Search

Background: A quadrivalent split-virion inactivated influenza vaccine (VaxigripTetra™, Sanofi Pasteur; IIV4) containing two A strains (H1N1 and H3N2) and B strains from both lineages (Victoria and Yamagata) was approved in Europe in 2016 for individuals aged ≥ 3 years. This study examined the efficacy and safety of IIV4 in children aged 6-35 months., Methods: This was a phase III randomised controlled trial conducted in Latin America, Asia, Africa, and Europe during the Northern Hemisphere 2014/2015 and 2015/2016 and Southern Hemisphere 2014 and 2015 influenza seasons. Healthy children aged 6-35 months not previously vaccinated against influenza were randomised to receive two full doses 28 days apart of IIV4, placebo, the licensed trivalent split-virion inactivated vaccine (IIV3), an investigational IIV3 containing a B strain from the alternate lineage. The primary objective was to demonstrate efficacy against influenza illness caused by any strain or vaccine-similar strains., Results: The study enrolled 5806 participants. Efficacy, assessed in 4980 participants completing the study according to protocol, was demonstrated for IIV4. Vaccine efficacy was 50.98% (97% CI, 37.36-61.86%) against influenza caused by any A or B type and 68.40% (97% CI, 47.07-81.92%) against influenza caused by vaccine-like strains. Safety profiles were similar for IIV4, placebo, and the IIV3s, although injection-site reactions were slightly more frequent for IIV4 than placebo., Conclusions: IIV4 was safe and effective for protecting children aged 6-35 months against influenza illness caused by vaccine-similar or any circulating strains., Clinical Trial Registration: EudraCT no. 2013-001231-51., (Copyright © 2018 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Japanese Encephalitis (JE) virus occurs in wide regions of Asia with over 3 billion people living in areas at risk for JE. An estimated 68,000 clinical cases of JE occur every year, and vaccination is the most effective prophylactic measure. One internationally licensed vaccine containing the inactivated JE virus strain SA14-14-2 is Ixiaro (Valneva, Austria). According to recommendations, basic immunization consists of vaccinations on day 0, day 28, and a booster dose 12-24 months later. Protection in terms of neutralizing antibody titers has been assessed up to 12 months after the third dose of the vaccine. The current investigation was designed to evaluate antibody decline over time and to predict long-term duration of seroprotection after a booster dose., Method: In a preceding trial, volunteers received basic immunization (day 0, day 28) and one booster dose against JE 15 months later. A follow up blood draw 6 years following their booster dose was carried out in 67 subjects. For antibody testing, a 50% plaque reduction neutralization test (PRNT50-test) was used. PRNT50 values of 10 and above are surrogate levels of protection according to WHO standards., Result: Seventy-six months following the booster dose, 96% of the tested subjects had PRNT50 titers of 10 or higher. Geometric mean titer (GMT) was 148 (95% CI confidence interval: 107-207). Antibody titers were lower in volunteers 50 years of age and older. Vaccination history against other flaviviruses (yellow fever or tick borne encephalitis) did not significantly influence PRNT50 titers. A two-step log-linear decline model predicted protection against JE of approximately 14 years after the booster dose., Conclusion: Six years after a booster dose against JE, long-term protection could be demonstrated. According to our results, further booster doses should be scheduled 10 years following the first booster dose., (Copyright © 2015 Elsevier Ltd. All rights reserved.)

Enterovirus A infections are the primary cause of hand, foot and mouth disease in infants and young children. Enterovirus 71 (EV71) and coxsackievirus A16 have emerged as neurotropic viruses responsible for severe neurological complications and a serious public health threat across the Asia-Pacific region. Formalin-inactivated EV71 vaccines have elicited protection against EV71 but not against coxsackievirus A16 infections. The development of a bivalent formalin-inactivated EV71/FI coxsackievirus A16 vaccine should be the next step towards that of multivalent hand, foot and mouth disease vaccines which should ultimately include other prevalent pathogenic coxsackieviruses and echovirus 30. This editorial summarizes the major challenges faced by the development of hand, foot and mouth disease vaccines.

Enterovirus 71 (EV71), an emerging neurotropic virus and coxsackieviruses (CV) are the major causative agents of hand, foot and mouth diseases (HFMD). These viruses have become a serious public health threat in the Asia Pacific region. Formalin-inactivated EV71 (FI-EV71) vaccines have been developed, evaluated in human clinical trials and were found to elicit full protection against EV71. Their failure to prevent CVA16 infections could compromise the acceptability of monovalent EV71 vaccines. Bivalent FI-EV71/FI-CVA16 vaccines have been found to elicit strong neutralizing antibody responses against both viruses in animal models but did not protect against CVA6 and CVA10 viral infections in cell culture neutralization assay. In this review, we discuss the critical bottlenecks in the development of multivalent HFMD vaccines, including the selection of vaccine strains, animal models to assess vaccine potency, the definition of end-points for efficacy trials, and the need for improved manufacturing processes to produce affordable vaccines., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

The mosquito-borne Japanese encephalitis virus causes an estimated 50,000 cases in Asia, accounting for at least 10,000 deaths and 15,000 cases of neuropsychiatric sequelae. IXIARO (Intercell AG, Vienna, Austria), an inactivated, Vero cell-derived vaccine against Japanese encephalitis was introduced in 2009. The vaccine is highly immunogenic, showing significantly higher geometric mean antibody titers compared with previous, mouse brain-derived vaccines. Postmarketing studies have confirmed the excellent safety profile. Studies on children aged 2 months to 18 years have been published. Based on these data, positive opinion from the EMA for vaccination of children has recently been given. Since a safe and effective vaccine against Japanese encephalitis is now available, outdated guidelines and recommendations have to be revised: travelers to rural areas of Asia should generally be recommended vaccination.

Enterotoxigenic Escherichia coli(ETEC) is the most common cause of bacterial diarrhea in children in Africa, Asia and Latin America and in travelers to these regions. Despite this, no effective vaccine for ETEC is available. ETEC causes disease by colonizing the small intestine with colonization factors, most of which are fimbriae, and production of heat-labile and/or heat-stable enterotoxins. Antibodies against heat-labile enterotoxin and the colonization factors have been shown to be protective, and local immunity in the gut seems to be of prime importance for protection. Hence, several inactivated and live candidate ETEC vaccines consisting of toxin antigens, alone or together with colonization factors, have been evaluated in clinical trials. In this review, the authors describe ETEC vaccine development in progress and the rationale for constructing different types of vaccines. They also discuss possibilities of enhancing immune responses to candidate ETEC vaccines, particularly in children.

Background: Japanese encephalitis (JE) is a flaviviral disease of public health concern in many parts of Asia. JE often occurs in large epidemics, has a high case-fatality ratio and, among survivors, frequently causes persistent neurological sequelae and mental disabilities. In 1997, the Vietnamese government initiated immunization campaigns targeting all children aged 1-5 years. Three doses of a locally-produced, mouse brain-derived, inactivated JE vaccine (MBV) were given. This study aims at evaluating the effectiveness of Viet Nam's MBV., Methodology: A matched case-control study was conducted in Northern Viet Nam. Cases were identified through an ongoing hospital-based surveillance. Each case was matched to four healthy controls for age, gender, and neighborhood. The vaccination history was ascertained through JE immunization logbooks maintained at local health centers., Principal Findings: Thirty cases and 120 controls were enrolled. The effectiveness of the JE vaccine was 92.9% [95% CI: 66.6-98.5]. Confounding effects of other risk variables were not observed., Conclusions: Our results strongly suggest that the locally-produced JE-MBV given to 1-5 years old Vietnamese children was efficacious.

Background: Genotype I (GI) Japanese encephalitis virus (JEV) that replaced GIII virus has become the dominant circulating virus in Asia. Currently, all registered live and inactivated JEV vaccines are derived from genotype III viruses. In Taiwan, the compulsory JEV vaccination policy recommends that children receives four doses of formalin-inactivated Nakayama (GIII) JEV vaccine., Methodology/principal Findings: To evaluate the influence of genotype replacement on the post-vaccination viral neutralizing ability by GIII and GI viruses, the small panel of vaccinated-children serum specimens was assembled, and the reciprocal 50% plaque-reduction neutralizing antibody titers (PRNT(50)) were measured against Nakayama vaccine strain, CJN GIII human brain isolate and TC2009-1 GI mosquito isolate. The seropositivity rate (PRNT(50) ≥ 1:10) and geometric mean titers (GMT) against the TC2009-1 virus were the lowest among the three viruses. The protective threshold against the CJN and TC2009-1 viruses could only be achieved when the GMT against Nakayama virus was ≥ 1:20 or ≥ 1:80, respectively. Using undiluted vaccinees' sera, the enhancement of JEV infection in K562 cells was observed in some low or non-neutralizing serum specimens., Conclusions/significance: Our preliminary study has shown that neutralizing antibodies, elicited by the mouse brain-derived and formalin-inactivated JEV Nakayama vaccine among a limited number of vaccinees, have reduced neutralizing capacity against circulating GI virus, but more detailed studies are needed to address the potential impact on the future vaccine policy.

Japanese encephalitis (JE) virus, a mosquito-borne flavivirus, is an important cause of encephalitis in Asia with a case fatality rate of 20%--30% and neurologic or psychiatric sequelae in 30%--50% of survivors (1). Travelers to JE-endemic countries and laboratory personnel who work with infectious JE virus are at potential risk for JE virus infection. In 2010, CDC's Advisory Committee on Immunization Practices (ACIP) updated recommendations for prevention of JE. The updated recommendations included information on use of a new inactivated, Vero cell culture--derived JE vaccine (JE-VC [manufactured as Ixiaro]) that was licensed in the United States in 2009. Data on the need for and timing of booster doses with JE-VC were not available when the vaccine was licensed. This report summarizes new data on the persistence of neutralizing antibodies following primary vaccination with JE-VC and the safety and immunogenicity of a booster dose of JE-VC. The report also provides updated guidance to health-care personnel regarding use of a booster dose of JE-VC for U.S. travelers and laboratory personnel. ACIP recommends that if the primary series of JE-VC was administered >1 year previously, a booster dose may be given before potential JE virus exposure.

Purpose of Review: Japanese encephalitis is the most common vaccine-preventable viral encephalitis in Asia. In view of the production cessation of the inactivated mouse brain-derived Japanese encephalitis vaccine, it is timely to provide an update on new Japanese encephalitis vaccines and revised vaccine recommendations., Recent Findings: A new inactivated, adjuvanted, Vero cell-culture-based Japanese encephalitis vaccine, IC51, was licensed in Europe and the United States in 2009. Administered in a two-dose regimen at 0 and 28 days, it was shown to be well tolerated and produce high seroconversion rates. In addition, Chimerivax Japanese encephalitis, a novel live-attenuated one-dose chimeric vaccine comprising the structural genes of SA 14-14-2 virus and nonstructural genes of yellow fever 17D virus, is in the process of getting licensed in Australia and in south east Asia., Summary: Previous recommendations for Japanese encephalitis vaccination of travelers were predicated on minimizing exposure to a mouse-brain-derived vaccine with a poorly understood and worrisome safety profile, whereas the risk of acquiring Japanese encephalitis itself during travel was assessed to be relatively low. With the availability of a new cell-culture-derived vaccine IC51 with an excellent safety profile, it is appropriate to reconsider benefit-risk considerations for the vaccination of travelers. These considerations are reflected in the March 2010 revised recommendations by the United States Advisory Committee on Immunization Practices.

Hand, foot, and mouth disease (HFMD) is a common viral illness in infants and children caused by viruses that belong to the enterovirus genus of the picornavirus family. Although most HFMD do not result in serious complications, outbreaks of HFMD caused by enterovirus 71 (EV71) can present with a high rate of neurological complications, including meningoencephalitis, pulmonary complications, and possibly death. HFMD caused by EV71 has become a major emerging infectious disease in Asia and the highly pathogenic potential of EV71 clearly requires the attention of world medical community. Although vaccine development for EV71 is active and ongoing in Asian countries, a greater joint effort is needed for vaccine researchers and developers in both developed and developing countries to produce a safe and effective EV71 vaccine., ((c) 2010 Elsevier Ltd. All rights reserved.)

Japanese encephalitis (JE) is a mosquito-borne flavivirus infection responsible for significant morbidity and mortality across Asia. Indigenous populations and those who undertake short- and long-term travel to endemic regions are at risk of infection and development of neuroinvasive disease. Effective mouse brain-derived vaccines have been available in select countries, including the United States, for decades. Limited access in Asia and safety concerns with regard to mouse brain products prompted the Chinese to develop a live, attenuated virus vaccine (SA14-14-2; Chengdu Institute of Biological Products), which has proven to be safe and efficacious following administration of >300 million doses. Recently, the portfolio of JE vaccines increased again with licensure in the United States, Europe, and Australia of a purified, inactivated virus JE vaccine (IC51; Intercell AG) and filing for licensure in Thailand and Australia of a Yellow fever-JE chimeric vaccine (ChimeriVax-JE; Sanofi Pasteur). JE is a vaccine-preventable disease with numerous options now available for active immunization. Aggressive and responsible vaccination programs should greatly diminish the burden of disease.

The mosquito-borne Japanese encephalitis virus (JEV) is a major threat to human health in Asia. An estimated 50,000 cases occur in the region, accounting for at least 10,000 deaths and 15,000 cases of neuropsychiatric sequelae. A new purified, inactivated JEV vaccine (IC51, Ixiaro) has been developed. Since early 2009, the vaccine has been licensed in Australia, the USA and Europe. A series of successful Phase III studies has been published. Results indicate a very good safety and efficacy profile. The vaccine promises to become a modern approach to active immunization against Japanese encephalitis. With the availability of a new product, wider use of Japanese encephalitis vaccine will be prudent in the future, and guidelines and recommendations should be revised.

Waterfowl represent the natural reservoir of all subtypes of influenza A viruses, including H5N1. Ducks are especially considered major contributors to the spread of H5N1 influenza A viruses because they exhibit diversity in morbidity and mortality. Therefore, as a preventive strategy against endemic as well as pandemic influenza, it is important to reduce the spread of H5N1 influenza A viruses in duck populations. Here, we describe the pathogenicity of dominant clades (clades 1 and 2) of H5N1 influenza A viruses circulating in birds in Asia. Four representatives of dominant clades of the viruses cause symptomatic infection but lead to different profiles of lethality in domestic ducks. We also demonstrate the efficacy, cross-protectiveness, and immunogenicity of three different inactivated oil emulsion whole-virus H5 influenza vaccines (derived by implementing reverse genetics) to the viruses in domestic ducks. A single dose of the vaccines containing 1 mug of hemagglutinin protein provides complete protection against a lethal A/Duck/Laos/25/06 (H5N1) influenza virus challenge, with no evidence of morbidity, mortality, or shedding of the challenge virus. Moreover, two of the three vaccines achieved complete cross-clade or cross-subclade protection against the heterologous avian influenza virus challenge. Interestingly, the vaccines induce low or undetectable titers of hemagglutination inhibition (HI), cross-HI, and/or virus neutralization antibodies. The mechanism of complete protection in the absence of detectable antibody responses remains an open question.

Japanese encephalitis (JE) is the most common viral encephalitis in Asia. IC51 is a new Vero cell-derived, inactivated JE virus vaccine with non-inferior immunogenicity (after 2 months) compared to the US-licensed vaccine JE-VAX (mouse brain-derived, inactivated) and with a more convenient (two injections instead of three) intramuscular dose schedule. Adult subjects from two studies were followed-up for comparative immunogenicity (JE-VAX) at 6 months and long-term immunogenicity of IC51 alone at 12 months. At 6 months, immunogenicity was higher with IC51 (seroconversion rate [SCR] 95%; geometric mean titer [GMT] 84) than with JE-VAX (SCR 74%; GMT 34). At 12 months, the SCR was 83% and the GMT (41) remained above the protective titer of 1:10. Most people immunized with IC51 will have protective neutralizing antibody levels for at least a year.

A reassortant influenza virus, A/duck/Hokkaido/Vac-1/2004 (H5N1) (Dk/Vac-1/04), was generated between non-pathogenic avian influenza viruses isolated from migratory ducks in Asia. Dk/Vac-1/04 (H5N1) virus particles propagated in embryonated chicken eggs were inactivated with formalin and adjuvanted with mineral oil to form a water-in-oil emulsion. The resulting vaccine was injected intramuscularly into chickens. The chickens were challenged with either of the highly pathogenic avian influenza virus strains A/chicken/Yamaguchi/7/2004 (H5N1) or A/swan/Mongolia/3/2005 (H5N1) at 21 days post-vaccination (p. v.), when the geometric mean serum HI titers of the birds was 64 with the challenge virus strains. The vaccinated chickens were protected from manifestation of disease signs upon challenge with either of the highly pathogenic avian influenza viruses. However, challenge virus was recovered at low titers from the birds at 2 and 4 days post-challenge (p.c.). All 3 chickens challenged at 6 days p.v. died, whereas 3 chickens challenged at 8 days p.v. survived. These results indicate that the present vaccine confers clinical protection and reduction of virus shedding against highly pathogenic avian influenza virus challenge and should be useful as an optional tool in emergency cases.

The Japanese encephalitis virus is the main cause of encephalitis in Asia. The vectors are mosquitoes. Every year 30,000 to 50,000 cases and 10,000 deaths from Japanese encephalitis are reported, and estimates go up to 100,000 cases. No effective antiviral therapy exists to treat this flavivirus infection. For prophylaxis vaccines are available. In Asia numerous vaccines are used regionally. The production of the only vaccine that was internationally licensed, JE-VAX, was ceased in 2005. Therefore a shortage of Japanese encephalitis vaccines might occur before new generation vaccines based on cell cultures will be available. An inactivated Vero cell-derived vaccine based on the Beijing-1 strain is developed in Japan by Biken and Kaketsuken. Another promising vaccine candidate is the inactivated whole-virus vaccine IC-51 (Strain SA14-14-2) by the Austrian company Intercell. The third interesting vaccine candidate being in the late stages of clinical trials is the genetically engineered, chimeric and live-attenuated vaccine ChimeriVaxtrade mark-JE by the UK/USA-based company Acambis. The new vaccines in the pipeline show promising results and market licensures are expected in the near future. Showing excellent tolerability, these vaccines will not only be used in the population living in endemic areas where the risk of infection is extremely high, but also for travellers and military personnel.

The hypervirulence of H5N1 influenza virus makes it impossible to produce a vaccine traditionally (with egg embryos), but there are alternative solutions. A live recombinant fowl-pox H5 virus is used for avian pathology. An inactivated H5N2 adjuvant vaccine is rendered immunogenic by using hemagglutinin H5 (DIVA technique). Disease prevention strategies differ between European and Asian countries. WHO has opted for a recombinant vaccine based on a non pathogenic virus (PR8) to which modified H5 and N1 from a pandemic virus are grafted The poor immunogenicity of this vaccine will require the use of large doses and immunostimulants. A live vaccine based on an adenovirus coupled to the H5 gene was recently developed. Finally, Chinese authors are examining the preventive and curative potential of hyperimmune serum raised in animals.

High-pathogenicity (HP) avian influenza (AI) virus of the H5N1 subtype has caused an unprecedented epizootic in birds within nine Asian countries/regions since it was first reported in 1996. Vaccination has emerged as a tool for use in managing the infection in view of future eradication. This study was undertaken to determine whether two divergent H5N2 commercial vaccine strains, one based on a European and the other a North American low-pathogenicity AI virus, could protect chickens against a recent Asian H5N1 HPAI virus. The North American and European vaccine viruses had 84 and 91% deduced amino acid sequence similarity to the HA1 segment of haemagglutinin protein of Indonesia H5N1 HPAI challenge virus, respectively. Both vaccine strains provided complete protection from clinical signs and death. The vaccines reduced the number of chickens infected and shedding virus from the respiratory and intestinal tracts at the peak of virus replication. In addition, the quantity of virus shed was reduced by 10(4) to 10(5) median embryo infectious doses. The use of specific neuraminidase inhibition tests allowed identification of infected chickens within the vaccinated groups. These data indicate that the currently available H5 vaccines of European and North American lineages will protect chickens against the Asian H5N1 HPAI virus and reduce environmental contamination by the H5N1 HPAI virus. They will be an adjunct to biosecurity measures to reduce virus transmission.

Japanese encephalitis (JE) is a severe disease that is widespread throughout Asia and is spreading beyond its traditional boundaries. Three vaccines are currently in use against JE but only one is available internationally, a mouse-brain-derived inactivated vaccine first used in the 1930s. Although this vaccine has been effective in reducing the incidence of JE, it is relatively expensive and has been linked to severe allergic and neurological reactions. Cell-culture-derived inactivated and attenuated vaccines have been developed but are only used in the People's Republic of China. Other vaccines currently in various stages of development are DNA vaccines, a chimeric yellow fever-JE viral vaccine, virus-like particle vaccines and poxvirus-based vaccines. Poxvirus-based vaccines and the chimeric yellow fever-JE vaccine have been tested in Phase I clinical trials. These new vaccines have the potential to significantly reduce the impact of JE in Asia, particularly if used in an oral vaccine delivery strategy.