Mucosal Delivery of Inactivated Influenza Vaccine Induces B-Cell-Dependent Heterosubtypic Cross-Protection against Lethal Influenza A H5N1 Virus Infection

Tumpey, Terrence M.; Renshaw, Mary; Clements, John D.; Katz, Jacqueline M.

doi:10.1128/jvi.75.11.5141-5150.2001

Cited by 236 publications

(223 citation statements)

References 70 publications

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“…These cells may be responsible for the level of protection observed in the nasal mucosa and, by extension, for the reduced transmission into the lungs of immunized mice. The possibility of nonneutralizing cross-reactive Abs contributing to heterosubtypic cross-protection has been demonstrated in a mucosal vaccine model that uses an inactivated influenza virus (20). However, whether such Abs play a role in our model is not known.…”

Section: Discussionmentioning

confidence: 55%

Antigen-Specific CD8+ T Cells Persist in the Upper Respiratory Tract Following Influenza Virus Infection

Wiley

Hogan

Woodland

et al. 2001

The Journal of Immunology

134

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Because little is known about lymphocyte responses in the nasal mucosa, lymphocyte accumulation in the nasal mucosa, nasal-associated lymphoid tissue (NALT), and cervical lymph nodes (CLN) were determined after primary and heterosubtypic intranasal influenza challenge of mice. T cell accumulation peaked in the nasal mucosa on day 7, but peaked slightly earlier in the CLN (day 5) and later (day 10) in the NALT. Tetrameric staining of nasal mucosal cells revealed a peak accumulation of CD8 T cells specific for either the H-2Db influenza nucleoprotein epitope 366–374 (DbNP366) or the H-2Db polymerase 2 protein epitope 224–233 (DbPA224) at 7 days. By day 13, DbPA224-specific CD8 T cells were undetectable in the mucosa, whereas DbNP366-specific CD8 T cells persisted for at least 35 days in the mucosa and spleen. After heterosubtypic virus challenge, the accumulation of CD8 T cells in the nasal mucosa was quicker, more intense, and predominantly DbNP366 specific relative to the primary inoculation. The kinetics and specificity of the CD8 T cell response were similar to those in the CLN, but the responses in the NALT and spleen were again slower and more protracted. These results indicate that similar to what was reported in the lung, DbNP366-specific CD8 T cells persist in the nasal mucosa after primary influenza infection and predominate in an intensified nasal mucosal response to heterosubtypic challenge. In addition, differences in the kinetics of the CD8 T cell responses in the CLN, NALT, and spleen suggest different roles of these lymphoid tissues in the mucosal response.

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Section: Discussionmentioning

confidence: 55%

Antigen-Specific CD8+ T Cells Persist in the Upper Respiratory Tract Following Influenza Virus Infection

Wiley

Hogan

Woodland

et al. 2001

The Journal of Immunology

134

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“…These results were consistent with the estimates obtained from the western blot analysis that showed approximately a 3:1 ratio. The HA content in influenza virus is estimated to be 29 % of the total protein [18]. Therefore, influenza VLPs contain approximately 0.95 µg per 10 µg of total VLP protein whereas inactivated virus contained 2.9 ug HA per 10 ug total protein.…”

Section: Production Of Vlps Containing Influenza M1 and H1 Or H3 Hamentioning

confidence: 99%

A bivalent influenza VLP vaccine confers complete inhibition of virus replication in lungs

Quan

Steinhauer

Huang

et al. 2008

Vaccine

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The conventional egg-grown influenza vaccines are trivalent. To test the feasibility of using multivalent influenza virus-like particles (VLPs) as an alternative influenza vaccine, we developed cell-derived influenza VLPs containing the hemagglutinin (HA) of the H1 subtype virus A/PR/ 8/34 or the H3 subtype virus A/Aichi/2/68. Mice immunized intramuscularly with bivalent influenza VLPs containing H1 and H3 HAs induced neutralizing activities against the homologous and closely related H1N1 strains A/PR/8/34 and A/WSN/33 as well as the H3N2 strains A/Aichi/ 2/68 and A/Hong Kong/68, but not the A/Philippines/2/82 strain isolated 14 years later. HA sequence and structure analysis indicated that antigenic distance could be a major factor in predicting cross-protection by VLP vaccines. The bivalent influenza VLP vaccine demonstrated advantages in broadening the protective immunity after lethal challenge infections when compared to a monovalent influenza VLP vaccine. High levels of the inflammatory cytokine IL-6 were observed in naïve or unprotected immunized mice but not in protected mice upon lethal challenge. These results indicate that multivalent influenza VLP vaccines can be an effective strategy for developing safe and alternative vaccine to control the spread of influenza viruses.

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“…Moreover, immunization with conserved proteins, like NP or matrix-2 (M2), leads to demonstrable heterosubtypic immunity (17,21,23,24), as does immunization with peptide Ags that elicit influenza-specific memory CD8 T cells (22,(25)(26)(27). However, CD8 T cells appear to be dispensable for heterosubtypic immunity in some studies (16,28), possibly because CD4, CD8, NK T, and ␥␦T cells play partially redundant roles in heterosubtypic immunity, and elimination of any one of these populations does not substantially impair the response as a whole (4).…”

Section: B Cells Promote Resistance To Heterosubtypic Strains Ofmentioning

confidence: 99%

B Cells Promote Resistance to Heterosubtypic Strains of Influenza via Multiple Mechanisms

Rangel-Moreno

Carragher

Misra

et al. 2008

The Journal of Immunology

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Immunity to heterosubtypic strains of influenza is thought to be mediated primarily by memory T cells, which recognize epitopes in conserved proteins. However, the involvement of B cells in this process is controversial. We show in this study that influenza-specific memory T cells are insufficient to protect mice against a lethal challenge with a virulent strain of influenza in the absence of B cells. B cells contribute to protection in multiple ways. First, although non-neutralizing Abs by themselves do not provide any protection to challenge infection, they do reduce weight loss, lower viral titers, and promote recovery of mice challenged with a virulent heterosubtypic virus in the presence of memory T cells. Non-neutralizing Abs also facilitate the expansion of responding memory CD8 T cells. Furthermore, in cooperation with memory T cells, naive B cells also promote recovery from infection with a virulent heterosubtypic virus by generating new neutralizing Abs. These data demonstrate that B cells use multiple mechanisms to promote resistance to heterosubtypic strains of influenza and suggest that vaccines that elicit both memory T cells and Abs to conserved epitopes of influenza may be an effective defense against a wide range of influenza serotypes.

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Mucosal Delivery of Inactivated Influenza Vaccine Induces B-Cell-Dependent Heterosubtypic Cross-Protection against Lethal Influenza A H5N1 Virus Infection

Cited by 236 publications

References 70 publications

Antigen-Specific CD8+ T Cells Persist in the Upper Respiratory Tract Following Influenza Virus Infection

Antigen-Specific CD8+ T Cells Persist in the Upper Respiratory Tract Following Influenza Virus Infection

A bivalent influenza VLP vaccine confers complete inhibition of virus replication in lungs

B Cells Promote Resistance to Heterosubtypic Strains of Influenza via Multiple Mechanisms

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