Safety of an attenuated West Nile virus vaccine, live <i>Flavivirus</i> chimera in horses

Long, Maureen T.; Gibbs, E. P. J.; Mellencamp, M W; Zhang, S.; Barnett, D. Craig; Seino, Kathy K.; Beachboard, S. E.; Humphrey, Pamela P.

doi:10.2746/042516407x214473

Cited by 20 publications

(11 citation statements)

References 18 publications

(19 reference statements)

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“…Samples for pyrosequencing and array analysis consisted of 1) naïve horses infected intrathecally with 1×10 5 WNV/NY99/crow, 2) non naïve horses vaccinated utilizing a modified live attenuated Yellow Fever (YF) chimera vaccine for protection against WNV (Prevenile, Intervet-Schering-Plough) and infected intrathecally with 1×10 5 WNV/NY99/crow , and 3) horses that were not infected or vaccinated. Experimental infection and vaccination of horses occurred according to previously published data [4], [21], [22]. Horses from groups 1 and 2 were euthanized (University of Florida IACUC protocols #F077, #F093, #D163) if demonstrating clinical signs or at the end of the study (day 21) if not demonstrating clinical signs.…”

Section: Methodsmentioning

confidence: 99%

“…Neurological exams and clinical scoring were performed on horses in all groups weekly after vaccination and daily after infection for the horses exposed to WNV as according to previously published data [4], [21], [22]. Neurological exams and clinical scoring were also performed upon receipt for the normal control horses.…”

Section: Methodsmentioning

confidence: 99%

“…Comparatively, mice develop disease that is primarily focused in a cerebral and cerebellar localization of virus. Histopathologically, inflammatory lesions characterized by layer of monocellular perivascular cuffing and gliosis are present in horses, humans, and mice, while necrosis is the primary lesion in hamsters [3], [4]. This pathology is likely a result of many complex factors, as there is increasing evidence that the host response to viral infection is one of the main causes of pathology and survival during WNV infection in the CNS [5], [6].…”

Section: Introductionmentioning

confidence: 99%

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Gene Expression Analysis in the Thalamus and Cerebrum of Horses Experimentally Infected with West Nile Virus

et al. 2011

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Gene expression associated with West Nile virus (WNV) infection was profiled in the central nervous system of horses. Pyrosequencing and library annotation was performed on pooled RNA from the CNS and lymphoid tissues on horses experimentally infected with WNV (vaccinated and naïve) and non-exposed controls. These sequences were used to create a custom microarray enriched for neurological and immunological sequences to quantitate gene expression in the thalamus and cerebrum of three experimentally infected groups of horses (naïve/WNV exposed, vaccinated/WNV exposed, and normal).From the sequenced transcriptome, 41,040 sequences were identified by alignment against five databases. 31,357 good sequence hits (e<10−4) were obtained with 3.1% of the sequences novel to the equine genome project. Sequences were compared to human expressed sequence tag database, with 31,473 equine sequences aligning to human sequences (69.27% contigs, 78.13% seed contigs, 80.17% singlets). This indicated a high degree of sequence homology between human and equine transcriptome (average identity 90.17%).Significant differences (p<0.05) in gene expression were seen due to virus exposure (9,020), survival (7,395), and location (7,649). Pathways analysis revealed many genes that mapped to neurological and immunological categories. Involvement of both innate and adaptive components of immunity was seen, with higher levels of expression correlating with survival. This was highlighted by increased expression of suppressor of cytokine signaling 3 in horses exposed to WNV which functions to suppress innate immunity. Pentraxin 3 was most increased in expression for all horses exposed to WNV.Neurological pathways that demonstrated the greatest changes in gene expression included neurotransmitter and signaling pathways. Decreased expression of transcripts in both the glutamate and dopamine signaling pathways was seen in horses exposed to WNV, providing evidence of possible glutamate excitotoxicity and clinical signs associated with decreased dopamine. Many transcripts mapped to non-infectious neurological disease functions, including mental disorders and degenerative neuropathies.

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Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Gene Expression Analysis in the Thalamus and Cerebrum of Horses Experimentally Infected with West Nile Virus

et al. 2011

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“…West Nile Virus appeared in horses along the eastern seaboard of North America in 1999 and rapidly spread over the whole of the continent (Malan et al 2004 (Seino et al 2007, Long et al 2007a, Long et al 2007b. In November 2008, the first WNV vaccine (inactivated whole virus; Duvaxyn WNV ® , Fort Dodge) was approved by the European Medicines Agency (EMEA) for European use.…”

Section: Introductionmentioning

confidence: 99%

West Nile Virus Vaccination in Horses – IgM and IgG responses after injection in different muscles

Jonquière¹,

Heijden²,

Maanen³

et al. 2011

PHK

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West Nile Virus (WNV) may cause significant morbidity and mortality in birds, humans and horses. WNV is not (yet) present in the Netherlands, but it is steadily approaching from south-eastern Europe. Recently, a WNV-vaccine (Duvaxyn ® -WNV) became available in Europe. It is claimed that vaccination results not or only infrequently in an IgM response making it possible to differentiate acutely-infected horses from vaccinated horses by using an IgM-based ELISA. The aims of the study were to investigate the supposition that vaccination does not result in IgM production, to evaluate whether different intramuscular injection sites influence the immunological responses and whether any local or systemic adverse reactions would occur. Twenty horses and ponies, 3 to 21 years old, were divided into four groups and horses of each group were vaccinated twice (day 0 and 21) at different intramuscular sites (neck, pectoral muscles, rump and thigh). Weekly blood samples were collected over a period of 42 days and tested for Flavivirus IgM antibodies using a WNV-IgM ELISA and for Flavivirus Ig antibodies using a WNV blocking ELISA. None of the horses tested positive for WNV antibodies prior to vaccination. All horses showed a clear Ig (total antibody) response to the WNV vaccination, but in two horses this response was limited. Surprisingly, ten horses also gave a (limited) positive IgM response. This suggests that an IgM capture ELISA will not distinguish horses with an acute WNV infections from recently vaccinated horses with certainty. The location of the intramuscular injections had no significant effect on the immunogenic response. No systemic reactions were encountered nor were there local reactions at any of the injection sites.

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“…Safety of the vaccine was exhaustively studied, with emphasis on transmission to nontarget animals. Horses were given an overdose of virus, euthanized and examined for virus in tissues and pathological effects at 14 days postvaccination [144]. In addition, overdosed horses were evaluated for virus shedding and transmission to sentinel animals.…”

Section: Development Of a Veterinary Chimeric Wn/yf Vaccinementioning

confidence: 99%

Recombinant, Chimeric, Live, Attenuated Vaccines Against Flaviviruses and Alphaviruses

Monath¹

2010

Replicating Vaccines

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Many arthropod-borne flaviviruses are important human pathogens responsible for diverse illnesses, including yellow fever (YF), Japanese encephalitis (JE), and TBE and dengue. Live, attenuated vaccines have afforded the most effective and economical means of prevention and control, as illustrated by YF 17D and JE SA14-14-2 vaccines. Recent advances in recombinant DNA technology have made it possible to explore a novel approach for developing live attenuated flavivirus vaccines against other flaviviruses. Full-length cDNA clones allow construction of infectious virus bearing attenuating mutations or deletions incorporated in the viral genome. It is also possible to create chimeric flaviviruses in which the structural protein genes for the target antigens of a flavivirus are replaced by the corresponding genes of another flavivirus. By combining these molecular techniques, the DNA sequences of DEN4 containing a deletion in the 3 0 NCR, a DEN2 PDK-53 candidate vaccine and YF 17D vaccine have been used as the genetic backbone to construct chimeric flaviviruses with the required attenuation phenotype and expression of the target antigens. Encouraging results from preclinical and clinical studies have shown that several chimeric flavivirus vaccines have the safety profile and satisfactory immunogenicity and protective efficacy to warrant development as products for human use. The chimeric flavivirus strategy has led to the rapid development of novel live, attenuated vaccines against DEN, TBE, JE and WN. This chapter reviews an extensive body of work on the development of these vaccine candidates, one of which is licensed and others are in advanced clinical development.A similar approach is being used to create vaccines against alphaviruses. Here the experience is less, but some promising data have been developed, particularly using SIN virus as a vector for structural genes of heterologous alphaviruses. The principal issues for this technology will be to achieve convincing nonclinical data on safety, the proper balance of attenuation and immunogenicity, and proof of concept in large animal models and ultimately humans.

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Safety of an attenuated West Nile virus vaccine, live Flavivirus chimera in horses

Abstract: These studies establish that this live attenuated Flavivirus chimera is safe to use for immunoprophylaxis against WNV disease in horses.

Cited by 20 publications

References 18 publications

Gene Expression Analysis in the Thalamus and Cerebrum of Horses Experimentally Infected with West Nile Virus

Gene Expression Analysis in the Thalamus and Cerebrum of Horses Experimentally Infected with West Nile Virus

West Nile Virus Vaccination in Horses – IgM and IgG responses after injection in different muscles

Recombinant, Chimeric, Live, Attenuated Vaccines Against Flaviviruses and Alphaviruses

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