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Neutralization And Antibody Dependent Enhancement Of Dengue Viruses Pdf

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Antibody-Dependent Enhancement of Viral Infections

The challenges associated with whole DENV-based vaccine strategies necessitate re-focusing our attention toward the designed dengue vaccine candidates, capable of inducing predominantly type-specific immune responses. The generation of type-specific antibodies to each of the four DENV serotypes by the designed vaccines could avoid the immune evasion mechanisms of DENVs. For the enhanced vaccine safety, all dengue vaccine candidates should be assessed for the extent of type-specific minimal ADE vs.

The type-specific EDIII antibodies may be more directly related to protection from disease in the absence of ADE promoted by the cross-reactive antibodies. The world needs a dengue vaccine for all age groups, regardless of whether they may, or may not have been previously exposed to one of the four dengue viruses.

Overall VE was At 3 years post-dose 1, vaccinated children in the 2—5 year age group, were found to be nearly 8 times likely to be hospitalized for severe dengue, compared to children in the placebo group Hadinegoro et al. VE was subsequently found to be related to the pre-vaccination serostatus of the trial subjects. Long-term follow-up studies until 5 years reveal that in seronegative recipients, there is increased risk of severe dengue from the 3rd year onwards, post-dose 1. Clearly, developing a safe and efficacious dengue vaccine constitutes quite a formidable challenge.

Several unique factors, associated with the biology, and pathogenesis of dengue, taken together with lessons of the Dengvaxia experience, necessitates exploring alternate dengue vaccine development options.

There are additional whole virus-based dengue vaccines in advance stages of clinical trials Clinicaltrials. Moreover, a few recombinant dengue vaccine candidates are also at various stages of development Vannice et al. It is great that the pipeline of dengue vaccines continue to increase.

A safe and effective dengue vaccine could soon become a reality. Two of the structural proteins, the envelope E and the pre-membrane prM proteins, form the glycoprotein shell of the virus. The EDI participates in the confirmation changes required for virus entry. The prM protein helps mask the FL of EDII to avoid premature fusion and release into cytosol during virus maturation within the infected cell.

The immature virus is decorated with spikes of trimers of prM-E dimers. As a final step in virus maturation in the trans-Golgi network, prM is cleaved by host-encoded furin, leaving a peptide pr still covering the FL. Upon secretion to the outside of the infected cell, pr peptide dissociates from the virion, which is now fully mature and smooth Screaton et al.

In most clinically apparent cases, DENVs cause a self-limiting febrile illness known as dengue fever. However, a small proportion of DENV infections cause severe dengue. This is a potentially fatal form of dengue disease, characterized by increased capillary permeability leading to plasma leakage and shock Simmons et al.

Severe dengue has often been associated with sequential infection with DENVs of different serotypes. It has been proposed that antibodies to a given DENV serotype induced during a first infection, bind to, but do not neutralize, a different DENV serotype, encountered during a subsequent infection Tsai et al.

Figure 1. Left half DENV attaches to a host cell surface and is endocytosed followed by virus-endosomal membrane fusion leading to the release of viral genome. Post-release, viral RNA is translated and the viral genome is replicated.

Virus assembly occurs on the surface of the endoplasmic reticulum, and immature viral particles mature into their infectious form in the Golgi network. These mature viruses are then released from the cell and ready to infect other cells. Right half Cross-reactive Abs bind with immature non-infectious particles turning into infectious virus-Ab immune complexes V-Ab IC which then bind with the Fc receptor bearing cells.

Henceforth, controlled mature DENV production is lost, resulting into manifold increase in wide-range of immature viruses which leads to the extrinsic-ADE pathway by infecting other cells via binding with cross-reactive Abs Figure is adapted from Halstead et al.

There are several in vitro and in vivo studies that support ADE mediated enhanced disease outcome. Non-human primates passively immunized with dengue virus antibodies promoted higher level of viremia as compared to dengue virus infection in the absence of antibodies Muhammad Azami et al. A similar outcome was reported earlier using AG mouse model, where, passively transferred DENV-induced antibodies enhanced non-lethal DENV infection into a lethal infection, associated with vascular leakage and cytokine storm Watanabe et al.

Apart from this, two longitudinal clinical studies from Thailand and Nicaragua Katzelnick et al. These clinical studies provide strong evidence that highest risk of severe dengue is associated with low levels of pre-existing dengue antibodies. These studies have revealed that low level pre-existing antibody levels are correlated with an increased likelihood of severe dengue disease only during secondary heterotypic infections Katzelnick et al.

However, ADE is not observed during secondary homotypic infection. This is because highly neutralizing type-specific Abs elicited during primary infection can neutralize a secondary homotypic infection even at low Ab concentrations, preventing the incidence of ADE Ripoll et al. In homotypic infection, neutralization is determined by type-specific antibodies and ADE is limited to a very low level of type-specific antibody concentration.

During heterotypic infection both type-specific and cross-reactive antibodies contribute to virus neutralization, but at a lower efficiency. Molecular simulations have shown that rough form of the virus become particularly pathogenic in case of heterotypic infection, as the neutralization is determined by cross-reactive Abs Ripoll et al. Each of these four DENV serotypes can cause dengue disease ranging from mild to severe manifestations Simmons et al. Further, when DENVs replicate within a host, the error-prone viral RNA replication machinery, generates an array of genetically related, yet distinct genomic variants, giving rise to intrahost diversity Parameswaran et al.

It has become increasingly apparent that the DENV maturation process is far from complete as the virions exocytosed from the infected cell display a high degree of heterogeneity. This is inferred from time- and temperature-dependent accessibility of certain virion epitopes to antibodies Dowd et al.

The immune responses to DENV infections are mainly targeted against structural proteins i. Apart from above, studies by Chuang et al. However, complete contrary results are also reported, where, mouse raised polyclonal NS1 antiserum or anti-NS1 mAbs protects mice from the lethal dose of DENV-2 and also reduces the vascular leakage Beatty et al.

Thus, further studies are required to delineate the role of NS1 associated outcomes during dengue virus infection. Investigations have revealed that prM and the FL epitope FLE are particularly immunodominant and elicit cross-reactive, disease-spreading antibodies Beltramello et al.

These are highly cross-reactive antibodies, which are capable of recognizing prM of all four DENV serotypes. Once within the cell, these immature virions can undergo maturation and become inherently infectious, and spread to other cells. The FLE, which is conserved among flaviviruses, is normally buried in the mature virion, but becomes accessible upon virus breathing Cockburn et al.

Table 1. Protective antibodies appear to be elicited by non-immunodominant epitopes, and are either type-specific or pan-DENV specific. However, EDIII antibodies possess the highest DENV neutralizing capacity with minimal or no disease enhancing potential, when tested using in vivo dengue sensitive mouse models Watanabe et al.

The high mortality was accompanied by intestinal pathology, vascular leak, increased cytokine storm, and small intestinal tissue virus load. Figure 2. Investigators Watanabe et al. On the contrary, fully neutralized TS-ICs exhibited full protection accompanied by very low virus load. TS sub-neutralizing ICs showed a very minimal level of mortality accompanied by low virus load. ND, data not available The illustrative figure created with Biorender.

Moreover, an anti-EDIII monoclonal antibody has been shown to be capable of protecting humanized mice from all symptoms associated with severe dengue Robinson et al. These mAbs recognize conformational epitopes, found only when E is displayed on the virion surface, and are known as quaternary epitopes. Many of these are serotype-specific Teoh et al. In addition, broadly neutralizing mAbs, which target conserved quaternary epitopes among the four DENV serotypes, have been identified recently Dejnirattisai et al.

However, mimicking quaternary epitopes for a dengue vaccine candidate has been highly challenging. Further studies show EDE antibodies to be dominant toward the infecting serotype with lower avidity against the other serotypes Thomas et al. Several excellent publications on cellular immune responses during DENV natural infection are available Mathew and Rothman, ; Yauch et al. John and Rathore, ; Tian et al.

Nonetheless, precise nature of a protective T cell response in the context of DENV infection and vaccination is yet to be delineated. Like the antibody response, T cell responses also are implicated both in protection as well as pathogenesis Beaumier et al. However, unlike in the case of antibodies for which there is greater clarity on the nature of epitopes that elicit protective vs. Nonetheless, a few publications Simmons et al. Similar to the B-cell cross-reactive epitopes, the Dengvaxia and the other whole virus-based dengue vaccines do carry some level of cross-reactive T-cell epitopes.

Thus, the sub-optimal performance of Dengvaxia cannot be solely attributed to the absence of DENV specific T-cell epitopes. Additional research is required to shed more light on the specific features of both arms of the adaptive immune system in the context of their opposing roles in protection and pathogenesis.

However, mixing four monovalent dengue LAVs into a tetravalent formulation is associated with one component replicating better at the expense of the others, leading to a phenomenon known as viral interference Dittmar et al.

Intuitively, one may posit a role for the dynamics of intra-host microevolution, referred to above, in viral interference. However, this remains to be experimentally ascertained. Viral interference was historically noticed by Thai Kanesa-Thasan et al.

The consequence of such interference is that the immune response tends to be skewed toward one DENV serotype. This can lead to the situation wherein, though the LAV is a physically tetravalent mixture, it is essentially immunologically monovalent.

In fact, the observation that Dengvaxia predisposed seronegative recipients to increased risk of severe dengue, starting at 3 years after the first dose Hadinegoro et al. This would undoubtedly be true for other whole virus-based vaccines as well.

This makes ADE evaluation a mandatory step during pre-clinical vaccine development. Most live attenuated, killed or chimeric whole dengue virus-based vaccine candidates will mimic natural DENV infections and thus will elicit predominantly cross-reactive disease enhancing antibodies with limited type-specific protective antibodies.

Therefore, there is a need for designing a dengue vaccine candidate that elicits predominantly protective antibodies like anti-EDIII in the absence of pathogenic antibodies anti-prM and anti-FLE Lam et al. The ideal dengue vaccine should be tetravalent and generate long lasting, type-specific neutralizing antibodies against all the four-dengue virus serotypes. Figure 3. Comparison of conventional DENV vaccine strategy vs. Designer DENV vaccine candidate immune responses.

The whole DENV-based vaccine inherently poses to induce imbalance immune responses with high load of cross-reactive Abs against all four DENV serotype, suggests to explore designer DENV vaccine strategy, which may induce non-enhancing type-specific neutralizing immune response in human Figure designed with Biorender.

A recent study on molecular simulations of dengue virus infection and experimental data suggest that the interplay between epitope accessibility, Ab specificity, Ab affinity, Ab concentration, and mature content of the virus significantly influence the degree of ADE Ripoll et al. Since both Ab concentration and type specificity are critical host determinants of ADE, it is important to quantify not only the neutralizing antibody titer but also fine specificity type-specific vs.

For the safety and efficacy of a vaccine, it is vital that the vaccine immunogen should be well-characterized However, the maturation states of dengue serotypes in a whole virus-based dengue may be difficult to control.

The Complexity of Antibody-Dependent Enhancement of Dengue Virus Infection

If the address matches an existing account you will receive an email with instructions to reset your password. If the address matches an existing account you will receive an email with instructions to retrieve your username. In general, virus-specific antibodies are considered antiviral and play an important role in the control of virus infections in a number of ways. However, in some instances, the presence of specific antibodies can be beneficial to the virus. This activity is known as antibody-dependent enhancement ADE of virus infection. This phenomenon has been reported in vitro and in vivo for viruses representing numerous families and genera of public health and veterinary importance.

Infection with each DENV serotype causes an array of clinical diseases, ranging from dengue without warning signs, dengue with warning signs to severe dengue-dengue haemorrhagic fever and dengue shock syndrome 1 — 4. Individuals infected with one serotype can acquire lifelong homotypic immunity 5 ; however, those suffering secondary DENV infection with another serotype may have a greater risk of progressing to severe dengue 6. The presence of ADE impedes the development of dengue vaccines to induce protective neutralizing antibodies without enhancing viral replication. The surface of the mature DENV particle is covered with 90 head-to-tail homodimers of envelope glycoprotein E 8 , which is the major surface protein of flaviviruses involved in multiple processes, such as viral adsorption, membrane fusion and cell tropism. EDIII-reactive antibodies are found in convalescent sera from patients infected with dengue 10 , The EDIII-reactive antibodies can function as effective neutralizers and also may possess varying degrees of enhancing activity 12 — Recent studies have revealed that these antibodies from virus-infected serum are considered to contribute little to neutralizing and enhancing activities 11 , 20 —


Neutralization and Antibody-Dependent Enhancement of Dengue Viruses. February ; Advances Request Full-text Paper PDF. To read the full-text of this.


Antibody-Dependent Enhancement of Virus Infection and Disease

The 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. Genomic variation of dengue virus and subgenomic flavivirus RNA sfRNA suppressing host immune response are viral determinants of disease severity.

The challenges associated with whole DENV-based vaccine strategies necessitate re-focusing our attention toward the designed dengue vaccine candidates, capable of inducing predominantly type-specific immune responses. The generation of type-specific antibodies to each of the four DENV serotypes by the designed vaccines could avoid the immune evasion mechanisms of DENVs. For the enhanced vaccine safety, all dengue vaccine candidates should be assessed for the extent of type-specific minimal ADE vs.

Protocol DOI: This chapter outlines methods for the production of dengue virus DENV reporter virus particles RVPs and their use in assays that measure antibody-mediated neutralization and enhancement of DENV infection. RVPs are pseudo-infectious virions. RVPs are pseudo-infectious virions produced by complementation of a self-replicating flavivirus replicon with the DENV structural genes in trans.

Current Understanding of the Pathogenesis of Dengue Virus Infection

Metrics details. Antibodies are critical responses to protect the host from dengue virus DENV infection. Antibodies target DENV by two pathologic mechanisms: virus neutralization and infection enhancement. A total of pair serum samples from adult healthy volunteers were obtained during the dengue season in Ha Noi in for evaluation of neutralizing and infection-enhancing activity. Additionally, 20 serum samples from acute secondary DENV infection patients were also used as the patient group in this study.

Antibody-dependent enhancement ADE has been proposed as a mechanism to explain dengue hemorrhagic fever DHF in the course of a secondary dengue infection. Very recently, Dejnirattisai et al. The complexity of ADE in the context of a secondary dengue infection is discussed here. A rapid increase in dengue reports has been observed in the last three decades. Today, dengue infections are a serious cause of morbidity and mortality in most tropical and subtropical regions of the world: an estimated 50— million people are infected annually and over 2. These are transmitted to humans by Aedes mosquito bites, and Aedes aegypti is the main vector.

Dengue virus DENV is the cause of dengue fever. It is a mosquito -borne, single positive-stranded RNA virus of the family Flaviviridae ; genus Flavivirus. Dengue virus has increased dramatically within the last 20 years, becoming one of the worst mosquito-borne human pathogens with which tropical countries have to deal. Current estimates indicate that as many as million infections occur each year, and many dengue infections are increasingly understood to be asymptomatic or subclinical. Based on the analysis of the envelope protein, at least three genotypes 1 to 3 are known. In , a fourth serotype was reported.


Request PDF | On Mar 29, , Tadahiro Sasaki and others published Dengue virus neutralization and antibody-dependent enhancement activities of and/or human monoclonal antibodies (MAbs) specific to viral surface.


Antibody-Dependent Enhancement: A Challenge for Developing a Safe Dengue Vaccine

Introduction

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1 Comments

Peppin G. 28.05.2021 at 23:22

Antiviral antibodies constitute an important component of the host immune response against viral infections and serve to neutralize and reduce infectivity of the virus.

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