Sachiko Kuno

Oral Dextran Sulfate (UAOO1) in the Treatment of the Acquired Immunodeficiency Syndrome (AIDS) and AIDS-Related Complex

STUDY OBJECTIVE To evaluate the tolerance and safety of oral dextran sulfate (UA001), a potent in-vitro inhibitor of human immunodeficiency virus (HIV) in patients with the acquired immunodeficiency syndrome (AIDS) and AIDS-related complex. DESIGN Unblinded, dose-escalation 8-week trial. SETTING An AIDS outpatient clinic of a university-affiliated municipal hospital. PATIENTS Thirty-four patients with stage III or IV HIV infection were enrolled. Five patients in six different dosage cohorts completed the study. The population was predominantly homosexual men with persistent generalized lymphadenopathy (stage III). INTERVENTIONS Oral dextran sulfate was given three times daily in total daily doses of 900 to 5400 mg for 8 weeks. Patients were monitored for tolerance and toxicity. Immunologic and virologic values were also followed. MEASUREMENTS AND MAIN RESULTS Oral dextran sulfate was given without significant side effects. The commonest minor subjective complications were mental hyperexcitability and gastrointestinal complaints. The most frequent laboratory abnormalities were leukopenia and hepatic transaminase elevations. Eleven patients required dose reductions, and therapy was stopped in 4 because of toxicities. The CD4 lymphocyte numbers did not change appreciably. No decline in beta-2 microglobulin levels occurred. The HIV antigen levels were unchanged from baseline. No assay for dextran sulfate plasma levels has yet proven successful. CONCLUSIONS Oral dextran sulfate appears to be well tolerated. No evidence of systemic absorption of the parent compound is available. However, in view of the promising in vitro effects and acceptable toxicity, oral dextran sulfate as a potential antiretroviral agent continues to be studied.

An Envelope-Modified Tetravalent Dengue Virus-Like-Particle Vaccine Has Implications for Flavivirus Vaccine Design

ABSTRACT Dengue viruses (DENV) infect 50 to 100 million people each year. The spread of DENV-associated infections is one of the most serious public health problems worldwide, as there is no widely available vaccine or specific therapeutic for DENV infections. To address this, we developed a novel tetravalent dengue vaccine by utilizing virus-like particles (VLPs). We created recombinant DENV1 to -4 (DENV1-4) VLPs by coexpressing precursor membrane (prM) and envelope (E) proteins, with an F108A mutation in the fusion loop structure of E to increase the production of VLPs in mammalian cells. Immunization with DENV1-4 VLPs as individual, monovalent vaccines elicited strong neutralization activity against each DENV serotype in mice. For use as a tetravalent vaccine, DENV1-4 VLPs elicited high levels of neutralization activity against all four serotypes simultaneously. The neutralization antibody responses induced by the VLPs were significantly higher than those with DNA or recombinant E protein immunization. Moreover, antibody-dependent enhancement (ADE) was not observed against any serotype at a 1:10 serum dilution. We also demonstrated that the Zika virus (ZIKV) VLP production level was enhanced by introducing the same F108A mutation into the ZIKV envelope protein. Taken together, these results suggest that our strategy for DENV VLP production is applicable to other flavivirus VLP vaccine development, due to the similarity in viral structures, and they describe the promising development of an effective tetravalent vaccine against the prevalent flavivirus. IMPORTANCE Dengue virus poses one of the most serious public health problems worldwide, and the incidence of diseases caused by the virus has increased dramatically. Despite decades of effort, there is no effective treatment against dengue. A safe and potent vaccine against dengue is still needed. We developed a novel tetravalent dengue vaccine by using virus-like particles (VLPs), which are noninfectious because they lack the viral genome. Previous attempts of other groups to use dengue VLPs resulted in generally poor yields. We found that a critical amino acid mutation in the envelope protein enhances the production of VLPs. Our tetravalent vaccine elicited potent neutralizing antibody responses against all four DENV serotypes. Our findings can also be applied to vaccine development against other flaviviruses, such as Zika virus or West Nile virus.

Development of a Novel Virus-Like Particle Vaccine Platform That Mimics the Immature Form of Alphavirus

ABSTRACT Virus-like particles (VLPs) are noninfectious multiprotein structures that are engineered to self-assemble from viral structural proteins. Here, we developed a novel VLP-based vaccine platform utilizing VLPs from the chikungunya virus. We identified two regions within the envelope protein, a structural component of chikungunya, where foreign antigens can be inserted without compromising VLP structure. Our VLP displays 480 copious copies of an inserted antigen on the VLP surface in a highly symmetric manner and is thus capable of inducing strong immune responses against any inserted antigen. Furthermore, by mimicking the structure of the immature form of the virus, we altered our VLPs in vivo dynamics and enhanced its immunogenicity. We used the circumsporozoite protein (CSP) of the Plasmodium falciparum malaria parasite as an antigen and demonstrated that our VLP-based vaccine elicits strong immune responses against CSP in animals. The sera from immunized monkeys protected mice from malaria infection. Likewise, mice vaccinated with P. yoelii CSP-containing VLPs were protected from an infectious sporozoite challenge. Hence, our uniquely engineered VLP platform can serve as a blueprint for the development of vaccines against other pathogens and diseases.