Nine μg intradermal influenza vaccine and 15 μg intramuscular influenza vaccine induce similar cellular and humoral immune responses in adults

Abstract

Intanza® 9 μg (Sanofi Pasteur), a trivalent split-virion vaccine administered by intradermal (ID) injection, was approved in Europe in 2009 for the prevention of seasonal influenza in adults 18 to 59 years. Here, we examined the immune responses induced in adults by the ID 9 μg vaccine and the standard trivalent intramuscular (IM) vaccine (Vaxigrip® 15 μg, Sanofi Pasteur). This trial was a randomized, controlled, single-center, open-label study in healthy adults 18 to 40 years of age during the 2007/8 influenza season. Subjects received a single vaccination with the ID 9 μg (n=38) or IM 15 μg (n=42) vaccine. Serum, saliva, and peripheral blood mononuclear cells were collected up to 180 days post-vaccination. Geometric mean hemagglutination inhibition titers, seroprotection rates, seroconversion rates, and pre-vaccination-to-post-vaccination ratios of geometric mean hemagglutination inhibition titers did not differ between the two vaccines. Compared with pre-vaccination, the vaccines induced similar increases in vaccine-specific circulating B cells at day 7 but did not induce significant increases in vaccine-specific memory B cells at day 180. Cell-mediated immunity to all three vaccine strains, measured in peripheral blood mononuclear cells, was high at baseline and not increased by either vaccine. Neither vaccine induced a mucosal immune response. These results show that the humoral and cellular immune responses to the ID 9 μg vaccine are similar to those to the standard IM 15 μg vaccine.

Keywords: BSA, bovine serum albumin; CHMP, Committee for Medicinal Products for Human Use; ELISA, enzyme-linked immunosorbent assay; ELISPOT, enzyme-linked immunospot; HI, hemagglutination inhibition; ID, intradermal; IM, intramuscular; Ig, immunoglobulin; PBMC, peripheral blood mononuclear cells; PBS, phosphate-buffered saline; adult; immunogenicity; intradermal influenza vaccine; intramuscular vaccination; trivalent influenza vaccine.

Figures

Figure 1.

Humoral immune response in subjects receiving the ID and IM influenza vaccines (A) Geometric mean titers (GMTs) at days 0, 14, 21, and 180. (B) Seroprotection rates pre-vaccination (day 0) and at post-vaccination days 14, 21, and 180. Seroprotection was defined as a HI titer ≥40. (C) Seroconversion rates at post-vaccination days 14, 21, and 180. Seroconversion was defined as a post-vaccination HI titer ≥40 in subjects with a pre-vaccination titer <10 or a ≥4-fold increase compared with pre-vaccination titer in subjects with a pre-vaccination titer ≥10. (D) Geometric mean titer ratios (GMTRs). The GMTR was the ratio of post-vaccination HI titer vs. the pre-vaccination titer (day 0). Bars indicate means and error bars indicate 95% CI.

Figure 2.

Salivary secreted IgA response to the ID and IM influenza vaccines Shown is the ratio of virus-specific to total IgA levels pre-vaccination (day 0) and 10, 14, 21, and 180 d post-vaccination. Bars represent geometric means and error bars indicate 95% CIs.

Figure 3.

B cell responses to the ID and IM influenza vaccines (A) Number of circulating influenza virus-specific IgG-secreting cells pre-vaccination (day 0) and 7 d after vaccination. (B) Percent influenza virus-specific IgG-secreting memory B cells. PBMC were treated for 5 d as previously described to generate antibody-secreting B cells. Bars indicate geometric means and error bars indicate interquartile ranges.

Figure 4.

Activated CD8+ T cells (CD3+CD8+CD69+) and T helper cells (CD3+CD8−CD69+) in response to the ID and IM influenza vaccines Intracellular cytokine staining for CD3, CD8, CD69, IFN-γ, TNF-α, and IL-2 was performed in PBMC stimulated in vitro for 20–24 h with the indicated strains of influenza virus. Shown are the fractions of IFN-γ+, TNF-α+, and IL-2+ T-helper lymphocytes (CD3+CD8−CD69+; left panel) and CD8+ T cells (CD3+CD8+CD69+; right panel). Bars indicate medians and error bars indicate interquartile ranges.