Flavonoids as antiviral agents for Enterovirus A71 (EV-A71)

Flavonoids are natural biomolecules that are known to be effective antivirals. These biomolecules can act at different stages of viral infection, particularly at the molecular level to inhibit viral growth. Enterovirus A71 (EV-A71), a non-enveloped RNA virus, is one of the causative agents of hand, foot and mouth disease (HFMD), which is prevalent in Asia. Despite much effort, no clinically approved antiviral treatment is available for children suffering from HFMD. Flavonoids from plants serve as a vast reservoir of therapeutically active constituents that have been explored as potential antiviral candidates against RNA and DNA viruses. Here, we reviewed flavonoids as evidence-based natural sources of antivirals against non-picornaviruses and picornaviruses

Peptides as therapeutic agents for dengue virus

Dengue is an important global threat caused by dengue virus (DENV) that records an estimated 390 million infections annually. Despite the availability of CYD-TDV as a commercial vaccine, its long-term efficacy against all four dengue virus serotypes remains unsatisfactory. There is therefore an urgent need for the development of antiviral drugs for the treatment of dengue. Peptide was once a neglected choice of medical treatment but it has lately regained interest from the pharmaceutical industry following pioneering advancements in technology. In this review, the design of peptide drugs, antiviral activities and mechanisms of peptides and peptidomimetics (modified peptides) action against dengue virus are discussed. The development of peptides as inhibitors for viral entry, replication and translation is also described, with a focus on the three main targets, namely, the host cell receptors, viral structural proteins and viral non-structural proteins. The antiviral peptides designed based on these approaches may lead to the discovery of novel anti-DENV therapeutics that can treat dengue patients

Development of dengue vaccines

Background: Dengue virus (DENV) causes up to 390 million infections yearly, of which 96 million are clinically manifested. Approximately 500,000 people with severe dengue require hospitalization each year and there are at least 25,000 deaths among children from Asian and Latin American countries. DENV is endemic in more than 100 countries. Chemical and biological controls have been implemented in targeting Aedes aegypti and Aedes albopictus mosquitoes, but these control practices failed to stem the dengue transmission. As a result, dengue vaccine has become a potential option recommended by WHO to be implemented in dengue endemic regions. Currently, several vaccine candidates are being evaluated in clinical studies. Amongst the vaccine candidates, live attenuated vaccines (LAV) are the furthest along the development pipeline. The most advanced vaccine, CYD-TDV (Dengvaxia) has been licensed in 19 countries. Several other live attenuated vaccines, as well as DNA, subunit, inactivated virus, viral-vectored and subunit-based vaccines, are under development and evaluation in preclinical or clinical studies. Each of the live-attenuated vaccine candidates targets on molecular determinants of virulence in DENV, with the emphasis on attenuating the DENV and inducing a balanced tetravalent immune response against all the four dengue serotypes. Aims: This review presents several different vaccine approaches and their construction strategies, providing an insight into the development of future dengue vaccines such as live attenuated vaccines, DNA vaccines, sub-unit protein vaccines and viral vectored vaccines. Methods: Recent development status of dengue vaccine candidates was reviewed based on the published data and an online registry for clinical trials (ClinicalTrials.gov) which is run by the U.S. National Library of Medicine, National Institutes of Health. Results: Increasing burden of dengue necessitates the development of a safe and efficacious tetravalent dengue vaccine. Various vaccine strategies are being developed for disease prevention, each has its own strengths and limitations. Dengvaxia is a licensed dengue vaccine in 19 countries but it has been suspended in the Philippines in December 2017 due to its potential risks in children <9 years of age and seronegative vaccinees. TDV was able to elicit neutralizing antibodies as well as cross protective T cell responses against all four dengue serotypes and protected mice and nonhuman primates against challenge with wild type DENV. Seroconversion was achieved in both seronegative and seropositive adults and children <1.5 years of age with a single dose. TV003/TV005 was able to elicit multifunctional T cell response in addition to the humoral response. Seroconversion in 90 per cent of seronegative adults was observed with a single dose of TV005. However, eliciting a balanced immune response against all the four dengue serotypes remained the major impediment. Conclusion : Dengvaxia has been launched in 11 countries but it has been withdrawn in the Philippines due to adverse effects in young children. Experimental vaccines such as TDV and TV003/TV005 are live attenuated vaccines which are currently in phase III clinical trials. Continued field trials will further our understanding of immune correlates of protection or risk

Recent advances in delivery of veterinary DNA vaccines against avian pathogens

International audienceAbstractVeterinary vaccines need to have desired characteristics, such as being effective, inexpensive, easy to administer, suitable for mass vaccination and stable under field conditions. DNA vaccines have been proposed as potential solutions for poultry diseases since they are subunit vaccines with no risk of infection or reversion to virulence. DNA vaccines can be utilized for simultaneous immunizations against multiple pathogens and are relatively easy to design and inexpensive to manufacture and store. Administration of DNA vaccines has been shown to stimulate immune responses and provide protection from challenges in different animal models. Although DNA vaccines offer advantages, setbacks including the inability to induce strong immunity, and the fact that they are not currently applicable for mass vaccination impede the use of DNA vaccines in the poultry industry. The use of either biological or physical carriers has been proposed as a solution to overcome the current delivery limitations of DNA vaccines for veterinary applications. This review presents an overview of the recent development of carriers for delivery of veterinary DNA vaccines against avian pathogens

Development of novel miRNA-based vaccines and antivirals against Enterovirus 71

The Hand, Foot and Mouth Disease (HFMD) is caused by Enterovirus 71 (EV-A71) and Coxsackie viruses. Common HFMD symptoms are high fever (≥ 39oC), rashes, and ulcers but complications due to virulent EV-A71 may arise leading to cardiopulmonary failure and death. The lack of vaccines and antiviral drugs against EV-A71 highlights the urgency of developing preventive and treatment agents. Recent studies have reported the emergence of novel antiviral agents and vaccines that utilize microRNAs (miRNAs). They belong to a class of small (19-24 nt) non coding RNA molecules. As miRNAs play a major role in the host regulatory system, there is a huge opportunity for interplay between host miRNAs and EV-A71 expressions. A total of 42 out of 64 miRNAs were up-regulated in EV-A71-infected cells. There was consistent up-regulation of miR-1246 gene expression that targeted the DLG3 gene which contributes to neurological pathogenesis. In contrast, miR-30a that targets calcium channels for membrane transportation was down-regulated. This leads to repression of EV-A71 replication. The impact of host miRNAs on immune activation, shutdown of host protein synthesis, apoptosis, signal transduction and viral replication are discussed. miRNAs have been used in the construction of live attenuated vaccines (LAV) such as the poliovirus LAV that has miRNA binding sites for let-7a or miR-124a. The miRNA-bearing vaccine will not replicate in neuronal cells carrying the corresponding miRNA but could still replicate in the gastrointestinal tract and hence remains to act as immunogens. As such, miRNAs are attractive candidates to be developed as vaccines and antivirals

Impact of genetic changes, pathogenicity and antigenicity on Enterovirus- A71 vaccine development

Enterovirus-A71 (EV-A71) is an etiological agent of the hand, foot and mouth disease (HFMD). EV-A71 infection produces high fever and ulcers in children. Some EV-A71 strains produce severe infections leading to pulmonary edema and death. Although the protective efficacy of the inactivated vaccine (IV) was ≥ 90% against mild HFMD, there was approximately 80% protection against severe HFMD. The monovalent EV-A71 IV elicits humoral immunity but lacks long-term immunogenicity. Spontaneous mutations of the EV A71 genome could lead to antigenicity changes and the virus may not be neutralized by antibodies elicited by the IV. A better alternative would be the live attenuated vaccine (LAV) that elicits cellular and humoral immunity. The LAV induces excellent antigenicity and chances of reversion is reduced by presence of multiple mutations which could reduce pathogenicity. Besides CV-A16, outbreaks have been caused by CV-A6 and CV-A10, hence the development of bivalent and trivalent vaccines is required

T Cell immunity to enterovirus 71 infection in humans and implications for vaccine development

Enterovirus 71 (EV-A71) is one of the major pathogens causing hand, foot and mouth disease (HFMD). Some strains can lead to neurological disease and fatality in children. Up to date, there is no FDA-approved vaccine to prevent severe HFMD and mortality. Although the inactivated vaccine has advanced to production in China, lack of long-term protection and the requirement of multiple boosters have necessitated the development of other types of vaccines. Recent studies indicate that cellular and not humoral immunity determines the clinical outcome of EV-A71 infections. High levels of cytokines such as IL-1β, IL-6, IL-10 and IFN-γ tend to correlate with clinical severity in patients with pulmonary edema and encephalitis. The live attenuated vaccine may serve as the preferred choice as it can induce excellent humoral and cellular immunity as well as live-long immunity. Expression of certain HLA alleles such as TNF-α promoter type II (-308 allele), HLA-A33 and HLA-DR17 responses have been linked to severe HFMD. However, the high variability of MHC genes could restrict T cell recognition and be a major obstacle in the design of peptide vaccines. Hence, the development of a T cell universal vaccine (incorporating both CD4+ and CD8+ T cell epitopes) that induces broad, multifunctional and cross-reactive CD8+ T cell responses maybe desirable

Development of novel vaccines against Enterovirus-71

The hand, foot and mouth disease is caused by a group of Enteroviruses such as Enterovirus 71 (EV-A71) and Coxsackievirus CV-A5, CV-A8, and CV-A16. Mild symptoms of EV-A71 infection in children range from high fever, vomiting, rashes and ulcers in mouth but can produce more severe symptoms such as brainstem and cerebellar encephalitis, leading up to cardiopulmonary failure and death. The lack of vaccines and antiviral drugs against EV-A71 highlights the urgency of developing preventive and treatment agents against EV-A71 to prevent further fatalities. Research groups have developed experimental inactivated vaccines, recombinant Viral Protein 1 (VP1) vaccine and virus-like particles (VLPs). The inactivated EV-A71 vaccine is considered the safest viral vaccine, as there will be no reversion to the infectious wild type strain. The recombinant VP1 vaccine is a cost-effective immunogen, while VLPs contain an arrangement of epitopes that can elicit neutralizing antibodies against the virus. As each type of vaccine has its advantages and disadvantages, increased studies are required in the development of such vaccines, whereby high efficacy, long-lasting immunity, minimal risk to those vaccinated, safe and easy production, low cost, dispensing the need for refrigeration and convenient delivery are the major goals in their design