Human T-cell responses after vaccination with the Norwegian group B meningococcal outer membrane vesicle vaccine

Abstract

We have analyzed human T-cell responses in parallel with serum immunoglobulin G (IgG) antibody levels after systemic vaccination with the Norwegian group B Neisseria meningitidis outer membrane vesicle (OMV) vaccine. Ten adult volunteers, with no or very low levels of serum IgG antibodies against meningococci, received three doses intramuscularly of the OMV vaccine (at weeks 0, 6, and 46). T-cell proliferation against the OMV vaccine, purified outer membrane proteins (PorA and PorB), and control antigens (Mycobacterium bovis BCG vaccine and tetanus toxoid) was measured by thymidine incorporation of peripheral blood mononuclear cells before and after vaccination. The results showed that vaccination with OMV elicits strong primary and booster T-cell responses specific to OMV as well as the PorA (class 1) protein and significant, but markedly lower, responses against the PorB (class 3) protein. The median responses to OMV and PorA were 26 and 16 times the prevaccination levels, respectively. Most of the vaccinees showed low T-cell responses against OMV and PorA before vaccination, and the maximum T-cell responses to all vaccine antigens were usually obtained after the second vaccine dose. We found a positive correlation between T-cell responses and anti-OMV IgG antibody levels (r = 0.50, P < 0.0001, for OMV and PorA). In addition, we observed a progressive increase in the percentage of CD45R0+ (memory) CD4-positive T cells (P = 0.002). In conclusion, we have shown that the Norwegian OMV vaccine against meningococcal B disease induced antigen-specific T-cell responses, kinetically accompanied by serum IgG responses, and that vaccination increased the proportion of memory T-helper cells.

FIG. 1

T-cell responses in 10 adult vaccinees receiving three doses of OMV vaccine measured as in vitro proliferative responses in disintegrations per minute after 6 days of stimulation with vaccine antigens: OMV vaccine (A), purified PorA outer membrane protein (B), and purified PorB outer membrane protein (C). Left panels show responses for individual vaccinees, and immunizations are indicated by arrows. Right panels show maximum T-cell responses obtained before vaccination, after the first and second dose, 10 months after the first dose, and after the third dose given. Boxes extend from the 25th to the 75th percentile, with a horizontal line at the median. Vertical bars show the range of the data. Significant responses after vaccination were observed after each immunization (OMV, P = 0.002; PorA, P = 0.002; and PorB, P = 0.002 after the first dose and P = 0.0039 after the second and third doses).

FIG. 2

T-cell responses against control antigens in the OMV-vaccinated individuals after 6 days of stimulation with BCG vaccine and PHA. Maximum responses (in disintegrations per minute) obtained before vaccination, after the first and second doses, 10 months after the first dose, and after the third dose are shown. Boxes extend from the 25th to the 75th percentile, with a horizontal line at the median. Vertical bars show the range of the data.

FIG. 3

OMV-specific IgG antibody responses in serum measured by enzyme-linked immunosorbent assay for 10 adult vaccinees given three doses of OMV vaccine at weeks 0, 6, and 46. Data are expressed as maximum responses obtained 1, 2, or 6 weeks after each dose given. Boxes extend from the 25th to the 75th percentile, with a horizontal line at the median. Vertical bars show the range of the data. Significant responses after vaccination were observed after each immunization (P = 0.002).

FIG. 4

Correlation between OMV-specific IgG antibody responses in vaccinee sera and T-cell responses against OMV vaccine and PorA and PorB outer membrane proteins. Spearman correlation coefficients are shown.

FIG. 5

Percentages of CD4⁺-CD45R0⁺ memory T cells measured by flow cytometry in PBMCs from 10 vaccinees before OMV vaccination, after one dose, after a second dose given 6 weeks after the first, after a third dose given after 10 months, and 2 years after the first dose was given. Boxes extend from the 25th to the 75th percentile, with a horizontal line at the median. Vertical bars show the range of the data. P is 0.0039 for the increase after one dose, and P is 0.002 for the increase after the third dose.