Search

Although there are now approved treatments and vaccines for Ebola virus disease, the case fatality rate remains unacceptably high even when patients are treated with the newly approved therapeutics. Furthermore, these countermeasures are not expected to be effective against disease caused by other filoviruses. A meeting of subject-matter experts was held during the 10th International Filovirus Symposium to discuss strategies to address these gaps. Several investigational therapeutics, vaccine candidates, and combination strategies were presented. The greatest challenge was identified to be the implementation of well-designed clinical trials of safety and efficacy during filovirus disease outbreaks. Preparing for this will require agreed-upon common protocols for trials intended to bridge multiple outbreaks across all at-risk countries. A multinational research consortium including at-risk countries would be an ideal mechanism to negotiate agreement on protocol design and coordinate preparation. Discussion participants recommended a follow-up meeting be held in Africa to establish such a consortium. [ABSTRACT FROM AUTHOR]

Vaccines are needed to disrupt or prevent continued outbreaks of filoviruses in humans across Western and Central Africa, including outbreaks of Marburg virus (MARV). As part of a filovirus vaccine product development plan, it is important to investigate dose response early in preclinical development to identify the dose range that may be optimal for safety, immunogenicity, and efficacy, and perhaps demonstrate that using lower doses is feasible, which will improve product access. To determine the efficacious dose range for a manufacturing-ready live recombinant vesicular stomatitis virus vaccine vector (rVSV∆G-MARV-GP) encoding the MARV glycoprotein (GP), a dose-range study was conducted in cynomolgus macaques. Results showed that a single intramuscular injection with as little as 200 plaque-forming units (PFUs) was 100% efficacious against lethality and prevented development of viremia and clinical pathologies associated with MARV Angola infection. Across the vaccine doses tested, there was nearly a 2000-fold range of anti-MARV glycoprotein (GP) serum IgG titers with seroconversion detectable even at the lowest doses. Virus-neutralizing serum antibodies also were detected in animals vaccinated with the higher vaccine doses indicating that vaccination induced functional antibodies, but that the assay was a less sensitive indicator of seroconversion. Collectively, the data indicates that a relatively wide range of anti-GP serum IgG titers are observed in animals that are protected from disease implying that seroconversion is positively associated with efficacy, but that more extensive immunologic analyses on samples collected from our study as well as future preclinical studies will be valuable in identifying additional immune responses correlated with protection that can serve as markers to monitor in human trials needed to generate data that can support vaccine licensure in the future. [ABSTRACT FROM AUTHOR]

Background Recent importation of Lassa fever into Germany, the Netherlands, the United Kingdom, and the United States by travelers on commercial airlines from Africa underscores the public health challenge of emerging viruses. Currently, there are no licensed vaccines for Lassa fever, and no experimental vaccine has completely protected nonhuman primates against a lethal challenge. Methods and Findings We developed a replication-competent vaccine against Lassa virus based on attenuated recombinant vesicular stomatitis virus vectors expressing the Lassa viral glycoprotein. A single intramuscular vaccination of the Lassa vaccine elicited a protective immune response in nonhuman primates against a lethal Lassa virus challenge. Vaccine shedding was not detected in the monkeys, and none of the animals developed fever or other symptoms of illness associated with vaccination. The Lassa vaccine induced strong humoral and cellular immune responses in the four vaccinated and challenged monkeys. Despite a transient Lassa viremia in vaccinated animals 7 d after challenge, the vaccinated animals showed no evidence of clinical disease. In contrast, the two control animals developed severe symptoms including rashes, facial edema, and elevated liver enzymes, and ultimately succumbed to the Lassa infection. Conclusion Our data suggest that the Lassa vaccine candidate based on recombinant vesicular stomatitis virus is safe and highly efficacious in a relevant animal model that faithfully reproduces human disease. [ABSTRACT FROM AUTHOR]

Recent occurrences of filoviruses and the arenavirus Lassa virus (LASV) in overlapping endemic areas of Africa highlight the need for a prophylactic vaccine that would confer protection against all of these viruses that cause lethal hemorrhagic fever (HF). We developed a quadrivalent formulation of VesiculoVax that contains recombinant vesicular stomatitis virus (rVSV) vectors expressing filovirus glycoproteins and that also contains a rVSV vector expressing the glycoprotein of a lineage IV strain of LASV. Cynomolgus macaques were vaccinated twice with the quadrivalent formulation, followed by challenge 28 days after the boost vaccination with each of the 3 corresponding filoviruses (Ebola, Sudan, Marburg) or a heterologous contemporary lineage II strain of LASV. Serum IgG and neutralizing antibody responses specific for all 4 glycoproteins were detected in all vaccinated animals. A modest and balanced cell-mediated immune response specific for the glycoproteins was also detected in most of the vaccinated macaques. Regardless of the level of total glycoprotein-specific immune response detected after vaccination, all immunized animals were protected from disease and death following lethal challenges. These findings indicate that vaccination with attenuated rVSV vectors each expressing a single HF virus glycoprotein may provide protection against those filoviruses and LASV most commonly responsible for outbreaks of severe HF in Africa. [ABSTRACT FROM AUTHOR]

Ebolaviruses Bundibugyo virus (BDBV) and Ebola virus (EBOV) cause fatal hemorrhagic disease in humans and nonhuman primates. While the host response to EBOV is well characterized, less is known about BDBV infection. Moreover, immune signatures that mediate natural protection against all ebolaviruses remain poorly defined. To explore these knowledge gaps, we transcriptionally profiled BDBV-infected rhesus macaques, a disease model that results in incomplete lethality. This approach enabled us to identify prognostic indicators. As expected, survival (∼60%) correlated with reduced clinical pathology and circulating infectious virus, although peak viral RNA loads were not significantly different between surviving and nonsurviving macaques. Survivors had higher anti-BDBV antibody titers and transcriptionally derived cytotoxic T cell-, memory B cell-, and plasma cell-type quantities, demonstrating activation of adaptive immunity. Conversely, a poor prognosis was associated with lack of an appropriate adaptive response, sustained innate immune signaling, and higher expression of myeloid-derived suppressor cell (MDSC)-related transcripts ( S100A8 , S100A9 , CEBPB , PTGS2 , CXCR1 , and LILRA3 ). MDSCs are potent immunosuppressors of cellular and humoral immunity, and therefore, they represent a potential therapeutic target. Circulating plasminogen activator inhibitor 1 (PAI-1) and tissue plasminogen activator (tPA) levels were also elevated in nonsurvivors and in survivors exhibiting severe illness, emphasizing the importance of maintaining coagulation homeostasis to control disease progression. IMPORTANCE Bundibugyo virus (BDBV) and Ebola virus (EBOV) are ebolaviruses endemic to Africa that cause severe, often fatal hemorrhagic disease. BDBV is considered a less pathogenic ebolavirus due to its reduced lethality during human outbreaks, as well as in experimentally infected nonhuman primates. The reduced mortality of BDBV in NHP models, resulting in a pool of survivors, afforded us the unique opportunity of identifying immune correlates that confer protection against ebolaviruses. In this study, we discovered that the survival of BDBV-infected nonhuman primates (NHPs) was dependent on early development of adaptive (memory) immune responses and reduced myeloid-derived suppressor cell (MDSC)-related signaling. MDSCs are a heterogenous group of immune cells implicated in a number of diseases that are powerful immunosuppressors of cellular and humoral immunity. Thus, MDSCs represent a novel therapeutic target to prevent ebolavirus disease. To our knowledge, this is the first study to link increased morbidity with recruitment of these potent immunosuppressive cells.