scholarly journals A mRNA-LNP vaccine against Dengue Virus elicits robust, serotype-specific immunity

2021 ◽  
Author(s):  
Clayton J. Wollner ◽  
Michelle Richner ◽  
Mariah A. Hassert ◽  
Amelia K. Pinto ◽  
James D. Brien ◽  
...  
Keyword(s):  
Immune Responses ◽  
Dengue Virus ◽  
Viral Infection ◽  
Neutralizing Antibody ◽  
Viral Disease ◽  
Structural Proteins ◽  
Severe Dengue ◽  
Antibody Dependent Enhancement ◽  
Specific Immunity ◽  
Serotype 1

ABSTRACTDengue virus (DENV) is the most common vector-borne viral disease with nearly 400 million worldwide infections each year concentrated in the tropical and subtropical regions of the world. Severe dengue complications are often associated with a secondary heterotypic infection of one of the four circulating serotypes. In this scenario, humoral immune responses targeting cross-reactive, poorly-neutralizing epitopes can lead to increased infectivity of susceptible cells via antibody-dependent enhancement (ADE). In this way, antibodies produced in response to infection or vaccination are capable of contributing to enhanced disease in subsequent infections. Currently, there are no available therapeutics to combat DENV disease, and there is an urgent need for a safe and efficacious vaccine. Here, we developed a nucleotide-modified mRNA vaccine encoding for the membrane and envelope structural proteins from DENV serotype 1 encapsulated into lipid nanoparticles (prM/E mRNA-LNP). Vaccination of mice elicited robust antiviral immune responses comparable to viral infection with high levels of neutralizing antibody titers and antiviral CD4+ and CD8+ T cells. Immunocompromised AG129 mice vaccinated with the prM/E mRNA-LNP vaccine were protected from a lethal DENV challenge. Vaccination with either a wild-type vaccine, or a vaccine with mutations in the immunodominant fusion-loop epitope, elicited equivalent humoral and cell mediated immune responses. Neutralizing antibodies elicited by the vaccine were sufficient to protect against a lethal challenge. Both vaccine constructs demonstrated serotype specific immunity with minimal serum cross-reactivity and reduced ADE compared to a live DENV1 viral infection.IMPORTANCEWith 400 million worldwide infections each year, dengue is the most common vector-born viral disease. 40% of the world’s population is at risk with dengue experiencing consistent geographic spread over the years. With no therapeutics available and vaccines performing sub optimally, the need for an effective dengue vaccine is urgent. Here we develop and characterize a novel mRNA vaccine encoding for the dengue serotype 1 envelope and premembrane structural proteins that is delivered via a lipid nanoparticle. Our DENV1 prM/E mRNA-LNP vaccine induces neutralizing antibody and cellular immune responses in immunocompetent mice and protects an immunocompromised mouse from a lethal DENV challenge. Existing antibodies against dengue can enhance subsequent infections via antibody-dependent enhancement. Importantly our vaccine only induced serotype specific immune responses and did not induce ADE.

scholarly journals A Dengue Virus Serotype 1 mRNA-LNP Vaccine Elicits Protective Immune Responses

2021 ◽  
Author(s):  
Clayton J. Wollner ◽  
Michelle Richner ◽  
Mariah A. Hassert ◽  
Amelia K. Pinto ◽  
James D. Brien ◽  
...  
Keyword(s):  
Immune Responses ◽  
Dengue Virus ◽  
Viral Infection ◽  
Neutralizing Antibody ◽  
Viral Disease ◽  
Structural Proteins ◽  
Severe Dengue ◽  
Antibody Dependent Enhancement ◽  
Virus Serotype ◽  
Serotype 1

Dengue virus (DENV) is the most common vector-borne viral disease with nearly 400 million worldwide infections each year concentrated in the tropical and subtropical regions of the world. Severe dengue complications are often associated with a secondary heterotypic infection of one of the four circulating serotypes. In this scenario, humoral immune responses targeting cross-reactive, poorly-neutralizing epitopes can lead to increased infectivity of susceptible cells via antibody-dependent enhancement (ADE). In this way, antibodies produced in response to infection or vaccination are capable of contributing to enhanced disease in subsequent infections. Currently, there are no available therapeutics to combat DENV disease, and there is an urgent need for a safe and efficacious vaccine. Here, we developed a nucleotide-modified mRNA vaccine encoding for the membrane and envelope structural proteins from DENV serotype 1 encapsulated into lipid nanoparticles (prM/E mRNA-LNP). Vaccination of mice elicited robust antiviral immune responses comparable to viral infection with high levels of neutralizing antibody titers and antiviral CD4+ and CD8+ T cells. Immunocompromised AG129 mice vaccinated with the prM/E mRNA-LNP vaccine were protected from a lethal DENV challenge. Vaccination with either a wild-type vaccine, or a vaccine with mutations in the immunodominant fusion-loop epitope, elicited equivalent humoral and cell mediated immune responses. Neutralizing antibodies elicited by the vaccine were sufficient to protect against a lethal challenge. Both vaccine constructs demonstrated serotype specific immunity with minimal serum cross-reactivity and reduced ADE compared to a live DENV1 viral infection. IMPORTANCE With 400 million worldwide infections each year, dengue is the most common vector-born viral disease. 40% of the world's population is at risk with dengue experiencing consistent geographic spread over the years. With no therapeutics available and vaccines performing sub optimally, the need for an effective dengue vaccine is urgent. Here we develop and characterize a novel mRNA vaccine encoding for the dengue serotype 1 envelope and premembrane structural proteins that is delivered via a lipid nanoparticle. Our DENV1 prM/E mRNA-LNP vaccine induces neutralizing antibody and cellular immune responses in immunocompetent mice and protects an immunocompromised mouse from a lethal DENV challenge. Existing antibodies against dengue can enhance subsequent infections via antibody-dependent enhancement. Importantly our vaccine only induced serotype specific immune responses and did not induce ADE.

scholarly journals Simulation Model for Dynamics of Dengue with Innate and Humoral Immune Responses

2018 ◽  
Vol 2018 ◽  
pp. 1-18 ◽  
Author(s):  
S. D. Perera ◽  
S. S. N. Perera
Keyword(s):  
Immune Response ◽  
Immune Responses ◽  
Dengue Virus ◽  
Dengue Infection ◽  
Asymptomatic Infection ◽  
Severe Dengue ◽  
Viral Kinetics ◽  
Humoral Immune ◽  
Humoral Immune Responses ◽  
Kinetics Of

Dengue virus is a mosquito borne Flavivirus and the most prevalent arbovirus in tropical and subtropical regions around the world. The incidence of dengue has increased drastically over the last few years at an alarming rate. The clinical manifestation of dengue ranges from asymptomatic infection to severe dengue. Even though the viral kinetics of dengue infection is lacking, innate immune response and humoral immune response are thought to play a major role in controlling the virus count. Here, we developed a computer simulation mathematical model including both innate and adaptive immune responses to study the within-host dynamics of dengue virus infection. A sensitivity analysis was carried out to identify key parameters that would contribute towards severe dengue. A detailed stability analysis was carried out to identify relevant range of parameters that contributes to different outcomes of the infection. This study provides a qualitative understanding of the biological factors that can explain the viral kinetics during a dengue infection.

scholarly journals Current Understanding of the Pathogenesis of Dengue Virus Infection

2020 ◽  
Author(s):  
Puneet Bhatt ◽  
Sasidharan Pillai Sabeena ◽  
Muralidhar Varma ◽  
Govindakarnavar Arunkumar
Keyword(s):  
Immune Response ◽  
T Cells ◽  
Virus Infection ◽  
Dengue Virus ◽  
Genetic Factors ◽  
Host Immune Response ◽  
Severe Dengue ◽  
Ns1 Protein ◽  
Dengue Virus Infection ◽  
Antibody Dependent Enhancement

AbstractThe pathogenesis of dengue virus infection is attributed to complex interplay between virus, host genes and host immune response. Host factors such as antibody-dependent enhancement (ADE), memory cross-reactive T cells, anti-DENV NS1 antibodies, autoimmunity as well as genetic factors are major determinants of disease susceptibility. NS1 protein and anti-DENV NS1 antibodies were believed to be responsible for pathogenesis of severe dengue. The cytokine response of cross-reactive CD4+ T cells might be altered by the sequential infection with different DENV serotypes, leading to further elevation of pro-inflammatory cytokines contributing a detrimental immune response. Fcγ receptor-mediated antibody-dependent enhancement (ADE) results in release of cytokines from immune cells leading to vascular endothelial cell dysfunction and increased vascular permeability. Genomic variation of dengue virus and subgenomic flavivirus RNA (sfRNA) suppressing host immune response are viral determinants of disease severity. Dengue infection can lead to the generation of autoantibodies against DENV NS1antigen, DENV prM, and E proteins, which can cross-react with several self-antigens such as plasminogen, integrin, and platelet cells. Apart from viral factors, several host genetic factors and gene polymorphisms also have a role to play in pathogenesis of DENV infection. This review article highlights the various factors responsible for the pathogenesis of dengue and also highlights the recent advances in the field related to biomarkers which can be used in future for predicting severe disease outcome.

scholarly journals Tracking the polyclonal neutralizing antibody response to a dengue virus serotype 1 type-specific epitope across two populations in Asia and the Americas

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Daniela V. Andrade ◽  
Colin Warnes ◽  
Ellen Young ◽  
Leah C. Katzelnick ◽  
Angel Balmaseda ◽  
...  
Keyword(s):  
Dengue Virus ◽  
Neutralizing Antibodies ◽  
Neutralizing Antibody ◽  
Sri Lankan ◽  
Human Monoclonal Antibodies ◽  
Virus Serotype ◽  
Serotype 1 ◽  
Dengue Virus Serotypes ◽  
Kinetics Of ◽  
Two Populations

Abstract The four dengue virus serotypes (DENV1-4) cause major public health problems worldwide. Highly neutralizing type-specific human monoclonal antibodies (hmAbs) target conformation-dependent epitopes on the DENV envelope protein, including 1F4, a DENV1 type-specific hmAb. Using a recombinant DENV2 virus displaying the DENV1 1F4 epitope (rDENV2/1), we measured the proportion and kinetics of DENV1 neutralizing antibodies targeting the 1F4 epitope in individuals living in Asia and the Americas where different DENV1 genotypes were circulating. Samples from 20 individuals were analyzed 3 and 18 months post-primary DENV1 infection, alongside samples from 4 individuals collected annually for four years post-primary DENV1 infection, from two studies in Nicaragua. We also analyzed convalescent post-primary DENV1 plasma samples from Sri Lankan individuals. We found that neutralizing antibodies recognizing the 1F4 epitope vary in prevalence across both populations and were detected from 20 days to four years post-infection. Additionally, both populations displayed substantial variability, with a range of high to low proportions of DENV1 type-specific neutralizing antibodies recognizing the 1F4 epitope seen across individuals. Thus, the 1F4 epitope is a major but not exclusive target of type-specific neutralizing antibodies post-primary infection with different DENV1 genotypes in Asia and Latin America, and additional epitopes likely contribute to type-specific neutralization of DENV1.

scholarly journals Epitope Addition and Ablation via Manipulation of a Dengue Virus Serotype 1 Infectious Clone

mSphere ◽  
2017 ◽  
Vol 2 (1) ◽  
Author(s):  
Emily N. Gallichotte ◽  
Vineet D. Menachery ◽  
Boyd L. Yount ◽  
Douglas G. Widman ◽  
Kenneth H. Dinnon ◽  
...  
Keyword(s):  
Immune Responses ◽  
Dengue Virus ◽  
Applied Research ◽  
Infectious Clone ◽  
Severe Infection ◽  
Recombinant Viruses ◽  
Serotype 1 ◽  
Basic And Applied Research ◽  
Antibody Epitopes ◽  
Antigenic Relationships

ABSTRACT Dengue viruses (DENVs) are significant mosquito-transmitted pathogens that cause widespread infection and can lead to severe infection and complications. Here we further characterize a novel and robust DENV serotype 1 (DENV1) infectious clone system that can be used to support basic and applied research. We demonstrate how the system can be used to probe the antigenic relationships between strains by creating viable recombinant viruses that display or lack major antibody epitopes. The DENV1 clone system and recombinant viruses can be used to analyze existing vaccine immune responses and inform second-generation bivalent vaccine designs. Despite the clinical relevance, dengue virus (DENV) research has been hampered by the absence of robust reverse genetic systems to manipulate the viral serotypes for propagation and generation of mutant viruses. In this article, we describe application of an infectious clone system for DENV serotype 1 (DENV1). Similar to previous clones in both flaviviruses and coronaviruses, the approach constructs a panel of contiguous cDNAs that span the DENV genome and can be systematically and directionally assembled to produce viable, full-length viruses. Comparison of the virus derived from the infectious clone with the original viral isolate reveals identical sequence, comparable endpoint titers, and similar focus staining. Both focus-forming assays and percent infection by flow cytometry revealed overlapping replication levels in two different cell types. Moreover, serotype-specific monoclonal antibodies (MAbs) bound similarly to infectious clone and the natural isolate. Using the clone, we were able to insert a DENV4 type-specific epitope recognized by primate MAb 5H2 into envelope (E) protein domain I (EDI) of DENV1 and recover a viable chimeric recombinant virus. The recombinant DENV1 virus was recognized and neutralized by the DENV4 type-specific 5H2 MAb. The introduction of the 5H2 epitope ablated two epitopes on DENV1 EDI recognized by human MAbs (1F4 and 14C10) that strongly neutralize DENV1. Together, the work demonstrates the utility of the infectious clone and provides a resource to rapidly manipulate the DENV1 serotype for generation of recombinant and mutant viruses. IMPORTANCE Dengue viruses (DENVs) are significant mosquito-transmitted pathogens that cause widespread infection and can lead to severe infection and complications. Here we further characterize a novel and robust DENV serotype 1 (DENV1) infectious clone system that can be used to support basic and applied research. We demonstrate how the system can be used to probe the antigenic relationships between strains by creating viable recombinant viruses that display or lack major antibody epitopes. The DENV1 clone system and recombinant viruses can be used to analyze existing vaccine immune responses and inform second-generation bivalent vaccine designs.

scholarly journals Dengue Virus and Vaccines: How Can DNA Immunization Contribute to This Challenge?

2021 ◽  
Vol 3 ◽  
Author(s):  
Ada Maria Barcelos Alves ◽  
Simone Morais Costa ◽  
Paolla Beatriz Almeida Pinto
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Dengue Virus ◽  
Antibody Production ◽  
Dna Vaccines ◽  
Yellow Fever Virus ◽  
T Cell Responses ◽  
Hemorrhagic Fever ◽  
Severe Dengue ◽  
Cell Responses

Dengue infections still have a tremendous impact on public health systems in most countries in tropical and subtropical regions. The disease is systemic and dynamic with broad range of manifestations, varying from mild symptoms to severe dengue (Dengue Hemorrhagic Fever and Dengue Shock Syndrome). The only licensed tetravalent dengue vaccine, Dengvaxia, is a chimeric yellow fever virus with prM and E genes from the different dengue serotypes. However, recent results indicated that seronegative individuals became more susceptible to develop severe dengue when infected after vaccination, and now WHO recommends vaccination only to dengue seropositive people. One possibility to explain these data is the lack of robust T-cell responses and antibody-dependent enhancement of virus replication in vaccinated people. On the other hand, DNA vaccines are excellent inducers of T-cell responses in experimental animals and it can also elicit antibody production. Clinical trials with DNA vaccines have improved and shown promising results regarding the use of this approach for human vaccination. Therefore, in this paper we review preclinical and clinical tests with DNA vaccines against the dengue virus. Most of the studies are based on the E protein since this antigen is the main target for neutralizing antibody production. Yet, there are other reports with DNA vaccines based on non-structural dengue proteins with protective results, as well. Combining structural and non-structural genes may be a solution for inducing immune responses aging in different infection moments. Furthermore, DNA immunizations are also a very good approach in combining strategies for vaccines against dengue, in heterologous prime/boost regimen or even administering different vaccines at the same time, in order to induce efficient humoral and cellular immune responses.

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

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.

scholarly journals Aging and Interferons: Impacts on Inflammation and Viral Disease Outcomes

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 708
Author(s):  
Emily Feng ◽  
Elizabeth Balint ◽  
Sophie M. Poznanski ◽  
Ali A. Ashkar ◽  
Mark Loeb
Keyword(s):  
Immune Responses ◽  
Viral Infection ◽  
Adaptive Immune Response ◽  
Severe Infection ◽  
Viral Disease ◽  
Type I ◽  
Adaptive Immune ◽  
Disease Outcomes ◽  
Global Pandemic ◽  
Immune Mediated

As highlighted by the COVID-19 global pandemic, elderly individuals comprise the majority of cases of severe viral infection outcomes and death. A combined inability to control viral replication and exacerbated inflammatory immune activation in elderly patients causes irreparable immune-mediated tissue pathology in response to infection. Key to these responses are type I, II, and III interferons (IFNs), which are involved in inducing an antiviral response, as well as controlling and suppressing inflammation and immunopathology. IFNs support monocyte/macrophage-stimulated immune responses that clear infection and promote their immunosuppressive functions that prevent excess inflammation and immune-mediated pathology. The timing and magnitude of IFN responses to infection are critical towards their immunoregulatory functions and ability to prevent immunopathology. Aging is associated with multiple defects in the ability of macrophages and dendritic cells to produce IFNs in response to viral infection, leading to a dysregulation of inflammatory immune responses. Understanding the implications of aging on IFN-regulated inflammation will give critical insights on how to treat and prevent severe infection in vulnerable individuals. In this review, we describe the causes of impaired IFN production in aging, and the evidence to suggest that these impairments impact the regulation of the innate and adaptive immune response to infection, thereby causing disease pathology.

scholarly journals HITUNG JENIS LEUKOSIT PADA PASIEN ANAK DENGAN INFEKSI VIRUS DENGUE DI MANADO

2015 ◽  
Vol 3 (2) ◽  
Author(s):  
Ellisabeth M. Harahap ◽  
Arthur E. Mongan ◽  
Maya F. Memah
Keyword(s):  
Virus Infection ◽  
Dengue Virus ◽  
Viral Infection ◽  
Viral Disease ◽  
Differential Count ◽  
Dengue Virus Infection ◽  
Cross Sectional ◽  
The Third ◽  
The World ◽  
Cross Sectional Design

Abstract: Dengue is the most rapidly spreading mosquito-borne viral disease in the world. The decreasing leukocytes can be found between the third and eighth day with normal differential telling. The number of granulocytes decreases on the third until the eighth day. This study used a cross-sectional design. esearch. Samples were children with dengue virus infection at Wolter Mongisidi Hospital, Advent Hospital, and Pancaran Kasih Hospital in Manado from December 2014 until January 2015. There were 36 children as samples. The results showed that 48.6% of samples had increases of basophils, 54% had decreases of eosinophils, 64.8% had decreases of neutrophils, 54% had increases of lymphocytes, and 59.4% had increases of monocytes. Conclusion: In this study, most of the children with dengue viral infection had decreased number of neutrophil.Keywords: dengue viral infection, children, differential count, leukocyteAbstrak: Infeksi virus dengue adalah penyakit virus ditularkan oleh nyamuk dengan penyebaran paling cepat di dunia. Penurunan leukosit dapat dijumpai antara hari ke 1-3 demam dengan hitung jenis yang masih dalam batas normal. Jumlah granulosit menurun pada hari ke 3-8. Penelitian ini bertujuan untuk mengetahui hitung jenis leukosit pada anak terinfeksi virus dengue di Manado. bersifat potong lintang. Penelitian ini menggunakan desain potong lintang. Sampel penelitian ialah pasien anak yang terinfeksi virus dengue di RS Wolter Mongisidi Manado, RS Advent Manado, dan RS Pancaran Kasih Manado selama bulan Desember 2014 sampai Januari 2015. Jumlah sampel sebanyak 36 anak. Hasil penelitian menunjukkan 48,6% sampel mengalami peningkatan jumlah basofil, 54% penurunan eosinofil, 64,8% penurunan neutrofil, 54% peningkatan limfosit, dan 59,4% peningkatan monosit. Simpulan: Pada penelitian ini sebagian besar pasien anak terinfeksi virus dengue menunjukkan penurunan neutrofil.Kata kunci: infeksi virus dengue, anak, hitung jenis, leukosit

scholarly journals FEVER AS INDICATOR TO SECONDARY INFECTION IN DENGUE VIRAL INFECTION

2018 ◽  
Vol 7 (1) ◽  
pp. 21
Author(s):  
Soegeng Soegijanto ◽  
Sufiandika Nuryandari ◽  
Siti Churrotin ◽  
Teguh Hari Sucipto
Keyword(s):  
Virus Infection ◽  
Dengue Virus ◽  
Viral Infection ◽  
Dengue Fever ◽  
Clinical Manifestation ◽  
Secondary Infection ◽  
Salmonella Typhi ◽  
Severe Dengue ◽  
Concurrent Infection ◽  
Dengue Virus Infection

Dengue Virus Infections are distributed in tropical and sub-tropical regions and transmitted by the mosquitoes such as Aedes aegypti and Aedes albopictus. Dengue virus can cause dengue fever, dengue hemorrhagic fever and dengue shock syndrome or dengue and severe dengue classified by World Health Organization. Beside it concurrent infection virus salmonella had been found some cases who showed fever more than 7 days. Concurrent infection with two agents can result in an illness having overlapping symptoms creating a diagnostic dilemma for treating physician, such as dengue fever with typhoid fever. The aim of this research is detection of dengue virus and secondary infection with Salmonella typhi in patients suspected dengue virus infection. Detection of dengue virus and Salmonella typhi using immunochromatography test such as NS1, IgG/IgM for dengue virus infection, and IgM/IgG Salmonella and blood culture. The fifty children with dengue virus infection came to Soerya hospital and 17 cases suspected dengue virus infection, five cases showed a positive NS1 on the second day of fever and one case concurrent with clinical manifestation of convulsi on the third days of fever there were five cases only showed positive. It was showed in this study that on the fourth to six day of fever in dengue virus infection accompanied by antibody IgM & IgG dengue. There were 12 cases showed the clinical manifestation of concurrent dengue viral infection and Salmonella, all of them showed a mild clinical manifestation and did not show plasma leakage and shock. In this study we found the length of stay of concurrent Dengue Virus Infection and Salmonella infection is more than 10 days. These patients were also more likely to have co-existing haemodynamic disturbances and bacterial septicaemia which would have required treatment with inotropes and antibiotics. This idea is very important to make update dengue viral management to decrease mortality in outbreak try to gain new prevention method before the occurrence of outbreak.

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