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A special issue of Vaccines (ISSN 2076-393X). This special issue belongs to the section "Vaccines against Tropical and other Infectious Diseases".

Deadline for manuscript submissions: closed (31 October 2019) | Viewed by 56604

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Special Issue Editors

Dr. James D. Brien

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Guest Editor

Department of Molecular Microbiology and Immunology, St. Louis University, 1100 S Grand Blvd, MO 63103, USA
Interests: antigen specific B cell responses; antibody responses

Dr. Amelia K. Pinto

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Guest Editor

Department of Molecular Microbiology and Immunology, St. Louis University, 1100 South Grand Blvd., St. Louis, MO 63103, USA
Interests: antigen specific T cell responses; cytokine regulation of immune responses

Special Issue Information

Dear Colleagues,

Climate change, rising populations, and increases in global travel have led to the emergence of a broad array of pathogenic human flavivirus, including Dengue (DENV), Japanese encephalitis (JEV), Rocio (ROCV), Spondweni (SPOV), Tick Borne encephalitis (TBE), Usutu (USUV), West Nile (WNV) yellow fever (YFV), and the Zika (ZIKV) virus. Individually and in combination these viruses are an increasing threat to global health and economic stability with billions of individuals exposed each year.

Vaccinations are one of the most effective interventions to improve public health by reducing infection rate, complications, and death. To establish the scientific foundation for effective vaccine development, several core factors must be defined, including the fundamental mechanisms of disease, correlates of protection, and the natural history of disease. Vaccine approaches then require further adaption for special populations, such as children, the elderly, and the obese. These are the challenges facing virologists and immunologist working toward the development of effective vaccines for flaviviruses.

Dr. James D. Brien
Dr. Amelia K. Pinto
Guest Editors

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Keywords

Flavivirus Animal Model Vaccine Antigen Specific lymphocytes

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Published Papers (12 papers)

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Editorial

Jump to: Research, Review, Other

5 pages, 190 KiB

Open AccessEditorial

Current Flavivirus Research Important for Vaccine Development

by Elizabeth Geerling, Tara L. Steffen, James D. Brien and Amelia K. Pinto

Vaccines 2020, 8(3), 477; https://doi.org/10.3390/vaccines8030477 - 27 Aug 2020

Cited by 3 | Viewed by 2414

Abstract

The Flaviviridae family of RNA viruses includes numerous human disease-causing pathogens that largely are increasing in prevalence due to continual climate change, rising population sizes and improved ease of global travel [...] Full article

(This article belongs to the Special Issue Current Flavivirus Research Important for Vaccine Development )

Research

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16 pages, 2202 KiB

Open AccessArticle

Immunogenicity and Efficacy of a Recombinant Human Adenovirus Type 5 Vaccine against Zika Virus

by Tara Steffen, Mariah Hassert, Stella G. Hoft, E. Taylor Stone, Jianfeng Zhang, Elizabeth Geerling, Brian T. Grimberg, M. Scot Roberts, Amelia K. Pinto and James D. Brien

Vaccines 2020, 8(2), 170; https://doi.org/10.3390/vaccines8020170 - 7 Apr 2020

Cited by 17 | Viewed by 5226

Abstract

Zika virus (ZIKV) is a significant public health concern due to the pathogen’s ability to be transmitted by either mosquito bite or sexual transmission, allowing spread to occur throughout the world. The potential consequences of ZIKV infection to human health, specifically neonates, necessitates the development of a safe and effective Zika virus vaccine. Here, we developed an intranasal Zika vaccine based upon the replication-deficient human adenovirus serotype 5 (hAd5) expressing ZIKV pre-membrane and envelope protein (hAd5-ZKV). The hAd5-ZKV vaccine is able to induce both cell-mediated and humoral immune responses to ZIKV epitopes. Importantly, this vaccine generated CD8⁺ T cells specific for a dominant ZIKV T cell epitope and is shown to be protective against a ZIKV challenge by using a pre-clinical model of ZIKV disease. We also demonstrate that the vaccine expresses pre-membrane and envelope protein in a confirmation recognized by ZIKV experienced individuals. Our studies demonstrate that this adenovirus-based vaccine expressing ZIKV proteins is immunogenic and protective in mice, and it encodes ZIKV proteins in a conformation recognized by the human antibody repertoire. Full article

(This article belongs to the Special Issue Current Flavivirus Research Important for Vaccine Development )

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9 pages, 1503 KiB

Open AccessCommunication

Using Next Generation Sequencing to Study the Genetic Diversity of Candidate Live Attenuated Zika Vaccines

by Natalie D. Collins, Chao Shan, Bruno T.D. Nunes, Steven G. Widen, Pei-Yong Shi, Alan D.T. Barrett and Vanessa V. Sarathy

Vaccines 2020, 8(2), 161; https://doi.org/10.3390/vaccines8020161 - 3 Apr 2020

Cited by 3 | Viewed by 4313

Abstract

Zika virus (ZIKV) is a mosquito-transmitted positive-sense RNA virus in the family Flaviviridae. Candidate live-attenuated vaccine (LAV) viruses with engineered deletions in the 3’ untranslated region (UTR) provide immunity and protection in animal models of ZIKV infection, and phenotypic studies show that LAVs retain protective abilities following in vitro passage. The present study investigated the genetic diversity of wild-type (WT) parent ZIKV and its candidate LAVs using next generation sequencing analysis of five sequential in vitro passages. The results show that genomic entropy of WT ZIKV steadily increases during in vitro passage, whereas that of LAVs also increased by passage number five but was variable throughout passaging. Additionally, clusters of single nucleotide variants (SNVs) were found to be present in the pre-membrane/membrane (prM), envelope (E), nonstructural protein NS1 (NS1), and other nonstructural protein genes, depending on the specific deletion, whereas in the parent WT ZIKV, they are more abundant in prM and NS1. Ultimately, both the parental WT and LAV derivatives increase in genetic diversity, with evidence of adaptation following passage. Full article

(This article belongs to the Special Issue Current Flavivirus Research Important for Vaccine Development )

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9 pages, 1135 KiB

Open AccessArticle

Vaccination with Aedes aegypti AgBR1 Delays Lethal Mosquito-Borne Zika Virus Infection in Mice

by Yuchen Wang, Alejandro Marin-Lopez, Junjun Jiang, Michel Ledizet and Erol Fikrig

Vaccines 2020, 8(2), 145; https://doi.org/10.3390/vaccines8020145 - 25 Mar 2020

Cited by 10 | Viewed by 3829

Abstract

Zika Virus (ZIKV) is transmitted primarily by Aedes aegypti mosquitoes, resulting in asymptomatic infection, or acute illness with a fever and headache, or neurological complications, such as Guillain-Barre syndrome or fetal microcephaly. Previously, we determined that AgBR1, a mosquito salivary protein, induces inflammatory responses at the bite site, and that passive immunization with AgBR1 antiserum influences mosquito-transmitted ZIKV infection. Here, we show that the active immunization of mice with AgBR1 adjuvanted with aluminum hydroxide delays lethal mosquito-borne ZIKV infection, suggesting that AgBR1 may be used as part of a vaccine to combat ZIKV. Full article

(This article belongs to the Special Issue Current Flavivirus Research Important for Vaccine Development )

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16 pages, 1223 KiB

Open AccessArticle

Addition of Partial Envelope Domain II into Envelope Domain III of Dengue Virus Antigen Potentiates the Induction of Virus-Neutralizing Antibodies and Induces Protective Immunity

by Jisang Park, Hyun-Young Lee, Ly Tuan Khai, Nguyen Thi Thu Thuy, Le Quynh Mai and Yong-Suk Jang

Vaccines 2020, 8(1), 88; https://doi.org/10.3390/vaccines8010088 - 15 Feb 2020

Cited by 9 | Viewed by 3693

Abstract

Dengue virus (DENV) comprises four serotypes in the family Flaviviridae and is a causative agent of dengue-related diseases, including dengue fever. Dengue fever is generally a self-limited febrile illness. However, secondary infection of patients with a suboptimal antibody (Ab) response provokes life-threatening severe dengue hemorrhagic fever or dengue shock syndrome. To develop a potent candidate subunit vaccine against DENV infection, we developed the EDII-cEDIII antigen, which contains partial envelope domain II (EDII) including the fusion loop and BC loop epitopes together with consensus envelope domain III (cEDIII) of all four serotypes of DENV. We purified Ab from mice after immunization with EDII-cEDIII or cEDIII and compared their virus neutralization and Ab-dependent enhancement of DENV infection. Anti-EDII-cEDIII Ab showed stronger neutralizing activity and lower Ab-dependent peak enhancement of DENV infection compared with anti-cEDIII Ab. Following injection of Ab-treated DENV into AG129 mice, anti-EDII-cEDIII Ab ameliorated DENV infection in tissues with primary and secondary infection more effectively than anti-cEDIII Ab. In addition, anti-EDII-cEDIII Ab protected against DENV1, 2, and 4 challenge. We conclude that EDII-cEDIII induces neutralizing and protective Abs, and thus, shows promise as a candidate subunit vaccine for DENV infection. Full article

(This article belongs to the Special Issue Current Flavivirus Research Important for Vaccine Development )

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13 pages, 1515 KiB

Open AccessArticle

Tick-Borne Encephalitis Virus Vaccines Contain Non-Structural Protein 1 Antigen and May Elicit NS1-Specific Antibody Responses in Vaccinated Individuals

by Jiri Salat, Kamil Mikulasek, Osmany Larralde, Petra Pokorna Formanova, Ales Chrdle, Jan Haviernik, Jana Elsterova, Dana Teislerova, Martin Palus, Ludek Eyer, Zbynek Zdrahal, Juraj Petrik and Daniel Ruzek

Vaccines 2020, 8(1), 81; https://doi.org/10.3390/vaccines8010081 - 12 Feb 2020

Cited by 29 | Viewed by 4250

Abstract

Vaccination against tick-borne encephalitis (TBE) is based on the use of formalin-inactivated, culture-derived whole-virus vaccines. Immune response following vaccination is primarily directed to the viral envelope (E) protein, the major viral surface antigen. In Europe, two TBE vaccines are available in adult and pediatric formulations, namely FSME-IMMUN^® (Pfizer) and Encepur^® (GlaxoSmithKline). Herein, we analyzed the content of these vaccines using mass spectrometry (MS). The MS analysis revealed that the Encepur vaccine contains not only proteins of the whole virus particle, but also viral non-structural protein 1 (NS1). MS analysis of the FSME-IMMUN vaccine failed due to the high content of human serum albumin used as a stabilizer in the vaccine. However, the presence of NS1 in FSME-IMMUN was confirmed by immunization of mice with six doses of this vaccine, which led to a robust anti-NS1 antibody response. NS1-specific Western blot analysis also detected anti-NS1 antibodies in sera of humans who received multiple doses of either of these two vaccines; however, most vaccinees who received ≤3 doses were negative for NS1-specific antibodies. The contribution of NS1-specific antibodies to protection against TBE was demonstrated by immunization of mice with purified NS1 antigen, which led to a significant (p < 0.01) prolongation of the mean survival time after lethal virus challenge. This indicates that stimulation of anti-NS1 immunity by the TBE vaccines may increase their protective effect. Full article

(This article belongs to the Special Issue Current Flavivirus Research Important for Vaccine Development )

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13 pages, 2134 KiB

Open AccessArticle

Efficient Delivery of Dengue Virus Subunit Vaccines to the Skin by Microprojection Arrays

by David A. Muller, Alexandra C. I. Depelsenaire, Ashleigh E. Shannon, Daniel Watterson, Simon R. Corrie, Nick S. Owens, Christiana Agyei-Yeboah, Stacey T. M. Cheung, Jin Zhang, Germain J. P. Fernando, Mark A. F. Kendall and Paul R. Young

Vaccines 2019, 7(4), 189; https://doi.org/10.3390/vaccines7040189 - 20 Nov 2019

Cited by 29 | Viewed by 4664

Abstract

Dengue virus is the most important arbovirus impacting global human health, with an estimated 390 million infections annually, and over half the world’s population at risk of infection. While significant efforts have been made to develop effective vaccines to mitigate this threat, the task has proven extremely challenging, with new approaches continually being sought. The majority of protective, neutralizing antibodies induced during infection are targeted by the envelope (E) protein, making it an ideal candidate for a subunit vaccine approach. Using truncated, recombinant, secreted E proteins (sE) of all 4 dengue virus serotypes, we have assessed their immunogenicity and protective efficacy in mice, with or without Quil-A as an adjuvant, and delivered via micropatch array (MPA) to the skin in comparison with more traditional routes of immunization. The micropatch contains an ultra-high density array (21,000/cm²) of 110 μm microprojections. Mice received 3 doses of 1 μg (nanopatch, intradermal, subcutaneous, or intra muscular injection) or 10 μg (intradermal, subcutaneous, or intra muscular injection) of tetravalent sE spaced 4 weeks apart. When adjuvanted with Quil-A, tetravalent sE vaccination delivered via MPA resulted in earlier induction of virus-neutralizing IgG antibodies for all four serotypes when compared with all of the other vaccination routes. Using the infectious dengue virus AG129 mouse infectious dengue model, these neutralizing antibodies protected all mice from lethal dengue virus type 2 D220 challenge, with protected animals showing no signs of disease or circulating virus. If these results can be translated to humans, MPA-delivered sE represents a promising approach to dengue virus vaccination. Full article

(This article belongs to the Special Issue Current Flavivirus Research Important for Vaccine Development )

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9 pages, 1958 KiB

Open AccessArticle

A GFP Reporter MR766-Based Flow Cytometry Neutralization Test for Rapid Detection of Zika Virus-Neutralizing Antibodies in Serum Specimens

by Etienne Frumence, Wildriss Viranaicken, Gilles Gadea and Philippe Desprès

Vaccines 2019, 7(3), 66; https://doi.org/10.3390/vaccines7030066 - 16 Jul 2019

Cited by 10 | Viewed by 5027

Abstract

Zika virus (ZIKV) is an emerging arthropod-borne virus of major public health concern. ZIKV infection is responsible for congenital Zika disease and other neurological defects. Antibody-mediated virus neutralization is an essential component of protective antiviral immunity against ZIKV. In the present study, we assessed whether our GFP reporter ZIKV derived from African viral strain MR766 could be useful for the development of a flow cytometry neutralization test (FNT), as an alternative to the conventional plaque-reduction neutralization test (PRNT). To improve the efficacy of GFP-expressing MR766, we selected virus variant MR766^GFP showing a high level of GFP signal in infected cells. A MR766^GFP-based FNT was assayed with immune sera from adult mice that received ZIKBeHMR-2. The chimeric ZIKV clone ZIKBeHMR-2 comprises the structural protein region of epidemic strain BeH819015 into MR766 backbone. We reported that adult mice inoculated with ZIKBeHMR-2 developed high levels of neutralizing anti-ZIKV antibodies. Comparative analysis between MR766^GFP-based FNT and conventional PRNT was performed using mouse anti-ZIKBeHMR-2 immune sera. Indistinguishable neutralization patterns were observed when compared with PRNT₅₀ and FNT₅₀. We consider that the newly developed MR766^GFP-based FNT is a valid format for measuring ZIKV-neutralizing antibodies in serum specimens. Full article

(This article belongs to the Special Issue Current Flavivirus Research Important for Vaccine Development )

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16 pages, 2186 KiB

Open AccessArticle

A Chimeric Zika Virus between Viral Strains MR766 and BeH819015 Highlights a Role for E-glycan Loop in Antibody-mediated Virus Neutralization

by Etienne Frumence, Wildriss Viranaicken, Sandra Bos, Maria-Teresa Alvarez-Martinez, Marjolaine Roche, Jacques-Damien Arnaud, Gilles Gadea and Philippe Desprès

Vaccines 2019, 7(2), 55; https://doi.org/10.3390/vaccines7020055 - 24 Jun 2019

Cited by 16 | Viewed by 4771

Abstract

Zika virus (ZIKV) is an emerging mosquito-borne flavivirus which is of major public health concern. ZIKV infection is recognized as the cause of congenital Zika disease and other neurological defects, with no specific prophylactic or therapeutic treatments. As the humoral immune response is an essential component of protective immunity, there is an urgent need for effective vaccines that confer protection against ZIKV infection. In the present study, we evaluate the immunogenicity of chimeric viral clone ZIKBeHMR-2, in which the region encoding the structural proteins of the African strain MR766 backbone was replaced with its counterpart from the epidemic strain BeH819015. Three amino-acid substitutions I152T, T156I, and H158Y were introduced in the glycan loop of the E protein (E-GL) making ZIKBeHMR-2 a non-glycosylated virus. Adult BALB/c mice inoculated intraperitoneally with ZIKBeHMR-2 developed anti-ZIKV antibodies directed against viral proteins E and NS1 and a booster dose increased antibody titers. Immunization with ZIKBeHMR-2 resulted in a rapid production of neutralizing anti-ZIKV antibodies. Antibody-mediated ZIKV neutralization was effective against viral strain MR766, whereas epidemic ZIKV strains were poorly sensitive to neutralization by anti-ZIKBeHMR-2 immune sera. From our data, we propose that the three E-GL residues at positions E-152, E-156, and E-158 greatly influence the accessibility of neutralizing antibody epitopes on ZIKV. Full article

(This article belongs to the Special Issue Current Flavivirus Research Important for Vaccine Development )

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Review

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21 pages, 1479 KiB

Open AccessReview

The Interplay between Dengue Virus and the Human Innate Immune System: A Game of Hide and Seek

by Nicolas Tremblay, Wesley Freppel, Aïssatou Aïcha Sow and Laurent Chatel-Chaix

Vaccines 2019, 7(4), 145; https://doi.org/10.3390/vaccines7040145 - 10 Oct 2019

Cited by 24 | Viewed by 7971

Abstract

With 40% of the world population at risk, infections with dengue virus (DENV) constitute a serious threat to public health. While there is no antiviral therapy available against this potentially lethal disease, the efficacy of the only approved vaccine is not optimal and its safety has been recently questioned. In order to develop better vaccines based on attenuated and/or chimeric viruses, one must consider how the human immune system is engaged during DENV infection. The activation of the innate immunity through the detection of viruses by cellular sensors is the first line of defence against those pathogens. This triggers a cascade of events which establishes an antiviral state at the cell level and leads to a global immunological response. However, DENV has evolved to interfere with the innate immune signalling at multiple levels, hence dampening antiviral responses and favouring viral replication and dissemination. This review elaborates on the interplay between DENV and the innate immune system. A special focus is given on the viral countermeasure mechanisms reported over the last decade which should be taken into consideration during vaccine development. Full article

(This article belongs to the Special Issue Current Flavivirus Research Important for Vaccine Development )

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20 pages, 359 KiB

Open AccessReview

Virus-Like Particle Systems for Vaccine Development against Viruses in the Flaviviridae Family

by Shu Hui Wong, Alagie Jassey, Jonathan Y. Wang, Wei-Cheng Wang, Ching-Hsuan Liu and Liang-Tzung Lin

Vaccines 2019, 7(4), 123; https://doi.org/10.3390/vaccines7040123 - 20 Sep 2019

Cited by 14 | Viewed by 6522

Abstract

Viruses in the Flaviviridae family are important human and animal pathogens that impose serious threats to global public health. This family of viruses includes emerging and re-emerging viruses, most of which are transmitted by infected mosquito or tick bites. Currently, there is no protective vaccine or effective antiviral treatment against the majority of these viruses, and due to their growing spread, several strategies have been employed to manufacture prophylactic vaccines against these infectious agents including virus-like particle (VLP) subunit vaccines. VLPs are genomeless viral particles that resemble authentic viruses and contain critical repetitive conformational structures on their surface that can trigger the induction of both humoral and cellular responses, making them safe and ideal vaccine candidates against these viruses. In this review, we focus on the potential of the VLP platform in the current vaccine development against the medically important viruses in the Flaviviridae family. Full article

(This article belongs to the Special Issue Current Flavivirus Research Important for Vaccine Development )

Other

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7 pages, 442 KiB

Open AccessCase Report

Severe Multiorgan Failure Following Yellow Fever Vaccination

by Cristina Domingo, Judith Lamerz, Daniel Cadar, Marija Stojkovic, Philip Eisermann, Uta Merle, Andreas Nitsche and Paul Schnitzler

Vaccines 2020, 8(2), 249; https://doi.org/10.3390/vaccines8020249 - 26 May 2020

Cited by 7 | Viewed by 3088

Abstract

Background: The yellow fever (YF) vaccination is recommended by the WHO for people traveling or living in endemic areas at risk for yellow fever infections in Africa and South America. Although the live attenuated yellow fever vaccine is a safe and efficient vaccine, rare serious adverse events after vaccination have been reported. Case presentation: We present the case of a 74-year-old male with multiorgan failure after yellow fever vaccination for a trip to Brazil. The patient required admission to the intensive care unit with a prolonged stay due to severe organ dysfunction. Five days after the YF vaccination, the patient experienced nausea, vomiting, diarrhea, and general illness. Three days later he sought medical attention and was transferred to the University Hospital Heidelberg with beginning multiorgan failure and severe septic shock, including hypotonia, tachypnea, thrombopenia, and acute renal failure the same day. Within one week after vaccination, antibodies against YF virus were already detectable and progressively increased over the next two weeks. Viral RNA was detected in serum on the day of admission, with a viral load of 1.0 × 10⁵ copies/mL. The YF virus (YFV) RNA was also present in tracheal secretions for several weeks and could be detected in urine samples up to 20 weeks after vaccination, with a peak viral load of 1.3 × 10⁶ copies/mL. After 20 weeks in the ICU with nine weeks of mechanical ventilation, the patient was transferred to another hospital for further recovery. Conclusions: The risk for severe adverse events due to the YF vaccination should be balanced against the risk of acquiring a severe YF infection, especially in elderly travelers. Full article

(This article belongs to the Special Issue Current Flavivirus Research Important for Vaccine Development )

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