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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 affords better protection than VSVG/LASVNP against a lethal homologous challenge in strain 13 guinea pigs.Adult, inbred strain 13 guinea pigs were immunized with 1 x106 pfu of VSVΔG/LASVGPC (n = 9), VSVG/LASVNP (n = 9) or VSVΔG/ANDVGPC (n = 4) and challenged 28 days later with a lethal dose of Lassa virus strain Josiah. Animals were monitored for disease progression for 45 days. At the time when control (VSVΔG/ANDVGPC immunized) animals demonstrated signs of advanced disease requiring euthanasia, three animals per group were euthanized and samples collected for virological analysis (inset). * p = 0.0048
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pntd.0003736.g001: VSVΔG/LASVGPC affords better protection than VSVG/LASVNP against a lethal homologous challenge in strain 13 guinea pigs.Adult, inbred strain 13 guinea pigs were immunized with 1 x106 pfu of VSVΔG/LASVGPC (n = 9), VSVG/LASVNP (n = 9) or VSVΔG/ANDVGPC (n = 4) and challenged 28 days later with a lethal dose of Lassa virus strain Josiah. Animals were monitored for disease progression for 45 days. At the time when control (VSVΔG/ANDVGPC immunized) animals demonstrated signs of advanced disease requiring euthanasia, three animals per group were euthanized and samples collected for virological analysis (inset). * p = 0.0048

Mentions: In the first experiment we sought to determine if immunization with a vaccine construct expressing the LASV nucleocapsid protein would provide similar levels of protection as a construct expressing the glycoproteins. Following challenge with LASV Josiah, mock-immunized guinea pigs began showing signs of disease including lethargy and weight loss around day 12, which progressed to terminal disease in all animals between days 16 and 18. Similar to the original description of the VSV LASV vaccine [23], animals immunized with VSVΔG/LASVGPC were completely protected against challenge with LASV Josiah and did not demonstrate any signs of disease throughout the course of the experiment (p = 0.0048). In contrast, all animals immunized with VSVG/LASVNP demonstrated signs of infection, including lethargy and weight loss averaging between 10 and 20% of the initial body weight. Disease progression in these animals mirrored that of the control group and ultimately two of six animals in the vaccinated group succumbed to infection, resulting in a survival rate of 66.6% (p = 0.0714, Fig 1). Analysis of viral loads in tissue samples supported the survival data in that infectious LASV could not be isolated from any sample collected from animals immunized with VSVΔG/LASVGPC, whereas tissue titers from animals immunized with VSVG/LASVNP were similar to those of the controls (Fig 1, inset). Although the VSVG/LASVNP construct afforded some protection against lethality in the guinea pig model, all animals experienced significant morbidity. Therefore, the subsequent non-homologous challenge experiments were conducted only with VSVΔG/LASVGPC.


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 affords better protection than VSVG/LASVNP against a lethal homologous challenge in strain 13 guinea pigs.Adult, inbred strain 13 guinea pigs were immunized with 1 x106 pfu of VSVΔG/LASVGPC (n = 9), VSVG/LASVNP (n = 9) or VSVΔG/ANDVGPC (n = 4) and challenged 28 days later with a lethal dose of Lassa virus strain Josiah. Animals were monitored for disease progression for 45 days. At the time when control (VSVΔG/ANDVGPC immunized) animals demonstrated signs of advanced disease requiring euthanasia, three animals per group were euthanized and samples collected for virological analysis (inset). * p = 0.0048
© Copyright Policy
Related In: Results  -  Collection

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

pntd.0003736.g001: VSVΔG/LASVGPC affords better protection than VSVG/LASVNP against a lethal homologous challenge in strain 13 guinea pigs.Adult, inbred strain 13 guinea pigs were immunized with 1 x106 pfu of VSVΔG/LASVGPC (n = 9), VSVG/LASVNP (n = 9) or VSVΔG/ANDVGPC (n = 4) and challenged 28 days later with a lethal dose of Lassa virus strain Josiah. Animals were monitored for disease progression for 45 days. At the time when control (VSVΔG/ANDVGPC immunized) animals demonstrated signs of advanced disease requiring euthanasia, three animals per group were euthanized and samples collected for virological analysis (inset). * p = 0.0048
Mentions: In the first experiment we sought to determine if immunization with a vaccine construct expressing the LASV nucleocapsid protein would provide similar levels of protection as a construct expressing the glycoproteins. Following challenge with LASV Josiah, mock-immunized guinea pigs began showing signs of disease including lethargy and weight loss around day 12, which progressed to terminal disease in all animals between days 16 and 18. Similar to the original description of the VSV LASV vaccine [23], animals immunized with VSVΔG/LASVGPC were completely protected against challenge with LASV Josiah and did not demonstrate any signs of disease throughout the course of the experiment (p = 0.0048). In contrast, all animals immunized with VSVG/LASVNP demonstrated signs of infection, including lethargy and weight loss averaging between 10 and 20% of the initial body weight. Disease progression in these animals mirrored that of the control group and ultimately two of six animals in the vaccinated group succumbed to infection, resulting in a survival rate of 66.6% (p = 0.0714, Fig 1). Analysis of viral loads in tissue samples supported the survival data in that infectious LASV could not be isolated from any sample collected from animals immunized with VSVΔG/LASVGPC, whereas tissue titers from animals immunized with VSVG/LASVNP were similar to those of the controls (Fig 1, inset). Although the VSVG/LASVNP construct afforded some protection against lethality in the guinea pig model, all animals experienced significant morbidity. Therefore, the subsequent non-homologous challenge experiments were conducted only with VSVΔG/LASVGPC.

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