Safety and immunogenicity of oral inactivated whole-cell Helicobacter pylori vaccine with adjuvant among volunteers with or without subclinical infection - PubMed (original) (raw)

Clinical Trial

Safety and immunogenicity of oral inactivated whole-cell Helicobacter pylori vaccine with adjuvant among volunteers with or without subclinical infection

K L Kotloff et al. Infect Immun. 2001 Jun.

Abstract

Helicobacter pylori infection of the gastric mucosa can be found in approximately 50% of the world's population and is associated with a range of pathology, including peptic ulcer, atrophic gastritis, and gastric cancer. To explore immunization as a strategy for preventing and treating H. pylori-associated disease, we assessed the safety and immunogenicity in healthy adults of a formalin-inactivated, oral H. pylori whole-cell (HWC) vaccine, administered with or without mutant Escherichia coli heat-labile toxin (LT(R192G)) as a mucosal adjuvant. In a dose-response study, 23 subjects with or without H. pylori infection were vaccinated with either 2.5 x 10(6) HWC, 2.5 x 10(8) HWC, or 2.5 x 10(10) HWC, plus 25 microg of LT(R192G). Thereafter, a randomized study was conducted in which 18 H. pylori-infected subjects were assigned, in a double-blind fashion, to receive either 2.5 x 10(10) HWC plus placebo-adjuvant, placebo-vaccine plus 25 microg of LT(R192G), placebo-vaccine plus placebo-adjuvant, or 2.5 x 10(10) HWC plus 25 microg of LT(R192G). Diarrhea (six subjects), low-grade fever (five subjects), and vomiting (two subjects) were observed, usually after the first dose. Significant rises in geometric mean mucosal (fecal and salivary) anti-HWC immunoglobulin A antibodies occurred among H. pylori-infected and uninfected subjects following inoculation with 2.5 x 10(10) HWC plus 25 microg of LT(R192G). Moreover, among H. pylori-negative volunteers, this regimen induced significant lymphoproliferative responses in 5 of 10 subjects and gamma interferon production responses to H. pylori sonicate in 7 of 10 subjects. There was no evidence that vaccination eradicated H. pylori in infected volunteers. These results suggest that it is possible to stimulate mucosal and systemic immune responses in humans to H. pylori antigens by using an HWC vaccine.

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Figures

FIG. 1

FIG. 1

Immune responses to HWC antigen according to H. pylori infection status and vaccine dose. Volunteers received an oral dose of either 2.5 × 106, 2.5 × 108, or 2.5 × 1010 inactivated HWC vaccine plus 25 μg of LTR192G adjuvant on days 0, 14, and 28. Responses are expressed as the geometric mean (GM) titer or geometric mean number of ASCs per 106 PBMC ± the back-transformed standard error measured prevaccination and postvaccination. Panels A, C, E, G, I, and K represent volunteers with no evidence of H. pylori infection (there were 3, 4, and 10 recipients of the 106, 108, and 1010 doses of HWC, respectively). Panels B, D, F, H, J, and L represent volunteers with subclinical H. pylori infection at baseline (there were 3, 3, and 8 recipients of the 106, 108, and 1010 doses of HWC, respectively). Comparisons of pre- and postvaccination titers: ∗, P < 0.05; ∗∗, P < 0.01; †, P = 0.06.

FIG. 2

FIG. 2

Immune responses to the mucosal adjuvant LTR192G according to H. pylori infection status and vaccine dose. Volunteers received an oral dose of either 2.5 × 106, 2.5 × 108, or 2.5 × 1010 inactivated HWC vaccine plus 25 μg of LTR192G adjuvant on days 0, 14, and 28. Responses are expressed as the geometric mean (GM) titer, the geometric mean OD, or the geometric mean number of ASCs per 106 PBMC ± the back-transformed standard error measured prevaccination and postvaccination. Panels A, C, E, G, I, and K represent volunteers with no evidence of H. pylori infection (there were 3, 4, and 10 recipients of the 106, 108, and 1010 doses of HWC, respectively). Panels B, D, F, H, J, and L represent volunteers with subclinical H. pylori infection at baseline (there were 3, 3, and 8 recipients of the 106, 108, and 1010 doses of HWC, respectively). Comparisons of pre- and postvaccination titers: ∗, P < 0.05; ∗∗, P < 0.01.

FIG. 3

FIG. 3

Proliferative responses by PBMC from eight H. pylori uninfected (A) and 10 _H. pylori_-infected (B) volunteers following ingestion of 2.5 × 1010 inactivated HWC vaccine plus 25 μg of LTR192G adjuvant. PBMC obtained from volunteers before or 56 days after immunization were evaluated for lymphoproliferative responses to an H. pylori sonicate or purified recombinant catalase. The results are expressed as the mean net cpm ± the standard error for all volunteers in each group †, P = 0.22 (paired t test) of mean postimmunization versus preimmunization values.

FIG. 4

FIG. 4

IFN-γ production by PBMC from eight _H. pylori_-uninfected (A) and 10 _H. pylori_-infected (B) volunteers following ingestion of 2.5 × 1010 inactivated HWC vaccine plus 25 μg of LTR192G adjuvant. PBMC obtained from the volunteers before or 56 days after immunization were evaluated for IFN-γ production to an H. pylori sonicate or purified recombinant catalase. The results are expressed as the mean net pg/ml ± the standard error for all volunteers in each group. ∗, P < 0.05 (paired t test) of mean postimmunization versus preimmunization measurements.

FIG. 5

FIG. 5

Postvaccination peak immune responses of _H. pylori_-infected subjects to HWC antigen according to a randomized immunizing regimen. Volunteers received an oral dose of either 2.5 × 1010 HWC vaccine (vaccine+) or placebo-vaccine (vaccine−), plus either 25 μg of LTR192G (adjuvant+) or placebo-adjuvant (adjuvant−). The responses are expressed as the geometric mean (GM) titer or the geometric mean number of ASCs per 106 PBMC ± the back-transformed standard error. ∗, P < 0.001, comparing recipients vaccine+ plus adjuvant− with recipients of vaccine− plus adjuvant−; †, P = 0.06, comparing recipients of vaccine+ plus adjuvant− with recipients of vaccine+ plus adjuvant+. Note that the responses in the group that received vaccine+ and adjuvant+ are also shown in Fig. 1.

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