Humanized Mice in Vaccinology: Opportunities and Challenges

A special issue of Vaccines (ISSN 2076-393X).

Deadline for manuscript submissions: closed (4 December 2019) | Viewed by 27032

Special Issue Editors


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Guest Editor
Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany
Interests: viral hemorrhagic fevers; immunology; dendritic cells; T cells
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
Guest Editor
Bernhard Nocht Institute for Tropical Medicine, 20359 Hamburg, Germany
Interests: humanized mice; viral persistence; viral pathogenesis; immunology

Special Issue Information

Dear Colleagues,

Over the last decade, the use of mice harboring human cells, in particular human immune cells, has increased exponentially. The wide variety of available models with improved engraftment, mature, and functional human T and B cells and reduced graft vs. host disease has allowed one to study human-restricted pathogens and a variety of tumors as well as autoimmune diseases to an unprecedented detail. Importantly, some efforts have also been devoted to further develop models harboring not only human immune cells but also human peripheral cells from tissues with relevance in disease pathophysiology. A number of recent studies have also used humanized mice as in vivo platforms to test vaccine immunogenicity and protection.

In this Special Issue, we will discuss all aspects related to the use of humanized mice in vaccinology and discuss the opportunities and the challenges ahead.

Dr. César Muñoz-Fontela
Dr. Estefanía Rodríguez
Guest Editors

Manuscript Submission Information

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Keywords

  • humanized mice
  • vaccine
  • viruses
  • cancer vaccines
  • dendritic cell vaccines
  • T cells
  • emerging viruses
  • persistent viruses
  • immunogenicity
  • NSG
  • BLT
  • uPA
  • xenografts

Published Papers (5 papers)

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Review

17 pages, 617 KiB  
Review
The Utility of Human Immune System Mice for High-Containment Viral Hemorrhagic Fever Research
by David M. Wozniak, Kerry J. Lavender, Joseph Prescott and Jessica R. Spengler
Vaccines 2020, 8(1), 98; https://doi.org/10.3390/vaccines8010098 - 22 Feb 2020
Cited by 3 | Viewed by 3499
Abstract
Human immune system (HIS) mice are a subset of humanized mice that are generated by xenoengraftment of human immune cells or tissues and/or their progenitors into immunodeficient mice. Viral hemorrhagic fevers (VHFs) cause severe disease in humans, typically with high case fatality rates. [...] Read more.
Human immune system (HIS) mice are a subset of humanized mice that are generated by xenoengraftment of human immune cells or tissues and/or their progenitors into immunodeficient mice. Viral hemorrhagic fevers (VHFs) cause severe disease in humans, typically with high case fatality rates. HIS mouse studies have been performed to investigate the pathogenesis and immune responses to VHFs that must be handled in high-containment laboratory facilities. Here, we summarize studies on filoviruses, nairoviruses, phenuiviruses, and hantaviruses, and discuss the knowledge gained from using various HIS mouse models. Furthermore, we discuss the complexities of designing and interpreting studies utilizing HIS mice while highlighting additional questions about VHFs that can still be addressed using HIS mouse models. Full article
(This article belongs to the Special Issue Humanized Mice in Vaccinology: Opportunities and Challenges)
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12 pages, 896 KiB  
Review
Modeling Human Cytomegalovirus in Humanized Mice for Vaccine Testing
by Johannes Koenig, Sebastian J. Theobald and Renata Stripecke
Vaccines 2020, 8(1), 89; https://doi.org/10.3390/vaccines8010089 - 17 Feb 2020
Cited by 12 | Viewed by 5168
Abstract
Human cytomegalovirus (HCMV or HHV-5) is a globally spread pathogen with strictly human tropism that establishes a life-long persistence. After primary infection, high levels of long-term T and B cell responses are elicited, but the virus is not cleared. HCMV persists mainly in [...] Read more.
Human cytomegalovirus (HCMV or HHV-5) is a globally spread pathogen with strictly human tropism that establishes a life-long persistence. After primary infection, high levels of long-term T and B cell responses are elicited, but the virus is not cleared. HCMV persists mainly in hematopoietic reservoirs, whereby occasional viral reactivation and spread are well controlled in immunocompetent hosts. However, when the immune system cannot control viral infections or reactivations, such as with newborns, patients with immune deficiencies, or immune-compromised patients after transplantations, the lytic outbursts can be severely debilitating or lethal. The development of vaccines for immunization of immune-compromised hosts has been challenging. Several vaccine candidates did not reach the potency expected in clinical trials and were not approved. Before anti-HCMV vaccines can be tested pre-clinically in immune-compromised hosts, reliable in vivo models recapitulating HCMV infection might accelerate their clinical translation. Therefore, immune-deficient mouse strains implanted with human cells and tissues and developing a human immune system (HIS) are being explored to test anti-HCMV vaccines. HIS-mice resemble immune-compromised hosts as they are equipped with antiviral human T and B cells, but the immune reactivity is overall low. Several groups have independently shown that HCMV infections and reactivations can be mirrored in HIS mice. However, these models and the analyses employed varied widely. The path forward is to improve human immune reconstitution and standardize the analyses of adaptive responses so that HIS models can be forthrightly used for testing novel generations of anti-HCMV vaccines in the preclinical pipeline. Full article
(This article belongs to the Special Issue Humanized Mice in Vaccinology: Opportunities and Challenges)
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23 pages, 981 KiB  
Review
Humanized Mice in Dengue Research: A Comparison with Other Mouse Models
by Carolina Coronel-Ruiz, Hernando Gutiérrez-Barbosa, Sandra Medina-Moreno, Myriam L. Velandia-Romero, Joel V. Chua, Jaime E. Castellanos and Juan C. Zapata
Vaccines 2020, 8(1), 39; https://doi.org/10.3390/vaccines8010039 - 22 Jan 2020
Cited by 21 | Viewed by 6152
Abstract
Dengue virus (DENV) is an arbovirus of the Flaviviridae family and is an enveloped virion containing a positive sense single-stranded RNA genome. DENV causes dengue fever (DF) which is characterized by an undifferentiated syndrome accompanied by fever, fatigue, dizziness, muscle aches, and in [...] Read more.
Dengue virus (DENV) is an arbovirus of the Flaviviridae family and is an enveloped virion containing a positive sense single-stranded RNA genome. DENV causes dengue fever (DF) which is characterized by an undifferentiated syndrome accompanied by fever, fatigue, dizziness, muscle aches, and in severe cases, patients can deteriorate and develop life-threatening vascular leakage, bleeding, and multi-organ failure. DF is the most prevalent mosquito-borne disease affecting more than 390 million people per year with a mortality rate close to 1% in the general population but especially high among children. There is no specific treatment and there is only one licensed vaccine with restricted application. Clinical and experimental evidence advocate the role of the humoral and T-cell responses in protection against DF, as well as a role in the disease pathogenesis. A lot of pro-inflammatory factors induced during the infectious process are involved in increased severity in dengue disease. The advances in DF research have been hampered by the lack of an animal model that recreates all the characteristics of this disease. Experiments in nonhuman primates (NHP) had failed to reproduce all clinical signs of DF disease and during the past decade, humanized mouse models have demonstrated several benefits in the study of viral diseases affecting humans. In DENV studies, some of these models recapitulate specific signs of disease that are useful to test drugs or vaccine candidates. However, there is still a need for a more complete model mimicking the full spectrum of DENV. This review focuses on describing the advances in this area of research. Full article
(This article belongs to the Special Issue Humanized Mice in Vaccinology: Opportunities and Challenges)
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42 pages, 2610 KiB  
Review
Humanized Mice for Live-Attenuated Vaccine Research: From Unmet Potential to New Promises
by Aoife K. O’Connell and Florian Douam
Vaccines 2020, 8(1), 36; https://doi.org/10.3390/vaccines8010036 - 21 Jan 2020
Cited by 5 | Viewed by 6349
Abstract
Live-attenuated vaccines (LAV) represent one of the most important medical innovations in human history. In the past three centuries, LAV have saved hundreds of millions of lives, and will continue to do so for many decades to come. Interestingly, the most successful LAVs, [...] Read more.
Live-attenuated vaccines (LAV) represent one of the most important medical innovations in human history. In the past three centuries, LAV have saved hundreds of millions of lives, and will continue to do so for many decades to come. Interestingly, the most successful LAVs, such as the smallpox vaccine, the measles vaccine, and the yellow fever vaccine, have been isolated and/or developed in a purely empirical manner without any understanding of the immunological mechanisms they trigger. Today, the mechanisms governing potent LAV immunogenicity and long-term induced protective immunity continue to be elusive, and therefore hamper the rational design of innovative vaccine strategies. A serious roadblock to understanding LAV-induced immunity has been the lack of suitable and cost-effective animal models that can accurately mimic human immune responses. In the last two decades, human-immune system mice (HIS mice), i.e., mice engrafted with components of the human immune system, have been instrumental in investigating the life-cycle and immune responses to multiple human-tropic pathogens. However, their use in LAV research has remained limited. Here, we discuss the strong potential of LAVs as tools to enhance our understanding of human immunity and review the past, current and future contributions of HIS mice to this endeavor. Full article
(This article belongs to the Special Issue Humanized Mice in Vaccinology: Opportunities and Challenges)
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11 pages, 459 KiB  
Review
Immune Control and Vaccination against the Epstein–Barr Virus in Humanized Mice
by Christian Münz
Vaccines 2019, 7(4), 217; https://doi.org/10.3390/vaccines7040217 - 17 Dec 2019
Cited by 5 | Viewed by 4718
Abstract
Mice with reconstituted human immune system components (humanized mice) offer the unique opportunity to test vaccines preclinically in the context of vaccine adjuvant sensing by human antigen presenting cells and priming of human cytotoxic lymphocyte populations. These features are particularly attractive for immune [...] Read more.
Mice with reconstituted human immune system components (humanized mice) offer the unique opportunity to test vaccines preclinically in the context of vaccine adjuvant sensing by human antigen presenting cells and priming of human cytotoxic lymphocyte populations. These features are particularly attractive for immune control of the Epstein–Barr virus (EBV), which represents the most potent growth-transforming pathogen in man and exclusively relies on cytotoxic lymphocytes for its asymptomatic persistence in the vast majority of healthy virus carriers. This immune control is particularly impressive because EBV infects more than 95% of the human adult population and persists without pathology for more than 50 years in most of them. This review will discuss the pathologies that EBV elicits in humanized mice, which immune responses control it in this model, as well as which passive and active vaccination schemes with adoptive T cell transfer and with virus-like particles or individual antigens, respectively, have been explored in this model so far. EBV-specific CD8+ T cell priming in humanized mice could provide crucial insights into how cytotoxic lymphocytes against other viruses and tumors might be elicited by vaccination in humans. Full article
(This article belongs to the Special Issue Humanized Mice in Vaccinology: Opportunities and Challenges)
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