DNA vaccine expressing conserved influenza virus proteins protective against H5N1 challenge infection in mice - PubMed (original) (raw)

DNA vaccine expressing conserved influenza virus proteins protective against H5N1 challenge infection in mice

Suzanne L Epstein et al. Emerg Infect Dis. 2002 Aug.

Abstract

Influenza vaccination practice, which is based on neutralizing antibodies, requires being able to predict which viral strains will be circulating. If an unexpected strain, as in the 1997 H5N1 Hong Kong outbreak, or even a pandemic emerges, appropriate vaccines may take too long to prepare. Therefore, strategies based on conserved influenza antigens should be explored. We studied DNA vaccination in mice with plasmids expressing conserved nucleoprotein (NP) and matrix (M) from an H1N1 virus. After vaccination, mice were challenged with A/H5N1 viruses of low, intermediate, and high lethality. A/NP+A/M DNA vaccination reduced replication of A/Hong Kong/486/97 (HK/486), a nonlethal H5N1 strain, and protected against lethal challenge with more virulent A/Hong Kong/156/97 (HK/156). After HK/156 exposure, mice survived rechallenge with A/Hong Kong/483/97 (HK/483), although the DNA vaccination alone protected poorly against this highly virulent strain. In the absence of antigenically matched hemagglutinin-based vaccines, DNA vaccination with conserved influenza genes may provide a useful first line of defense against a rapidly spreading pandemic virus.

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Figures

Figure 1

Figure 1

DNA vaccination induces T cell responses. a) Enzyme-linked immuno spot (ELISPOT) assay for interferon-γ (IFN-γ) secreting cells. Mice were immunized three times with A/NP+A/M or influenza B nucleoprotein DNA (B/NP DNA) intramuscularly. Spleen cells were analyzed by ELISPOT, using peptides at 1 μg/ml or A/PR/8 live virus. Results are the mean of three experiments. No response to A/PR/8 virus occurred in one experiment. Concanavalin A (Con A) responses: A/NP+A/M groups, >274 for all experiments; B/NP groups, >329 for all experiments. b) Cytotoxic T cell assay. Mice were vaccinated as above or with live A/PR/8 virus given on the day of the second DNA injection. Spleens were harvested 2½ weeks after the third DNA injection. Spleen cells were restimulated in vitro with live A/PR/8 or B/AA. After 7 days of culture, restimulated effector cells at various ratios were mixed with P815 target cells infected with A/PR/8 or B/AA, and lactate dehydrogenase (LDH) release measured.

Figure 2

Figure 2

Mice immunized with influenza A nucleoprotein and matrix DNA (A/NP+A/M DNA) are protected against lethal A/Hong Kong/156/97 (HK/156) challenge. Mice were vaccinated as in Figure 1 with A/NP+A/M DNA, with influenza B nucleoprotein DNA (B/NP+blank DNA), or with 100 mouse infectious dose (MID)50 of influenza A/Puerto Rico8/34 (A/PR/8) live virus. Sixteen days after the last dose of DNA, mice were challenged with 10,000 MID50 of HK/156/97 intranasally. a) Monitoring of morbidity by body weight loss. b) Viral titers of lung and brain homogenates. Each bar represents the result for one mouse. Dashed lines indicate detection limits. Compared to the B/NP DNA controls, lung titers were significantly reduced in the A/NP+A/M DNA group (p=0.001, analysis of variation (ANOVA)) and the A/PR/8 group (p<0.001, ANOVA). c) Survival after challenge with HK/156. d) Survival after rechallenge with 100 MID50 of HK/483 of mice primed with A/NP+A/M DNA and which had all survived the previous HK/156 infection.

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