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A Single Dose Respiratory Recombinant Adenovirus-Based Vaccine Provides Long-Term Protection for Non-Human Primates from Lethal Ebola Infection.

Choi JH, Jonsson-Schmunk K, Qiu X, Shedlock DJ, Strong J, Xu JX, Michie KL, Audet J, Fernando L, Myers MJ, Weiner D, Bajrovic I, Tran LQ, Wong G, Bello A, Kobinger GP, Schafer SC, Croyle MA - Mol. Pharm. (2014)

Bottom Line: All primates succumbed to infection.Three primates were immunized with 2.0×10(10) ivp/kg of vaccine by the SL route.To our knowledge, this is the first time that durable protection from a single dose respiratory adenovirus-based Ebola vaccine has been demonstrated in primates.

View Article: PubMed Central - PubMed

Affiliation: †Division of Pharmaceutics, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712, United States.

ABSTRACT
As the Ebola outbreak in West Africa continues and cases appear in the United States and other countries, the need for long-lasting vaccines to preserve global health is imminent. Here, we evaluate the long-term efficacy of a respiratory and sublingual (SL) adenovirus-based vaccine in non-human primates in two phases. In the first, a single respiratory dose of 1.4×10(9) infectious virus particles (ivp)/kg of Ad-CAGoptZGP induced strong Ebola glycoprotein (GP) specific CD8+ and CD4+ T cell responses and Ebola GP-specific antibodies in systemic and mucosal compartments and was partially (67%) protective from challenge 62 days after immunization. The same dose given by the SL route induced Ebola GP-specific CD8+ T cell responses similar to that of intramuscular (IM) injection, however, the Ebola GP-specific antibody response was low. All primates succumbed to infection. Three primates were then given the vaccine in a formulation that improved the immune response to Ebola in rodents. Three primates were immunized with 2.0×10(10) ivp/kg of vaccine by the SL route. Diverse populations of polyfunctional Ebola GP-specific CD4+ and CD8+ T cells and significant anti-Ebola GP antibodies were present in samples collected 150 days after respiratory immunization. The formulated vaccine was fully protective against challenge 21 weeks after immunization. While diverse populations of Ebola GP-specific CD4+ T cells were produced after SL immunization, antibodies were not neutralizing and the vaccine was unprotective. To our knowledge, this is the first time that durable protection from a single dose respiratory adenovirus-based Ebola vaccine has been demonstrated in primates.

No MeSH data available.


Related in: MedlinePlus

Study 2: Clinical parametersdemonstrating transient changes afterimmunization of naive non-human primates and those with pre-existingimmunity to adenovirus immunized by various routes. Naive cynomolgusmacaques were given a single dose of vaccine by the respiratory (IN/IT)or the SL routes. A separate group of animals first received a doseof an adenovirus serotype 5 host range mutant virus 42 days priorto immunization. Each line represents alterations for each parameterafter immunization for one individual primate. Blue lines/triangles:IN/IT immunization. Black lines/squares: SL immunization (primateswith pre-existing immunity to adenovirus). Orange lines/diamonds:SL immunization (naive primates).
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fig8: Study 2: Clinical parametersdemonstrating transient changes afterimmunization of naive non-human primates and those with pre-existingimmunity to adenovirus immunized by various routes. Naive cynomolgusmacaques were given a single dose of vaccine by the respiratory (IN/IT)or the SL routes. A separate group of animals first received a doseof an adenovirus serotype 5 host range mutant virus 42 days priorto immunization. Each line represents alterations for each parameterafter immunization for one individual primate. Blue lines/triangles:IN/IT immunization. Black lines/squares: SL immunization (primateswith pre-existing immunity to adenovirus). Orange lines/diamonds:SL immunization (naive primates).

Mentions: In contrastto the first study, a notable spike in creatine phosphokinase (CPK)was detected in the serum of all animals 24 h after immunization (Figure 8A). This enzyme increased to 8 times baseline inone animal immunized by the IN/IT route (810003, 8,209 IU/L) and to10 times baseline in a primate with pre-existing immunity to adenovirusimmunized by the sublingual route (804819, 4,483). A notable spikein serum lactate dehydrogenase (LDH) was also noted at the 24 h timepoint. This was not as sharp as that seen with CPK with the highestelevations found to be approximately 3 times baseline (804317, 849IU/L, Figure 8B). Both parameters returnedto normal within 3 days after treatment. As seen in the first study,serum AST increased in all primates after immunization. This occurredat the 24 h time point for animals immunized by the respiratory andsublingual routes but was not observed in primates with pre-existingimmunity to adenovirus until 48 h (Figure 8C). As in the first study, serum alkaline phosphatase (ALP) levelsvaried between primates, however, in this trial a distinct drop inthis parameter was noted in samples collected from most animals betweenthe 6 and 24 h time points, after which values remained constant (Figure 8D). Other serological parameters evaluated duringthe first week after immunization (calcium, creatinine, albumin, globulin,total protein, gamma glutamyl transferase (GGT), total bilirubin,alanine aminotransferase (ALT), BUN, glucose, sodium, potassium, phosphate,chloride, and cholesterol) all fell within normal limits throughoutthe course of the study (data not shown).


A Single Dose Respiratory Recombinant Adenovirus-Based Vaccine Provides Long-Term Protection for Non-Human Primates from Lethal Ebola Infection.

Choi JH, Jonsson-Schmunk K, Qiu X, Shedlock DJ, Strong J, Xu JX, Michie KL, Audet J, Fernando L, Myers MJ, Weiner D, Bajrovic I, Tran LQ, Wong G, Bello A, Kobinger GP, Schafer SC, Croyle MA - Mol. Pharm. (2014)

Study 2: Clinical parametersdemonstrating transient changes afterimmunization of naive non-human primates and those with pre-existingimmunity to adenovirus immunized by various routes. Naive cynomolgusmacaques were given a single dose of vaccine by the respiratory (IN/IT)or the SL routes. A separate group of animals first received a doseof an adenovirus serotype 5 host range mutant virus 42 days priorto immunization. Each line represents alterations for each parameterafter immunization for one individual primate. Blue lines/triangles:IN/IT immunization. Black lines/squares: SL immunization (primateswith pre-existing immunity to adenovirus). Orange lines/diamonds:SL immunization (naive primates).
© Copyright Policy - editor-choice
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4525323&req=5

fig8: Study 2: Clinical parametersdemonstrating transient changes afterimmunization of naive non-human primates and those with pre-existingimmunity to adenovirus immunized by various routes. Naive cynomolgusmacaques were given a single dose of vaccine by the respiratory (IN/IT)or the SL routes. A separate group of animals first received a doseof an adenovirus serotype 5 host range mutant virus 42 days priorto immunization. Each line represents alterations for each parameterafter immunization for one individual primate. Blue lines/triangles:IN/IT immunization. Black lines/squares: SL immunization (primateswith pre-existing immunity to adenovirus). Orange lines/diamonds:SL immunization (naive primates).
Mentions: In contrastto the first study, a notable spike in creatine phosphokinase (CPK)was detected in the serum of all animals 24 h after immunization (Figure 8A). This enzyme increased to 8 times baseline inone animal immunized by the IN/IT route (810003, 8,209 IU/L) and to10 times baseline in a primate with pre-existing immunity to adenovirusimmunized by the sublingual route (804819, 4,483). A notable spikein serum lactate dehydrogenase (LDH) was also noted at the 24 h timepoint. This was not as sharp as that seen with CPK with the highestelevations found to be approximately 3 times baseline (804317, 849IU/L, Figure 8B). Both parameters returnedto normal within 3 days after treatment. As seen in the first study,serum AST increased in all primates after immunization. This occurredat the 24 h time point for animals immunized by the respiratory andsublingual routes but was not observed in primates with pre-existingimmunity to adenovirus until 48 h (Figure 8C). As in the first study, serum alkaline phosphatase (ALP) levelsvaried between primates, however, in this trial a distinct drop inthis parameter was noted in samples collected from most animals betweenthe 6 and 24 h time points, after which values remained constant (Figure 8D). Other serological parameters evaluated duringthe first week after immunization (calcium, creatinine, albumin, globulin,total protein, gamma glutamyl transferase (GGT), total bilirubin,alanine aminotransferase (ALT), BUN, glucose, sodium, potassium, phosphate,chloride, and cholesterol) all fell within normal limits throughoutthe course of the study (data not shown).

Bottom Line: All primates succumbed to infection.Three primates were immunized with 2.0×10(10) ivp/kg of vaccine by the SL route.To our knowledge, this is the first time that durable protection from a single dose respiratory adenovirus-based Ebola vaccine has been demonstrated in primates.

View Article: PubMed Central - PubMed

Affiliation: †Division of Pharmaceutics, College of Pharmacy, The University of Texas at Austin, Austin, Texas 78712, United States.

ABSTRACT
As the Ebola outbreak in West Africa continues and cases appear in the United States and other countries, the need for long-lasting vaccines to preserve global health is imminent. Here, we evaluate the long-term efficacy of a respiratory and sublingual (SL) adenovirus-based vaccine in non-human primates in two phases. In the first, a single respiratory dose of 1.4×10(9) infectious virus particles (ivp)/kg of Ad-CAGoptZGP induced strong Ebola glycoprotein (GP) specific CD8+ and CD4+ T cell responses and Ebola GP-specific antibodies in systemic and mucosal compartments and was partially (67%) protective from challenge 62 days after immunization. The same dose given by the SL route induced Ebola GP-specific CD8+ T cell responses similar to that of intramuscular (IM) injection, however, the Ebola GP-specific antibody response was low. All primates succumbed to infection. Three primates were then given the vaccine in a formulation that improved the immune response to Ebola in rodents. Three primates were immunized with 2.0×10(10) ivp/kg of vaccine by the SL route. Diverse populations of polyfunctional Ebola GP-specific CD4+ and CD8+ T cells and significant anti-Ebola GP antibodies were present in samples collected 150 days after respiratory immunization. The formulated vaccine was fully protective against challenge 21 weeks after immunization. While diverse populations of Ebola GP-specific CD4+ T cells were produced after SL immunization, antibodies were not neutralizing and the vaccine was unprotective. To our knowledge, this is the first time that durable protection from a single dose respiratory adenovirus-based Ebola vaccine has been demonstrated in primates.

No MeSH data available.


Related in: MedlinePlus