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A recombinant vesicular stomatitis virus-based Lassa fever vaccine protects guinea pigs and macaques against challenge with geographically and genetically distinct Lassa viruses.

Safronetz D, Mire C, Rosenke K, Feldmann F, Haddock E, Geisbert T, Feldmann H - PLoS Negl Trop Dis (2015)

Bottom Line: Despite the high annual incidence and significant morbidity and mortality rates, currently there are no approved vaccines to prevent infection or disease in humans.Our results demonstrate the VSV-based LASV vaccine is capable of preventing morbidity and mortality associated with non-homologous LASV challenge in two animal models of Lassa fever.Additionally, this work highlights the need for the further development of disease models for geographical distinct LASV strains, particularly those from Nigeria, in order to comprehensively evaluate potential vaccines and therapies against this prominent agent of viral hemorrhagic fever.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Virology, Division of Intramural Research, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, United States of America.

ABSTRACT

Background: Lassa virus (LASV) is endemic in several West African countries and is the etiological agent of Lassa fever. Despite the high annual incidence and significant morbidity and mortality rates, currently there are no approved vaccines to prevent infection or disease in humans. Genetically, LASV demonstrates a high degree of diversity that correlates with geographic distribution. The genetic heterogeneity observed between geographically distinct viruses raises concerns over the potential efficacy of a "universal" LASV vaccine. To date, several experimental LASV vaccines have been developed; however, few have been evaluated against challenge with various genetically unique Lassa virus isolates in relevant animal models.

Methodologies/principle findings: Here we demonstrate that a single, prophylactic immunization with a recombinant vesicular stomatitis virus (VSV) expressing the glycoproteins of LASV strain Josiah from Sierra Leone protects strain 13 guinea pigs from infection / disease following challenge with LASV isolates originating from Liberia, Mali and Nigeria. Similarly, the VSV-based LASV vaccine yields complete protection against a lethal challenge with the Liberian LASV isolate in the gold-standard macaque model of Lassa fever.

Conclusions/significance: Our results demonstrate the VSV-based LASV vaccine is capable of preventing morbidity and mortality associated with non-homologous LASV challenge in two animal models of Lassa fever. Additionally, this work highlights the need for the further development of disease models for geographical distinct LASV strains, particularly those from Nigeria, in order to comprehensively evaluate potential vaccines and therapies against this prominent agent of viral hemorrhagic fever.

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VSVΔG/LASVGPC protects non-human primates from a lethal challenge with a Liberian Lassa virus isolate.Cynomolgus macaques were immunized with 1 x107 pfu of VSVΔG/LASVGPC (n = 3) or VSVΔG/ANDVGPC (n = 1) and challenged 28 days later with a previously determined lethal dose of Lassa virus strain Z-132. (A) Survival curve and infectious titers of Lassa virus in select tissues from the control animal collected at the time of euthanasia. (B) Selected hematological and biochemical parameters monitored from vaccinated (red lines) and control (blue line) macaques.
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pntd.0003736.g005: VSVΔG/LASVGPC protects non-human primates from a lethal challenge with a Liberian Lassa virus isolate.Cynomolgus macaques were immunized with 1 x107 pfu of VSVΔG/LASVGPC (n = 3) or VSVΔG/ANDVGPC (n = 1) and challenged 28 days later with a previously determined lethal dose of Lassa virus strain Z-132. (A) Survival curve and infectious titers of Lassa virus in select tissues from the control animal collected at the time of euthanasia. (B) Selected hematological and biochemical parameters monitored from vaccinated (red lines) and control (blue line) macaques.

Mentions: Based on the similarities to human disease, the apex animal model for viral hemorrhagic fevers, including LF, is widely considered to be NHPs. To further evaluate the VSV LF vaccine, three NHPs were immunized with VSVΔG/LASVGPC, while a single control NHP was immunized with an irrelevant VSV construct. Following immunization, all four animals appeared normal, with no clinically significant changes observed in any of the monitored parameters. At 28 days post-immunization, animals were challenged with a previously determined lethal dose of a non-homologous Liberian LASV (strain Z-132) [32]. Between days 5 and 7 post-infection the control animal began to demonstrate general signs of illness (reduced food-take, hunched posture, dull appearance, ruffled fur and reluctance to move) which progressed until day 13 at which point the animal was humanely euthanized (Fig 5A). At necropsy the animal presented with gross pathological abnormalities which were indicative of systemic disease; these included splenomegaly, hepatomegaly, pericardial effusion and slight pulmonary discoloration. Viral titrations (TCID50) confirmed the presence of LASV in selected organs (lung, liver and spleen) from the control animal, with organ titers ranging from 5.5 to 7.25 log10 TCID50’s per gram of tissue (Fig 5A). In contrast, the three NHPs immunized with VSVΔG/LASVGPC survived challenge with the Liberian LASV with no apparent signs of infection observed throughout the course of the study. The survival rate was statistically significant (100% versus 0%, p = 0.0286 by Fisher’s exact test) when one compares the three VSVΔG/LASVGPC-immunized animals to the single control animal utilized in this study combined with three previous control animals infected with LASV Z-132 (same route and dose) which succumbed to infection between days 10 and 13 post-challenge [32].


A recombinant vesicular stomatitis virus-based Lassa fever vaccine protects guinea pigs and macaques against challenge with geographically and genetically distinct Lassa viruses.

Safronetz D, Mire C, Rosenke K, Feldmann F, Haddock E, Geisbert T, Feldmann H - PLoS Negl Trop Dis (2015)

VSVΔG/LASVGPC protects non-human primates from a lethal challenge with a Liberian Lassa virus isolate.Cynomolgus macaques were immunized with 1 x107 pfu of VSVΔG/LASVGPC (n = 3) or VSVΔG/ANDVGPC (n = 1) and challenged 28 days later with a previously determined lethal dose of Lassa virus strain Z-132. (A) Survival curve and infectious titers of Lassa virus in select tissues from the control animal collected at the time of euthanasia. (B) Selected hematological and biochemical parameters monitored from vaccinated (red lines) and control (blue line) macaques.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4401668&req=5

pntd.0003736.g005: VSVΔG/LASVGPC protects non-human primates from a lethal challenge with a Liberian Lassa virus isolate.Cynomolgus macaques were immunized with 1 x107 pfu of VSVΔG/LASVGPC (n = 3) or VSVΔG/ANDVGPC (n = 1) and challenged 28 days later with a previously determined lethal dose of Lassa virus strain Z-132. (A) Survival curve and infectious titers of Lassa virus in select tissues from the control animal collected at the time of euthanasia. (B) Selected hematological and biochemical parameters monitored from vaccinated (red lines) and control (blue line) macaques.
Mentions: Based on the similarities to human disease, the apex animal model for viral hemorrhagic fevers, including LF, is widely considered to be NHPs. To further evaluate the VSV LF vaccine, three NHPs were immunized with VSVΔG/LASVGPC, while a single control NHP was immunized with an irrelevant VSV construct. Following immunization, all four animals appeared normal, with no clinically significant changes observed in any of the monitored parameters. At 28 days post-immunization, animals were challenged with a previously determined lethal dose of a non-homologous Liberian LASV (strain Z-132) [32]. Between days 5 and 7 post-infection the control animal began to demonstrate general signs of illness (reduced food-take, hunched posture, dull appearance, ruffled fur and reluctance to move) which progressed until day 13 at which point the animal was humanely euthanized (Fig 5A). At necropsy the animal presented with gross pathological abnormalities which were indicative of systemic disease; these included splenomegaly, hepatomegaly, pericardial effusion and slight pulmonary discoloration. Viral titrations (TCID50) confirmed the presence of LASV in selected organs (lung, liver and spleen) from the control animal, with organ titers ranging from 5.5 to 7.25 log10 TCID50’s per gram of tissue (Fig 5A). In contrast, the three NHPs immunized with VSVΔG/LASVGPC survived challenge with the Liberian LASV with no apparent signs of infection observed throughout the course of the study. The survival rate was statistically significant (100% versus 0%, p = 0.0286 by Fisher’s exact test) when one compares the three VSVΔG/LASVGPC-immunized animals to the single control animal utilized in this study combined with three previous control animals infected with LASV Z-132 (same route and dose) which succumbed to infection between days 10 and 13 post-challenge [32].

Bottom Line: Despite the high annual incidence and significant morbidity and mortality rates, currently there are no approved vaccines to prevent infection or disease in humans.Our results demonstrate the VSV-based LASV vaccine is capable of preventing morbidity and mortality associated with non-homologous LASV challenge in two animal models of Lassa fever.Additionally, this work highlights the need for the further development of disease models for geographical distinct LASV strains, particularly those from Nigeria, in order to comprehensively evaluate potential vaccines and therapies against this prominent agent of viral hemorrhagic fever.

View Article: PubMed Central - PubMed

Affiliation: Laboratory of Virology, Division of Intramural Research, Rocky Mountain Laboratories, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Hamilton, Montana, United States of America.

ABSTRACT

Background: Lassa virus (LASV) is endemic in several West African countries and is the etiological agent of Lassa fever. Despite the high annual incidence and significant morbidity and mortality rates, currently there are no approved vaccines to prevent infection or disease in humans. Genetically, LASV demonstrates a high degree of diversity that correlates with geographic distribution. The genetic heterogeneity observed between geographically distinct viruses raises concerns over the potential efficacy of a "universal" LASV vaccine. To date, several experimental LASV vaccines have been developed; however, few have been evaluated against challenge with various genetically unique Lassa virus isolates in relevant animal models.

Methodologies/principle findings: Here we demonstrate that a single, prophylactic immunization with a recombinant vesicular stomatitis virus (VSV) expressing the glycoproteins of LASV strain Josiah from Sierra Leone protects strain 13 guinea pigs from infection / disease following challenge with LASV isolates originating from Liberia, Mali and Nigeria. Similarly, the VSV-based LASV vaccine yields complete protection against a lethal challenge with the Liberian LASV isolate in the gold-standard macaque model of Lassa fever.

Conclusions/significance: Our results demonstrate the VSV-based LASV vaccine is capable of preventing morbidity and mortality associated with non-homologous LASV challenge in two animal models of Lassa fever. Additionally, this work highlights the need for the further development of disease models for geographical distinct LASV strains, particularly those from Nigeria, in order to comprehensively evaluate potential vaccines and therapies against this prominent agent of viral hemorrhagic fever.

Show MeSH
Related in: MedlinePlus