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Comparative Study
. 2011 Jan 18;108(3):1140-5.
doi: 10.1073/pnas.1009908108. Epub 2011 Jan 3.

Seasonal influenza infection and live vaccine prime for a response to the 2009 pandemic H1N1 vaccine

Grace L Chen  1 , Yuk-Fai Lau, Elaine W Lamirande, Amber W McCall, Kanta Subbarao
Affiliations
Comparative Study

Seasonal influenza infection and live vaccine prime for a response to the 2009 pandemic H1N1 vaccine

Grace L Chen et al. Proc Natl Acad Sci U S A. .

Abstract

The robust immune response to a single dose of pandemic 2009 H1N1 vaccine suggests that a large segment of the population has been previously primed. We evaluated the effect of seasonal (s) H1N1 infection, s-trivalent inactivated vaccine (s-TIV), and trivalent s-live attenuated influenza vaccine (s-LAIV) before immunization with a pandemic live attenuated influenza vaccine (p-LAIV) in mice. We compared serum and mucosal antibody and pulmonary CD8 and CD4 responses and the virologic response to challenge with a wild-type 2009 pandemic H1N1 (p-H1N1) virus. Two doses of p-LAIV induced cellular immune and robust ELISA and neutralizing antibody responses that were associated with complete protection from p-H1N1 challenge. A single dose of p-LAIV induced a cellular response and ELISA but not a neutralizing antibody response, and incomplete protection from p-H1N1 virus challenge. Primary infection with s-H1N1 influenza virus followed by a dose of p-LAIV resulted in cross-reactive ELISA antibodies and a robust cellular immune response that was also associated with complete protection from p-H1N1 virus challenge. A lower-magnitude but similar response associated with partial protection was seen in mice that received a dose of s-LAIV followed by p-LAIV. Mice that received a dose of s-TIV followed by p-LAIV did not show any evidence of priming. In summary, prior infection with a seasonal influenza virus or s-LAIV primed mice for a robust response to a single dose of p-LAIV that was associated with protection equivalent to two doses of the matched pandemic vaccine.

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Conflict of interest statement

The authors declare no conflict of interest.

Figures

Fig. 1.
Fig. 1.
Comparative efficacy of priming with s-TIV, s-LAIV, p-LAIV, or s-WT vaccine before immunization with p-LAIV in protection against p-H1N1 WT virus challenge in the respiratory tract of mice. Groups of mice received primary (1°) immunization as indicated and 4 wk later received p-LAIV for secondary (2°) immunization. Four weeks after 2° immunization, the mice were challenged i.n. with 106 TCID50 of p-H1N1 virus in 50 μL. Virus titers in the nasal turbinates (A) and lungs (B) were determined 2 and 4 d following challenge; virus titers are expressed as log10 TCID50/g of tissue. Horizontal bars represent mean titers from the group and symbols represent titers from individual mice. The lower limit of detection is represented by the dotted line.
Fig. 2.
Fig. 2.
The impact of different priming strategies on the induction of humoral immunity by p-LAIV. (A) ELISA: For 1° immunization, groups of three mice were vaccinated i.m. with 300 ng of the 2008–2009 s-TIV or i.n. with L-15 medium, 106 TCID50 of s-LAIV or p-LAIV, or 105 TCID50 of A/Brisbane/57/2007 (H1N1) s-WT virus. Serum samples were collected 24 d later. The mice were then given 106 TCID50 of p-LAIV (2° immunization) on day 31 and serum samples were collected again on day 52. Influenza-specific serum antibody titers (log10) were determined by ELISA using BPL-inactivated whole virus. Each dot presents the titer of an individual mouse and the bars represent the mean for each group. The lower limit of detection is represented by the dotted line. Asterisks denote that the difference between the indicated group and the group that received one dose of p-LAIV was statistically significant (P < 0.05). (B) Neutralizing antibodies: The serum neutralizing antibody titer (log2) against the p-H1N1 and s-WT viruses in mice immunized as indicated in A. Each dot represents the titer of an individual mouse and the bars represent the mean for the groups. (C) Mucosal antibody response: Influenza-specific ELISA and neutralizing antibodies in nasal turbinates (N.T.) and lungs (L.H.) of mice on day 52 in mice immunized as indicated in A. The left y axis represents ELISA titer (log5) and black dots represent the titer of each mouse. The right y axis represents the neutralizing titer (log2) and red squares represent the titer of each mouse.
Fig. 3.
Fig. 3.
s-LAIV or s-WT virus, but not s-TIV, prime mice for robust recall of pulmonary CD8+ CTL responses to p-LAIV. To evaluate the recall of cellular responses following receipt of p-LAIV, groups of three mice were vaccinated with s-TIV or s-LAIV, or infected with s-WT virus (1°) as described previously. On day 31, mice were vaccinated i.n. with p-LAIV (2°) and killed 5 or 8 d later. The numbers of NP147-specific CD8+ CTLs in the lungs were determined by ICS and expressed as percent of pulmonary CD8+ T cells. The dotted lines represent the magnitude of NP147-specific CD8+ T-cell response on day 8 during a primary response. A minimum of 30,000 lymphocytes were analyzed for lung samples. Asterisks indicate that the difference between the two groups was statistically significant (P < 0.05).
Fig. 4.
Fig. 4.
Recall of influenza-specific CD4+ T cells induced by s-LAIV, s-WT virus, and p-LAIV. Groups of three mice were primed and boosted as described previously in Fig. 1 and lymphocytes from lungs were collected 5 d after boosting and incubated with s-WT virus-pulsed splenocytes. The number of IFN-γ+ CD4+ T cells, minus the background, is expressed as a percent of total CD4+ T cells in the lungs. The bars represent the mean of the groups. The asterisk indicates that the difference between the two groups was statistically significant (P < 0.05).
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