Vaccines for emerging pathogens: from research to the clinic.

In this two-part series of reviews, we have invited experts in their fields to contribute articles on the status of vaccine research and development for emerging pathogens. This topic has been brought into sharp focus in recent years following significant outbreaks of viral diseases such as those causing severe acute respiratory syndrome and Middle East respiratory syndrome, as well as devastating outbreaks of diseases caused by the Ebola, Marburg, Zika and Lassa fever viruses, to name only a few examples. Additionally, bacterial infections leading to bubonic and pneumonic plague, most notably in Madagascar in 2018, as well as malaria in many tropical countries, melioidosis in south east Asia and tularaemia in northern Europe and North America, have incurred significant morbidity and mortality. In this review series, the life cycle of these pathogens and the epidemiology of disease have been reviewed in the context of potential points of intervention for the prevention of human infection. Many of the emerging pathogens are zoonoses and, as such, there is scope for intervention at the animal/insect/environmental reservoir. Other pathogens covered in this review series are considered to be re-emerging, such as multi-drug resistant tuberculosis.

Computational Prediction of Usutu Virus E Protein B Cell and T Cell Epitopes for Potential Vaccine Development.

Usutu virus (family Flaviviridae), once confined to Africa, has emerged in Europe a decade ago. The virus has been spreading throughout Europe at a greater pace mostly affecting avian species. While most bird species remain asymptomatic carriers of this virus, few bird species are highly susceptible. Lately, Usutu virus (USUV) infections in humans were reported sporadically with severe neuroinvasive symptoms like meningoencephalitis. As so much is unknown about this virus, which potentially may cause severe diseases in humans, there is a need for more studies of this virus. In this study, we have used computational tools to predict potential B cell and T cell epitopes of USUV envelope (E) protein. We found that amino acids between positions 68 and 84 could be a potential B cell epitope, while amino acids between positions 53 and 69 could be a potential major histocompatibility complex (MHC) class I- and class II-restricted T cell epitope. By homology 3D modeling of USUV E protein, we found that the predicted B cell epitope was predominantly located in the coil region, while T cell epitope was located in the beta-strand region of the E protein. Additionally, the potential MHC class I T cell epitope (LAEVRSYCYL) was predicted to bind to nearly 24 human leucocyte antigens (HLAs) (IC50 ≤5000 nm) covering nearly 86.44% of the Black population and 96.90% of the Caucasoid population. Further in vivo studies are needed to validate the predicted epitopes.

Infección importada por virus Zika en una zona colonizada por Aedes albopictus / Infection imported virus Zika in an area settled by Aedes albopictus

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Ministério da Saúde confirma relação entre vírus Zika e microcefalia

O achado reforça o chamado para uma mobilização nacional para conter o mosquito transmissor, o Aedes aegypti, responsável pela disseminação doença. O Instituto Evandro Chagas, órgão do ministério em Belém (PA), encaminhou o resultado de exames realizados em um bebê, nascida no Ceará, com microcefalia e outras malformações congênitas. Em amostras de sangue e tecidos, foi identificada a presença do vírus Zika A partir desse achado do bebê que veio à óbito, o Ministério da Saúde considera confirmada a relação entre o vírus e a ocorrência de microcefalia. Essa é uma situação inédita na pesquisa científica mundial. As investigações sobre o tema devem continuar para esclarecer questões como a transmissão desse agente, a sua atuação no organismo humano, a infecção do feto e período de maior vulnerabilidade para a gestante. Em análise inicial, o risco está associado aos primeiros três meses de gravidez.

Efficacy Evaluation of an Inactivated Duck Tembusu Virus Vaccine.

To evaluate the potential use of an inactivated virus-based vaccine for the control and prevention of the newly emerged duck Tembusu virus infection in China, a duck Tembusu virus isolate, Tembusu-HB, was propagated in 12-day-old duck embryos and inactivated by treatment with formaldehyde. The inactivated viral antigen was emulsified with mineral oil, and five batches of the vaccine were manufactured. The immunogenicity and protection efficacy of the vaccine were evaluated in Beijing ducks and Beijing white geese. Results showed that more than 80% of immunized ducks were protected against virulent virus challenge after two intramuscular or subcutaneous injections of the inactivated vaccine, as evidenced by the negative virus isolation results. The protection is also correlated with a positive virus-specific antibody response as detected by ELISA. In contrast, none of the control ducks and geese had any detectable antibody response. Virus was isolated from all control ducks and geese after virulent virus challenge. Interestingly, a variable level of protection (20%-80%) was observed in Beijing white geese immunized twice with the same batches of vaccine, suggesting a species-specific effect of the vaccine. Overall, the results clearly suggest that the inactivated duck Tembusu virus vaccine is immunogenic and provides protection against virulent virus challenge.

Vaccination and antiviral treatment of neglected diseases caused by flaviviral infections.

Flaviviral infections have a re-emerging impact on the health situation in developing countries with several billions of people living at risk. In the present review, we focus on three members of the genus Flavivirus belonging to the Flaviviridae family. They are transmitted to humans by mosquito bites, namely those viruses leading to Dengue Fever, Yellow Fever and mosquito-borne Japanese encephalitis. All three virus groups have a spherical structure with a diameter of approximately 50 nm. Although sharing a similar genomic structure and intracellular life cycle, they show different clinical manifestations. Infections are incurable, as there is no antiviral treatment available for either of the three viruses. Thus, prevention and vaccination are the best defenses. The most promising vaccines are live attenuated vaccines (LAVs), such as the YF17D strain against Yellow Fever or the SA-14-14-2 strain against Japanese encephalitis. Additionally, recombinant vaccines for Japanese encephalitis are in development. Although Dengue Fever is the most prevalent arthropode-borne flaviviral infection and a lot of research to develop a vaccine against all four Dengue Fever serotypes was undertaken, no vaccine is available on the market yet. Promising tetravalent vaccine candidates are currently undergoing clinical phase trials, including LAVs, recombinant and chimeric candidates as well as non-replicating vaccine approaches. Additionally, encouraging anti-flaviviral approaches target non-structural proteins, virus-specific proteases essential for cellular maturation of viral particles. Peptide inhibitors against the highly conserved NS2B and NS3 proteases are attractive as pan-flaviviral drug candidates.

[Investigation of hepatitis G virus prevalence in hemodialysis patients and blood donors in Denizli, Turkey]. / Denizli'de hemodiyaliz hastalarinda ve kan donörlerinde hepatit G virus prevalansinin arastirilmasi.

This study focuses on the prevalence of hepatitis G virus (GBV-C/HGV) in hemodialysis patients and blood donors in Denizli (located at Aegean region of Turkey). A total of 100 patients (mean age: 56.8 +/- 13.3 years; 46 female) receiving hemodialysis and 100 blood donors (mean age: 31.3 +/- 8.1 years; 8 female) were included in the study. The presence of GBV-C/HGV RNA was determined in all patients by reverse transcriptase-PCR and the presence of GBV-C/HGV anti-E2 antibodies was determined by a commercial enzyme immunoassay (Diagnostic Automation, INC). Viral RNA positivity was determined in 14 (14%) of the hemodialysis patients and 2 (2%) of the blood donors, the difference being statistically significant (p < 0.05). GBV-C/HGV anti-E2 antibodies were detected in 1 (1%) of the hemodialysis patients and 3 (3%) of the blood donors. Anti-E2 positive patient also revealed positive result for viral RNA. There was no statistically significant difference between the two groups in terms of anti-E2 positivity. The prevalence of GBV-C/HGV was 14% in hemodialysis patients and 5% in blood donors (p < 0.05). There was no significant difference in terms of duration of hemodialysis, serum ALT levels, age or gender between GBV-C/HGV positive and negative hemodialysis patients. In conclusion, since hemodialysis patients are at an increased risk of parenteral transmission, they have significantly higher GBV-C/HGV viremia rates and prevalence when compared to blood donors. However, the prevalence of GBV-C/HGV and coexistence between GBV-C/HGV and hepatitis C virus have been decreasing in our region owing to increased hygienic precautions in hemodialysis units, avoidance of unnecessary blood transfusions and more widespread use of erythropoietin.

Recent advances in the treatment of viral hepatitis.

The viral hepatitis viruses and the diseases they cause are presented in terms of their importance to the practice of dentistry. Each virus will be discussed in terms of its epidemiology, risk of transmission in dentistry, and steps that can be taken to avoid transmission. The scope of this review emphasizes publications from 1996-1999.

Defective adenoviruses as novel vaccines for the Flaviviridae.

BACKGROUND: Vaccines against many flaviviruses, such as Japanese encephalitis virus (JEV), yellow fever virus (YFV) and tick-borne encephalitis virus (TBEV), have been successfully used for many years. Other diseases such as dengue fever (DF) and hepatitis C are still major public health problems as no licensed vaccines are in use. OBJECTIVES: To review studies on the use of defective recombinant adenoviruses (Rads) as experimental flavivirus vaccines and comment on their use to prevent infections with other members of the Flaviviridae such as hepatitis C virus. STUDY DESIGN: Recombinant adenoviruses, defective in their replication strategy, contain deletions in the E1 and E3 regions of the genome to increase the amount of foreign genetic material that can be inserted. The expression of foreign genes, inserted into these regions, can be driven by the adenovirus's own promoter, or by an additional viral promoters. CONCLUSIONS: Rads have been successfully used to raise protective immunity in experimental models of infection with several viruses. They can elicit both humoral and cell-mediated immunity and can be given parenterally or by oral administration. In addition, their hepatotropism makes them suitable for tackling diseases such as hepatitis C. Careful design of the vaccine vectors is advised to ensure their efficacy and safety, and as hepatitis C is a persistent infection, it may be advisable to design Rads containing genes encoding for non-structural proteins in preference to structural proteins.

[Investigation of hepatitis G virus and human immunodeficiency virus infections in 831 healthy youths].

Antibodies to hepatitis G virus(HGV) and human immunodeficiency virus(HIV) by EIA were investigated in 831 healthy youths from 6 provinces. The results showed that the anti-HGV IgG positive rate was 2.53% (21/831). In 21 anti-HGV IgG positive sera, HGV RNA was detected in 8 sera by reverse transcription polymerase chain reaction(RT-PCR). The anti-HIV was negative in 827 sera. The data suggest that HGV infection actually exist in healthy youths.

The first Flaviviridae symposium.

The first annual Flaviviridae Symposium, sponsored by ICN Pharmaceuticals Inc., was held in Lyon, France, on 9 October, 1997, to communicate current understanding on the Flaviviridae. This multidisciplinary symposium attracted over 300 international delegates and presentations covered virology, viral pathogenesis, potential therapies and strategies for vaccine development. The symposium reviewed the research area that may lead to the discovery and design of human and veterinary medicines against members of this virus family.

Optimization of vaccine production for animal health.

Vaccines on the basis of mammalian cell cultures are of major importance for human and animal health. Therefore efforts are undertaken for the improved production of more effective vaccines. Of course, the main purpose of all these approaches is to save lives and improve the quality of life for human beings. However, there is also some remarkable effort in the food industry and the associated animal production, especially in the case of some Flaviviridal viruses (BVD), where > 80% of all cattle herds are found to be infected. These viruses can cause tremendous economic losses of calfs and embryos (Ames, 1990). Because of these facts, there is a continuous endeavour for improving the manufacturing of therapeutics or preventing agents such as vaccines for the treatment of cattle. The competitive economic situation and the specific market demands still require effective and high yield production methods, especially in the case of one of the most widespread viral diseases in cattle like BVD (Ames, 1990). We have succeeded in establishing an improved method for the production of BVD on the basis of a continuous fermentation mode, that consist of modifications of the corresponding process and media improvements.

Molecular approach to the development of flavivirus vaccines

The Flaviviridae is a family of about 70 mostly arthropod-borne viruses many of which are major public health problems with members present in most continents. Among the most important are yellow fever (YF), dengue (DEN) with its 4 serotypes and Japanese escephalitis (JE) virus. A live attenuated virus is used as a cost-effective, safe and efficacious vaccine against YF but no other live flavivirus vaccines have been licensed. The development of recombinant DNA technology and its application to study flavivirus genome structure and expression has opened new possibilities for flavivirus vaccine development. The new approaches include the use of cDNAs encompassing the whole viral genome to generate infectious RNA after in vitro transcription. This methodology allows the genetic mapping of specific viral functions and the design of viral mutants with considerable potential as new live attenuated virues. The use of infectious cDNA as a carrier for heterologous antigens is a gaining importance since chimeric viruses are shown to be viable, immunogenic and less virulent in some cases as compared to the parental viruses. The use of DNA to overcome intrinsic mutation rates of RNA virus populations in conjunction with vaccine production in cell culture should improve the reliability and lower the cost of live attenuated vaccines.