength (avidity) together with VZV-specific cellular responses have not been evaluated in solid organ transplant (SOT) recipients. METHODS Thus, we assessed the humoral and cellular immune responses to two doses of the VZV vaccine (vacc) and wild-type VZV infection (wt) in 23 kidney (KTx) and 19 liver transplant (LTx) recipients including children and adults compared to 48 healthy controls (HC) for measurement of IgG-anti-VZV relative avidity index (RAI) and frequency of VZV-specific peripheral blood mononuclear cells (PBMCs) in vaccinated individuals using an adapted ELISA and IFN-gamma ELISPOT, respectively. RESULTS KTx(wt) (median RAI 72.3%) or LTx(wt) (79.2%) and KTx(vacc) (91.0%) or LTx(vacc) (72.5%) showed lower avidities compared to HC(wt) (84.5%) and HC(vacc) (94.0%), respectively, despite equally distributed IgG-anti-VZV concentrations. RAI>60% (high avidity) was detected in all HC, but only in 69.0% of SOT patients. KTx(vacc) (median 64 spot forming units SFU/500,000 PBMCs) and LTx(vacc) (67 SFU) had significantly lower VZV-specific cellular responses compared to HC(vacc) (268 SFU). CONCLUSIONS The diminished cellular reactivity to VZV has to be considered in SOT patients receiving immunosuppressive treatments when evaluating immunity against VZV. IgG antibody avidity and VZV-specific cellular responses may serve as additional markers to evaluate immunity against VZV in SOT recipients. The role of wild-type exposures and endogenous VZV re-activation on long-term immunity in SOT patients has to be awaited to establish recommendations for vaccine spacing in these patients, considering immunogenicity and safety aspects.
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Affiliation(s)
- Martina Prelog
- Department of Pediatrics, Innsbruck Medical University, Innsbruck, Austria.
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26
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Willer DO, Ambagala APN, Pilon R, Chan JK, Fournier J, Brooks J, Sandstrom P, MacDonald KS. Experimental infection of Cynomolgus Macaques (Macaca fascicularis) with human varicella-zoster virus. J Virol 2012; 86:3626-34. [PMID: 22258257 PMCID: PMC3302534 DOI: 10.1128/jvi.06264-11] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2011] [Accepted: 01/06/2012] [Indexed: 11/20/2022] Open
Abstract
Varicella-zoster virus (VZV) is a member of the alphaherpesvirus family and the causative agent of chickenpox and shingles. To determine the utility of cynomolgus macaques (Macaca fascicularis) as a nonhuman primate model to evaluate VZV-based simian immunodeficiency virus/human immunodeficiency virus (SIV/HIV) vaccines, we experimentally inoculated 10 animals with the parental Oka (Oka-P) strain of VZV derived from MeWo or Telo-RF cells. VZV DNA could be detected in the lungs as late as 4 days postinfection, with replicating virus detected by shell vial culture assay in one case. Infection did not result in any overt clinical symptoms but was characterized by humoral and cell-mediated immunity in a time frame and at a magnitude similar to those observed following VZV vaccination in humans. The cell line source of VZV inoculum influenced both the magnitude and polyfunctionality of cell-mediated immunity. Animals mounted a vigorous anamnestic antibody response following a second inoculation 12 weeks later. Inoculations resulted in transient increases in CD4(+) T-cell activation and proliferation, as well as a sustained increase in CD4(+) T cells coexpressing CCR5 and α4β7 integrin. In contrast to previous failed attempts to successfully utilize attenuated VZV-Oka as an SIV vaccine vector in rhesus macaques due to suboptimal infectivity and cellular immunogenicity, the ability to infect cynomolgus macaques with Oka-P VZV should provide a valuable tool for evaluating VZV-vectored SIV/HIV vaccines.
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Affiliation(s)
- David O. Willer
- Department of Microbiology, Mount Sinai Hospital, Toronto, Ontario, Canada
- Clinical Sciences Division, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Aruna P. N. Ambagala
- Department of Microbiology, Mount Sinai Hospital, Toronto, Ontario, Canada
- Clinical Sciences Division, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Richard Pilon
- National HIV and Retrovirology Laboratories, National Microbiology Laboratory, Public Health Agency of Canada, Ottawa, Ontario, Canada
| | - Jacqueline K. Chan
- Department of Microbiology, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Jocelyn Fournier
- Scientific Services Division, Health Products and Food Branch, Health Canada, Ottawa, Ontario, Canada
| | - James Brooks
- National Laboratory for HIV Genetics, Public Health Agency of Canada, Ottawa, Ontario, Canada
| | - Paul Sandstrom
- National HIV and Retrovirology Laboratories, National Microbiology Laboratory, Public Health Agency of Canada, Ottawa, Ontario, Canada
| | - Kelly S. MacDonald
- Department of Microbiology, Mount Sinai Hospital, Toronto, Ontario, Canada
- Clinical Sciences Division, Faculty of Medicine, University of Toronto, Toronto, Ontario, Canada
- Department of Immunology, University of Toronto, Toronto, Ontario, Canada
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Halford WP, Püschel R, Gershburg E, Wilber A, Gershburg S, Rakowski B. A live-attenuated HSV-2 ICP0 virus elicits 10 to 100 times greater protection against genital herpes than a glycoprotein D subunit vaccine. PLoS One 2011; 6:e17748. [PMID: 21412438 PMCID: PMC3055896 DOI: 10.1371/journal.pone.0017748] [Citation(s) in RCA: 80] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2010] [Accepted: 02/09/2011] [Indexed: 11/19/2022] Open
Abstract
Glycoprotein D (gD-2) is the entry receptor of herpes simplex virus 2 (HSV-2), and is the immunogen in the pharmaceutical industry's lead HSV-2 vaccine candidate. Efforts to prevent genital herpes using gD-2 subunit vaccines have been ongoing for 20 years at a cost in excess of $100 million. To date, gD-2 vaccines have yielded equivocal protection in clinical trials. Therefore, using a small animal model, we sought to determine if a live-attenuated HSV-2 ICP0− virus would elicit better protection against genital herpes than a gD-2 subunit vaccine. Mice immunized with gD-2 and a potent adjuvant (alum+monophosphoryl lipid A) produced high titers of gD-2 antibody. While gD-2-immunized mice possessed significant resistance to HSV-2, only 3 of 45 gD-2-immunized mice survived an overwhelming challenge of the vagina or eyes with wild-type HSV-2 (MS strain). In contrast, 114 of 115 mice immunized with a live HSV-2 ICP0− virus, 0ΔNLS, survived the same HSV-2 MS challenges. Likewise, 0ΔNLS-immunized mice shed an average 125-fold less HSV-2 MS challenge virus per vagina relative to gD-2-immunized mice. In vivo imaging demonstrated that a luciferase-expressing HSV-2 challenge virus failed to establish a detectable infection in 0ΔNLS-immunized mice, whereas the same virus readily infected naïve and gD-2-immunized mice. Collectively, these results suggest that a HSV-2 vaccine might be more likely to prevent genital herpes if it contained a live-attenuated HSV-2 virus rather than a single HSV-2 protein.
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Affiliation(s)
- William P Halford
- Department of Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois, United States of America.
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Amanna IJ, Slifka MK. Mechanisms that determine plasma cell lifespan and the duration of humoral immunity. Immunol Rev 2010; 236:125-38. [PMID: 20636813 PMCID: PMC7165522 DOI: 10.1111/j.1600-065x.2010.00912.x] [Citation(s) in RCA: 244] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
Abstract
Summary: Humoral immunity following vaccination or infection is mainly derived from two types of cells: memory B cells and plasma cells. Memory B cells do not actively secrete antibody but instead maintain their immunoglobulin in the membrane‐bound form that serves as the antigen‐specific B‐cell receptor. In contrast, plasma cells are terminally differentiated cells that no longer express surface‐bound immunoglobulin but continuously secrete antibody without requiring further antigenic stimulation. Pre‐existing serum or mucosal antibody elicited by plasma cells (or other intermediate antibody‐secreting cells) represents the first line of defense against reinfection and is critical for protection against many microbial diseases. However, the mechanisms involved with maintaining long‐term antibody production are not fully understood. Here, we examine several models of long‐term humoral immunity and present a new model, described as the ‘Imprinted Lifespan’ model of plasma cell longevity. The foundation of this model is that plasma cells are imprinted with a predetermined lifespan based on the magnitude of B‐cell signaling that occurs during the induction of an antigen‐specific humoral immune response. This represents a testable hypothesis and may explain why some antigen‐specific antibody responses fade over time whereas others are maintained essentially for life.
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Halford WP, Püschel R, Rakowski B. Herpes simplex virus 2 ICP0 mutant viruses are avirulent and immunogenic: implications for a genital herpes vaccine. PLoS One 2010; 5:e12251. [PMID: 20808928 PMCID: PMC2923193 DOI: 10.1371/journal.pone.0012251] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2010] [Accepted: 07/24/2010] [Indexed: 11/19/2022] Open
Abstract
Herpes simplex virus 1 (HSV-1) ICP0(-) mutants are interferon-sensitive, avirulent, and elicit protective immunity against HSV-1 (Virol J, 2006, 3:44). If an ICP0(-) mutant of herpes simplex virus 2 (HSV-2) exhibited similar properties, such a virus might be used to vaccinate against genital herpes. The current study was initiated to explore this possibility. Several HSV-2 ICP0(-) mutant viruses were constructed and evaluated in terms of three parameters: i. interferon-sensitivity; ii. virulence in mice; and iii. capacity to elicit protective immunity against HSV-2. One ICP0(-) mutant virus in particular, HSV-2 0DeltaNLS, achieved an optimal balance between avirulence and immunogenicity. HSV-2 0DeltaNLS was interferon-sensitive in cultured cells. HSV-2 0DeltaNLS replicated to low levels in the eyes of inoculated mice, but was rapidly repressed by an innate, Stat 1-dependent host immune response. HSV-2 0DeltaNLS failed to spread from sites of inoculation, and hence produced only inapparent infections. Mice inoculated with HSV-2 0DeltaNLS consistently mounted an HSV-specific IgG antibody response, and were consistently protected against lethal challenge with wild-type HSV-2. Based on their avirulence and immunogenicity, we propose that HSV-2 ICP0(-) mutant viruses merit consideration for their potential to prevent the spread of HSV-2 and genital herpes.
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Affiliation(s)
- William P Halford
- Department of Microbiology and Immunology, Southern Illinois University School of Medicine, Springfield, Illinois, United States of America.
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30
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Abstract
BACKGROUND The attenuated live varicella vaccine had been shown to be effective in preventing varicella and reducing the disease burden in the United States. However, little work has been done on investigating vaccine effectiveness in China where 3 varicella vaccines are available. Although the vaccines contain the same strain of virus, the vaccines licensed in China were from manufacturers different from the one licensed in the United States. We conducted a matched case-control study to assess the effectiveness of the 3 varicella vaccines in use in China. METHODS In 2005, we enrolled 1000 cases from Guangzhou, China and 1000 controls matched by age and place of residence. The cases were children clinically diagnosed with acute onset of a diffuse maculopapulovesicular rash without other apparent cause. We interviewed the legal guardians of the participants for demographic information and disease history after obtaining informed consent. We collected information on vaccination status from electronic vaccination records. RESULTS The 3 varicella vaccines in China (Varilrix from GlaxoSmithKline, Changchun and Shanghai from Changchun and Shanghai Institutes of Biologic Products, respectively) had similar effectiveness: Varilrix 86.4% (95% confidence interval [CI]: 72.6, 93.2), Changchun 79.5% (95% CI: 58.1, 90.0), and Shanghai 92.6% (95% CI: 68.9, 98.2). Vaccine effectiveness was higher during the first year after vaccination than during the subsequent 5 years, but the differences did not reach statistical significance. CONCLUSIONS The varicella vaccines in China are highly effective in preventing clinical varicella. Further studies on laboratory-confirmed cases are needed to verify the change of vaccine-induced immunity over time.
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Ambagala APN, Krogmann T, Qin J, Pesnicak L, Cohen JI. A varicella-zoster virus mutant impaired for latency in rodents, but not impaired for replication in cell culture. Virology 2010; 399:194-200. [PMID: 20116820 DOI: 10.1016/j.virol.2010.01.007] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2009] [Revised: 10/06/2009] [Accepted: 01/05/2010] [Indexed: 10/19/2022]
Abstract
While trying to generate a site-directed deletion in the ORF63 latency-associated gene of varicella-zoster virus (VZV) Oka, we constructed a virus with an unexpected rearrangement. The virus has a small deletion in both copies of ORF63 and two copies of a cassette inserted between ORFs 64/65 and 68/69 containing (a) truncated ORF62, (b) ORF63 with a small deletion, and (c) full-length ORF64. The virus was not impaired for growth in human cells, induced higher levels of neutralizing antibodies in guinea pigs, and was impaired for latency in cotton rats compared with parental virus (p=0.0022). Additional mutants containing the same truncation in ORF62, with or without the ORF63 deletion, were less impaired for latency. A VZV Oka mutant, replicating to similar titers and inducing a comparable immune response as parental virus, but impaired for latency, might serve as a safer vaccine and be less likely to reactivate to cause zoster.
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Affiliation(s)
- Aruna P N Ambagala
- Medical Virology Section, Laboratory of Clinical Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA
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Abstract
Reports about efficacy and safety of live-virus attenuated vaccines in patients before and after transplantation are mainly based on small patient numbers, making general recommendations for this patient population difficult. Children and adults as well as their close relatives and contact persons should be preferably immune to VZV before solid organ transplantation to avoid VZV-associated complications, thus making VZV vaccination necessary in susceptible individuals. The following literature review focused on efficacy and safety of VZV vaccination in pediatric kidney and liver transplant recipients. Review of literature also revealed that in all pediatric transplant candidates, humoral and cellular immunity against VZV should be consistently monitored to assess waning immunity under immunosuppressive treatment. This approach is desirable to estimate the risk of severe varicella disease after exposure in these patients.
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Affiliation(s)
- Martina Prelog
- Department of Pediatrics, Pediatrics I, Medical University Innsbruck, Anichstr. 35, A-6020 Innsbruck, Austria.
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Donahue JG, Kieke BA, Gargiullo PM, Jumaan AO, Berger NR, McCauley JS, Belongia EA. Herpes zoster and exposure to the varicella zoster virus in an era of varicella vaccination. Am J Public Health 2010; 100:1116-22. [PMID: 20075320 DOI: 10.2105/ajph.2009.160002] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022]
Abstract
OBJECTIVES We performed a case-control study to determine if participants with herpes zoster had fewer contacts with persons with varicella or zoster, and with young children, to explore the hypothesis that exposure to persons with varicella zoster virus (VZV) results in "immune boosting." METHODS Participants were patients of the multispecialty Marshfield Clinic in Wisconsin. We identified patients aged 40 to 79 years with a new diagnosis of zoster from August 2000 to July 2005. We frequency matched control participants to case participants for age. We confirmed diagnoses by chart review and assessed exposures by interview. RESULTS Interviews were completed by 633 of 902 eligible case participants (70.2%) and 655 of 1149 control participants (57.0%). The number of varicella contacts was not associated with zoster; there was no trend even at the highest exposure level (3 or more contacts). Similarly, there was no association with exposure to persons with zoster or to children, or with workplace exposures. CONCLUSIONS Although exposure to VZV in our study was relatively low, the absence of a relationship with zoster reflects the uncertain influence of varicella circulation on zoster epidemiology.
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Affiliation(s)
- James G Donahue
- Epidemiology Research Center, ML-2, Marshfield Clinic Research Foundation, 1000 N Oak Ave, Marshfield, WI 54449, USA.
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Daley AJ, Thorpe S, Garland SM. Varicella and the pregnant woman: prevention and management. Aust N Z J Obstet Gynaecol 2008; 48:26-33. [PMID: 18275568 DOI: 10.1111/j.1479-828x.2007.00797.x] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Infection with varicella zoster virus (VZV) is often considered a childhood 'right of passage'; however, primary infection occurring in women of child-bearing age can have significant adverse consequences both for the mother and for her fetus. During the first trimester, primary VZV infection may result in stillbirth or a baby born with the stigmata of the congenital varicella syndrome, while infection in the peripartum period can result in neonatal varicella, which carries a significant mortality rate despite appropriate antiviral therapy. Varicella in pregnant women can progress to pneumonitis and other severe sequelae that may also compromise the viability of the fetus. Exposure to VZV most commonly occurs in the community or from children in the household, but occasionally, exposure may occur in the hospital environment. Determining a woman's serostatus prior to pregnancy is advised, as effective vaccines are now available and should be administered to non-pregnant seronegative women of child-bearing age. Clinical practice guidelines for management of a pregnant woman exposed to VZV are presented.
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Affiliation(s)
- Andrew J Daley
- Infection Control Department, The Royal Women's Hospital and The Royal Children's Hospital, Melbourne, Australia.
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Malavige GN, Jones L, Black AP, Ogg GS. Varicella zoster virus glycoprotein E-specific CD4+ T cells show evidence of recent activation and effector differentiation, consistent with frequent exposure to replicative cycle antigens in healthy immune donors. Clin Exp Immunol 2008; 152:522-31. [PMID: 18363743 PMCID: PMC2453195 DOI: 10.1111/j.1365-2249.2008.03633.x] [Citation(s) in RCA: 62] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/11/2008] [Indexed: 12/23/2022] Open
Abstract
Varicella zoster viru (VZV)-specific T cell responses are believed to be vital in recovery from primary VZV infection and also in the prevention of viral reactivation. While glycoprotein E (gE) is the most abundant and one of the most immunogenic proteins of the virus, there are no data addressing potential T cell epitopes within gE, nor the phenotype of specific T cells. Using interferon gamma enzyme-linked immunospot assays and intracellular cytokine assays, we identified gE-specific immune responses in 20 adult healthy immune donors which were found to be dominated by the CD4+ subset of T cells. We characterized three immune dominant epitopes within gE restricted through DRB1*1501, DRB1*07 and DRB4*01, and used DRB1*1501 class II tetrameric complexes to determine the ex vivo frequency and phenotype of specific T cells. In healthy immune donors, the cells were largely positive for CCR7, CD28 and CD27, but expressed variable CD62L and low levels of cutaneous lymphocyte associated antigen with evidence of recent activation. In summary, we show that circulating gE-specific CD4+ T cells are detected at a relatively high frequency in healthy immune donors and show evidence of recent activation and mixed central and effector memory phenotype. These data would be compatible with frequent exposure to replicative cycle antigens in healthy donors and are consistent with a role for gE-specific CD4+ T cells in the control of viral replication.
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Affiliation(s)
- G N Malavige
- MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, UK
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Reynolds MA, Chaves SS, Harpaz R, Lopez AS, Seward JF. The impact of the varicella vaccination program on herpes zoster epidemiology in the United States: a review. J Infect Dis 2008; 197 Suppl 2:S224-7. [PMID: 18419401 DOI: 10.1086/522162] [Citation(s) in RCA: 85] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Speculation that a universal varicella vaccination program might lead to an increase in herpes zoster (HZ) incidence has been supported by modeling studies that assume that exposure to varicella boosts immunity and protects against reactivation of varicella-zoster virus (VZV) as HZ. Such studies predict an increase in HZ incidence until the adult population becomes predominantly composed of individuals with vaccine-induced immunity who do not harbor wild-type VZV. In the United States, a varicella vaccination program was implemented in 1995. Since then, studies monitoring HZ incidence have shown inconsistent findings: 2 studies have shown no increase in overall incidence, whereas 1 study has shown an increase. Studies from Canada and the United Kingdom have shown increasing rates of HZ incidence in the absence of a varicella vaccination program. Data suggest that heretofore unidentified risk factors for HZ also are changing over time. Further studies are needed to identify these factors, to isolate possible additional effects from a varicella vaccination program. Untangling the contribution of these different factors on HZ epidemiology will be challenging.
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Affiliation(s)
- Meredith A Reynolds
- Division of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia 30333, USA.
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Mohr CA, Cîcîn-Saîn L, Wagner M, Sacher T, Schnee M, Ruzsics Z, Koszinowski UH. Engineering of cytomegalovirus genomes for recombinant live herpesvirus vaccines. Int J Med Microbiol 2008; 298:115-25. [PMID: 17702650 DOI: 10.1016/j.ijmm.2007.07.008] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022] Open
Abstract
The advances of sequence knowledge and genetic engineering hold a great promise for a rational approach to vaccine development. Herpesviruses are important pathogens of all vertebrates. They cause acute and chronic infections and persist in their hosts for life. In man there are eight herpesviruses known and most of them can be linked to diseases. To date only one licensed vaccine against a human herpesvirus exists and there is no proven successful concept on rational design for herpesvirus vaccines available. Here, we use new reverse genetic systems, based on the 230-kb mouse cytomegalovirus genome to explore new methods of vaccine delivery and of virus attenuation. With regard to virus delivery, we show that the bacterial transfer of the infectious DNA in vivo is theoretically possible but not yet a practical option. With regard to a rational approach of virus attenuation, we consider a selective deletion of viral genes that modulate the immune response of the host.
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Affiliation(s)
- Christian A Mohr
- Max von Pettenkofer-Institut, Pettenkoferstrasse 9a, D-80336 Munich, Germany
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Bekker V, Westerlaken GHA, Scherpbier H, Alders S, Zaaijer H, van Baarle D, Kuijpers T. Varicella vaccination in HIV-1-infected children after immune reconstitution. AIDS 2006; 20:2321-9. [PMID: 17117018 DOI: 10.1097/qad.0b013e3280113f29] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
Abstract
BACKGROUND HIV-1-infected children have an increased risk of severe chickenpox. However, vaccination is not recommended in severely immunocompromised children. OBJECTIVE Can the live-attenuated varicella zoster virus (VZV) Oka strain be safely and effectively given to HIV-1-infected children despite previously low CD4 T-cell counts? METHODS VZV vaccine was administered twice to 15 VZV-seronegative HIV-1-infected children when total lymphocyte counts were greater than 700 lymphocytes/microl, and six HIV-negative VZV-seronegative siblings. Weekly clinical follow-up and sampling were performed. RESULTS None of the children developed any clinical symptom or serious adverse reaction after immunization. Only nine (60%) of the HIV-1-infected children had VZV-specific antibodies after two immunizations, whereas 100% of the siblings seroconverted. Age at baseline was negatively correlated with the VZV IgG titre at 6 weeks after the second vaccination in HIV-1-infected children. VZV-specific antibody titres after two immunizations were at a similar level to those found after wild-type infection in non-vaccinated HIV-1-infected patients, but significantly lower than in HIV-negative siblings. Importantly, VZV-specific T-cell responses increased after vaccination and were comparable in both groups over time. Documented wild-type VZV contact in three vaccinated patients did not result in breakthrough infections. CONCLUSION VZV vaccination of previously immunocompromised HIV-1-infected children was safe. Vaccination induced specific immune responses in some of the vaccinated HIV-1-infected children, suggesting that previously immunocompromised individuals are protected against severe forms of varicella.
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Rouse BT, Kaistha SD. A tale of 2 alpha-herpesviruses: lessons for vaccinologists. Clin Infect Dis 2006; 42:810-7. [PMID: 16477558 DOI: 10.1086/500141] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2005] [Accepted: 11/03/2005] [Indexed: 12/20/2022] Open
Abstract
Of the 8 known herpesviruses that affect human beings, we only have successful vaccines against varicella zoster virus. This brief review compares the pathogenesis of varicella zoster virus with that of the closely related alpha-herpesviruses herpes simplex virus 1 and 2, for which we have no satisfactory vaccines. The main objective of this review is to learn lessons from the success of varicella zoster virus vaccine that could be exploited for the development of successful vaccines against herpes simplex virus and perhaps against other herpes viruses.
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Affiliation(s)
- Barry T Rouse
- Department of Microbiology, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA.
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40
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Abstract
In 1995, the Varicella Active Surveillance Project (VASP) was established in Antelope Valley (California), a geographically distinct high-desert community of 300,000 residents, as one of three sites in the nation in a cooperative agreement with the Centers for Disease Control and Prevention (CDC) to collect baseline demographic and clinical data and to monitor trends in varicella (chickenpox) following introduction of varicella vaccine. Herpes zoster (shingles) was added to the active surveillance January 1, 2000. The universal varicella program has proven effective in terms of reducing the number of reported verified varicella cases by 85%, from 2,934 in 1995 to 412 in 2002. Prior to this dramatic reduction, immunologic boosting due to exogenous exposures to wild-type varicella-zoster virus (VZV) in the community (1) caused mean serum anti-VZV levels among vaccines to increase with time after vaccination and (2) served as a mechanism that helped suppress the reactivation of herpes zoster (HZ), especially among individuals with a previous history of wild-type varicella. That immunologic boosting might play a significant role in both varicella and the closely related HZ epidemiology is evidenced by (1) a decline in vaccine efficacy by over 20%, from 95.7% (95% C.I., 82.7% to 98.9%) in 1999 to 73.9% (95% C.I., 57.9% to 83.8%) in 2001 and (2) an unexpectedly high cumulative (2000 to 2003) true incidence rate of 223 (95% C.I. 180-273) per 100,000 person-years (p-y) among children <10 years old with a previous history of varicella. Because capture-recapture methods demonstrate a likely lower bound of 50% underreporting, the actual rate is likely double or 446 per 100,000 p-y, approaching the HZ rate reported among older adults. Other recent studies based on VASP data have mitigated against discovery of the above trends that challenge several initial assumptions inherent to the universal varicella program, namely, (1) a single dose confers long-term immunity and (2) there is no immunologically mediated link between varicella and HZ incidence. As vaccinated children replace those with a prior history of wild-type varicella in the <10 age group, increasing HZ incidence among this cohort will be of less concern in the near future. However, previous scientific studies, including the present preliminary results from active surveillance indicate that HZ may be increasing among adults. It may be difficult to design booster interventions that are cost-effective and meet or exceed the level of protection provided by immunologic boosting that existed naturally in the community in the prelicensure era.
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Affiliation(s)
- Gary S Goldman
- Medical Veritas International (MVI), Pearblossom, California 93553, USA.
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41
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Abstract
For the first time, a live attenuated varicella vaccine with an indication for universal vaccination is licensed in all EU countries. It is now time to consider whether in Europe there should be widespread vaccination against varicella to prevent this common and highly infectious disease. Increasing numbers of countries are adopting vaccination programmes against the disease. In those countries where a routine vaccination policy has been adopted, the success of the vaccine has been significant. The USA, which prior to the launch of a universal vaccination programme in 1995 had 4 million cases of varicella per year, has seen a dramatic reduction in varicella morbidity and mortality rates. A universal varicella vaccination policy is an option that needs to be considered for Europe not only in medical terms but also because it would be socially and economically appropriate.
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Affiliation(s)
- J Ramet
- Universiteit Antwerpen, UZA and Paola Kinderziekenhuis ZNA, Antwerp, Belgium.
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42
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Abstract
Two vaccines against varicella are now being licensed in France, both deriving from the Oka strain. Seroconversion has been obtained in almost 100% of the cases after one dose in toddlers and children, and two doses in adolescents and adults. Efficacy has been mainly established from the US experience, where a universal immunisation programme of children aged > 12 months with a catch-up for susceptible adolescents and adults was begun in 1995. The incidence of varicella has decreased by about 85% over all age groups. The safety of the vaccine is good, and most adverse events are represented by fever, reactions at the injection site and varicella-like rashes. For the time being, France has adopted restrictive recommendations for the use of this vaccine because of uncertainties with respect to the duration of protection, a shift of the disease towards older age and the potential increase of the incidence of herpes-zoster.
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Affiliation(s)
- Daniel Floret
- Urgence et Réanimation Pédiatriques, Hôpital Edouard Herriot, Lyon, France.
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Coudeville L, Brunot A, Szucs TD, Dervaux B. The economic value of childhood varicella vaccination in France and Germany. VALUE IN HEALTH : THE JOURNAL OF THE INTERNATIONAL SOCIETY FOR PHARMACOECONOMICS AND OUTCOMES RESEARCH 2005; 8:209-22. [PMID: 15877593 DOI: 10.1111/j.1524-4733.2005.04005.x] [Citation(s) in RCA: 37] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/02/2023]
Abstract
OBJECTIVE To determine the economic impact of childhood varicella vaccination in France and Germany. METHODS A common methodology based on the use of a varicella transmission model was used for the two countries. Cost data (2002 per thousand) were derived from two previous studies. The analysis focused on a routine vaccination program for which three different coverage rates (CRs) were considered (90%, 70%, and 45%). Catch-up strategies were also analyzed. A societal perspective including both direct and indirect costs and a third-party payer perspective were considered (Social Security in France and Sickness Funds in Germany). RESULTS A routine vaccination program has a clear positive impact on varicella-related morbidity in both countries. With a 90% CR, the number of varicella-related deaths was reduced by 87% in Germany and by 84% in France. In addition, with a CR of 90%, routine varicella vaccination induces savings in both countries from both societal (Germany 61%, France 60%) and third-party payer perspectives (Germany 51%, France 6.7%). For lower CRs, routine vaccination remains cost saving from a third-party payer perspective in Germany but not in France, where it is nevertheless cost-effective (cost per life-year gained of 6521 per thousand in the base case with a 45% CR). CONCLUSION Considering the impact of vaccination on varicella morbidity and costs, a routine varicella vaccination program appears to be cost saving in Germany and France from both a societal and a third-party payer perspective. For France, routine varicella vaccination remains cost-effective in worst cases when a third-party payer perspective is adopted. Catch-up programs provide additional savings.
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Lowe GL, Salmon RL, Thomas DR, Evans MR. Declining incidence of chickenpox in the absence of universal childhood immunisation. Arch Dis Child 2004; 89:966-9. [PMID: 15383443 PMCID: PMC1719669 DOI: 10.1136/adc.2002.021618] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
OBJECTIVE To examine the epidemiology of chickenpox in Wales from 1986 to 2001. DESIGN Descriptive analysis of chickenpox consultations reported by the Welsh general practice sentinel surveillance scheme for infectious diseases, compared with annual shingles consultation rates from the same scheme to exclude reporting fatigue and data from a general practice morbidity database to validate results. SETTING A total of 226,884 patients registered with one of 30 volunteer general practices participating in the sentinel surveillance scheme. MAIN OUTCOME MEASURES Age standardised and age specific incidence of chickenpox. RESULTS Crude and age standardised consultation rates for chickenpox declined from 1986 to 2001, with loss of epidemic cycling. Rates remained stable in 0-4 year olds but declined in all older age groups, particularly those aged 5-14 years. Shingles consultation rates remained constant over the same period. Data from the morbidity database displayed similar trends. CONCLUSION General practitioner consultation rates for chickenpox are declining in Wales except in pre-school children. These findings are unlikely to be a reporting artefact but may be explained either by an overall decline in transmission or increased social mixing in those under 5 years old, through formal child care and earlier school entry, and associated increasing rates of mild or subclinical infection in this age group. Further investigation, particularly by serological surveillance, is necessary before universal varicella immunisation can be considered in the UK.
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Affiliation(s)
- G L Lowe
- National Public Health Service Communicable Disease Surveillance Centre, Abton House, Cardiff CF14 3QX, UK.
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Staprans SI, Barry AP, Silvestri G, Safrit JT, Kozyr N, Sumpter B, Nguyen H, McClure H, Montefiori D, Cohen JI, Feinberg MB. Enhanced SIV replication and accelerated progression to AIDS in macaques primed to mount a CD4 T cell response to the SIV envelope protein. Proc Natl Acad Sci U S A 2004; 101:13026-31. [PMID: 15326293 PMCID: PMC516468 DOI: 10.1073/pnas.0404739101] [Citation(s) in RCA: 118] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/18/2022] Open
Abstract
Given the dual role of CD4 T cells as both immune effectors and targets for HIV infection, the balance of CD4 versus CD8 T cell-mediated responses induced by candidate AIDS vaccines may be critical in determining postvaccination infection outcomes. An attenuated recombinant varicella-zoster virus vaccine expressing the simian immunodeficiency virus (SIV) envelope (Env) elicited nonneutralizing Env-binding antibodies and little if any cytotoxic T lymphocyte responses in rhesus macaques (Macaca mulatta). After challenge with SIV, Env vaccinees manifested increased levels of SIV replication, more rapid CD4 depletion, and accelerated progression to AIDS compared with controls. Enhanced SIV replication correlated with increased CD4 T cell proliferation soon after SIV challenge, apparently the result of an anamnestic response to SIV antigens. Thus activation of virus-specific CD4 T cells at the time of exposure to a CD4 T cell-tropic lentivirus, in the absence of an effective CD8 response, may enhance virus replication and disease. These data suggest suggest that candidate AIDS vaccines may not simply be either efficacious or neutral; they may also have the potential to be harmful.
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48
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Karrer U, Wagner M, Sierro S, Oxenius A, Hengel H, Dumrese T, Freigang S, Koszinowski UH, Phillips RE, Klenerman P. Expansion of protective CD8+ T-cell responses driven by recombinant cytomegaloviruses. J Virol 2004; 78:2255-64. [PMID: 14963122 PMCID: PMC369208 DOI: 10.1128/jvi.78.5.2255-2264.2004] [Citation(s) in RCA: 97] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/21/2003] [Accepted: 11/21/2003] [Indexed: 12/27/2022] Open
Abstract
CD8(+) T cells are critical for the control of many persistent viral infections, such as human immunodeficiency virus, hepatitis C virus, Epstein-Barr virus, and cytomegalovirus (CMV). In most infections, large CD8(+)-T-cell populations are induced early but then contract and are maintained thereafter at lower levels. In contrast, CD8(+) T cells specific for murine CMV (MCMV) have been shown to gradually accumulate after resolution of primary infection. This unique behavior is restricted to certain epitopes, including an immunodominant epitope derived from the immediate-early 1 (IE1) gene product. To explore the mechanism behind this further, we measured CD8(+)-T-cell-mediated immunity induced by recombinant MCMV-expressing epitopes derived from influenza A virus or lymphocytic choriomeningitis virus placed under the control of an IE promoter. We observed that virus-specific CD8(+)-T-cell populations were induced and that these expanded gradually over time. Importantly, these CD8(+) T cells provided long-term protection against challenge without boosting. These results demonstrate a unique pattern of accumulating T cells, which provide long-lasting immune protection, that is independent of the initial immunodominance of the epitope and indicates the potential of T-cell-inducing vaccines based on persistent vectors.
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Affiliation(s)
- Urs Karrer
- Nuffield Department of Clinical Medicine, Peter Medawar Building for Pathogen Research, University of Oxford, Oxford OX1 3SY, United Kingdom.
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Kuter B, Matthews H, Shinefield H, Black S, Dennehy P, Watson B, Reisinger K, Kim LL, Lupinacci L, Hartzel J, Chan I. Ten year follow-up of healthy children who received one or two injections of varicella vaccine. Pediatr Infect Dis J 2004; 23:132-7. [PMID: 14872179 DOI: 10.1097/01.inf.0000109287.97518.67] [Citation(s) in RCA: 277] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND The rate of varicella and persistence of varicella antibody after a one dose vs. a two dose regimen of varicella virus vaccine live Oka/Merck (VARIVAX; Merck & Co., Inc., West Point, PA) in approximately 2000 children were compared during a 9- to 10-year follow-up period. METHODS Children 12 months to 12 years of age with a negative history of varicella were randomized in late 1991 to early 1993 to receive either one or two injections of varicella vaccine given 3 months apart. Subjects were actively followed for varicella, any varicella-like illness or zoster and any exposures to varicella or zoster on a yearly basis for 10 years after vaccination. Persistence of varicella antibody was measured yearly for 9 years. RESULTS Most cases of varicella reported in recipients of one or two injections of vaccine were mild. The risk of developing varicella >42 days postvaccination during the 10-year observation period was 3.3-fold lower (P < 0.001) in children who received two injections than in those who received one injection (2.2% vs. 7.3%, respectively). The estimated vaccine efficacy for the 10-year observation period was 94.4% for one injection and 98.3% for two injections (P < 0.001). Measurable serum antibody persisted for 9 years in all subjects. CONCLUSIONS Administration of either one or two injections of varicella vaccine to healthy children results in long term protection against most varicella disease. The two dose regimen was significantly more effective than a single injection.
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Affiliation(s)
- Barbara Kuter
- Merck Research Laboratories, PO Box 4, West Point, PA 19486, USA.
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Coudeville L, Brunot A, Giaquinto C, Lucioni C, Dervaux B. Varicella vaccination in Italy : an economic evaluation of different scenarios. PHARMACOECONOMICS 2004; 22:839-855. [PMID: 15329030 DOI: 10.2165/00019053-200422130-00003] [Citation(s) in RCA: 33] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/24/2023]
Abstract
AIM To determine the economic impact (cost-benefit analysis) of childhood varicella vaccination, with the Oka/Merck varicella zoster virus vaccine live (Varivax) in Italy. METHODS This analysis is based on an epidemiological model of varicella zoster virus (VZV) dynamics adapted to the Italian situation. Cost data (Euro, 2002 values) were collected through a literature review. Several vaccination scenarios were analysed: (i) routine vaccination programme for children aged 1-2 years with different levels of vaccination coverage (90%, 70% and 45%) without any catch-up programme; (ii) routine vaccination programme for children aged 1-2 years with different levels of vaccination coverage (90%, 70% and 45%) completed by a catch-up programme for 6-year-old children over the first 5 years of vaccine marketing; and (iii) routine vaccination programme for children aged 1-2 years with different levels of vaccination coverage (90%, 70% and 45%) completed by a catch-up programme during the first year of vaccine marketing for children aged 2-11 years. PERSPECTIVES A societal perspective, including both direct and indirect costs, and a health-system perspective, limited to costs supported by Italian Health Authorities, were considered. RESULTS A routine vaccination programme has a clearly positive impact on chickenpox morbidity. Respectively, 68% and 57% of chickenpox-related hospitalisations and deaths could be prevented with a 90% coverage rate. With vaccination costs being more than offset by a reduction in chickenpox treatment costs in the base case, such a programme could also induce savings from both a societal and a health-system perspective (40% and 12% savings, respectively for a 90% coverage rate). A lower coverage rate reduces cost savings, but there is still a 9% decrease in overall societal costs for a 45% coverage rate. Although the reduction in total societal costs was robust to the sensitivity analyses performed, a slight uncertainty remains regarding cost reduction from a health-system perspective. However, in this latter perspective, even in the worst-case scenario of the sensitivity analysis, routine vaccination programmes may be cost effective, the worst-case scenario for cost parameters leading to cost per life-year gained of Euro2853. Catch-up programmes combined with routine vaccination should lead to further cost reductions from a societal perspective: 15% for a massive catch-up during the first year of vaccine marketing compared with toddlers' vaccination alone, and 11% for a catch-up focused on 6-year-old children for a period of 5 years. However, the impact of catch-up programmes on the costs from an Italian health-system perspective remains close to zero (+/-1%). CONCLUSION This model suggests, with its underlying assumptions and data, that routine ZVZ vaccination may be cost saving from both a societal and a health system perspective in the base case. In the worst-case scenario of the sensitivity analysis, vaccination remains cost effective.
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