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. 2010 Jan 18:7:9.
doi: 10.1186/1743-422X-7-9.

An M2e-based multiple antigenic peptide vaccine protects mice from lethal challenge with divergent H5N1 influenza viruses

Guangyu Zhao  1 , Yongping Lin, Lanying Du, Jie Guan, Shihui Sun, Hongyan Sui, Zhihua Kou, Chris Cs Chan, Yan Guo, Shibo Jiang, Bo-Jian Zheng, Yusen Zhou
Affiliations

An M2e-based multiple antigenic peptide vaccine protects mice from lethal challenge with divergent H5N1 influenza viruses

Guangyu Zhao et al. Virol J. .

Abstract

Background: A growing concern has raised regarding the pandemic potential of the highly pathogenic avian influenza (HPAI) H5N1 viruses. Consequently, there is an urgent need to develop an effective and safe vaccine against the divergent H5N1 influenza viruses. In the present study, we designed a tetra-branched multiple antigenic peptide (MAP)-based vaccine, designated M2e-MAP, which contains the sequence overlapping the highly conserved extracellular domain of matrix protein 2 (M2e) of a HPAI H5N1 virus, and investigated its immune responses and cross-protection against different clades of H5N1 viruses.

Results: Our results showed that M2e-MAP vaccine induced strong M2e-specific IgG antibody responses following 3-dose immunization of mice with M2e-MAP in the presence of Freunds' or aluminium (alum) adjuvant. M2e-MAP vaccination limited viral replication and attenuated histopathological damage in the challenged mouse lungs. The M2e-MAP-based vaccine protected immunized mice against both clade1: VN/1194 and clade2.3.4: SZ/406H H5N1 virus challenge, being able to counteract weight lost and elevate survival rate following lethal challenge of H5N1 viruses.

Conclusions: These results suggest that M2e-MAP presenting M2e of H5N1 virus has a great potential to be developed into an effective subunit vaccine for the prevention of infection by a broad spectrum of HPAI H5N1 viruses.

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Figures

Figure 1
Figure 1
M2e-specific antibody responses induced by M2e-MAP vaccine. Mice were vaccinated with M2e-MAP plus FCA/FIA (s.c.) or alum (i.m.) adjuvant for a total of 3 times. Mice receiving FCA/FIA or alum alone were served as adjuvant controls. Mouse sera were collected pre-immunization and 10 days post-each immunization for detection of M2e-specific antibodies by ELISA. The end-point titer of each sample was determined as the highest dilution that yielded an OD450 nm value greater than twice that of similarly diluted serum sample collected pre-vaccination. The data are expressed as geometric mean titer (GMT) ± standard deviation (SD) of 10 mice per group. The lower limit detection (1:10) is indicated by a dotted line. Experiments were repeated three times.
Figure 2
Figure 2
Virus titers in challenged mouse lungs. Two weeks post-last boost, mice were challenged with 10LD50 of H5N1 virus, clade1: VN/1194 (A.) or clade2.3.4: SZ/406H (B.), and lungs were collected for detection of virus titer five days later. The data are expressed as Log10TCID50/g of lung tissues. The lower limit of detection is 1.5 Log10TCID50/g of tissues as indicated by a dotted line. The data are presented as GMT ± SD of 5 mice per group. * indicates P < 0.0001 compared to the FCA/FIA control group; ** means P < 0.0001 compared to the alum control group. Experiments were repeated three times.
Figure 3
Figure 3
Histopathological changes in the lungs of virus challenged mice. Mouse lungs were collected for histopathological analysis 5 days after virus challenge. The figure indicates the representative images of histopathological damage from H&E-stained lungs of mice vaccinated with M2e-MAP plus adjuvant or adjuvant only (magnification, 100×).
Figure 4
Figure 4
Weight loss and survival in lethal H5N1 virus challenged mice. Mice were challenged with 10LD50 of H5N1 virus, clade1: VN/1194 or clade2.3.4: SZ/406H, and monitored daily for 2 weeks post-challenge. A. Percentage change (%) of mouse body weight. Each point represents mean body weight of 10 mice per group. B. Survival rate. The significant differences (P < 0.0001) of M2e-MAP+FCA/FIA versus FCA/FIA and M2e-MAP+alum versus alum are indicated as * and **, respectively.
Figure 5
Figure 5
Construction and sequence of M2e-MAP. The final form of M2e-MAP was synthesized on [Fmoc-Lys(Fmoc)]2-Lys-Cys(Acm)-βAla-Wang Resin in tetra-branched form, which carries four copies of M2e peptide. The sequence of M2e from highly pathogenic avian influenza H5N1 virus VN/1194 strain is shown at the bottom.
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