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Influenza virus vaccine based on the conserved hemagglutinin stalk domain.

Steel J, Lowen AC, Wang TT, Yondola M, Gao Q, Haye K, García-Sastre A, Palese P - MBio (2010)

Bottom Line: The strain specificity of vaccines presently in use mirrors the exquisite specificity of the neutralizing antibodies that they induce, that is, antibodies which bind to the highly variable globular head domain of hemagglutinin (HA).Furthermore, the headless HA vaccine provided full protection against death and partial protection against disease following lethal viral challenge.Our results suggest that the response induced by headless HA vaccines is sufficiently potent to warrant their further development toward a universal influenza virus vaccine.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Mount Sinai School of Medicine, New York, New York, USA.

ABSTRACT
Although highly effective in the general population when well matched to circulating influenza virus strains, current influenza vaccines are limited in their utility due to the narrow breadth of protection they provide. The strain specificity of vaccines presently in use mirrors the exquisite specificity of the neutralizing antibodies that they induce, that is, antibodies which bind to the highly variable globular head domain of hemagglutinin (HA). Herein, we describe the construction of a novel immunogen comprising the conserved influenza HA stalk domain and lacking the globular head. Vaccination of mice with this headless HA construct elicited immune sera with broader reactivity than those obtained from mice immunized with a full-length HA. Furthermore, the headless HA vaccine provided full protection against death and partial protection against disease following lethal viral challenge. Our results suggest that the response induced by headless HA vaccines is sufficiently potent to warrant their further development toward a universal influenza virus vaccine.

No MeSH data available.


Related in: MedlinePlus

Vaccination of mice with headless HA constructs provides protection from death. The average body weight loss in each group of vaccinated mice following challenge with PR8 virus is shown. Error bars represent standard deviations. A star indicates the death of a mouse.
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f5: Vaccination of mice with headless HA constructs provides protection from death. The average body weight loss in each group of vaccinated mice following challenge with PR8 virus is shown. Error bars represent standard deviations. A star indicates the death of a mouse.

Mentions: The potential of vaccination with a headless HA construct to induce a protective immune response was evaluated in the mouse model. The following three-dose vaccine regimen was used: mice received plasmid DNA on days 0 and 21, and VLP preparations were delivered with Freund’s adjuvant on day 56. Each DNA vaccine comprised pGag-EGFP alone or in combination with a protein expression vector encoding the PR8 full-length HA, the PR8 4G headless HA, or the HK68 4G headless HA and was administered intramuscularly with electroporation. For a final boost, VLP preparations with an HA content of 150 ng (or an equivalent amount of Gag-only VLP) were combined with Freund’s complete adjuvant and administered intraperitoneally to each mouse. The VLPs used for this purpose were produced in the absence of trypsin and comprised Gag-EGFP alone or in combination with full-length PR8 HA and PR8 NA, the PR8 4G headless HA, or the HK68 4G headless HA. On day 77, mice were challenged intranasally with PR8 virus and then monitored daily for morbidity and mortality for 10 days. In the Gag-only-vaccinated group, three out of four mice lost >25% of their initial body weight and were therefore scored as dead, and the fourth animal was seen to lose 15% of its initial body weight. In contrast, all mice vaccinated with the PR8 4G headless HA survived and experienced a maximum average weight loss of only 6% (Fig. 5).


Influenza virus vaccine based on the conserved hemagglutinin stalk domain.

Steel J, Lowen AC, Wang TT, Yondola M, Gao Q, Haye K, García-Sastre A, Palese P - MBio (2010)

Vaccination of mice with headless HA constructs provides protection from death. The average body weight loss in each group of vaccinated mice following challenge with PR8 virus is shown. Error bars represent standard deviations. A star indicates the death of a mouse.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2912658&req=5

f5: Vaccination of mice with headless HA constructs provides protection from death. The average body weight loss in each group of vaccinated mice following challenge with PR8 virus is shown. Error bars represent standard deviations. A star indicates the death of a mouse.
Mentions: The potential of vaccination with a headless HA construct to induce a protective immune response was evaluated in the mouse model. The following three-dose vaccine regimen was used: mice received plasmid DNA on days 0 and 21, and VLP preparations were delivered with Freund’s adjuvant on day 56. Each DNA vaccine comprised pGag-EGFP alone or in combination with a protein expression vector encoding the PR8 full-length HA, the PR8 4G headless HA, or the HK68 4G headless HA and was administered intramuscularly with electroporation. For a final boost, VLP preparations with an HA content of 150 ng (or an equivalent amount of Gag-only VLP) were combined with Freund’s complete adjuvant and administered intraperitoneally to each mouse. The VLPs used for this purpose were produced in the absence of trypsin and comprised Gag-EGFP alone or in combination with full-length PR8 HA and PR8 NA, the PR8 4G headless HA, or the HK68 4G headless HA. On day 77, mice were challenged intranasally with PR8 virus and then monitored daily for morbidity and mortality for 10 days. In the Gag-only-vaccinated group, three out of four mice lost >25% of their initial body weight and were therefore scored as dead, and the fourth animal was seen to lose 15% of its initial body weight. In contrast, all mice vaccinated with the PR8 4G headless HA survived and experienced a maximum average weight loss of only 6% (Fig. 5).

Bottom Line: The strain specificity of vaccines presently in use mirrors the exquisite specificity of the neutralizing antibodies that they induce, that is, antibodies which bind to the highly variable globular head domain of hemagglutinin (HA).Furthermore, the headless HA vaccine provided full protection against death and partial protection against disease following lethal viral challenge.Our results suggest that the response induced by headless HA vaccines is sufficiently potent to warrant their further development toward a universal influenza virus vaccine.

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology, Mount Sinai School of Medicine, New York, New York, USA.

ABSTRACT
Although highly effective in the general population when well matched to circulating influenza virus strains, current influenza vaccines are limited in their utility due to the narrow breadth of protection they provide. The strain specificity of vaccines presently in use mirrors the exquisite specificity of the neutralizing antibodies that they induce, that is, antibodies which bind to the highly variable globular head domain of hemagglutinin (HA). Herein, we describe the construction of a novel immunogen comprising the conserved influenza HA stalk domain and lacking the globular head. Vaccination of mice with this headless HA construct elicited immune sera with broader reactivity than those obtained from mice immunized with a full-length HA. Furthermore, the headless HA vaccine provided full protection against death and partial protection against disease following lethal viral challenge. Our results suggest that the response induced by headless HA vaccines is sufficiently potent to warrant their further development toward a universal influenza virus vaccine.

No MeSH data available.


Related in: MedlinePlus