Vaccination of Pigs against Swine Influenza Viruses by Using an NS1-Truncated Modified Live-Virus Vaccine

Richt, Jürgen A.; Lekcharoensuk, Porntippa; Lager, Kelly M.; Vincent, Amy L.; Loiacono, Christina M.; Janke, Bruce H.; Wu, Wai-Hong; Yoon, Kyoung‐Jin; Webby, Richard J.; Solórzano, Alicia; Garcı́a-Sastre, Adolfo

doi:10.1128/jvi.00787-06

Cited by 163 publications

(144 citation statements)

References 56 publications

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“…It was hypothesized that this class of mutant viruses would elicit robust adaptive immune responses, despite attenuated replication, because restraints on the early innate response would be relaxed. Indeed, viruses with deleted or truncated NS1 have been shown to protect against virulent challenge in mice and pigs [20,29]. A recent study investigated adaptive immune responses in mice given intranasal inoculation with H1N1 strain A/Puerto Rico/8/1934 (PR8) mutated by deletion or truncations of NS1 [30].…”

Section: Discussionmentioning

confidence: 99%

“…Molecular approaches have been used to construct mutated SIV genomes which confer attenuated replication properties, including reduced NS1 suppression of type I interferon, dependence on the enzyme elastase for HA cleavage, and temperature-sensitive mutations in polymerase genes [17][18][19]. Truncation of NS1 protein in triple reassortant H3N2 strain A/Sw/Texas/4199-2/98, from a length of 230 amino acids to 126, produced a mutant with restricted replication in the swine respiratory tract but strong immunogenic properties [20]. Intranasal inoculation of pigs with this virus (NS1 126 TX98) resulted in robust protection against homologous challenge and significantly reduced viral replication and clinical signs upon challenge with a drift variant strain [21].…”

Section: Introductionmentioning

confidence: 99%

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Vaccination with NS1-truncated H3N2 swine influenza virus primes T cells and confers cross-protection against an H1N1 heterosubtypic challenge in pigs

Kappes

Sandbulte

Platt

et al. 2012

Vaccine

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The diversity of contemporary swine influenza virus (SIV) strains impedes effective immunization of swine herds. Mucosally delivered, attenuated virus vaccines are one approach with potential to provide broad crossprotection. Reverse genetics-derived H3N2 SIV virus with truncated NS1 (NS1Δ126 TX98) is attenuated and immunogenic when delivered intranasally in young pigs. We analyzed T-cell priming and cross-protective efficacy in weanling piglets after intranasal inoculation with NS1Δ126 TX98 versus wild type TX98. In vivo replication of the truncation mutant was minimal compared to the wild type virus. T-cell responses were greater in magnitude in pigs infected with the wild type virus in in vitro restimulation assays. According to the expression of activation marker CD25, peripheral T cell recall responses in NS1Δ126 TX98 infected pigs were minimal. However, intracellular IFN-γ data indicate that the attenuated virus induced virus-specific CD4 + CD8 -, CD4 + CD8 + , CD4 -CD8 + , and γδ T cells within 28 days. The IFN-γ response appeared to contract, as responses were reduced at later time points prior to challenge. CD4 + CD8 + cells isolated 5 days after heterosubtypic H1N1 challenge (day 70 overall) showed an elevated CD25 response to virus restimulation. Pigs previously infected with wild type TX98 were protected from replication of the H1N1 challenge virus. Vaccination with NS1Δ126 TX98 was associated with significantly lower levels of Th1-associated cytokines in infected lungs but provided partial cross-protection against the H1N1 challenge. These results demonstrate that NS1Δ SIV vaccines can elicit cell-mediated cross-protection against antigenically divergent strains. The diversity of contemporary swine influenza virus (SIV) strains impedes effective immunization of swine herds. Mucosally delivered, attenuated virus vaccines are one approach with potential to provide broad cross-protection. Reverse genetics-derived H3N2 SIV virus with truncated NS1 (NS1 126 TX98) is attenuated and immunogenic when delivered intranasally in young pigs. We analyzed T-cell priming and cross-protective efficacy in weanling piglets after intranasal inoculation with NS1 126 TX98 versus wild type TX98. In vivo replication of the truncation mutant was minimal compared to the wild type virus. T-cell responses were greater in magnitude in pigs infected with the wild type virus in in vitro restimulation assays. According to the expression of activation marker CD25, peripheral T cell recall responses in NS1 126 TX98 infected pigs were minimal. However, intracellular IFN-␥ data indicate that the attenuated virus induced virus-specific CD4 + CD8 -, CD4 + CD8 + , CD4 -CD8 + , and ␥␦ T cells within 28 days. The IFN-␥ response appeared to contract, as responses were reduced at later time points prior to challenge. CD4 + CD8 + cells isolated 5 days after heterosubtypic H1N1 challenge (day 70 overall) showed an elevated CD25 response to virus restimulation. Pigs previously infected with wild type TX98 were protected from replicatio...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Vaccination with NS1-truncated H3N2 swine influenza virus primes T cells and confers cross-protection against an H1N1 heterosubtypic challenge in pigs

Kappes

Sandbulte

Platt

et al. 2012

Vaccine

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“…In addition to the cold-adapted, temperature-sensitive strains used in the available human and equine vaccines, NS-1 deletion mutants have been demonstrated to be highly attenuated in a natural host [7]. In addition, the NS-1 mutant viruses are capable of stimulating a protective immune response as demonstrated against the homologous wild type virus and partial protection against a heterosubtypic virus after intratracheal application [8]. The need for swine vaccines that stimulate broader crossprotection against heterologous SIV is great due to the current milieu of various subtypes and genetic variants within subtypes circulating in the U.S. swine population.…”

Section: Introductionmentioning

confidence: 99%

Efficacy of intranasal administration of a truncated NS1 modified live influenza virus vaccine in swine

Vincent

Lager

et al. 2007

Vaccine

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127

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In the U.S., despite available swine influenza virus (SIV) vaccines, multiple influenza subtypes as well as antigenic and genetic variants within subtypes continue to circulate in the swine population. One of the challenges to control and eliminate SIV is that the currently used inactivated influenza virus vaccines do not provide adequate cross-protection against multiple antigenic variants of SIV in the field. We previously generated a recombinant H3N2 swine influenza virus (SIV) based on the influenza A/SW/TX/4199-2/98 virus (TX98) containing an NS1 gene expressing a truncated NS1 protein of 126 amino acids, TX98-NS1Δ126 virus. This recombinant strain was demonstrated to be highly attenuated in swine and showed potential for use as a modified live-virus vaccine (MLV) after intratracheal application in pigs. However, this route of inoculation is not practical for vaccination in the field. In the present study, we first compared intramuscular and intranasal routes of application of the MLV, and found that the intranasal route was superior in priming the local (mucosal) immune response. Pigs were then vaccinated via the intranasal route and challenged with wild type homologous TX98 H3N2 virus, with a genetic and antigenic variant H3N2 SIV (influenza A/SW/ CO/23619/99 virus, CO99) and a heterosubtypic H1N1 SIV (influenza A/SW/IA/00239/2004 virus, IA04). The intranasally vaccinated pigs were completely protected against homologous challenge. In addition, MLV vaccination provided nearly complete protection against the antigenic H3N2 variant CO99 virus. When challenged with the H1N1 IA04 virus, MLV vaccinated animals displayed reduced fever and virus titers despite minimal reduction in lung lesions. In vaccinated pigs, there was no serologic cross-reactivity by HI assays with the heterologous or heterosubtypic viruses. However, there appeared to be substantial cross-reactivity in antibodies at the mucosal level with the CO99 virus in MLV vaccinated pigs.

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“…These LAIV are attenuated based on the incorporation of cold-adapted (ca) and/or temperature sensitive (ts) phenotypes into vaccine strains by recombination with a donor strain or by multiple passages of the vaccine strain at low temperatures (47)(48)(49). Several different experimental live attenuated SIV vaccines have been demonstrated to induce strong cell-mediated immunity (CMI) and humoral immunity, as well as cross-protection against homologous heterotypic and heterologous SIV isolates (11,16). Even though these experimental SIV LAIV have advantages over their inactivated counterparts, no LAIV is currently registered for use against SIV infections worldwide.…”

Section: Discussionmentioning

confidence: 99%

“…Previously, it was shown that SIVs generated by genetic modifications within the hemagglutinin (HA) or nonstructural (NS) genes are attenuated in pigs (12,13). These viruses demonstrated the ability to induce strong cell-mediated and humoral immunity and to provide full protection against homologous SIVs and partial protection against heterologous SIVs (11,(14)(15)(16)(17). In this study, we describe a novel approach that generates a LAIV candidate containing an H3 subtype of HA derived from a circulating SIV in the genetic background of H1N1 SIV.…”

mentioning

confidence: 99%

An Eight-Segment Swine Influenza Virus Harboring H1 and H3 Hemagglutinins Is Attenuated and Protective against H1N1 and H3N2 Subtypes in Pigs

Mašić

Pyo

Babiuk

et al. 2013

J Virol

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Swine influenza virus (SIV) infections continue to cause production losses in the agricultural industry in addition to being a human public health concern. The primary method of controlling SIV is through vaccination. The killed SIV vaccines currently in use must be closely matched to the challenge virus, and their protective efficacy is limited. Live attenuated influenza vaccines (LAIV) provide strong, long-lived cell-mediated and humoral immunity against different influenza virus subtypes with no need for antigen matching. Here we report the generation of a new potential LAIV, an eight-segment SIV harboring two different SIV hemagglutinins (HAs), H1 and H3, in the genetic background of H1N1 SIV. This mutant SIV was generated by fusing the H3 HA ectodomain from A/Swine/Texas/4199-2/98 (H3N2) to the cytoplasmic tail, transmembrane domain, and stalk region of neuraminidase (NA) from A/Swine/Saskatchewan/18789/02 (H1N1) SIV. While this H1-H3 chimeric SIV, when propagated in vitro in the presence of exogenous neuraminidase, showed kinetics and growth properties similar to those of the parental wild-type virus, in vivo it was highly attenuated in pigs, demonstrating a great potential for serving as a dual LAIV. Furthermore, vaccination with the H1-H3 virus elicited robust immune responses, which conferred complete protection against infections with both H1 and H3 SIV subtypes in pigs.

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Vaccination of Pigs against Swine Influenza Viruses by Using an NS1-Truncated Modified Live-Virus Vaccine

Cited by 163 publications

References 56 publications

Vaccination with NS1-truncated H3N2 swine influenza virus primes T cells and confers cross-protection against an H1N1 heterosubtypic challenge in pigs

Vaccination with NS1-truncated H3N2 swine influenza virus primes T cells and confers cross-protection against an H1N1 heterosubtypic challenge in pigs

Efficacy of intranasal administration of a truncated NS1 modified live influenza virus vaccine in swine

An Eight-Segment Swine Influenza Virus Harboring H1 and H3 Hemagglutinins Is Attenuated and Protective against H1N1 and H3N2 Subtypes in Pigs

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