Liu H.,University of Groningen |
Bungener L.,University of Groningen |
ter Veer W.,University of Groningen |
Coller B.-A.,Hawaii Biotech, Inc. |
And 2 more authors.
Vaccine | Year: 2011
With the current global influenza vaccine production capacity the large demand for vaccines in case of a pandemic can only be fulfilled when antigen dose sparing strategies are employed. Here we used a murine challenge model to evaluate the potential of GPI-0100, a semi-synthetic saponin derivative, to serve as a dose-sparing adjuvant for influenza subunit vaccine. Balb/c mice were immunized with different doses of A/PR8 (H1N1) subunit antigen alone or in combination with varying doses of GPI-0100. The addition of GPI-0100 significantly stimulated antibody and cellular immune responses, especially of the Th1 phenotype. Furthermore, virus titers detected in the lungs of mice challenged one week after the second immunization were significantly reduced among the animals that received GPI-0100-adjuvanted vaccines. Remarkably, adjuvantation of subunit vaccine with GPI-0100 allowed a 25-fold reduction in hemagglutinin dose without compromising the protective potential of the vaccine. © 2011 Elsevier Ltd.
PubMed | Hawaii Biotech, Inc., Infectious Disease Research Institute and Colorado State University
Type: Journal Article | Journal: PloS one | Year: 2016
West Nile virus (WNV) is a mosquito-transmitted member of the Flaviviridae family that has emerged in recent years to become a serious public health threat. Given the sporadic nature of WNV epidemics both temporally and geographically, there is an urgent need for a vaccine that can rapidly provide effective immunity. Protection from WNV infection is correlated with antibodies to the viral envelope (E) protein, which encodes receptor binding and fusion functions. Despite many promising E-protein vaccine candidates, there are currently none licensed for use in humans. This study investigates the ability to improve the immunogenicity and protective capacity of a promising clinical-stage WNV recombinant E-protein vaccine (WN-80E) by combining it with a novel synthetic TLR-4 agonist adjuvant. Using the murine model of WNV disease, we find that inclusion of a TLR-4 agonist in either a stable oil-in-water emulsion (SE) or aluminum hydroxide (Alum) formulation provides both dose and dosage sparing functions, whereby protection can be induced after a single immunization containing only 100 ng of WN-80E. Additionally, we find that inclusion of adjuvant with a single immunization reduced viral titers in sera to levels undetectable by viral plaque assay. The enhanced protection provided by adjuvanted immunization correlated with induction of a Th1 T-cell response and the resultant shaping of the IgG response. These findings suggest that inclusion of a next generation adjuvant may greatly enhance the protective capacity of WNV recombinant subunit vaccines, and establish a baseline for future development.
Pusic K.M.,University of Hawaii at Manoa |
Hashimoto C.N.,University of Hawaii at Manoa |
Lehrer A.,Hawaii Biotech, Inc. |
Aniya C.,Hawaii Biotech, Inc. |
And 3 more authors.
PLoS ONE | Year: 2011
The C-terminal 42 kDa fragments of the P. falciparum Merozoite Surface Protein 1, MSP1-42 is a leading malaria vaccine candidate. MSP1-33, the N-terminal processed fragment of MSP1-42, is rich in T cell epitopes and it is hypothesized that they enhance antibody response toward MSP1-19. Here, we gave in vivo evidence that T cell epitope regions of MSP1-33 provide functional help in inducing anti-MSP1-19 antibodies. Eleven truncated MSP1-33 segments were expressed in tandem with MSP1-19, and immunogenicity was evaluated in Swiss Webster mice and New Zealand White rabbits. Analyses of anti-MSP1-19 antibody responses revealed striking differences in these segments' helper function despite that they all possess T cell epitopes. Only a few fragments induced a generalized response (100%) in outbred mice. These were comparable to or surpassed the responses observed with the full length MSP1-42. In rabbits, only a subset of truncated antigens induced potent parasite growth inhibitory antibodies. Notably, two constructs were more efficacious than MSP1-42, with one containing only conserved T cell epitopes. Moreover, another T cell epitope region induced high titers of non-inhibitory antibodies and they interfered with the inhibitory activities of anti-MSP1-42 antibodies. In mice, this region also induced a skewed TH2 cellular response. This is the first demonstration that T cell epitope regions of MSP1-33 positively or negatively influenced antibody responses. Differential recognition of these regions by humans may play critical roles in vaccine induced and/or natural immunity to MSP1-42. This study provides the rational basis to re-engineer more efficacious MSP1-42 vaccines by selective inclusion and exclusion of MSP1-33 specific T cell epitopes. © 2011 Pusic et al.
Johnson A.T.,Hawaii Biotech, Inc.
Journal of Chemical Education | Year: 2015
At present, small molecule drug design follows a retrospective path when considering what analogs are to be made around a current hit or lead molecule with the focus often on identifying a compound with higher intrinsic potency. What this approach overlooks is the simultaneous need to also improve the physicochemical (PC) and pharmacokinetic (PK) properties of these compounds, and illustrates the multivariate problem the chemist must face when targeting new analogs for synthesis. To address this problem, a simple method is presented which allows the chemist to integrate PC properties into small molecule drug design in a prospective manner, prioritize new target molecules for synthesis, and potentially shorten the path to the clinic. This simple method also provides a tool for the student of medicinal chemistry to see how changes in PC properties and intrinsic potency can influence drug-like properties of small molecules during the drug discovery process. © 2014 The American Chemical Society and Division of Chemical Education, Inc.
Agency: Department of Defense | Branch: Army | Program: SBIR | Phase: Phase I | Award Amount: 99.89K | Year: 2015
Dengue virus (DENV) is a mosquito-borne flavivirus that poses a tremendous public health threat throughout the world. The U.S. military has also been challenged by dengue for over a hundred years and the pursuit of an effective DENV vaccine is a high priority for the Department of Defense (DoD). Despite over 70 years of efforts, there is still no registered dengue vaccine. While significant progress has been made in the last decade, challenges still remain. To help enhance development of a DENV vaccine candidate there two key areas that need to be addressed; robust immunogenicity, both antibody titers and durability, and shorting the duration of immunization schedule. This application is directed at demonstrating the enhanced immunogenicity of formulations comprised of an inactivated DENV and novel adjuvants. The use of novel adjuvants with the potential for clinical use will help accelerate the development of an enhanced inactivated DENV vaccine. For the first phase of this effort the technical objectives are to first screen and select formulations with robust immunogenicity and then to demonstrate protective efficacy in a lethal mouse challenge model. In this manner we will demonstrate the feasibility of developing an adjuvanted-inactivated dengue vaccine with enhanced and durable immune responses.
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase II | Award Amount: 2.11M | Year: 2015
DESCRIPTION provided by applicant The tick borne flavivirus TBFV group includes a number of important human pathogens that result in serious encephalitic or hemorrhagic diseases that are either Category B or C priority pathogens The TBFV are considered to be emerging or re emerging pathogens due to increases in the number of human cases the expansion of geographic distribution and emergence of new viruses This application is directed at the development of a multivalent TBFV vaccine that provides broad cross protection against at least five viruses in this group Central European subtype of tick borne encephalitis TBE TBEV Eu Far Eastern subtype TBE FE Alkhurma hemorrhagic fever virus AHFV Kyasanur Forest disease virus KFDV and Omsk hemorrhagic fever virus OHFV Inactivated vaccines exist for TBEV Eu TBE FE and KFD in some endemic countries but there are no vaccines for AHFV and OHFV The development of monotypic vaccines against individual pathogens provides a strategy to mitigate the threat posed on a regional basis however the number of different viruses in the TBFV group poses a challenge in providing protection against all of the viruses in the group Furthermore there is no registered TBFV vaccine in the U S The lack of a vaccine in the U S has been deemed an unmet need by NIAID An approach to provide broad protection against the TBFV group is the development of a multivalent vaccine that provides cross protection against most if not all of the TBFVs This vaccine will be developed by evaluating various combinations of soluble recombinant subunits proteins representing the envelope E protein from these five TBFVs Preliminary data with recombinant TBEV Eu has established a proof of principle for the potential of this approach The monovalent rTBEV EU vaccine has been demonstrated to provide monotypic and partial cross protection and will serve as the core on which the multivalent vaccine will be established The Specific Aims of this project are development and evaluation of the immunogenicity and cross reactive potential cross virus neutralizing ability of additional E subunit proteins for inclusio in the multivalent vaccine assess the cross protective potential of selected combinations of recombinant TBFV E proteins in a mouse challenge model and assess the potency of the selected multivalent vaccine to support further development of the vaccine To accomplish these goals an established stable insect expression system with demonstrated FDA regulatory experience will be utilized to produce the recombinant E proteins This includes the use of a modern adjuvant that has potential for advancement to human clinical trials The selection of the multivalent candidate vaccine will focus on a vaccine composition with the least number of components E proteins that provides the greatest level of cross protection To accomplish the objectives of the proposed research a strong multidisciplinary team of scientists has been assembled that provides the means to develop and evaluate a successful multivalent TBFV cross protective vaccine The development of multivalent TBFV vaccine would be of great value and in line with the priorities of NIH NIAID to develop multivalent and cross protective vaccine technologies PUBLIC HEALTH RELEVANCE The proposed research is focused on developing a candidate vaccine that protects against a family of related viruses in the tick borne flavivirus TBFV group which causes disease in humans The vaccine candidate would be a single multivalent vaccine that would provide protection against many viruses in the TBFV group The approach is based on a technology to produce vaccine components comprised of recombinant subunit envelope proteins Although TBFVs are normally found outside the U S they are identified as priority pathogens so a multivalent vaccine would help meet the mission of providing protection for U S citizens against several priority pathogens biothreat agents with a single vaccine Such a multivalent TBFV vaccine can be utilized to protect military and state department personnel first responders and U S TBFV virus researchers who are currently forced to go abroad for vaccination in addition to travelers or people at risk in endemic areas
Agency: Department of Health and Human Services | Branch: National Institutes of Health | Program: SBIR | Phase: Phase I | Award Amount: 300.00K | Year: 2016
DESCRIPTION provided by applicant Chikungunya virus CHIKV is an alphavirus classified as a category C priority pathogen that causes fever rash and arthralgia in humans In the past decade CHIKV outbreaks have spread beyond the endemic regions of Africa and Asia first to the islands in the Indian Ocean and most recently to the Americas The World Health Organization has reported that as of October over suspected cases of Chikungunya have been recorded in the Caribbean islands Latin American countries and some South American countries Due to this geographic expansion of its range and the increase in the number of human cases CHIKV is considered to be a re emerging pathogen a contributing factor to this re emergence is the virus adapting to transmission by Aedes albopictus mosquitoes Currently there are no licensed vaccines or therapeutics to protect against infection with CHIKV As with many viral infections supportive care is the only available treatment Given the severe morbidity caused by CHIKV its swift emergence and the lack of any targeted interventions a preventative vaccine would provide an effective means to reduce the burden caused by this disease This application is directed at the development of a CHIKV recombinant subunit vaccine There are several candidate vaccines under development using a variety of platform technologies including inactivated viruses live attenuated viruses chimeric live attenuated viruses virus like particles and subunits As with all vaccines and in particula for priority pathogens such as CHIKV which requires BSL handling a combination of safety and economics in manufacturing are of paramount importance The proposed recombinant subunit approach provides a means to deliver a safe and stable manufacturing platform and allow for easy adjustment of dosing in order to elicit a robust immune response providing strong protection against CHIKV infection To accomplish this goal recombinant subunit proteins focused on specific domains with relevant epitopes from the CHIKV envelope glycoproteins will be evaluated The Specific Aims of this project are produce recombinant CHIKV E subunit proteins demonstrate immunogenicity of candidate vaccines in mice and demonstrate protective efficacy of candidate vaccines in mice To achieve these goals the recombinant E subunit proteins will be produced in an established stable insect expression system for which multiple IND applications have now been filed A candidate vaccine will be selected on the basis of a composition that maintains native like protein structure and which elicits a relevant and robust immune response that is capable of preventing disease following CHIKV challenge A collaboration between Hawaii Biotech and Baylor College of Medicine has been established to develop and evaluate a successful a CHIKV vaccine The development of CHIKV recombinant subunit vaccine would be of great value in slowing the spread of this re emerging Category C virus and preventing the severe morbidity caused by CHIKV infection PUBLIC HEALTH RELEVANCE The proposed research is focused on development of a candidate vaccine that protects against Chikungunya virus CHIKV which causes disease in humans The vaccine will be based on technology which allows for production recombinant subunit envelope proteins Although CHIKV is not yet established in the U S recent epidemics in the Americas provide the potential for the virus to become endemic in the U S CHIKV is also classified as a category C priority pathogen The proposed vaccine would be used to protect U S citizens against the potential spread of this virus as well as protect military and state department personnel and travelers that may be at risk in endemic areas The vaccine could also protect the populations of countries where the virus is already established
Hawaii Biotech, Inc. | Date: 2016-04-14
Compounds of formula I are provided: R_(1 )is an alkoxy or O(CH_(2))_(p)X, p is an integer from 2 to 3 and X is OH, NH_(2), or CO_(2)H, m is an integer from 0 to 5, n is an integer from 0 to 5, each R_(2 )is independently selected from hydrogen, alkenyl, hydroxyalkyl, alkoxymethyl, heterocyclyl, hetereocyclylmethyl, amino, amido, hydroxamido, any of which may be optionally substituted with one or more of acyl, alkyl, alkoxy, hydroxyalkyl, or halogen, each R_(3 )is independently selected from hydrogen, halogen, alkyl, alkenyl, carboxy, hydroxymethyl, amido, and at least one of R_(2 )and R_(3 )is not hydrogen.
Agency: Department of Health and Human Services | Branch: | Program: SBIR | Phase: Phase I | Award Amount: 530.90K | Year: 2012
DESCRIPTION (provided by applicant): Emerging and reemerging infectious diseases continue to pose serious health threats world-wide. Consequently, the development of measures to mitigate the natural, as well as potential bioterrorist threats of these infectious diseases is an important endeavor. The NIAID Strategic Plan for Biodefense Research is specifically directed at promoting research that can provide solutions to mitigate the threat posed by Category A, B, and C priority pathogens. The development ofvaccines against these pathogens provides a strategy to mitigate the potential threat. Crimean-Congo hemorrhagic fever virus (CCHFV) is a significant human pathogen due to it ability cause severe disease and its high fatality rate. CCHFV is classified as acategory C priority pathogen due the concern that it could be used as a biological agent. There is currently no effective vaccine or therapy that is widely available to mitigate such a threat. New technologies and production methods may offer the most effective responses to such disease threats. The proposed research aims to develop a vaccine to protect against disease caused by infection with CCHFV using a stable insect cell line expression platform that has previously been used to produce vaccine candidates for other priority pathogens. The platform is based on the production of recombinant subunit proteins that maintain structural and immunogenic integrity. Candidate vaccines against dengue and West Nile virus have already been produced in this system and both have entered clinical trials. Thus, this platform can be scaled for cGMP production and meet FDA regulatory requirements. The expression of the CCHFV Gn and Gc envelope glycoprotein will be evaluated. The complex nature of viral envelope glycoproteins presents challenges in designing and expressing recombinant subunits that maintain native-like structure. The platform proposed for use in this project has the demonstrated capability of producing complex viral envelope proteins with native-like conformation. Successfully expressed recombinant products will be evaluated for immunogenic potential using two novel adjuvant formulations that have dose sparing potential. Based on immunogenicity studies, selected combinations of recombinant proteins and adjuvant will be evaluated in protective efficacy studies utilizing a recently developed mouse challenge model for CCHFV. In addition to vaccine development, the protein subunits produced can be used for development of diagnostic reagents, as well as targets forantiviral drug development. The successful development of a CCHFV vaccine utilizing this stable insect cell platform will not only meet the need for a safe and effective vaccine against CCHFV, it will also help to demonstrate the utility of the platform and pave the way for the development of additional vaccines against NIAID viral priority pathogens. PUBLIC HEALTH RELEVANCE: The proposed research is focused on the development of a vaccine to protect against disease caused by Crimean-Congo hemorrhagic fever virus (CCHFV), which is a member of the Bunyaviridae family and is the causative agent of a clinical febrile illness with a propensity to cause significant hemorrhagic fever. Due to the hemorrhagic nature of the disease and the high mortality rate, CCHF has been classified as a NIAID category C priority pathogen. Threat of CCHF as an emerging disease continues as the number of cases continues to increase. The development of vaccines against viral diseases on the NIAID priority pathogens list hasproven to be a challenging endeavor. Aside from vaccines for yellow fever and Japanese encephalitis, no other licensed vaccines have been developed for any of the other viral priority pathogens. The proposed work to develop a CCHF vaccine is based on a cell culture expression system that has been demonstrated to be capable of meeting FDA regulatory requirements and producing safe vaccine candidates. The vaccine manufacturing platform is based on the expression of recombinant subunit proteins in stably transformed insect cells. The successful development of a CCHF recombinant subunit vaccine based on this platform supports the concept that a single platform can be utilized to produce vaccines against a number of viral priority pathogens.