Section on Safety of Medicines and Teratology, Centre for Biological Medicines and Medical Technology, National Institute for Public Health and the Environment, PO Box 1, 3720 BA Bilthoven, The Netherlands.
The threat of a pandemic outbreak of influenza A H5N1 and H2N2 has brought attention to the development of new vaccines. Regulatory authorities require companies to provide data proving the effectiveness of vaccines, which cannot, however, be based on real efficacy data in humans. A weight-of-evidence approach may be used, based on evidence of protection in an appropriate animal model and the satisfaction of the surrogate end points in the clinical situation. In this review, we will discuss various animal species that can be infected with influenza. The main animals used for testing vaccines destined for human use are laboratory mice and ferrets and, to a lesser extent, macaques. We will focus particularly on these species.
"A ferret model was used in this study as ferrets resemble disease in humans when infected with Influenza A viruses ,. This ferret model is also the gold standard to demonstrate both the immunogenicity and the protective efficacy of Influenza vaccines ,,,,. "
[Show abstract][Hide abstract] ABSTRACT: We investigated the protective efficacy of two intranasal chitosan (CSN and TM-CSN) adjuvanted H5N1 Influenza vaccines against highly pathogenic avian Influenza (HPAI) intratracheal and intranasal challenge in a ferret model.
Six groups of 6 ferrets were intranasally vaccinated twice, 21 days apart, with either placebo, antigen alone, CSN adjuvanted antigen, or TM-CSN adjuvanted antigen. Homologous and intra-subtypic antibody cross-reacting responses were assessed. Ferrets were inoculated intratracheally (all treatments) or intranasally (CSN adjuvanted and placebo treatments only) with clade 1 HPAI A/Vietnam/1194/2004 (H5N1) virus 28 days after the second vaccination and subsequently monitored for morbidity and mortality outcomes. Clinical signs were assessed and nasal as well as throat swabs were taken daily for virology. Samples of lung tissue, nasal turbinates, brain, and olfactory bulb were analysed for the presence of virus and examined for histolopathological findings.
In contrast to animals vaccinated with antigen alone, the CSN and TM-CSN adjuvanted vaccines induced high levels of antibodies, protected ferrets from death, reduced viral replication and abrogated disease after intratracheal challenge, and in the case of CSN after intranasal challenge. In particular, the TM-CSN adjuvanted vaccine was highly effective at eliciting protective immunity from intratracheal challenge; serologically, protective titres were demonstrable after one vaccination. The 2-dose schedule with TM-CSN vaccine also induced cross-reactive antibodies to clade 2.1 and 2.2 H5N1 viruses. Furthermore ferrets immunised with TM-CSN had no detectable virus in the respiratory tract or brain, whereas there were signs of virus in the throat and lungs, albeit at significantly reduced levels, in CSN vaccinated animals.
This study demonstrated for the first time that CSN and in particular TM-CSN adjuvanted intranasal vaccines have the potential to protect against significant mortality and morbidity arising from infection with HPAI H5N1 virus.
PLoS ONE 05/2014; 9(5):e93761. DOI:10.1371/journal.pone.0093761 · 3.23 Impact Factor
"To evaluate effective therapies and elucidate influenza pathogenesis, it is essential to have laboratory animal models that replicated the major features of illness in human. The animal models currently in use for influenza include mice, ferrets, rats , pigs , cats , dogs , and nonhuman primates . Mice and ferrets are currently the most intensively employed models, and mice remain the primary model due to their cost, inbreeding, and ability to utilize genetically modified animals. "
[Show abstract][Hide abstract] ABSTRACT: Well-characterized mice models will afford a cheaper, easy-handling opportunity for a more comprehensive understanding of 2009 influenza A (H1N1) virus's pathogenesis potential. We aimed to provide a robust description of pulmonary immune responses in the mice infected by the virus.
BALB/c mice were inoculated intranasally with A/Beijing/501/2009 (H1N1) (BJ501) and A/PR/8/34 (H1N1) (PR8) viruses and compared for survival rate, viral replication, and kinetics of pulmonary immune responses.
BJ501 virus replicated less efficiently in the lungs than PR8, and both caused lethal illness in the mice. The transient increases of pulmonary TNF-alpha 2 days post infection for BJ501 and of INF-gamma and IL-10 at 6 days post infection for PR8 were observed. IL-2+ and IL-4+ secreting cells showed significant increase 12 days post infection, while IFN-gamma+, IgG+ and IgA+ secreting cells increased 6 days post infection. The different patterns of pulmonary immunological parameters between two viruses were at most seen in IL-6, IL-17 secretion and IgG1/IgG2a ratio.
The BALB/c mouse is evaluated as a good pathogenic model for studying BJ501 2009 H1N1 virus. The work provided some basic and detailed data, which might be referred when further evaluating innate and adapted pulmonary immune responses and local viral load in mice.
"As well, exogenous peptide was added to an H1N1-2009 HA DNA vaccine and efficacy was evaluated in ferrets to test the efficacy of 5mer4 in a different animal species relevant to influenza infection. Ferrets display similar clinical symptoms as humans, including disease progression, viral pathogenesis, and immune responses  (reviewed in  and ). It is, therefore, a good pre-clinical model to further assess the efficacy of combining 5mer4 with an HA vaccine and a system to measure changes in humoral and cellular immune responses. "
[Show abstract][Hide abstract] ABSTRACT: Certain short peptides do not occur in humans and are rare or non-existent in the universal proteome. Antigens that contain rare amino acid sequences are in general highly immunogenic and may activate different arms of the immune system. We first generated a list of rare, semi-common, and common 5-mer peptides using bioinformatics tools to analyze the UniProtKB database. Experimental observations indicated that rare and semi-common 5-mers generated stronger cellular responses in comparison with common-occurring sequences. We hypothesized that the biological process responsible for this enhanced immunogenicity could be used to positively modulate immune responses with potential application for vaccine development. Initially, twelve rare 5-mers, 9-mers, and 13-mers were incorporated in frame at the end of an H5N1 hemagglutinin (HA) antigen and expressed from a DNA vaccine. The presence of some 5-mer peptides induced improved immune responses. Adding one 5-mer peptide exogenously also offered improved clinical outcome and/or survival against a lethal H5N1 or H1N1 influenza virus challenge in BALB/c mice and ferrets, respectively. Interestingly, enhanced anti-HBsAg antibody production by up to 25-fold in combination with a commercial Hepatitis B vaccine (Engerix-B, GSK) was also observed in BALB/c mice. Mechanistically, NK cell activation and dependency was observed with enhancing peptides ex vivo and in NK-depleted mice. Overall, the data suggest that rare or non-existent oligopeptides can be developed as immunomodulators and supports the further evaluation of some 5-mer peptides as potential vaccine adjuvants.
PLoS ONE 08/2012; 7(8):e43802. DOI:10.1371/journal.pone.0043802 · 3.23 Impact Factor
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