RESUMEN
NS1 is an elusive dengue protein, involved in viral replication, assembly, pathogenesis, and immune evasion. Its levels in blood plasm are positively related to disease severity like thrombocytopenia, hemorrhage, and vascular leakage. Despite its pathogenic roles, NS1 is being used in various vaccine formulations due to its sequence conservancy, ability to produce protective antibodies and low risk for inducing antibody-dependent enhancement. In this study, we have used bioinformatics tools and reported literature to develop an NS1 variant (dNS1). Molecular docking studies were performed to evaluate the receptor-binding ability of the NS1 and dNS1 with TLR4. NS1 and dNS1 (153 to 312 amino acid region) genes were cloned, expressed and protein was purified followed by refolding. Docking studies showed the binding of NS1 and dNS1 with the TLR4 receptor which suggests that N and C-terminal sequences of NS1 are not critical for receptor binding. Antibodies against NS1 and dNS1 were raised in rabbits and binding affinity of anti-dNS1 anti-NS1 sera was evaluated against both NS1 and dNS1. Similar results were observed through western blotting which highlight that N and C-terminal deletion of NS1 does not compromise the immunogenic potential of dNS1 hence, supports its use in future vaccine formulations as a substitute for NS1.
Asunto(s)
Vacunas contra el Dengue , Virus del Dengue , Simulación del Acoplamiento Molecular , Proteínas no Estructurales Virales , Proteínas no Estructurales Virales/inmunología , Proteínas no Estructurales Virales/genética , Proteínas no Estructurales Virales/química , Proteínas no Estructurales Virales/metabolismo , Virus del Dengue/inmunología , Virus del Dengue/genética , Animales , Vacunas contra el Dengue/inmunología , Vacunas contra el Dengue/genética , Desarrollo de Vacunas , Conejos , Humanos , Dengue/prevención & control , Dengue/inmunología , Dengue/virología , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/sangre , Unión Proteica , Receptor Toll-Like 4/metabolismo , Receptor Toll-Like 4/inmunología , Eliminación de SecuenciaRESUMEN
Dengue virus (DENV) is a considerable public health threat affecting millions of people globally. Vaccines for dengue are an important strategy to reduce the disease burden. We expressed capsid (C2) and envelope domain III of dengue virus serotype 2 (2EDIII) separately in the silkworm expression system. We conjugated them employing the monomeric streptavidin (mSA2) and biotin affinity to display the antigenic 2EDIII on the C2-forming capsid-like particle (CLP). Purified 2EDIII-displaying C2 (CLP/2EDIII) was immunogenic in BALB/c mice, eliciting neutralizing antibodies confirmed by a single-round infectious particle (SRIP) neutralization assay. Th1 cytokine levels were upregulated for the CLP/2EDIII group, and the anti-inflammatory IL-10 and pro-inflammatory IL-6 cytokine levels were also raised compared to the 2EDIII and the control groups. Elevated cytokine levels for CLP/2EDIII indicate the importance of displaying the 2EDIII as CLP/2EDIII rather than as an individual subunit. This study is the first to express the C2 protein as self-assembling CLP in vivo and 2EDIII separately in the silkworm expression system and conjugate them to form a monovalent CLP. Thus, this CLP/2EDIII display method may pave the way for an efficient tetravalent dengue vaccine candidate.
Asunto(s)
Anticuerpos Neutralizantes , Bombyx , Virus del Dengue , Ratones Endogámicos BALB C , Proteínas del Envoltorio Viral , Animales , Bombyx/genética , Bombyx/virología , Bombyx/metabolismo , Virus del Dengue/genética , Virus del Dengue/inmunología , Ratones , Proteínas del Envoltorio Viral/genética , Proteínas del Envoltorio Viral/inmunología , Proteínas del Envoltorio Viral/química , Proteínas del Envoltorio Viral/biosíntesis , Anticuerpos Neutralizantes/inmunología , Proteínas de la Cápside/genética , Proteínas de la Cápside/inmunología , Proteínas de la Cápside/química , Proteínas de la Cápside/biosíntesis , Vacunas contra el Dengue/inmunología , Vacunas contra el Dengue/genética , Anticuerpos Antivirales/inmunología , Dengue/inmunología , Dengue/virología , Serogrupo , Dominios Proteicos , FemeninoRESUMEN
Serum-neutralizing antibody titers are a critical measure of vaccine immunogenicity and are used to determine flavivirus seroprevalence in study populations. An effective dengue virus (DENV) vaccine must confer simultaneous protection against viruses grouped within four antigenic serotypes. Existing flavivirus neutralization assays, including the commonly used plaque/focus reduction neutralization titer (PRNT/FRNT) assay, require an individual assay for each virus, serotype, and strain and easily become a labor-intensive and time-consuming effort for large epidemiological studies or vaccine trials. Here, we describe a multiplex reporter virus particle neutralization titer (TetraPlex RVPNT) assay for DENV that allows simultaneous quantitative measures of antibody-mediated neutralization of infection against all four DENV serotypes in a single low-volume clinical sample and analyzed by flow cytometry. Comparative studies confirm that the neutralization titers of antibodies measured by the TetraPlex RVPNT assay are similar to FRNT/PRNT assay approaches performed separately for each viral strain. The use of this high-throughput approach enables the careful serological study in DENV endemic populations and vaccine recipients required to support the development of a safe and effective tetravalent DENV vaccine. IMPORTANCE: As a mediator of protection against dengue disease and a serological indicator of prior infection, the detection and quantification of neutralizing antibodies against DENV is an important "gold standard" tool. However, execution of traditional neutralizing antibody assays is often cumbersome and requires repeated application for each virus or serotype. The optimized RVPNT assay described here is high-throughput, easily multiplexed across multiple serotypes, and targets reporter viral particles that can be robustly produced for all four DENV serotypes. The use of this transformative RVPNT assay will support the expansion of neutralizing antibody datasets to answer research and public health questions often limited by the more cumbersome neutralizing antibody assays and the need for greater quantities of test serum.
Asunto(s)
Anticuerpos Neutralizantes , Anticuerpos Antivirales , Virus del Dengue , Dengue , Pruebas de Neutralización , Serogrupo , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/sangre , Virus del Dengue/inmunología , Virus del Dengue/clasificación , Humanos , Anticuerpos Antivirales/inmunología , Anticuerpos Antivirales/sangre , Pruebas de Neutralización/métodos , Dengue/inmunología , Dengue/virología , Vacunas contra el Dengue/inmunología , Virión/inmunología , AnimalesRESUMEN
The Middle East has witnessed a greater spread of infectious Dengue viruses, with serotype 2 (DENV-2) being the most prevalent form. Through this work, multi-epitope peptide vaccines against DENV-2 that target E and nonstructural (NS1) proteins were generated through an immunoinformatic approach. MHC class I and II and LBL epitopes among NS1 and envelope E proteins sequences were predicted and their antigenicity, toxicity, and allergenicity were investigated. Studies of the population coverage denoted the high prevalence of NS1 and envelope-E epitopes among different countries where DENV-2 endemic. Further, both the CTL and HTL epitopes retrieved from NS1 epitopes exhibited high conservancies' percentages with other DENV serotypes (1, 3, and 4). Three vaccine constructs were created and the expected immune responses for the constructs were estimated using C-IMMSIM and HADDOCK (against TLR 2,3,4,5, and 7). Molecular dynamics simulation for vaccine construct 2 with TLR4 denoted high binding affinity and stability of the construct with the receptor which might foretell favorable in vivo interaction and immune responses.
Asunto(s)
Vacunas contra el Dengue , Virus del Dengue , Dengue , Serogrupo , Vacunas de Subunidad , Proteínas no Estructurales Virales , Virus del Dengue/inmunología , Vacunas de Subunidad/inmunología , Vacunas contra el Dengue/inmunología , Humanos , Dengue/prevención & control , Dengue/inmunología , Dengue/virología , Proteínas no Estructurales Virales/inmunología , Biología Computacional/métodos , Epítopos de Linfocito T/inmunología , Proteínas del Envoltorio Viral/inmunología , Simulación de Dinámica Molecular , Epítopos/inmunología , Epítopos/química , Vacunas de Subunidades ProteicasRESUMEN
Protective immunity to dengue virus (DENV) requires antibody response to all four serotypes. Systems vaccinology identifies a multi-OMICs pre-vaccination signature and mechanisms predictive of broad antibody responses after immunization with a tetravalent live attenuated DENV vaccine candidate (Butantan-DV/TV003). Anti-inflammatory pathways, including TGF-ß signaling expressed by CD68low monocytes, and the metabolites phosphatidylcholine (PC) and phosphatidylethanolamine (PE) positively correlate with broadly neutralizing antibody responses against DENV. In contrast, expression of pro-inflammatory pathways and cytokines (IFN and IL-1) in CD68hi monocytes and primary and secondary bile acids negatively correlates with broad DENV-specific antibody responses. Induction of TGF-ß and IFNs is done respectively by PC/PE and bile acids in CD68low and CD68hi monocytes. The inhibition of viral sensing by PC/PE-induced TGF-ß is confirmed in vitro. Our studies show that the balance between metabolites and the pro- or anti-inflammatory state of innate immune cells drives broad and protective B cell response to a live attenuated dengue vaccine.
Asunto(s)
Anticuerpos Antivirales , Vacunas contra el Dengue , Virus del Dengue , Vacunas contra el Dengue/inmunología , Humanos , Virus del Dengue/inmunología , Anticuerpos Antivirales/inmunología , Dengue/inmunología , Dengue/prevención & control , Dengue/virología , Monocitos/inmunología , Monocitos/metabolismo , Formación de Anticuerpos/inmunología , Factor de Crecimiento Transformador beta/metabolismo , Factor de Crecimiento Transformador beta/inmunología , Vacunación , Anticuerpos Neutralizantes/inmunologíaRESUMEN
As dengue expands globally and many vaccines are under trials, there is a growing recognition of the need for assessing T cell immunity in addition to assessing the functions of neutralizing antibodies during these endeavors. While several dengue-specific experimentally validated T cell epitopes are known, less is understood about which of these epitopes are conserved among circulating dengue viruses and also shared by potential vaccine candidates. As India emerges as the epicenter of the dengue disease burden and vaccine trials commence in this region, we have here aligned known dengue specific T cell epitopes, reported from other parts of the world with published polyprotein sequences of 107 dengue virus isolates available from India. Of the 1305 CD4 and 584 CD8 epitopes, we found that 24% and 41%, respectively, were conserved universally, whereas 27% and 13% were absent in any viral isolates. With these data, we catalogued epitopes conserved in circulating dengue viruses from India and matched them with each of the six vaccine candidates under consideration (TV003, TDEN, DPIV, CYD-TDV, DENVax and TVDV). Similar analyses with viruses from Thailand, Brazil and Mexico revealed regional overlaps and variations in these patterns. Thus, our study provides detailed and nuanced insights into regional variation that should be considered for itemization of T cell responses during dengue natural infection and vaccine design, testing and evaluation.
Asunto(s)
Linfocitos T CD4-Positivos , Linfocitos T CD8-positivos , Vacunas contra el Dengue , Virus del Dengue , Dengue , Epítopos de Linfocito T , Humanos , Anticuerpos Neutralizantes/inmunología , Anticuerpos Neutralizantes/sangre , Brasil , Linfocitos T CD4-Positivos/inmunología , Linfocitos T CD8-positivos/inmunología , Dengue/inmunología , Dengue/virología , Vacunas contra el Dengue/inmunología , Virus del Dengue/inmunología , Virus del Dengue/genética , Virus del Dengue/clasificación , Epítopos de Linfocito T/inmunología , India , México , TailandiaRESUMEN
The profiles of vaccine-induced dengue antibodies may differ from those produced following natural infection and could potentially interfere with the interpretation of diagnostic tests. We assessed anti-dengue IgG and IgM antibodies, and nonstructural protein 1 antigen profiles in the serum of adults who received a single dose of the tetravalent dengue vaccine TAK-003 as either an initially developed high-dose formulation or the standard approved formulation in a phase 2 study in Singapore (#NCT02425098). Immunoglobulin G and IgM profiles during the first 30 days postvaccination varied by baseline serostatus (microneutralization assay). Nonstructural protein 1 antigen was not detected in the serum of any participants. Vaccine-induced IgG and IgM antibodies can affect serological confirmation of subsequent dengue infection in vaccinees. These results highlight the limitations of using serological tests for dengue diagnosis, particularly in a postvaccination setting, and emphasize the need for more sensitive antigen- and molecular-based testing for accurate dengue diagnosis.
Asunto(s)
Anticuerpos Antivirales , Vacunas contra el Dengue , Virus del Dengue , Dengue , Inmunoglobulina G , Inmunoglobulina M , Proteínas no Estructurales Virales , Humanos , Vacunas contra el Dengue/inmunología , Vacunas contra el Dengue/administración & dosificación , Inmunoglobulina M/sangre , Inmunoglobulina G/sangre , Dengue/prevención & control , Dengue/inmunología , Dengue/diagnóstico , Proteínas no Estructurales Virales/inmunología , Anticuerpos Antivirales/sangre , Adulto , Virus del Dengue/inmunología , Masculino , Femenino , Singapur , Adulto Joven , Persona de Mediana Edad , AdolescenteRESUMEN
Vaccine could take a central role in the strategy to reduce the burden of dengue. The development of an effective and safe vaccine must address various immunological challenges. Several vaccines are currently in development. To date, two live-attenuated vaccines have been deployed. Both have an effectiveness that varies depending on the serotypes. The deployment of the Dengvaxia vaccine, which began in 2015, was marked by a major safety alert leading to its use being restricted to previously dengue-seropositive people over 9 years old. The Qdenga vaccine is currently being deployed. There is for now insufficient data to ensure its safety in seronegative people. Some travelers, who have previously been infected with dengue, are a group for whom a vaccination recommendation applies.
Les vaccins pourraient occuper une place centrale dans la stratégie de réduction du fardeau de la dengue. Le développement d'un vaccin efficace et sûr est complexe car il doit relever plusieurs défis immunologiques. Différents vaccins sont en développement. À ce jour, deux vaccins vivants atténués ont été déployés. Tous deux ont une efficacité qui varie selon les sérotypes. Le déploiement du vaccin Dengvaxia, débuté en 2015, a été marqué par une alerte de sécurité majeure conduisant à restreindre son usage aux personnes de plus de 9 ans, préalablement séropositives pour la dengue. Le vaccin Qdenga est en cours de déploiement. Le recul est insuffisant pour assurer son innocuité chez les séronégatifs. Certains voyageurs, ayant déjà été infectés par la dengue, constituent un groupe pour lequel une recommandation vaccinale s'applique.
Asunto(s)
Vacunas contra el Dengue , Dengue , Vacunas Atenuadas , Humanos , Vacunas contra el Dengue/administración & dosificación , Vacunas contra el Dengue/inmunología , Vacunas contra el Dengue/efectos adversos , Dengue/prevención & control , Vacunas Atenuadas/administración & dosificación , Vacunación/métodos , Vacunación/tendenciasRESUMEN
Background. Dengue is an important arboviral infection of considerable public health significance. It occurs in a wide global belt within a variety of tropical regions. The timely laboratory diagnosis of Dengue infection is critical to inform both clinical management and an appropriate public health response. Vaccination against Dengue virus is being introduced in some areas.Discussion. Appropriate diagnostic strategies will vary between laboratories depending on the available resources and skills. Diagnostic methods available include viral culture, the serological detection of Dengue-specific antibodies in using enzyme immunoassays (EIAs), microsphere immunoassays, haemagglutination inhibition or in lateral flow point of care tests. The results of antibody tests may be influenced by prior vaccination and exposure to other flaviviruses. The detection of non-structural protein 1 in serum (NS1) has improved the early diagnosis of Dengue and is available in point-of-care assays in addition to EIAs. Direct detection of viral RNA from blood by PCR is more sensitive than NS1 antigen detection but requires molecular skills and resources. An increasing variety of isothermal nucleic acid detection methods are in development. Timing of specimen collection and choice of test is critical to optimize diagnostic accuracy. Metagenomics and the direct detection by sequencing of viral RNA from blood offers the ability to rapidly type isolates for epidemiologic purposes.Conclusion. The impact of vaccination on immune response must be recognized as it will impact test interpretation and diagnostic algorithms.
Asunto(s)
Vacunas contra el Dengue , Virus del Dengue , Dengue , Humanos , Dengue/diagnóstico , Dengue/prevención & control , Dengue/inmunología , Virus del Dengue/inmunología , Virus del Dengue/genética , Vacunas contra el Dengue/inmunología , Vacunas contra el Dengue/administración & dosificación , Técnicas de Laboratorio Clínico/métodos , Anticuerpos Antivirales/sangre , ARN Viral/genética , Proteínas no Estructurales Virales/inmunología , Proteínas no Estructurales Virales/genéticaRESUMEN
BACKGROUND: Dengue human infection models (DHIMs) are important tools to down-select dengue vaccine candidates and establish tetravalent efficacy before advanced clinical field trials. We aimed to provide data for the safety and immunogenicity of DHIM and evaluate dengue vaccine efficacy. METHODS: We performed an open-label, phase 1 trial at the University of Maryland (Baltimore, MD, USA). Eligible participants were healthy individuals aged 18-50 years who either previously received a tetravalent dengue purified inactivated vaccine prime followed by a live-attenuated vaccine boost (ie, the vaccinee group), or were unvaccinated flavivirus-naive participants (ie, the control group). Participants in the vaccinee group with detectable pre-challenge dengue virus-1 neutralising antibody titres and flavivirus-naive participants in the control group were inoculated with dengue virus-1 strain 45AZ5 in the deltoid region, 27-65 months following booster dosing. These participants were followed-up from days 4-16 following dengue virus-1 live virus human challenge, with daily real-time quantitative PCR specific to dengue virus-1 RNA detection, and dengue virus-1 solicited local and systemic adverse events were recorded. The primary outcomes were safety (ie, solicited local and systemic adverse events) and vaccine efficacy (ie, dengue virus-1 RNAaemia) following dengue challenge. This study is registered with ClinicalTrials.gov, number NCT04786457. FINDINGS: In January 2021, ten eligible participants were enrolled; of whom, six (60%) were in the vaccinee group and four (40%) were in the control group. Daily quantitative PCR detected dengue virus-1 RNA in nine (90%) of ten participants (five [83%] of six in the vaccinee group and all four [100%] in the control group). The mean onset of RNAaemia occurred on day 5 (SD 1·0) in the vaccinee group versus day 8 (1·5) in the control group (95% CI 1·1-4·9; p=0·007), with a trend towards reduced RNAaemia duration in the vaccinee group compared with the control group (8·2 days vs 10·5 days; 95% CI -0·08 to 4·68; p=0·056). Mild-to-moderate symptoms (nine [90%] of ten), leukopenia (eight [89%] of nine), and elevated aminotransferases (seven [78%] of nine) were commonly observed. Severe adverse events were detected only in the vaccinee group (fever ≥38·9°C in three [50%] of six, headache in one [17%], and transient grade 4 aspartate aminotransferase elevation in one [17%]). No deaths were reported. INTERPRETATION: Participants who had tetravalent dengue purified inactivated vaccine prime and live-attenuated vaccine boost were unprotected against dengue virus-1 infection and further showed increased clinical, immunological, and transcriptomic evidence for inflammation potentially mediated by pre-existing infection-enhancing antibodies. This study highlights the impact of small cohort, human challenge models studying dengue pathogenesis and downstream vaccine development. FUNDING: Military Infectious Disease Research Program and Medical Technology Enterprise Consortium and Advanced Technology International.
Asunto(s)
Anticuerpos Antivirales , Vacunas contra el Dengue , Virus del Dengue , Dengue , Humanos , Vacunas contra el Dengue/inmunología , Vacunas contra el Dengue/efectos adversos , Vacunas contra el Dengue/administración & dosificación , Adulto , Masculino , Dengue/prevención & control , Dengue/inmunología , Virus del Dengue/inmunología , Femenino , Anticuerpos Antivirales/sangre , Adulto Joven , Adolescente , Persona de Mediana Edad , Anticuerpos Neutralizantes/sangre , Vacunas Atenuadas/inmunología , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/efectos adversos , Eficacia de las Vacunas , Inmunización Secundaria , Inmunogenicidad VacunalRESUMEN
Dengue becomes the most common life-threatening infectious arbovirus disease globally, with prevalence in the tropical and subtropical areas. The major clinical features include dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS), a condition of hypovolemic shock. Four different serotypes of the dengue virus, known as dengue virus serotype (DENV)- 1, 2, 3 and 4 can infect humans. Only one vaccine is available in the market, named Dengvaxia by Sanofi Pasteur, but there is no desired outcome of this treatment due the antibody dependent enhancement (ADE) of the multiple dengue serotypes. As of now, there is no cure against dengue disease. Our goal in this work was to create a subunit vaccine based on several epitopes that would be effective against every serotype of the dengue virus. Here, computational methods like- immunoinformatics and bioinformatics were implemented to find out possible dominant epitopes. A total of 21 epitopes were chosen using various in-silico techniques from the expected 133 major histocompatibility complex (MHC)- I and major histocompatibility complex (MHC)- II epitopes, along with 95 B-cell epitopes which were greatly conserved. Immune stimulant, non-allergenic and non-toxic immunodominant epitopes (super epitopes) with a suitable adjuvant (Heparin-Binding Hemagglutinin Adhesin, HBHA) were used to construct the vaccine. Following the physicochemical analysis, vaccine construct was docked with Toll-like receptors (TLRs) to predict the immune stimulation. Consequently, the optimal docked complex that demonstrated the least amount of ligand-receptor complex deformability was used to conduct the molecular dynamics analysis. By following the codon optimization, the final vaccine molecule was administered into an expressing vector to perform in-silico cloning. The robust immune responses were generated in the in-silico immune simulation analysis. Hence, this study provides a hope to control the dengue infections. For validation of the immune outcomes, in-vitro as well as in-vivo investigations are essential.
Asunto(s)
Vacunas contra el Dengue , Virus del Dengue , Dengue , Epítopos de Linfocito B , Serogrupo , Vacunas contra el Dengue/inmunología , Humanos , Virus del Dengue/inmunología , Dengue/prevención & control , Dengue/inmunología , Epítopos de Linfocito B/inmunología , Simulación por Computador , Vacunas de Subunidad/inmunología , Biología Computacional/métodos , Epítopos Inmunodominantes/inmunología , Acrecentamiento Dependiente de Anticuerpo/inmunología , Epítopos/inmunología , Anticuerpos Antivirales/inmunologíaRESUMEN
Dengue virus (DENV) represents a significant global health burden, with 50% of the world's population at risk of infection, and there is an urgent need for next-generation vaccines. Virus-like particle (VLP)-based vaccines, which mimic the antigenic structure of the virus but lack the viral genome, are an attractive approach. Here, we describe a dengue VLP (DENVLP) vaccine which generates a neutralizing antibody response against all four DENV serotypes in 100% of immunized non-human primates for up to 1 year. Additionally, DENVLP vaccination produced no ADE response against any of four DENV serotypes in vitro. DENVLP vaccination reduces viral replication in a non-human primate challenge model. We also show that transfer of purified IgG from immunized monkeys into immunodeficient mice protects against subsequent lethal DENV challenge, indicating a humoral mechanism of protection. These results indicate that this DENVLP vaccine is immunogenic and can be considered for clinical evaluation. Immunization of non-human primates with a tetravalent DENVLP vaccine induces high levels of neutralizing antibodies and reduces the severity of infection for all four dengue serotypes.IMPORTANCEDengue is a viral disease that infects nearly 400 million people worldwide and causes dengue hemorrhagic fever, which is responsible for 10,000 deaths each year. Currently, there is no therapeutic drug licensed to treat dengue infection, which makes the development of an effective vaccine essential. Virus-like particles (VLPs) are a safe and highly immunogenic platform that can be used in young children, immunocompromised individuals, as well as healthy adults. In this study, we describe the development of a dengue VLP vaccine and demonstrate that it induces a robust immune response against the dengue virus for over 1 year in monkeys. The immunity induced by this vaccine reduced live dengue infection in both murine and non-human primate models. These results indicate that our dengue VLP vaccine is a promising vaccine candidate.
Asunto(s)
Anticuerpos Neutralizantes , Anticuerpos Antivirales , Vacunas contra el Dengue , Virus del Dengue , Dengue , Vacunas de Partículas Similares a Virus , Animales , Femenino , Ratones , Anticuerpos Neutralizantes/inmunología , Anticuerpos Antivirales/inmunología , Dengue/prevención & control , Dengue/inmunología , Dengue/virología , Vacunas contra el Dengue/inmunología , Vacunas contra el Dengue/administración & dosificación , Virus del Dengue/inmunología , Modelos Animales de Enfermedad , Inmunoglobulina G/inmunología , Macaca fascicularis , Macaca mulatta , Serogrupo , Vacunación , Vacunas de Partículas Similares a Virus/inmunología , Vacunas de Partículas Similares a Virus/administración & dosificación , Replicación ViralRESUMEN
Dengue human infection models present an opportunity to explore the potential of a vaccine, anti-viral or immuno-compound for clinical benefit in a controlled setting. Here we report the outcome of a phase 1 open-label assessment of a low-dose dengue virus 3 (DENV-3) challenge model (NCT04298138), in which nine participants received a subcutaneous inoculation with 0.5 ml of a 1.4 × 103 plaque-forming unit per ml suspension of the attenuated DENV-3 strain CH53489. The primary and secondary endpoints of the study were to assess the safety of this DENV-3 strain in healthy flavivirus-seronegative individuals. All participants developed RNAaemia within 7 days after inoculation with peak titre ranging from 3.13 × 104 to 7.02 × 108 genome equivalents per ml. Solicited symptoms such as fever and rash, clinical laboratory abnormalities such as lymphopenia and thrombocytopenia, and self-reported symptoms such as myalgia were consistent with mild-to-moderate dengue in all volunteers. DENV-3-specific seroconversion and memory T cell responses were observed within 14 days after inoculation as assessed by enzyme-linked immunosorbent assay and interferon-gamma-based enzyme-linked immunospot. RNA sequencing and serum cytokine analysis revealed anti-viral responses that overlapped with the period of viraemia. The magnitude and frequency of clinical and immunologic endpoints correlated with an individual's peak viral titre.
Asunto(s)
Anticuerpos Antivirales , Vacunas contra el Dengue , Virus del Dengue , Dengue , Viremia , Humanos , Virus del Dengue/inmunología , Dengue/inmunología , Dengue/virología , Adulto , Vacunas contra el Dengue/inmunología , Vacunas contra el Dengue/administración & dosificación , Vacunas contra el Dengue/efectos adversos , Masculino , Anticuerpos Antivirales/sangre , Anticuerpos Antivirales/inmunología , Femenino , Adulto Joven , Citocinas/sangre , Citocinas/metabolismo , ARN Viral/sangre , Seroconversión , Células T de Memoria/inmunología , Persona de Mediana EdadRESUMEN
BACKGROUND: A three-dose dengue vaccine (CYD-TDV) was licensed for use in children aged 9 years and older starting in 2015 in several dengue-endemic countries. In 2016, the Philippine Department of Health implemented a dengue vaccination programme, which was discontinued because of safety concerns. We assessed the relative risk of developing virologically confirmed dengue among children who did or did not receive a single dose of CYD-TDV by previous dengue virus (DENV) infections at baseline classified as none, one, and two or more infections. METHODS: In this longitudinal, prospective, population-based cohort study, we enrolled healthy children (aged 9-14 years) residing in Bogo or Balamban, Cebu, Philippines, between May 2, and June 2, 2017, before a mass dengue vaccination campaign, via the Rural Health Unit in Bogo and three Rural Health Units in Balamban. We collected demographic information and sera for baseline DENV serostatus and conducted active surveillance for acute febrile illness. Children who developed acute febrile illness were identified, clinical data were collected, and blood was drawn for confirmation of dengue by RT-PCR. The primary outcome was the relative risk of developing virologically confirmed dengue among children who received or did not receive a single dose of CYD-TDV by DENV serostatus at baseline. FINDINGS: A single dose of CYD-TDV did not confer protection against virologically confirmed dengue in children who had none or one previous DENV infection at baseline. One dose conferred significant protection against hospital admission for virologically confirmed dengue among participants who had two or more previous DENV infections at baseline during the first 3 years (70%, 95% CI 20-88; p=0·017) and the entire follow-up period (67%, 19-87; p=0·016). INTERPRETATION: The risk of developing virologically confirmed dengue after a single dose of CYD-TDV varied by baseline DENV serostatus. Since the study assessed the effect of only a single dose, the findings cannot inform decisions on vaccination by public health officers. However, the findings have implications for children who receive an incomplete vaccination regimen and these results should prompt more detailed analyses in future trials on dengue vaccines. FUNDING: The Philippine Department of Health, Hanako Foundation, WHO, Swedish International Development Cooperation Agency, International Vaccine Institute, University of North Carolina, and US National Institute of Allergy and Infectious Diseases.
Asunto(s)
Vacunas contra el Dengue , Dengue , Vacunas Atenuadas , Humanos , Filipinas/epidemiología , Niño , Dengue/prevención & control , Dengue/epidemiología , Vacunas contra el Dengue/administración & dosificación , Vacunas contra el Dengue/inmunología , Estudios Prospectivos , Femenino , Masculino , Adolescente , Estudios Longitudinales , Vacunas Atenuadas/administración & dosificación , Vacunas Atenuadas/inmunología , Virus del Dengue/inmunología , VacunaciónAsunto(s)
Vacunas contra el Dengue , Dengue , Programas de Inmunización , Humanos , Brasil/epidemiología , Dengue/epidemiología , Dengue/inmunología , Dengue/prevención & control , Dengue/virología , Vacunas contra el Dengue/administración & dosificación , Vacunas contra el Dengue/inmunología , Vacunas contra el Dengue/provisión & distribución , Virus del Dengue/inmunologíaRESUMEN
Tropical infectious diseases inflict an unacceptable burden of disease on humans living in developing countries. Although anti-pathogenic drugs have been widely used, they carry a constant threat of selecting for resistance. Vaccines offer a promising means by which to enhance the global control of tropical infectious diseases; however, these have been difficult to develop, mostly because of the complex nature of the pathogen lifecycles. Here, we present recently developed vaccine candidates for five tropical infectious diseases in the form of a catalog that have either entered clinical trials or have been licensed for use. We deliberate on recently licensed dengue vaccines, provide evidence why combination vaccination could have a synergistic impact on schistosomiasis, critically appraise the value of typhoid conjugate vaccines, and discuss the potential of vaccines in the efforts to eliminate vivax malaria and hookworms.