Robust and Balanced Immune Responses to All 4 Dengue Virus Serotypes Following Administration of a Single Dose of a Live Attenuated Tetravalent Dengue Vaccine to Healthy, Flavivirus-Naive Adults

ABSTRACT Dengue virus infections can cause hemorrhagic fever, shock, encephalitis, and even death. Worldwide, approximately 2.5 billion people live in dengue-infested regions with about 100 million new cases each year, although many of these infections are believed to be silent. There are four antigenically distinct serotypes of dengue virus; thus, immunity from one serotype will not cross-protect from infection with the other three. The difficulties that hamper vaccine development include requirements of the natural conformation of the envelope glycoprotein to induce neutralizing immune responses and the necessity of presenting antigens of all four serotypes. Currently, the only way to meet these requirements is to use a mixture of four serotypes of live attenuated dengue viruses, but safety remains a major problem. In this study, we have developed the basis for a tetravalent dengue vaccine using a novel complex adenovirus platform that is capable of expressing multiple antigens de novo. This dengue vaccine is constructed as a pair of vectors that each expresses the premembrane and envelope genes of two different dengue virus serotypes. Upon vaccination, the vaccine expressed high levels of the dengue virus antigens in cells to mimic a natural infection and induced both humoral and cellular immune responses against multiple serotypes of dengue virus in an animal model. Further analyses show the humoral responses were indeed neutralizing against all four serotypes. Our studies demonstrate the concept of mimicking infections to induce immune responses by synthesizing dengue virus membrane antigens de novo and the feasibility of developing an effective tetravalent dengue vaccine by vector-mediated expression of glycoproteins of the four serotypes.

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A Tetravalent Dengue Vaccine Based on a Complex Adenovirus Vector Provides Significant Protection in Rhesus Monkeys against All Four Serotypes of Dengue Virus

Journal of Virology ◽

10.1128/jvi.02724-07 ◽

2008 ◽

Vol 82 (14) ◽

pp. 6927-6934 ◽

Cited By ~ 72

Author(s):

Kanakatte Raviprakash ◽

Danher Wang ◽

Dan Ewing ◽

David H. Holman ◽

Karla Block ◽

...

Keyword(s):

Immune Responses ◽

Dengue Virus ◽

Rhesus Macaques ◽

High Titer ◽

Adenovirus Vector ◽

Significant Protection ◽

Dengue Vaccine ◽

Live Virus ◽

Dengue Viruses ◽

Dengue Virus Serotypes

ABSTRACT Nearly a third of the human population is at risk of infection with the four serotypes of dengue viruses, and it is estimated that more than 100 million infections occur each year. A licensed vaccine for dengue viruses has become a global health priority. A major challenge to developing a dengue vaccine is the necessity to produce fairly uniform protective immune responses to all four dengue virus serotypes. We have developed two bivalent dengue virus vaccines, using a complex adenovirus vector, by incorporating the genes expressing premembrane (prM) and envelope (E) proteins of dengue virus types 1 and 2 (dengue-1 and -2, respectively) (CAdVax-Den12) or dengue-3 and -4 (CAdVax-Den34). Rhesus macaques were vaccinated by intramuscular inoculation of a tetravalent dengue vaccine formulated by combining the two bivalent vaccine constructs. Vaccinated animals produced high-titer antibodies that neutralized all four serotypes of dengue viruses in vitro. The ability of the vaccine to induce rapid, as well as sustained, protective immune responses was examined with two separate live-virus challenges administered at 4 and 24 weeks after the final vaccination. For both of these virus challenge studies, significant protection from viremia was demonstrated for all four dengue virus serotypes in vaccinated animals. Viremia from dengue-1 and dengue-3 challenges was completely blocked, whereas viremia from dengue-2 and dengue-4 was significantly reduced, as well as delayed, compared to that of control-vaccinated animals. These results demonstrate that the tetravalent dengue vaccine formulation provides significant protection in rhesus macaques against challenge with all four dengue virus serotypes.

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Production of a Recombinant Dengue Virus 2 NS5 Protein and Potential Use as a Vaccine Antigen

Clinical and Vaccine Immunology ◽

10.1128/cvi.00081-16 ◽

2016 ◽

Vol 23 (6) ◽

pp. 460-469 ◽

Cited By ~ 10

Author(s):

Rúbens Prince dos Santos Alves ◽

Lennon Ramos Pereira ◽

Denicar Lina Nascimento Fabris ◽

Felipe Scassi Salvador ◽

Robert Andreata Santos ◽

...

Keyword(s):

Immune Responses ◽

Dengue Virus ◽

Nonstructural Protein ◽

Vaccine Antigen ◽

Dependent Manner ◽

Nonstructural Proteins ◽

Necrosis Factor Alpha ◽

Content Type ◽

Factor Alpha ◽

Dengue Virus Serotypes

ABSTRACTDengue fever is caused by any of the four known dengue virus serotypes (DENV1 to DENV4) that affect millions of people worldwide, causing a significant number of deaths. There are vaccines based on chimeric viruses, but they still are not in clinical use. Anti-DENV vaccine strategies based on nonstructural proteins are promising alternatives to those based on whole virus or structural proteins. The DENV nonstructural protein 5 (NS5) is the main target of anti-DENV T cell-based immune responses in humans. In this study, we purified a soluble recombinant form of DENV2 NS5 expressed inEscherichia coliat large amounts and high purity after optimization of expression conditions and purification steps. The purified DENV2 NS5 was recognized by serum from DENV1-, DENV2-, DENV3-, or DENV4-infected patients in an epitope-conformation-dependent manner. In addition, immunization of BALB/c mice with NS5 induced high levels of NS5-specific antibodies and expansion of gamma interferon- and tumor necrosis factor alpha-producing T cells. Moreover, mice immunized with purified NS5 were partially protected from lethal challenges with the DENV2 NGC strain and with a clinical isolate (JHA1). These results indicate that the recombinant NS5 protein preserves immunological determinants of the native protein and is a promising vaccine antigen capable of inducing protective immune responses.

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Immunogenicity of a Live-Attenuated Dengue Vaccine Using a Heterologous Prime-Boost Strategy in a Phase 1 Randomized Clinical Trial

The Journal of Infectious Diseases ◽

10.1093/infdis/jiaa603 ◽

2020 ◽

Author(s):

Leyi Lin ◽

Michael A Koren ◽

Kristopher M Paolino ◽

Kenneth H Eckels ◽

Rafael De La Barrera ◽

...

Keyword(s):

Immune Responses ◽

Dengue Virus ◽

Phase 1 ◽

Vaccination Strategy ◽

Neutralizing Antibody ◽

Dengue Vaccine ◽

Serious Adverse Events ◽

Live Attenuated Vaccine ◽

Antibody Titers ◽

Global Health Problem

Abstract Background Dengue is a global health problem and the development of a tetravalent dengue vaccine with durable protection is a high priority. A heterologous prime-boost strategy has the advantage of eliciting immune responses through different mechanisms and therefore may be superior to homologous prime-boost strategies for generating durable tetravalent immunity. Methods In this phase 1 first-in-human heterologous prime-boost study, 80 volunteers were assigned to 4 groups and received a tetravalent dengue virus (DENV-1–4) purified inactivated vaccine (TDENV-PIV) with alum adjuvant and a tetravalent dengue virus (DENV-1–4) live attenuated vaccine (TDENV-LAV) in different orders and dosing schedules (28 or 180 days apart). Results All vaccination regimens had acceptable safety profiles and there were no vaccine-related serious adverse events. TDEN-PIV followed by TDEN-LAV induced higher neutralizing antibody titers and a higher rate of tetravalent seroconversions compared to TDEN-LAV followed by TDEN-PIV. Both TDEN-PIV followed by TDEN-LAV groups demonstrated 100% tetravalent seroconversion 28 days following the booster dose, which was maintained for most of these subjects through the day 180 measurement. Conclusions A heterologous prime-boost vaccination strategy for dengue merits additional evaluation for safety, immunogenicity, and potential for clinical benefit. Clinical Trials Registration NCT02239614.

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A tetravalent dengue vaccine induced potent and balanced immune responses against four types of dengue virus

Journal of Vaccines & Vaccination ◽

10.4172/2157-7560.s1.001 ◽

2012 ◽

Vol 01 (S1) ◽

Author(s):

John Dong

Keyword(s):

Immune Responses ◽

Dengue Virus ◽

Dengue Vaccine

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Advancements in developing an effective and preventive dengue vaccine

Future Virology ◽

10.2217/fvl-2019-0080 ◽

2020 ◽

Vol 15 (2) ◽

pp. 127-138

Author(s):

Khadija Zahid ◽

Sana Shakoor ◽

Hina Afzal Sajid ◽

Samia Afzal ◽

Liaqat Ali ◽

...

Keyword(s):

Recombinant Protein ◽

Dengue Virus ◽

Dna Vaccine ◽

Yellow Fever ◽

Yellow Fever Virus ◽

Protein Vaccine ◽

Vaccine Recombinant ◽

Dengue Vaccine ◽

Dengue Virus Serotypes ◽

Recombinant Protein Vaccine

Every year millions of people in various tropical and subtropical regions encounter infection with dengue virus. Within the last few decades, its prevalence has increased up to 30-fold globally and presently these viruses have been transmitted in more than 100 countries. Scientists contributed to the development of tetravalent dengue vaccine by adopting numerous approaches including live vaccine, recombinant protein vaccine, DNA vaccine and virus-vectored vaccines. A vaccine should be genetically stable, equally effective against all serotypes, must be in-expensive and commercially available. Chimeric yellow fever virus-tetravalent dengue vaccine (CYD-TDV) is the first licensed vaccine developed by Sanofi Pasteur in December 2015, but this vaccine is not fully effective against different dengue virus serotypes (Sanofi Pasteur, Lyon, France). This review explores the advancements and challenges involved in the development of dengue vaccine.

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Dengue Vaccine Development at the Dengue virus serotypes

International Islamic Medical Journal ◽

10.33086/iimj.v1i1.1360 ◽

2019 ◽

Vol 1 (1) ◽

pp. 9-15

Author(s):

Adinda Desi Irawati ◽

Hotimah Masdan Salim

Keyword(s):

Dengue Virus ◽

Vaccine Development ◽

Hemorrhagic Fever ◽

Severe Dengue ◽

Vaccine Recombinant ◽

Dengue Vaccine ◽

Live Attenuated Vaccine ◽

Virus Particles ◽

Dengue Virus Serotypes ◽

Official Data

Dengue hemorrhagic fever (DHF) is a disease caused by dengue virus (DENV1-4) and is transmitted by the Aedes aegypti mosquito. However, in 2015, official data from the member countries, WHO reported more than 3.2 million cases, including 10,200 severe dengue cases and 1181 deaths. The protein encoded by the genome of dengue virus. Major structural and non structural proteins making up the genome of dengue. From genomic data several studies found that mechanism of vaccine that can use in dengue virus. Several vaccines was establish in the world for example Live attenuated Vaccine, Chimera Vaccine, Subunit Vaccine, DNA vaccines DENV, Activated DENV Vaccine - Whole Virus Particles, Activated DENV Vaccine - Recombinant Subunit DENV, and DENV Vaccine 5.

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Defining levels of dengue virus serotype-specific neutralizing antibodies induced by a live attenuated tetravalent dengue vaccine (TAK-003)

PLoS Neglected Tropical Diseases ◽

10.1371/journal.pntd.0009258 ◽

2021 ◽

Vol 15 (3) ◽

pp. e0009258

Author(s):

Laura J. White ◽

Ellen F. Young ◽

Mark J. Stoops ◽

Sandra R. Henein ◽

Elizabeth C. Adams ◽

...

Keyword(s):

Dengue Virus ◽

Neutralizing Antibodies ◽

Protective Immunity ◽

Severe Disease ◽

Dengue Vaccine ◽

Unique Type ◽

Tropical Regions ◽

Efficacy Trials ◽

Virus Serotype ◽

Dengue Virus Serotypes

The four dengue virus serotypes (DENV1-4) infect several hundred million people each year living in tropical and sub-tropical regions. Clinical development of DENV vaccines is difficult because immunity to a single serotype increases risk of severe disease during a second infection with a new serotype. Leading vaccines are based on tetravalent formulations to induce simultaneous and balanced protective immunity to all 4 serotypes. TAK-003 is a tetravalent live attenuated dengue vaccine candidate developed by Takeda Vaccines Inc, which is currently being evaluated in phase 3 efficacy trials. Here, we use antibody depletion methods and chimeric, epitope transplant DENVs to characterize the specificity of neutralizing antibodies in dengue-naïve adults and non-human primates immunized with TAK-003. Our results demonstrate that TAK-003 induced high levels of DENV2 neutralizing antibodies that recognized unique (type-specific) epitopes on DENV2. In contrast, most vaccinated subjects developed lower levels of DENV1, DENV3 and DENV4 neutralizing antibodies that mainly targeted epitopes that were conserved (cross-reactive) between serotypes. Trial Registration: ClinicalTrials.gov NCT02425098.

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Pre-vaccination Frequency of Circulatory Tfh is associated with Robust Immune Response to TV003 Dengue Vaccine

10.1101/2021.08.19.456926 ◽

2021 ◽

Author(s):

Abdullah M Izmirly ◽

Adam-Nicolas Pelletier ◽

Jennifer Connors ◽

Bhavani Taramangalam ◽

Sawsan O. Alturki ◽

...

Keyword(s):

Immune Response ◽

Immune Responses ◽

Dengue Virus ◽

Vaccine Design ◽

Neutralizing Antibody ◽

Dengue Vaccine ◽

Tfh Cells ◽

Follicular Helper ◽

Tetravalent Vaccine ◽

Immunological Mechanisms

AbstractIt has been estimated that more than 390 million people are infected with Dengue virus every year; around 96 millions of these infections result in clinical pathologies. To date, there is only one licensed viral vector-based Dengue virus vaccine CYD-TDV approved for use in dengue endemic areas. While initially approved for administration independent of serostatus, the current guidance only recommends the use of this vaccine for seropositive individuals. Therefore, there is a critical need for investigating the influence of Dengue virus serostatus and immunological mechanisms that influence vaccine outcome. Here, we provide comprehensive evaluation of sero-status and host immune factors that correlate with robust immune responses to a Dengue virus vector based tetravalent vaccine (TV003) in a Phase II clinical cohort of human participants. We observed that sero-positive individuals demonstrate a much stronger immune response to the TV003 vaccine. Our multi-layered immune profiling revealed that sero-positive subjects have increased baseline/pre-vaccination frequencies of circulating T follicular helper (cTfh) cells and the Tfh related chemokine CXCL13/BLC. Importantly, this baseline/pre-vaccination cTfh profile correlated with the vaccinees’ ability to launch neutralizing antibody response against all four sero-types of Dengue virus, an important endpoint for Dengue vaccine clinical trials. Overall, we provide novel insights into the favorable cTfh related immune status that persists in Dengue virus sero-positive individuals that correlate with their ability to mount robust vaccine specific immune responses. Such detailed interrogation of cTfh cell biology in the context of clinical vaccinology will help uncover mechanisms and targets for favorable immuno-modulatory agents.Author summaryDengue virus (DENV) is a worldwide threat that causes significant health and economic burden. Currently, there are several challenges in the development of a DENV vaccine including the existence of four different serotypes all; capable of causing disease and antibody dependent enhancement (ADE). For complete protection, a vaccine must be able to generate neutralizing antibodies against all 4 serotypes to avoid ADE. Currently, there is one licensed DENV vaccine, CYD-TDV (DENGVAXIATM). However, this vaccine is only efficacious in protecting against severe disease in DENV seropositive individuals therefore serostatus effect must be further studied for optimal vaccine design. A subset of CD4+ T cells called T-follicular helper (Tfh) cells have been well known to play a major role in aiding high affinity antibody production. Therefore, we chose to look at subsets of Tfh and the cytokines they produce in human blood that can serve as biomarkers for effective vaccine design. We found that DENV sero-positive participants had increased pre-vaccination frequencies of Tfh cells and higher levels of the Tfh related chemokine CXCL13/BLC that plays a role in directing antigen-specific responses. This pre-vaccination Tfh profile and CXCL13/BLC are then correlated positively with the vaccinees’ ability to produce neutralizing antibody against all four sero-types (breadth of the Response) of DENV, an important goal for all DENV vaccine trials.

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