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Cross-Protective Immunity Against Influenza A/H1N1 Virus Challenge in Mice Immunized with Recombinant Vaccine Expressing HA Gene

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Cross-Protective Immunity Against Influenza A/H1N1 Virus Challenge in Mice Immunized with Recombinant Vaccine Expressing HA Gene Yang et al. Virology Journal 2013, 10:291 http://www.virologyj.com/content/10/1/291 RESEARCH Open Access Cross-protective immunity against influenza A/H1N1 virus challenge in mice immunized with recombinant vaccine expressing HA gene of influenza A/H5N1 virus Song Yang1,2, Shumeng Niu1, Zhihua Guo1, Ye Yuan1, Kun Xue1, Sinan Liu1 and Hong Jin1* Abstract Background: Influenza virus undergoes constant antigenic evolution, and therefore influenza vaccines must be reformulated each year. Time is necessary to produce a vaccine that is antigenically matched to a pandemic strain. A goal of many research works is to produce universal vaccines that can induce protective immunity to influenza A viruses of various subtypes. Despite intensive studies, the precise mechanisms of heterosubtypic immunity (HSI) remain ambiguous. Method: In this study, mice were vaccinated with recombinant virus vaccine (rL H5), in which the hemagglutinin (HA) gene of influenza A/H5N1 virus was inserted into the LaSota Newcastle disease virus (NDV) vaccine strain. Following a challenge with influenza A/H1N1 virus, survival rates and lung index of mice were observed. The antibodies to influenza virus were detected using hemagglutination inhibition (HI). The lung viral loads, lung cytokine levels and the percentages of both IFN-γ+CD4+ and IFN-γ+CD8+ T cells in spleen were detected using real-time RT-PCR, ELISA and flow cytometry respectively. Results: In comparison with the group of mice given phosphate-buffered saline (PBS), the mice vaccinated with rL H5 showed reductions in lung index and viral replication in the lungs after a challenge with influenza A/H1N1 virus. The antibody titer in group 3 (H1N1-H1N1) was significantly higher than that in other groups which only low levels of antibody were detected. IFN-γ levels increased in both group 1 (rL H5-H1N1) and group 2 (rL H5 + IL-2-H1N1). And the IFN-γ level of group 2 was significantly higher than that of group 1. The percentages of both IFN-γ+CD4+ and IFN-γ+CD8+ T cells in group 1 (rL H5-H1N1) and group 2 (rL H5 + IL-2-H1N1) increased significantly, as measured by flow cytometry. Conclusion: After the mice were vaccinated with rL H5, cross-protective immune response was induced, which was against heterosubtypic influenza A/H1N1 virus. To some extent, cross-protective immune response can be enhanced by IL-2 as an adjuvant. Cellular immune responses may play an important role in HSI against influenza virus. Keywords: Influenza virus, Heterosubtypic immunity, Vaccine, Cellular immune response, Cytotoxic T-lymphocytes * Correspondence: [email protected] 1Department of Pathogen Biology, China Medical University, Shenyang, Liaoning, PR China Full list of author information is available at the end of the article © 2013 Yang et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Yang et al. Virology Journal 2013, 10:291 Page 2 of 8 http://www.virologyj.com/content/10/1/291 Introduction 14 post-infection (p.i.). The mice in group 4 (PBS-H1N1) Influenza A virus (IAV), a member of the Orthomyxoviridae were all dead at day 7 p.i. (Figure 1A). The survival rate of family, possesses a negative strand RNA genome made group 2 (rL H5 + IL-2-H1N1) was higher than the survival up of eight gene segments. Based on surface proteins rate of group 1 (rL H5-H1N1). Mice vaccinated with NDV hemagglutinin (HA) and neuraminidase (NA), IAV are were all dead at day 7 p.i. (data not shown). These results classified 17 HA and 10 NA subtypes [1,2]. Influenza demonstrated that there was cross-protection between the virus undergoes rapid antigenic evolution by accumula- H5 and H1 subtypes of influenza virus and that IL-2 as tion of mutations and through genetic reassortments of adjuvant could increase the survival rate of mice. NDV segments. and IAV had not cross-protection. IAV causes frequent epidemics, occasional pandemics The low lung index correlated well with strong pro- and yearly seasonal outbreaks in humans, resulting in tection during IAV infection. The lung index of group 1 significant morbidity and mortality worldwide [3-5]. (rL H5-H1N1) was 0.87%, group 2 (rL H5 + IL-2-H1N1) Vaccination has been one of the most effective means of was 0.74%, and group 4 (PBS-H1N1) was 1.51% at day 7 p.i.. protection against IAV. Due to the constant antigenic The lung indexes of group 1 and group 2 were lower than evolution of IAV, influenza vaccines must be reformulated in group 4 at day 7 p.i. (P < 0.05) (Figure 1B). These data each year. Although these vaccines are efficacious, they showed that rL H5 vaccine could prevent the mice from arrive late and after the peak of a pandemic. Therefore, we weights loss and inflammation of lung when they were wish to investigate universal vaccines that can induce challenged with influenza A/H1N1 virus. protective immunity to IAV of various subtypes [6]. Heterosubtypic immunity (HSI)isthebasisofcreating Viral load in the lungs of mice universal influenza vaccines. Evidence supports that The viral loads in the lungs of the mice were assessed cytokines and T cell responses play crucial roles in HSI using a real-time RT-PCR method at day 5 p.i. (Figure 1C). to influenza virus [7,8]. Despite intensive studies, the The lung viral loads of group 1 (rL H5-H1N1) and group precise mechanisms of HSI remain ambiguous. 2 (rL H5 + IL-2-H1N1) were significantly lower than In this study, mice were vaccinated with recombinant group 4 (P < 0.05). The lung viral loads of group 2 were virus vaccine (rL H5), in which the HA gene of influenza lower than group 1 (P < 0.05). These data demonstrated A/H5N1 virus was inserted into LaSota Newcastle disease that rL H5 induced cross-protection against A/H1N1 virus virus(NDV)vaccinestrain.Themicewerethenchal- infection which may be enhanced by IL-2. lenged with influenza A/H1N1 virus. Furthermore, we co-administered intraperitoneally recombinant murine Hemagglutination inhibition antibody responses interleukin-2 (rIL-2) with the rL H5 to enhance HSI. To determine whether the antibody had the protective We found that vaccination with rL H5 provided cross- effect against influenza A/H1N1 virus, we detected the protection against a lethal challenge with an antigeni- levels of antibodies against influenza A/H1N1 virus in cally distinct influenza A/H1N1 virus and produced sera of mice by Hemagglutination inhibition (HI) assay significant changes in the levels of some cytokines and (Table 1). The antibody titer in group 3 (H1N1-H1N1) the percentages of both IFN-γ+CD4+ and IFN-γ+CD8+ was 640 at day 14 p.i.. It was significantly higher compared T cells in lung and spleen. We also found that rIL-2 co- with the other groups that only low levels of antibody administered with the rL H5 could increase the survival were detected. These data demonstrated that the levels of rate of mice, reduce viral replication in lung and improve antibody might play a critical role in homologous influ- the IFN-γ production. enza virus infection, but showed a negative correlation between HSI and antibody levels. Results Clinical outcome and lung index following influenza A/H1N1 Cytokine expression in the lungs of mice virus infection Lung suspensions were analyzed for Th1-type and Th2- To determine whether primary immunization with the type cytokine levels using ELISA. High levels of IFN-γ rL H5 vaccine can protect against a subsequent infection were detected in group 1 (rL H5-H1N1) and group 2 (rL with heterosubtypic influenza virus, female 6–8 weeks- H5 + IL-2-H1N1). The IFN-γ and IL-10 levels of group 1 old C57BL/6 mice were immunized with the rL H5 (rL H5-H1N1) were significantly higher than in group 3 vaccine and infected with influenza A/H1N1 virus with (H1N1-H1N1) at day 7 p.i. (P < 0.05). The IFN-γ level of or without IL-2. The mice were monitored for body group 2 (rL H5 + IL-2-H1N1) was significantly higher weight loss and survival rates. than in group 1 (rL H5-H1N1) at day 7 p.i. (P < 0.05). The mice in group 2 (rL H5 + IL-2-H1N1) and group The IFN-γ and IL-10 levels of group 1 and group 2 were 3 (H1N1-H1N1) all survived after infection. The survival significantly elevated after infection as compared to day rate of mice in group 1 (rL H5-H1N1) was 58% at day 0 (P < 0.05) (Figure 2A and D). Yang et al. Virology Journal 2013, 10:291 Page 3 of 8 http://www.virologyj.com/content/10/1/291 Figure 1 Clinical outcome and lung index following influenza A/H1N1 virus infection. (A) Survival rate of mice after infection with influenza A/H1N1 virus, which was significantly higher after day 6 for the rL H5-primed mice. n = 12/group. (B) The lung index of mice after infection with influenza A/H1N1 virus (*, as compare with group 4 [PBS-H1N1], P < 0.05). n = 3/group. (C) Lung viral loads on day 5 p.i. with influenza A/H1N1 virus (a, as compare with group 1 [rL H5-H1N1], P < 0.05; b, as compare with group 3 [H1N1- H1N1], P < 0.05; c, as compare with group 4 [PBS-H1N1], P < 0.05). n = 3/group. The IL-2 and IL-4 levels were not significantly different that rL H5 vaccine induced high frequencies of Th1 in all groups of mice (Figure 2B and C).
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