Safety testing for neurovirulence of novel live, attenuated flavivirus vaccines: Infant mice provide an accurate surrogate for the test in monkeys

Monath, Thomas P.; Myers, Gene; Beck, Robert A.; Knauber, Michael; Scappaticci, Kelly; Pullano, Thad; Archambault, W. Tad; Catalan, John; Miller, Catherine M.; Zhang, Zhenxi; Shin, Sunheang; Пугачев, К. В.; Draper, Ken; Levenbook, Inessa S.; Guirakhoo, Farshad

doi:10.1016/j.biologicals.2005.03.009

Cited by 57 publications

(33 citation statements)

References 22 publications

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“…One such model in suckling mice has been shown to be an acceptable alternative to NHP models. 18 After i.c. inoculation in both mice and NHPs, all four CYD viruses were significantly attenuated, even compared with the parental YFV 17D vaccine.…”

Section: Preclinical Evaluationmentioning

confidence: 99%

Development of sanofi pasteur tetravalent dengue vaccine

Guy

Saville²,

Lang³

2010

Human Vaccines

113

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The Sanofi Pasteur tetravalent dengue vaccine candidate is composed of four recombinant live attenuated vaccines based on a yellow fever vaccine 17D (YFv 17D) backbone, each expressing the prM and envelope genes of one of the four dengue virus serotypes. Pre-clinical studies have demonstrated that the Tv dengue vaccine is genetically and phenotypically stable, non-hepatotropic, less neurovirulent than YFv 17D and does not infect mosquitoes by the oral route. in vitro and in vivo preclinical studies also showed that the Tv dengue vaccine induced controlled stimulation in human dendritic cells and significant immune responses in monkeys. Tv dengue vaccine reactogenicity, viramia induction and antibody responses were investigated in three Phase i trials in the USA, the Philippines and Mexico, in a two or three-dose regimen over a 12 month period. results showed that the majority of adverse events were mild to moderate and transient in nature. viremia was transient and low, and was not increased after initial dengue Tv administration, even in the case of incomplete responses. fSeropositivity (≥10 in a PrNT 50 assay) was 100% for all four serotypes in flavivirus-naive adults injected with 3 doses of Tv dengue vaccine in the USA. Similarly, seropositivity was 88-100% following three administrations in flavivirus-naive Mexican children aged 2-5 years. Furthermore, the proportion of seropositive subjects increased with each dengue Tv injection in the Philippines where baseline flavivirus immunity was high. responses were also monitored at the cellular level in humans, and their level and nature were in good agreement with the observed safety and the immunogenicity of the vaccine. Finally, the challenges inherent to the development of such Tv dengue vaccines will also be discussed in the last part of this review.in conclusion, preclinical and clinical results support the favorable immunogenicity and short-term safety of the dengue Tv vaccine. An extensive clinical development program for dengue Tv is underway including completion of the enrollment of 4,000 4-11 years old children in an efficacy trial in Thailand, in an area of high dengue incidence. Assuming continued successful outcomes, initial submissions to regulatory authorities are envisaged within a 5-year period.

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Section: Preclinical Evaluationmentioning

confidence: 99%

Development of sanofi pasteur tetravalent dengue vaccine

Guy

Saville²,

Lang³

2010

Human Vaccines

113

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“…In spite of the fact that monkeys do not show disease symptoms, the antibody responses in monkeys are qualitatively similar to those in human patients, and they become viremic after subcutaneous inoculation with live DENV, although in many instances the antibody titers and/or duration of viremia in humans is greater (23). Currently, this model is widely employed in pathogenicity and vaccine investigations (4,26,32).…”

mentioning

confidence: 99%

Primary and Secondary Infections ofMacaca fascicularisMonkeys with Asian and American Genotypes of Dengue Virus 2

Bernardo

Izquierdo

Prado

et al. 2008

Clin Vaccine Immunol

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The goal of this study was to compare the immune response and the protection capacity induced by the dengue virus 2 (DENV-2) American and Asian genotypes in Macaca fascicularis monkeys. Animals were infected with American or Asian DENV-2 strains and challenged 1 year later with a DENV-2 Asian genotype strain. The viremia and monkey antibody levels were similar for the different strains after primary and secondary infection; however, the functionality of the antibody response was different. A limited viral replication was demonstrated after the secondary infection in all the monkeys. No virus was isolated in tissue culture, while reverse transcription-PCR showed a late positive reaction in four of five challenged monkeys. The immunoglobulin M response pattern and the detection of antibodies to specific proteins by Western blotting supported the protection data. Despite the demonstration of the protective effect after homologous challenge, a strong anamnestic antibody response was observed.Dengue fever and dengue hemorrhagic fever/dengue shock syndrome (DHF/DSS) are caused by any of four closely related but antigenically distinct dengue virus (DENV) serotypes (DENV-1, DENV-2, DENV-3, and DENV-4).

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“…Thus the nonclinical and clinical behavior of chimeric YF vaccines can be measured against comparator groups that receive the commercial YF 17D vaccine. The safety of YF 17D vaccine and chimeric vaccines derived therefrom may be tested preclinically by intracerebral (IC) inoculation of mice and monkeys, and neurovirulence compared to parental YF 17D in dose response experiments (establishing PFU/LD 50 ) or by semiquantitative scoring of histopathologic lesions [34,56]. These methods (particularly dose response neurovirulence tests in infant mice) can detect the biological effects of single mutations [34].…”

Section: Chimeric Flaviviruses Using Yellow Fever 17d Vaccine As the mentioning

confidence: 99%

“…These assessments generally include evaluation of neuroinvasiveness and neurovirulence in suitable animal models [34], since all flaviviruses have the capacity to infect and cause damage to brain and spinal cord tissue. Viscerotropism or special pathogenic features may be more difficult to assess in animal models, but viremia (mean peak, mean duration, area under the curve), levels of virus replication in tissues of the host, tissue specific enzymes, and levels of proinflammatory cytokines may be useful markers [28,30].…”

Section: Molecular Construction and Rationale Designmentioning

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 testing for neurovirulence of novel live, attenuated flavivirus vaccines: Infant mice provide an accurate surrogate for the test in monkeys

Cited by 57 publications

References 22 publications

Development of sanofi pasteur tetravalent dengue vaccine

Development of sanofi pasteur tetravalent dengue vaccine

Primary and Secondary Infections ofMacaca fascicularisMonkeys with Asian and American Genotypes of Dengue Virus 2

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

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