Vaccine Dengvaxia Research Articles

Did Dengvaxia-associated deaths result in an increase in vaccine hesitancy in the Philippines?

The development of the Dengvaxia vaccine and the subsequent vaccination campaign of 2016 in the Philippines proved to be an outstanding failure. This case study focuses on the impact of the vaccination campaign, which had a goal of vaccinating one million schoolchildren, ultimately reaching 830 000 students. Sanof Pasteur’s failure to adequately warn the Filipino public about Dengvaxia’s effect on antibody-dependent enhancement (ADE), coupled with rushing the implementation of the program by the Department of Health, ultimately led to the shutdown of the campaign in 2017. Therefore, we predict that the media sensationalization of the campaign, which created a public outrage, led to distrust of the healthcare system and vaccine hesitancy as well as an increase in vaccine-preventable diseases such as measles in the Philippines.

Vaccination and vector control effect on dengue virus transmission dynamics: Modelling and simulation

Abstract This paper presents a two-strain compartmental dengue model with variable humans and mosquitoes populations sizes. The model incorporates two control measures: Dengvaxia vaccine and insecticide (adulticide) to forecast the transmission and effective control strategy for dengue in Madeira Island if there is a new outbreak with a different virus serotype after the first outbreak in 2012. The basic reproduction number, R 0 = max { R 01 , R 0 j } , associated with the model is computed using the next generation matrix operator. The disease-free equilibrium is found to be locally asymptotically stable when both R 01 , R 0 j 1 , but unstable otherwise. The global asymptotic stability of the model is derived using the comparison theorem. Sensitivity analysis is carried out on the model parameters. The results of the analysis show that mosquito biting and death rates are the most sensitive parameters. Three strategies: the use of Dengvaxia vaccine only, the use of adulticide only, and the combination of Dengvaxia vaccine and adulticide, are considered for the control implementation under two scenarios (less and more aggressive cases). The numerical results show that a strategy which is based on Dengvaxia vaccine and adulticide is the most effective strategy for controlling dengue disease transmission in both scenarios among the considered strategies.

Global Stability and Optimal Control of Dengue with Two Coexisting Virus Serotypes

This study presents a two-strain deterministic model which incorporates Dengvaxia vaccine and insecticide (adulticide) control strategies to forecast the dynamics of transmission and control of dengue in Madeira Island if there is a new outbreak with a different virus serotypes after the first outbreak in 2012. We construct suitable Lyapunov functions to investigate the global stability of the disease-free and boundary equilibrium points. Qualitative analysis of the model which incorporates time-varying controls with the specific goal of minimizing dengue disease transmission and the costs related to the control implementation by employing the optimal control theory is carried out. Three strategies, namely the use of Dengvaxia vaccine only, application of adulticide only, and the combination of Dengvaxia vaccine and adulticide are considered for the controls implementation. The necessary conditions are derived for the optimal control of dengue. We examine the impacts of the control strategies on the dynamics of infected humans and mosquito population by simulating the optimality system. The disease-freeequilibrium is found to be globally asymptotically stable whenever the basic reproduction numbers associated with virus serotypes 1 and j (j 2 {2, 3, 4}), respectively, satisfy R01,R0j 1, and the boundary equilibrium is globally asymptotically stable when the related R0i (i = 1, j) is above one. It is shown that the strategy based on the combination of Dengvaxia vaccine and adulticide helps in an effective control of dengue spread in the Island.

REVIEW ARTICLE: DEVELOPEMENT AND USING DENGUE VACCINE FOR DENGUE INFECTION VIRUS

Abstract : Tropical and subtropical countries are regions with high incidence of dengue infection. Dengue virus infection is estimated to cause 300 million new infections in one year and approximately 1 million severe cases with 2 + 5% deaths. The case of dengue in Indonesia has continued to increase since 1968 until 1980 where all provinces in Indonesia have been affected by the dengue virus. Dengue virus is a virus carried by the Aedes aegypti mosquito in its salivary gland. The virus which is a family group of Flaviviruses has four homologous serotypes, namely DENV-1, DENV-2, DENV-3, and DENV-4, which can cause dengue infection in individuals. Currently there is a shift in the target population from children to adults. This is a problem that needs to be resolved by the government and the community itself. Solution to overcome this, the government needs early prevention efforts to reduce the severity of dengue infection by developing and researching dengue vaccines. Currently a vaccine has been found that can be used as prophylaxis for dengue virus, namely Dengvaxia. This vaccine has been recommended by the World Health Organization (WHO) as prophylaxis for dengue infection, but Dengvaxia is only used in areas that are very endemic to dengue fever. The Indonesian Food and Drug Supervisory Agency (BPOM RI) has also approved the use of Dengvaxia as an indication of prevention of dengue infection since August 31, 2016. This vaccine has been approved globally only given to individuals aged between 9-16 years. 
 Keyword : dengue virus, dengvaxia vaccine, Aedes aegypti, endemic

Potent Neutralizing Human Monoclonal Antibodies Preferentially Target Mature Dengue Virus Particles: Implication for Novel Strategy for Dengue Vaccine.

The four serotypes of dengue virus (DENV) cause the most important mosquito-borne viral disease in humans. The envelope (E) protein is the major target of neutralizing antibodies and contains 3 domains (domain I [DI], DII, and DIII). Recent studies reported that human monoclonal antibodies (MAbs) recognizing DIII, the D1/DII hinge, the E-dimer epitope, or a quaternary epitope involving DI/DII/DIII are more potently neutralizing than those recognizing the fusion loop (FL) of DII. Due to inefficient cleavage of the premembrane protein, DENV suspensions consist of a mixture of mature, immature, and partially immature particles. We investigated the neutralization and binding of 22 human MAbs to DENV serotype 1 (DENV1) virions with differential maturation status. Compared with FL MAbs, DIII, DI/DII hinge, and E-dimer epitope MAbs showed higher maximum binding and avidity to mature particles relative to immature particles; this feature may contribute to the strong neutralizing potency of such MAbs. FL-specific MAbs required 57 to 87% occupancy on mature particles to achieve half-maximal neutralization (NT50), whereas the potently neutralizing MAbs achieved NT50 states at 20 to 38% occupancy. Analysis of the MAb repertoire and polyclonal sera from patients with primary DENV1 infection supports the immunodominance of cross-reactive anti-E antibodies over type-specific antibodies. After depletion with viral particles from a heterologous DENV serotype, the type-specific neutralizing antibodies remained and showed binding features shared by potent neutralizing MAbs. Taken together, these findings suggest that the use of homogeneous mature DENV particles as an immunogen may induce more potent neutralizing antibodies against DENV than the use of immature or mixed particles.IMPORTANCE With an estimated 390 million infections per year, the four serotypes of dengue virus (DENV) cause the most important mosquito-borne viral disease in humans. The dengue vaccine Dengvaxia was licensed; however, its low efficacy among dengue-naive individuals and increased risk of causing severe dengue in children highlight the need for a better understanding of the role of human antibodies in immunity against DENV. DENV suspensions contain mature, immature, and partially immature particles. We investigated the binding of 22 human monoclonal antibodies (MAbs) to the DENV envelope protein on particles with different maturation states. Potently neutralizing MAbs had higher relative maximum binding and avidity to mature particles than weakly neutralizing MAbs. This was supported by analysis of MAb repertoires and polyclonal sera from patients with primary DENV infection. Together, these findings suggest that mature particles may be the optimal form of presentation of the envelope protein to induce more potent neutralizing antibodies against DENV.

Mathematical assessment of the role of Dengvaxia vaccine on the transmission dynamics of dengue serotypes

A new mathematical model is designed and used to assess the impact of the newly-released Dengvaxia vaccine on the transmission dynamics of two co-circulating dengue strains (where strain 1 consists of dengue serotypes 1, 3 and 4; and strain 2 consists of dengue serotype 2). It is shown that the model exhibits the phenomenon of backward bifurcation when the disease-induced mortality in the host population exceeds a certain threshold value or if the vaccine does not provide perfect protection against infection with the two strains. In the absence of backward bifurcation, the disease-free equilibrium of the model is shown to be globally-asymptotically stable whenever the associated reproduction number is less than unity. It is shown that the community-wide use of the vaccine could induce positive, negative or no population-level impact, depending on the sign of a certain epidemiological threshold quantity (known as the vaccine impact factor). Simulations of the model, using data from Oaxaca, Mexico, show that, although the community-wide use of the vaccine will significantly reduce dengue burden in the community, it is unable to lead to the elimination of the two dengue strains. It is further shown that the use of Dengvaxia vaccine in dengue-naive populations may induce increased risk of severe disease in these populations.

Politics and public trust shape vaccine risk perceptions.

Public mistrust of vaccines is heightening, fuelled by new communication environments such as social media. Using the recent case of the Dengvaxia vaccine, Heidi Larson explores public and political reactions to vaccine risks.

Plant-expressed Fc-fusion protein tetravalent dengue vaccine with inherent adjuvant properties.

SummaryDengue is a major global disease requiring improved treatment and prevention strategies. The recently licensed Sanofi Pasteur Dengvaxia vaccine does not protect children under the age of nine, and additional vaccine strategies are thus needed to halt this expanding global epidemic. Here, we employed a molecular engineering approach and plant expression to produce a humanized and highly immunogenic poly‐immunoglobulin G scaffold (PIGS) fused to the consensus dengue envelope protein III domain (cEDIII). The immunogenicity of this IgG Fc receptor‐targeted vaccine candidate was demonstrated in transgenic mice expressing human FcγRI/CD64, by induction of neutralizing antibodies and evidence of cell‐mediated immunity. Furthermore, these molecules were able to prime immune cells from human adenoid/tonsillar tissue ex vivo as evidenced by antigen‐specific CD4+ and CD8+ T‐cell proliferation, IFN‐γ and antibody production. The purified polymeric fraction of dengue PIGS (D‐PIGS) induced stronger immune activation than the monomeric form, suggesting a more efficient interaction with the low‐affinity Fcγ receptors on antigen‐presenting cells. These results show that the plant‐expressed D‐PIGS have the potential for translation towards a safe and easily scalable single antigen‐based tetravalent dengue vaccine.

Comparative proteomics reveals that YK51, a 4-Hydroxypandurantin-A analogue, downregulates the expression of proteins associated with dengue virus infection.

Dengue is endemic throughout tropical and subtropical regions of the world. Currently, there is no clinically approved therapeutic drug available for this acute viral infection. Although the first dengue vaccine Dengvaxia has been approved for use in certain countries, it is limited to those without a previous dengue infection while the safety and efficacy of the vaccine in those elderly and younger children still need to be identified. Therefore, it is becoming increasingly important to develop therapeutics/drugs to combat dengue virus (DENV) infection. YK51 is a synthetic analogue of 4-Hydroxypandurantin A (a compound found in the crude extract of the rhizomes of Boesenbergia rotunda) that has been extensively studied by our research group. It has been shown to possess outstanding antiviral activity due to its inhibitory activity against NS2B/NS3 DENV2 protease. However, it is not known how YK51 affects the proteome of DENV infected cells. Therefore, we performed a comparative proteomics analysis to identify changes in protein expression in DENV infected HepG2 cells treated with YK51. Classical two-dimensional gel electrophoresis followed by protein identification using tandem mass spectrometry was employed in this study. Thirty proteins were found to be down-regulated with YK51 treatment. In silico analysis predicted that the down-regulation of eight of these proteins may inhibit viral infection. Our results suggested that apart from inhibiting the NS2B/NS3 DENV2 protease, YK51 may also be causing the down-regulation of a number of proteins that may be responsible in, and/or essential to virus infection. However, functional characterization of these proteins will be necessary before we can conclusively determine their roles in DENV infection.

THE “UNHOLY” CHIKUNGUNYA–DENGUE–ZIKA TRINITY: A THEORETICAL ANALYSIS

Aedes aegypti is the vector for numerous diseases in humans and other (reservoir) hosts, such as chikungunya, dengue fever and Zika virus. A new deterministic model is designed and used to assess the dynamics of the three diseases in a population where Aedes mosquitoes are abundant. The model to be designed incorporates the recently-released imperfect vaccine against dengue virus (Dengvaxia[Formula: see text] vaccine by Sanofi Pasteur) as well as allow for sexual transmission of Zika. Further, the model allows for the assessment of the population-level impact of three biological hypotheses, namely a competitive dengue–chikungunya–Zika superinfection hierarchy, an antibody-dependent enhancement of dengue over Zika and that the Dengvaxia vaccine can induce reduced susceptibility to Zika infection in vaccinated individuals. After carrying out detailed theoretical analyses to gain insight into its qualitative features, the model is then fitted to the data recorded during the 2015–2016 outbreaks of the three diseases in Mexico. Simulations of the model show a reasonable fit to observed dynamics consistent with the competitive hierarchy assumed for the interactions of the viruses. Furthermore, Zika transmission dynamics is only mildly affected by changes in the parameter related to the infectiousness of Zika in relation to dengue, even in the region where antibody-dependent enhancement is assumed. The dengue vaccine has a very marginal impact on Zika transmission dynamics (and that the vaccine, no matter the coverage and efficacy levels, is unable to reduce the reproduction number for Zika transmission to a value less than unity). The model is extended to include the effect of seasonality and local weather variability (temperature and rainfall) on the dynamics of the three diseases. Simulations of the resulting non-autonomous model, using weather and demographic data for Mexico, show that for the current mean monthly rainfall value for Mexico, the burden of the three diseases increases with increasing mean monthly temperature in the range 16–29[Formula: see text]C, and decreases with increasing mean monthly temperature thereafter. Additionally, for the current fixed mean monthly temperature and rainfall data for Mexico, simulations show maximum transmission activity of all three diseases if the temperature and rainfall values lie in the range 25–26.4[Formula: see text]C and 90–128[Formula: see text]mm, respectively (these values are typically recorded in Mexico during the months of June, July and September). Simulations for two Mexican states (Oaxaca and Chiapas) where the three diseases are endemic show maximum transmission activity for all three diseases when temperature and rainfall lie in the ranges 20–25[Formula: see text]C and 51–102[Formula: see text]mm for Oaxaca (these ranges are recorded during the months of May through September) and 19–21[Formula: see text]C and 85–107[Formula: see text]mm for Chiapas (there ranges are recorded during the months of May, July, August and October), respectively. These simulations suggest suitable time when anti-mosquito control efforts should be intensified in Mexico (and the two selected states).

PHARMACOECONOMIC EVALUATION FOR DENGUE VACCINE PRICING FOR MALAYSIA: TOWARDS AFFORDABILITY, COST EFFECTIVENESS AND SUSTAINABILITY

Objective: Malaysian health ministry is currently evaluating the licensing of dengue vaccine Dengvaxia using a set of criteria including safety, efficacy and cost-effectiveness. The purpose of this research is to formulate a model framework to assist transparent decision-making.Methods: To quantify the cost-effective price of vaccine, pharmacoeconomic evaluation models are commonly used. We review in this paper dengue economic burdens and pharmacoeconomic models, with particular reference to cost-effectiveness.Results: A major weakness in current pharmacoeconomic models is the omission of cost of vaccine production, which is two orders of magnitude lower than the market price. This paper proposes an inclusive model that yields a highly cost-effective threshold price of dengue vaccine at USD 5 per dose for Malaysia.Conclusion: At USD 5 per dose, Dengue vaccine will be fair, Affordable and sustainable.

Which Dengue Vaccine Approach Is the Most Promising, and Should We Be Concerned about Enhanced Disease after Vaccination? The Challenges of a Dengue Vaccine.

A dengue vaccine has been pursued for more than 50 years and, unlike other flaviviral vaccines such as that against yellow fever, progress has been slow. In this review, we describe progress toward the first licensed dengue vaccine Dengvaxia, which does not give complete protection against disease. The antibody response to the dengue virion is reviewed, highlighting immunodominant yet poorly neutralizing responses in the context of a highly dynamic structurally flexible dengue virus particle. Finally, we review recent evidence for cross-reactivity between antibody responses to Zika and dengue viruses, which may further complicate the development of broadly protective dengue virus vaccines.

A Rapid and Improved Method to Generate Recombinant Dengue Virus Vaccine Candidates.

Dengue is one of the most important mosquito-borne infections accounting for severe morbidity and mortality worldwide. Recently, the tetravalent chimeric live attenuated Dengue vaccine Dengvaxia® was approved for use in several dengue endemic countries. In general, live attenuated vaccines (LAV) are very efficacious and offer long-lasting immunity against virus-induced disease. Rationally designed LAVs can be generated through reverse genetics technology, a method of generating infectious recombinant viruses from full length cDNA contained in bacterial plasmids. In vitro transcribed (IVT) viral RNA from these infectious clones is transfected into susceptible cells to generate recombinant virus. However, the generation of full-length dengue virus cDNA clones can be difficult due to the genetic instability of viral sequences in bacterial plasmids. To circumvent the need for a single plasmid containing a full length cDNA, in vitro ligation of two or three cDNA fragments contained in separate plasmids can be used to generate a full-length dengue viral cDNA template. However, in vitro ligation of multiple fragments often yields low quality template for IVT reactions, resulting in inconsistent low yield RNA. These technical difficulties make recombinant virus recovery less efficient. In this study, we describe a simple, rapid and efficient method of using LONG-PCR to recover recombinant chimeric Yellow fever dengue (CYD) viruses as potential dengue vaccine candidates. Using this method, we were able to efficiently generate several viable recombinant viruses without introducing any artificial mutations into the viral genomes. We believe that the techniques reported here will enable rapid and efficient recovery of recombinant flaviviruses for evaluation as vaccine candidates and, be applicable to the recovery of other RNA viruses.

Why are dengue virus serotypes so distantly related? Enhancement and limiting serotype similarity between dengue virus strains.

Dengue virus, the causative agent of dengue fever, has four major serotypes characterized by large genetic and immunological distances. We propose that the unusually large distances between the serotypes can be explained in the light of a process of antibody-dependent enhancement (ADE) leading to increased mortality. Antibody-dependent enhancement results from a new infection with a particular serotype in an individual with acquired immunity to a different serotype. Classical dengue fever causes negligible mortality, but ADE leads to the risk of developing the significantly more dangerous dengue haemorrhagic fever (DHF) and dengue shock syndrome (DSS). A mathematical model is presented that describes the epidemiological dynamics of two serotypes of a pathogen where there is the possibility of co-infection and reinfection by a different serotype, along with increased mortality as a result of enhancement. We show that if there is no or slightly increased mortality after reinfection (enhancement), serotypes with a small immunological distance can stably coexist. This suggests that a cloud of serotypes with minor serological differences will constitute the viral population. By contrast, if enhancement is sufficiently great, a substantial immunological distance is necessary for two serotypes to stably coexist in the population. Therefore, high mortality owing to enhancement leads to an evolutionarily stable viral community comprising a set of distantly separated serotypes.