Heterologous Combination of ChAdOx1 and MVA Vectors Expressing Protein NS1 as Vaccination Strategy to Induce Durable and Cross-Protective CD8+ T Cell Immunity to Bluetongue Virus

Abstract

The sequence of non-structural protein NS1 of bluetongue virus (BTV), which contains immunodominant CD8+ T cell epitopes, is highly conserved among BTV serotypes, and has therefore become a major tool in the development of a universal BTV vaccine. In this work, we have engineered multiserotype BTV vaccine candidates based on recombinant chimpanzee adenovirus (ChAdOx1) and modified vaccinia virus Ankara (MVA) vectors expressing the NS1 protein of BTV-4 or its truncated form NS1-Nt. A single dose of ChAdOx1-NS1 or ChAdOx1-NS1-Nt induced a moderate CD8+ T cell response and protected IFNAR(-/-) mice against a lethal dose of BTV-4/MOR09, a reassortant strain between BTV-1 and BTV-4, although the animals showed low viremia after infection. Furthermore, IFNAR(-/-) mice immunized with a single dose of ChAdOx1-NS1 were protected after challenge with a lethal dose of BTV-8 in absence of viremia nor clinical signs. Additionally, the heterologous prime-boost ChAdOx1/MVA expressing NS1 or NS1-Nt elicited a robust NS1 specific CD8+ T cell response and protected the animals against BTV-4/MOR09 even 16 weeks after immunization, with undetectable levels of viremia at any time after challenge. Subsequently, the best immunization strategy based on ChAdOx1/MVA-NS1 was assayed in sheep. Non-immunized animals presented fever and viremia levels up to 104 PFU/mL after infection. In contrast, although viremia was detected in immunized sheep, the level of virus in blood was 100 times lower than in non-immunized animals in absence of clinical signs.

Viral Vector Vaccines against Bluetongue Virus

“…Additionally, vaccinated sheep were aviremic for an RVFV challenge (except one animal at day 3 postinfection), maintaining stable biochemical parameters (aspartate transaminase, gamma-glutamyltransferase, lactate dehydrogenase, and albumin), and had mild histological lesions compared with the nonvaccinated group, which indicated the bivalent character of the designed vaccine [ 44 ]. A similar trend was observed when MVA-NS1 was used as a booster of ChAdOx1-NS1 in a heterologous prime-boost immunization, as immunized sheep showed reduced levels of viremia and lower temperatures than the control group [ 43 ].…”

“…In this case, this heterologous immunization strategy based on BTV-4 antigens was able to protect IFNAR(−/−) mice against serotypes 1 and 4 [ 42 ]. Moreover, MVAs have been combined with other viral vectors, like chimpanzee adenovirus Oxford 1 (ChadOx1), which will be discussed later [ 43 ]. In this study, the protective immune effect of MVA-NS1 was also evaluated in mice in a single-dose vaccination experiment, observing a delay in mortality and partial protection against a lethal challenge of BTV.…”

“…Subsequently, the best immunization strategy, based on ChAdOx1/MVA-NS1, was assayed in sheep. Despite viremia being detected in immunized sheep, the level of virus in the blood was 100 times lower than in non-immunized animals, which also presented clinical signs and pyrexia [ 43 ]. This study reaffirmed the important role of the NS1 antigen in eliciting a multiserotype protective effect mediated by the activation of the cellular cytotoxic CD8+ responses and showed the strong capacity of ChAdOx1 as a vector vaccine, inducing protection and CD8+ T cell activation just with a single shot.…”

Inhibition of Orbivirus Replication by Aurintricarboxylic Acid

“…Orbiviruses, such as BTV and AHSV, cause serious damage to animal health and have a significant economic impact on society [ 9 , 23 , 26 ]. Currently, the best approach to prevent BTV and AHSV infections is vaccination, although this approach presents multiple limitations, and vaccine strategies need to be improved [ 12 , 26 , 27 , 28 , 29 , 30 , 31 ]. More importantly, although vaccines can prevent infections creating protective immunity, they are not an effective method to treat infected animals, which usually need to be sacrificed causing important economic losses.…”

“…Vaccination is considered the most effective approach to protect against BTV or AHSV infections [ 12 , 26 , 27 , 28 , 29 , 30 , 31 ]. However, the control of these viral infections is a difficult task due to uncontrolled vector propagation, the number of circulating serotypes in combination with the lack of cross-protection between them, and the wide host range [ 5 , 6 , 7 , 8 , 9 , 25 , 32 ].…”