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Avian influenza virus (AIV) is an extraordinarily diverse pathogen that causes significant morbidity in domesticated poultry populations and threatens human life with looming pandemic potential. Controlling avian influenza in susceptible populations requires highly effective, economical and broadly reactive vaccines. Several AIV vaccines have proven insufficient despite their wide use, and better technologies are needed to improve their immunogenicity and broaden effectiveness. Previously, we developed a "mosaic" H5 subtype hemagglutinin (HA) AIV vaccine and demonstrated its broad protection against diverse highly pathogenic H5N1 and seasonal H1N1 virus strains in mouse and non-human primate models. There is a significant interest in developing effective and safe vaccines against AIV that cannot contribute to the emergence of new strains of the virus once circulating in poultry. Here, we report on the development of an H5 mosaic (H5M) vaccine antigen formulated with polyanhydride nanoparticles (PAN) that provide sustained release of encapsulated antigens. H5M vaccine constructs were immunogenic whether delivered by the modified virus Ankara (MVA) strain or encapsulated within PAN. Both humoral and cellular immune responses were generated in both specific-pathogen free (SPF) and commercial chicks. Importantly, chicks vaccinated by H5M constructs were protected in terms of viral shedding from divergent challenge with a low pathogenicity avian influenza (LPAI) strain at 8 weeks post-vaccination. In addition, protective levels of humoral immunity were generated against highly pathogenic avian influenza (HPAI) of the similar H5N1 and genetically dissimilar H5N2 viruses. Overall, the developed platform technologies (MVA vector and PAN encapsulation) were safe and provided high levels of sustained protection against AIV in chickens. Such approaches could be used to design more efficacious vaccines against other important poultry infections., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Dengue viruses (DENVs) infect >300 million people annually, causing 96 million cases of dengue disease and 22 000 deaths [1]. A safe vaccine that protects against DENV disease is a global health priority [2]., Methods: We enrolled 72 flavivirus-naive healthy adults in a phase 1 double-blinded, randomized, placebo-controlled dose-escalation trial (low and high dose) of a live attenuated recombinant tetravalent dengue vaccine candidate (TDV) given in 2 doses 90 days apart. Volunteers were followed for safety, vaccine component viremia, and development of neutralizing antibodies to the 4 DENV serotypes., Results: The majority of adverse events were mild, with no vaccine-related serious adverse events. Vaccinees reported injection site pain (52% vs 17%) and erythema (73% vs 25%) more frequently than placebo recipients. Low levels of TDV-serotype 2 (TDV-2), TDV-3, and TDV-4 viremia were observed after the first but not second administration of vaccine. Overall seroconversion rates and geometric mean neutralization titers after 2 doses were 84.2% and 54.1, respectively, for DENV serotype 1 (DENV-1); 92.1% and 292.8, respectively, for DENV-2; 86.8% and 32.3, respectively, for DENV-3; and 71.1% and 15.0, respectively, for DENV-4. More than 90.0% of high-dose recipients had trivalent or broader responses., Conclusions: TDV was generally well tolerated, induced trivalent or broader neutralizing antibodies to DENV in most flavivirus-naive vaccinees, and is undergoing further development., Clinical Trials Registration: NCT01110551., (© The Author 2015. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)

Prairie dogs (Cynomys spp.) are highly susceptible to Yersinia pestis and, along with other wild rodents, are significant reservoirs of plague for other wildlife and humans in the western United States. A recombinant raccoon poxvirus, expressing the F1 antigen of Y. pestis, was incorporated into a palatable bait and offered to three groups (n = 18, 19, and 20) of black-tailed prairie dogs (Cynomys ludovicianus) for voluntary consumption, either one, two, or three times, at roughly 3-wk intervals. A control group (n = 19) received baits containing raccoon poxvirus without the inserted antigen. Mean antibody titers to Y. pestis F1 antigen increased significantly in all groups ingesting the vaccine-laden baits, whereas the control group remained negative. Upon challenge with virulent Y. pestis, immunized groups had higher survival rates (38%) than the unimmunized control group (11%). The mean survival time of groups ingesting vaccine-laden baits either two or three times was significantly higher than that of animals ingesting vaccine-laden baits just one time and of animals in the control group. These results show that oral immunization of prairie dogs against plague provides some protection against challenge at dosages that simulate simultaneous delivery of the plague bacterium by numerous (3-10) flea bites.

The epidermis of the skin is both a sensitive immune organ and a practical target site for vaccine administration. However, administration of vaccines into the epidermis is difficult to achieve using conventional vaccine delivery methods employing a needle and syringe. A needle-free vaccine delivery system has been developed that efficiently delivers powdered or particulate DNA and protein vaccines into the epidermal tissue. The delivery system can be used to directly transfect antigen presenting cells (APCs) by formulating DNA or protein vaccines onto gold particles (particle-mediated immunization). Antigen can be directly presented to the immune system by the transfected APCs. Antigen can also be expressed and secreted by transfected keratinocytes and picked up by resident APCs through the exogenous antigen presentation pathway. Alternatively, protein antigens can be formulated into a powder and delivered into the extracellular environment where they are picked up by APCs (epidermal powder immunization). Using any of these formulations, epidermal immunization offers the advantage of efficiently delivering vaccines into the APC-rich epidermis. Recent studies demonstrate that epidermal vaccine delivery induces humoral, cellular, and protective immune responses against infectious diseases in both laboratory animals and man.

A reverse vaccinology system, Vaxign, was used to identify and select a subset of five African Swine Fever (ASF) antigens that were successfully purified from human embryonic kidney 293 (HEK) cells and produced in Modified vaccinia virus Ankara (MVA) viral vectors. Three HEK-purified antigens [B646L (p72), E183L (p54), and O61R (p12)], and three MVA-vectored antigens [B646L, EP153R, and EP402R (CD2v)] were evaluated using a prime-boost immunization regimen swine safety and immunogenicity study. Antibody responses were detected in pigs following prime-boost immunization four weeks apart with the HEK-293-purified p72, p54, and p12 antigens. Notably, sera from the vaccinees were positive by immunofluorescence on ASFV (Georgia 2007/1)-infected primary macrophages. Although MVA-vectored p72, CD2v, and EP153R failed to induce antibody responses, interferon-gamma (IFN-γ + ) spot forming cell responses against all three antigens were detected one week post-boost. The highest IFN-γ + spot forming cell responses were detected against p72 in pigs primed with MVA-p72 and boosted with the recombinant p72. Antigen-specific (p12, p72, CD2v, and EP153R) T-cell proliferative responses were also detected post-boost. Collectively, these results are the first demonstration that ASFV subunit antigens purified from mammalian cells or expressed in MVA vectors are safe and can induce ASFV-specific antibody and T-cell responses following a prime-boost immunization regimen in swine. [ABSTRACT FROM AUTHOR]

Bats (Order Chiroptera) are an abundant group of mammals with tremendous ecological value as insectivores and plant dispersers, but their role as reservoirs of zoonotic diseases has received more attention in the last decade. With the goal of managing disease in free-ranging bats, we tested modified vaccinia Ankara (MVA) and raccoon poxvirus (RCN) as potential vaccine vectors in the Brazilian Free-tailed bat ( Tadarida brasiliensis ), using biophotonic in vivo imaging and immunogenicity studies. Animals were administered recombinant poxviral vectors expressing the luciferase gene (MVA- luc , RCN- luc ) through oronasal (ON) or intramuscular (IM) routes and subsequently monitored for bioluminescent signal indicative of viral infection. No clinical illness was noted after exposure to any of the vectors, and limited luciferase expression was observed. Higher and longer levels of expression were observed with the RCN- luc construct. When given IM, luciferase expression was limited to the site of injection, while ON exposure led to initial expression in the oral cavity, often followed by secondary replication at another location, likely the gastric mucosa or gastric associated lymphatic tissue. Viral DNA was detected in oral swabs up to 7 and 9 days post infection (dpi) for MVA and RCN, respectively. While no live virus was detected in oral swabs from MVA-infected bats, titers up to 3.88 x 10 4 PFU/ml were recovered from oral swabs of RCN-infected bats. Viral DNA was also detected in fecal samples from two bats inoculated IM with RCN, but no live virus was recovered. Finally, we examined the immunogenicity of a RCN based rabies vaccine (RCN-G) following ON administration. Significant rabies neutralizing antibody titers were detected in the serum of immunized bats using the rapid fluorescence focus inhibition test (RFFIT). These studies highlight the safety and immunogenicity of attenuated poxviruses and their potential use as vaccine vectors in bats. [ABSTRACT FROM AUTHOR]

Background: The development of a vaccine against dengue faces unique challenges, including the complexity of the immune responses to the four antigenically distinct serotypes. Genome-wide transcriptional profiling provides insight into the pathways and molecular features that underlie responses to immune system stimulation, and may facilitate predictions of immune protection. Methodology/Principal Findings: In this study, we measured early transcriptional responses in the peripheral blood of cynomolgus macaques following vaccination with a live, attenuated tetravalent dengue vaccine candidate, TDV, which is based on a DENV-2 backbone. Different doses and routes of vaccine administration were used, and viral load and neutralizing antibody titers were measured at different time-points following vaccination. All 30 vaccinated animals developed a neutralizing antibody response to each of the four dengue serotypes, and only 3 of these animals had detectable serum viral RNA after challenge with wild-type dengue virus (DENV), suggesting protection of vaccinated animals to DENV infection. The vaccine induced statistically significant changes in 595 gene transcripts on days 1, 3, 5 and 7 as compared with baseline and placebo-treated animals. Genes involved in the type I interferon (IFN) response, including IFI44, DDX58, MX1 and OASL, exhibited the highest fold-change in transcript abundance, and this response was strongest following double dose and subcutaneous (versus intradermal) vaccine administration. In addition, modules of genes involved in antigen presentation, dendritic cell activation, and T cell activation and signaling were enriched following vaccination. Increased abundance of gene transcripts related to T cell activation on day 5, and the type I IFN response on day 7, were significantly correlated with the development of high neutralizing antibody titers on day 30. Conclusions/Significance: These results suggest that early transcriptional responses may be predictive of development of adaptive immunity to TDV vaccination in cynomolgus macaques, and will inform studies of human responses to dengue vaccines. [ABSTRACT FROM AUTHOR]

Dengue is a significant threat to public health worldwide. Currently, there are no licensed vaccines available for dengue. Takeda Vaccines Inc. is developing a live, attenuated tetravalent dengue vaccine candidate (TDV) that consists of an attenuated DENV-2 strain (TDV-2) and three chimeric viruses containing the prM and E protein genes of DENV-1, -3 and -4 expressed in the context of the attenuated TDV-2 genome backbone (TDV-1, TDV-3, and TDV-4, respectively). TDV has been shown to be immunogenic and efficacious in nonclinical animal models. In interferon-receptor deficient mice, the vaccine induces humoral neutralizing antibody responses and cellular immune responses that are sufficient to protect from lethal challenge with DENV-1, DENV-2 or DENV-4. In non-human primates, administration of TDV induces innate immune responses as well as long lasting antibody and cellular immunity. In Phase 1 clinical trials, the safety and immunogenicity of two different formulations were assessed after intradermal or subcutaneous administration to healthy, flavivirus-naïve adults. TDV administration was generally well-tolerated independent of dose and route. The vaccine induced neutralizing antibody responses to all four DENV serotypes: after a single administration of the higher formulation, 24–67%% of the subjects seroconverted to all four DENV and >80% seroconverted to three or more viruses. In addition, TDV induced CD8 + T cell responses to the non-structural NS1, NS3 and NS5 proteins of DENV. TDV has been also shown to be generally well tolerated and immunogenic in a Phase 2 clinical trial in dengue endemic countries in adults and children as young as 18 months. Additional clinical studies are ongoing in preparation for a Phase 3 safety and efficacy study. [ABSTRACT FROM AUTHOR]

Background: The rise in dengue fever cases and the absence of dengue vaccines will likely cause governments to consider various types of effective means for controlling the disease. Given strong public interests in potential dengue vaccines, it is essential to understand the private economic benefits of dengue vaccines for accelerated introduction of vaccines into the public sector program and private markets of high-risk countries. Methodology/Principal Findings: A contingent valuation study for a hypothetical dengue vaccine was administered to 400 households in a multi-country setting: Vietnam, Thailand, and Colombia. All respondents received a description of the hypothetical dengue vaccine scenarios of 70% or 95% effectiveness for 10 or 30 years with a three dose series. Five price points were determined after pilot tests in order to reflect different local situations such as household income levels and general perceptions towards dengue fever. We adopted either Poisson or negative binomial regression models to calculate average willingness-to-pay (WTP), as well as median WTP. We found that there is a significant demand for dengue vaccines. The parametric median WTP is $26.4 ($8.8 per dose) in Vietnam, $70.3 ($23.4 per dose) in Thailand, and $23 ($7.7 per dose) in Colombia. Our study also suggests that respondents place more value on vaccinating young children than school age children and adults. Conclusions/Significance: Knowing that dengue vaccines are not yet available, our study provides critical information to both public and private sectors. The study results can be used to ensure broad coverage with an affordable price and incorporated into cost benefit analyses, which can inform prioritization of alternative health interventions at the national level. [ABSTRACT FROM AUTHOR]

Summary Background Dengue virus is the most serious mosquito-borne viral threat to public health and no vaccines or antiviral therapies are approved for dengue fever. The tetravalent DENVax vaccine contains a molecularly characterised live attenuated dengue serotype-2 virus (DENVax-2) and three recombinant vaccine viruses expressing the prM and E structural genes for serotypes 1, 3, and 4 in the DENVax-2 genetic backbone. We aimed to assess the safety and immunogenicity of tetravalent DENVax formulations. Methods We undertook a randomised, double-blind, phase 1, dose-escalation trial between Oct 11, 2011, and Nov 9, 2011, in the Rionegro, Antioquia, Colombia. The first cohort of participants (aged 18–45 years) were randomly assigned centrally, via block randomisation, to receive a low-dose formulation of DENvax, or placebo, by either subcutaneous or intradermal administration. After a safety assessment, participants were randomly assigned to receive a high-dose DENVax formulation, or placebo, by subcutaneous or intradermal administration. Group assignment was not masked from study pharmacists, but allocation was concealed from participants, nurses, and investigators. Primary endpoints were frequency and severity of injection-site and systemic reactions within 28 days of each vaccination. Secondary endpoints were the immunogenicity of DENVax against all four dengue virus serotypes, and the viraemia due to each of the four vaccine components after immunisation. Analysis was by intention to treat for safety and per protocol for immunogenicity. Because of the small sample size, no detailed comparison of adverse event rates were warranted. The trial is registered with ClinicalTrials.gov , number NCT01224639 . Findings We randomly assigned 96 patients to one of the four study groups: 40 participants (42%) received low-dose vaccine and eight participants (8%) received placebo in the low-dose groups; 39 participants (41%) received high-dose vaccine, with nine (9%) participants assigned to receive placebo. Both formulations were well tolerated with mostly mild and transient local or systemic reactions. No clinically meaningful differences were recorded in the overall incidence of local and systemic adverse events between patients in the vaccine and placebo groups; 68 (86%) of 79 participants in the vaccine groups had solicited systemic adverse events compared with 13 (76%) of 17 of those in the placebo groups. By contrast, 67 participants (85%) in the vaccine group had local solicited reactions compared with five (29%) participants in the placebo group. Immunisation with either high-dose or low-dose DENVax formulations induced neutralising antibody responses to all four dengue virus serotypes; 30 days after the second dose, 47 (62%) of 76 participants given vaccine seroconverted to all four serotypes and 73 (96%) participants seroconverted to three or more dengue viruses. Infectious DENVax viruses were detected in only ten (25%) of 40 participants in the low-dose group and 13 (33%) of 39 participants in the high-dose group. Interpretation Our findings emphasise the acceptable tolerability and immunogenicity of the tetravalent DENVax formulations in healthy, flavivirus-naive adults. Further clinical testing of DENVax in different age groups and in dengue-endemic areas is warranted. Funding Takeda Vaccines. [ABSTRACT FROM AUTHOR]

Human enterovirus 71 (EV71) is a significant cause of morbidity and mortality from Hand, Foot and Mouth Disease (HFMD) and neurological complications, particularly in young children in the Asia-Pacific region. There are no vaccines or antiviral therapies currently available for prevention or treatment of HFMD caused by EV71. Therefore, the development of therapeutic and preventive strategies against HFMD is of growing importance. We report the immunogenic and safety profile of inactivated, purified EV71 preparations formulated with aluminum hydroxide adjuvant in preclinical studies in mice and rabbits. In mice, the candidate vaccine formulations elicited high neutralizing antibody responses. A toxicology study of the vaccine formulations planned for human use performed in rabbits showed no vaccine-related pathological changes and all animals remained healthy. Based on these preclinical studies, Phase 1 clinical testing of the EV71 inactivated vaccine was initiated. [ABSTRACT FROM AUTHOR]

Background: We have developed a manufacturing strategy that can improve the safety and genetic stability of recombinant live-attenuated chimeric dengue vaccine (DENVax) viruses. These viruses, containing the pre-membrane (prM) and envelope (E) genes of dengue serotypes 1–4 in the replicative background of the attenuated dengue-2 PDK-53 vaccine virus candidate, were manufactured under cGMP. Methodology/Principal Findings: After deriving vaccine viruses from RNA-transfected Vero cells, six plaque-purified viruses for each serotype were produced. The plaque-purified strains were then analyzed to select one stock for generation of the master seed. Full genetic and phenotypic characterizations of the master virus seeds were conducted to ensure these viruses retained the previously identified attenuating determinants and phenotypes of the vaccine viruses. We also assessed vector competence of the vaccine viruses in sympatric (Thai) Aedes aegypti mosquito vectors. Conclusion/Significance: All four serotypes of master vaccine seeds retained the previously defined safety features, including all three major genetic loci of attenuation, small plaques, temperature sensitivity in mammalian cells, reduced replication in mosquito cell cultures, and reduced neurovirulence in new-born mice. In addition, the candidate vaccine viruses demonstrated greatly reduced infection and dissemination in Aedes aegypti mosquitoes, and are not likely to be transmissible by these mosquitoes. This manufacturing strategy has successfully been used to produce the candidate tetravalent vaccine, which is currently being tested in human clinical trials in the United States, Central and South America, and Asia. [ABSTRACT FROM AUTHOR]

Abstract: Recently, Chikungunya virus (CHIKV) re-emerged in Africa and spread in the Indian subcontinent, South East Asia and Italy causing millions of cases of debilitating arthritis and fever in endemic ppulations and in travellers highlighting its growing impact on public health. Currently, there are no licensed vaccines to protect against CHIKV available. We developed a novel live attenuated CHIKV vaccine by using a rational attenuation mechanism that also prevents the infection of mosquito vectors. The subgenomic promoter was inactivated using 13 synonymous mutations and an internal ribosome entry site (IRES) from encephalomyocarditis virus was inserted into a cDNA CHIKV clone to drive translation of the structural protein genes. This new CHIKV vaccine strain was highly stable, safe, immunogenic and protective in mice. Current pre-clinical development efforts are aiming to test this vaccine in non-human primates and complete the Investigational New Drug (IND)-enabling studies necessary to begin human clinical testing. [Copyright &y& Elsevier]

Abstract: Dengue. virus infection is the leading arboviral cause of disease worldwide. A vaccine is being developed based on the attenuated DEN-2 virus, DEN-2 PDK-53. In this review, we summarize the characteristics of the parent DEN-2 PDK-53 strain as well as the chimeric viruses containing the prM and E genes of DEN-1, DEN-3 or DEN-4 virus in the genetic backbone of the DEN-2 PDK-53 virus (termed DENVax). Tetravalent DENVax formulations containing cloned, fully sequenced isolates of the DEN-2 PDK-53 virus and the three chimeras have been evaluated for safety and efficacy in preclinical animal models. Based on the safety, immunogenicity and efficacy in preclinical studies, Phase 1 clinical testing of DENVax has been initiated. [Copyright &y& Elsevier]

Chikungunya virus (CHIKV) is a reemerging mosquito-borne pathogen that has recently caused devastating urban epidemics of severe and sometimes chronic arthralgia. As with most other mosquito-borne viral diseases, control relies on reducing mosquito populations and their contact with people, which has been ineffective in most locations. Therefore, vaccines remain the best strategy to prevent most vector-borne diseases. Ideally, vaccines for diseases of resource-limited countries should combine low cost and single dose efficacy, yet induce rapid and long-lived immunity with negligible risk of serious adverse reactions. To develop such a vaccine to protect against chikungunya fever, we employed a rational attenuation mechanism that also prevents the infection of mosquito vectors. The internal ribosome entry site (IRES) from encephalomyocarditis virus replaced the subgenomic promoter in a cDNA CHIKV clone, thus altering the levels and host- specific mechanism of structural protein gene expression. Testing in both normal outbred and interferon response-defective mice indicated that the new vaccine candidate is highly attenuated, immunogenic and efficacious after a single dose. Furthermore, it is incapable of replicating in mosquito cells or infecting mosquitoes in vivo. This IRES-based attenuation platform technology may be useful for the predictable attenuation of any alphavirus. [ABSTRACT FROM AUTHOR]

The article discusses a research study on characterizing the vectors of recombinant raccoonpox vaccine in chickens. A discussion on previous research studies on poxviruses is detailed. Researchers studied the replicated raccoonpox virus (RCN) in chick embryo fibroblasts (CEF) using the highly pathogenic avian influenza virus (H5N1) hemagglutinin (HA) as model antigen while the reporter antigen used was luciferase (luc). Results of the study indicated that RCN has the potential to be used as vaccine vector for avian influenza and poultry pathogens.

In the present study, we evaluated both the immunogenicity and safety of recombinant raccoon poxvirus (RCN) as a mucosal vaccine vector for domestic cats. RCN is an orthopoxvirus that was isolated from healthy raccoons and has been used experimentally as a vaccine vector for rabies and other antigens in a variety of species, including raccoons, skunks, foxes, bobcats, rabbits, domestic cats, piglets, sheep and non-human primates. We evaluated the antibody response induced by a recombinant RCN vaccine expressing the rabies-G glycoprotein (RCN/rabies-G) administered to cats by the oral (PO), intranasal (IN), conjunctival (CO) or intranasal/conjunctival (IN/CO) route (dose: 10 8 plaque forming units or PFU). The IN route, either alone or combined with the CO route, induced the highest rabies virus neutralizing antibody (RVNA) titers. The RVNA titers remained high when measured at six months post-vaccination, demonstrating that the recombinant vaccine administered via these routes is very efficient at inducing long-lasting immunity. A dose-response was observed following IN vaccination in cats. Doses of 10 7 PFU induced strong antibody responses in 4 of 5 animals [geometric mean titer: 3.2 (log 10 )]. None of the animals vaccinated with 10 4 PFU developed detectable RVNA titers. In this study, RCN/rabies-G viral shedding was below detectable levels. Nasal, oral and fecal swabs collected from these cats were negative for RCN by both virus isolation and by nested-PCR. In addition, no horizontal transmission of the virus could be detected. Gang-housed sentinel animals for each group did not develop detectable anti-RVNA or -RCN antibodies. To study tissue tropism of recombinant raccoon poxvirus vaccines, a RCN that can express the lacZ gene (RCN/ lacZ ) was constructed. Expression of β-galactosidase (β-gal) was validated in vitro and in mice in vivo . Cats were vaccinated IN with 10 7 PFU of RCN/ lacZ . No histopathological lesions were detected in any of the tissues collected from these cats at 1, 4, 7 and 15 days post-vaccination. In addition, no virus or β-gal expression was detected in any of these tissues. Controls demonstrated that virus could be reisolated from nasal swabs immediately after administration of 10 8 PFU to cats. These results suggest that recombinant RCN vaccines undergo limited replication after intranasal administration in cats that is sufficient to elicit strong, long-lasting systemic antibody responses. [ABSTRACT FROM AUTHOR]

Summary Background Dengue is an important public health problem worldwide. A vaccine has recently been licensed in some countries of Latin America and Asia. Recommendations for dengue vaccine introduction include endemicity and a high serological prevalence of dengue in the territories considering its introduction. Methods A community-based survey was conducted to estimate dengue seroprevalence and age-specific seroconversion rates in a community in Medellin, Colombia, using a dengue serological test (IgG indirect ELISA). Residents were selected at random and were first screened for dengue infection; they were then followed over 2.5 years. Results A total of 3684 individuals aged between 1 and 65 years participated in at least one survey. The overall dengue seroprevalence was 61%, and only 3.3% of seropositive subjects self-reported a past history of dengue. Among dengue virus (DENV)-naïve subjects with more than two visits ( n = 1002), the overall seroconversion rate was 8.7% (95% confidence interval 7.3–10.4) per 1000 person-months, over the study period. Overall, the mean age of DENV prevalent subjects was significantly higher than the mean age of seroconverted subjects. Specifically, DENV seropositivity over 70% was observed in participants over 21 years old. Serotype-specific plaque-reduction neutralization tests (PRNT) revealed that all four dengue serotypes were circulating, with DENV4 being most prevalent. Conclusions These laboratory-based findings could inform dengue vaccine decisions, as they provide age-specific seroprevalence and seroconversion data, evidencing permanent and ongoing dengue transmission in the study area. This study provides evidence for the existing rates of secondary and heterotypic responses, presenting a challenge that must be addressed adequately by the new vaccine candidates. [ABSTRACT FROM AUTHOR]

Introduction A safe, effective dengue vaccine that can simultaneously induce immunity to all four dengue virus serotypes (DENV-1–4) is a public health priority. A chimeric tetravalent dengue vaccine (TDV) based on an attenuated DENV-2 serotype backbone was evaluated in healthy, flavivirus-seronegative adults. Methods In this randomized, multicenter, Phase 1b study conducted in the United States, the safety and immunogenicity of TDV were evaluated in 140 participants aged 18–45 years in six dosing regimen study groups. Participants were injected subcutaneously on Days 0 and 90; placebo (saline) was injected where appropriate to maintain double blinding. Three different TDV dosages (TDV, a vaccine in which TDV-4 had been increased three-fold, and a one-tenth TDV dose), and single or double dosing were evaluated in one and/or both arms. Primary endpoints were solicited and unsolicited adverse events (AEs) and seroconversion rates to DENV-1–4 at Day 120. Results The severity of all AEs was generally mild. The most common unsolicited AEs were headache (52%), fatigue (43%) and myalgia (29%). The incidence of injection site pain ranged from 29 to 64% and 5 to 52% among study groups after the first and second doses, respectively. At Day 120, the ranges of seroconversion rates among the groups were DEN-1: 84–100%; DEN-2: 96–100%; DEN-3: 83–100%; and DEN-4: 33–77%. More than 80% of participants in each group seroconverted to at least three dengue serotypes. Substantial GMT increases from baseline were observed for DEN-1–3 at all time points from Day 30 onward; DEN-4 GMT increases were lower. Increasing TDV-4 slightly increased DEN-4 GMT, did not impact DEN-2 and DEN-3 GMT, but reduced DEN-1 GMT. Neither multiple dosing in both arms, nor one-tenth TDV dosing meaningfully impacted GMT increases relative to TDV. Conclusions All TDV doses and dosing schedules were well tolerated and immunogenic in healthy flavivirus-naive adults (ClinicalTrials.gov NCT01511250 ). [ABSTRACT FROM AUTHOR]

Dengue (DEN) is the most important mosquito-borne viral disease, with a major impact on global health and economics, caused by four serologically and distinct viruses termed DENV-1 to DENV-4. Currently, there is no licensed vaccine to prevent DEN. We have developed a live attenuated tetravalent DENV vaccine candidate (TDV) (formally known as DENVax) that has shown promise in preclinical and clinical studies and elicits neutralizing antibody responses to all four DENVs. As these responses are lowest to DENV-4 we have used the AG129 mouse model to investigate the immunogenicity of monovalent TDV-4 or tetravalent TDV vaccines, and their efficacy against lethal DENV-4 challenge. Since the common backbone of TDV is based on an attenuated DENV-2 strain (TDV-2) we also tested the efficacy of TDV-2 against DENV-4 challenge. Single doses of the tetravalent or monovalent vaccines elicited neutralizing antibodies, anti-NS1 antibodies, and cellular responses to both envelope and nonstructural proteins. All vaccinated animals were protected against challenge at 60 days post-immunization, whereas all control animals died. Investigation of DENV-4 viremias post-challenge showed that only the control animals had high viremias on day 3 post-challenge, whereas vaccinated mice had no detectable viremia. Overall, these data highlight the excellent immunogenicity and efficacy profile of our candidate dengue vaccine in AG129 mice. [ABSTRACT FROM AUTHOR]

Highlights: [•] A single dose of CHIKV/IRES vaccine elicits neutralizing antibody and virus-specific T cell responses. [•] CHIKV/IRES immune CD4+ or CD8+ T cells do not protect A129 mice against CHIKV-LR challenge. [•] A correlate of a neutralizing antibody titer and protection has been established. [ABSTRACT FROM AUTHOR]

Abstract: Emerging mosquito-borne alphavirus infections caused by chikungunya virus (CHIKV) or o‘nyong-nyong virus (ONNV) are responsible for sporadic and sometimes explosive urban outbreaks. Currently, there is no licensed vaccine against either virus. We have developed a highly attenuated recombinant CHIKV candidate vaccine (CHIKV/IRES) that in preclinical studies was demonstrated to be safe, immunogenic and efficacious. In this study we investigated the potential of this vaccine to induce cross-protective immunity against the antigenically related ONNV. Our studies demonstrated that a single dose of CHIKV/IRES elicited a strong cross-neutralizing antibody response and conferred protection against ONNV challenge in the A129 mouse model. Moreover, CHIKV/IRES immune A129 dams transferred antibodies to their offspring that were protective, and passively transferred anti-CHIKV/IRES immune serum protected AG129 mice, independently of a functional IFN response. These findings highlight the potential of the CHIKV/IRES vaccine to protect humans against not only CHIKV but also against ONNV-induced disease. [Copyright &y& Elsevier]