Trained Immunity Based-Vaccines as a Prophylactic Strategy in Common Variable Immunodeficiency. A Proof of Concept Study

Abstract

Background: A major concern in the care of common variable immunodeficiency (CVID) patients is the persistence of subclinical or recurrent respiratory tract infections (RRTI) despite adequate trough IgG levels, which impacts the quality of life (QoL) and morbidity. Therefore, the development of new approaches to prevent and treat infection, especially RRTI, is necessary.

Objectives: We conducted a clinical observational study from May, 2016 to December, 2017 in 20 CVID patients; ten of these patients had a history of RRTI and received the polybacterial preparation MV130, a trained immunity-based vaccine (TIbV) to assess its impact on their QoL and prognosis.

Methods: Subjects with RRTI received MV130 for 3 months and were followed up to 12 months after initiation of the treatment. The primary endpoint was a reduction in RRTI at the end of the study. We analyzed the pharmacoeconomic impact on the RRTI group before and after immunotherapy by estimating the direct and indirect costs, and assessed CVID-QoL and cytokine profile. Specific antibody responses to the bacteria contained in MV130 were measured.

Results: The RRTI-group treated with TIbV MV130 showed a significant decrease in infection rate (p = 0.006) throughout the 12 months after initiation of the treatment. A decrease in antibiotic use and unscheduled outpatient visits was observed (p = 0.005 and p = 0.002, respectively). Significant increases in anti-pneumococcus and anti-MV130 IgA antibodies (p = 0.039 both) were detected after 12 months of MV130. Regarding the CVID QoL questionnaire, an overall decrease in the score by more than 50% was observed (p < 0.05) which demonstrated that patients experienced an improvement in their QoL. The pharmacoeconomic analysis showed that the real annual direct costs decreased up to 4 times per patient with the prophylactic intervention (p = 0.005).

Conclusion: The sublingual administration of the TIbV MV130 significantly reduced the rate of respiratory infections, antibiotic use and unscheduled visits, while increasing specific IgA responses in CVID patients. Additionally, the CVID population felt that their QoL was improved, and a decrease in expenses derived from health care was predicted.

Keywords: CVID; MV130; TIbV; prophylaxis; quality of life.

Conflict of interest statement

P.S.-L. and C.M.D.-R. belong to the Inmunotek R&D research team.

Figures

Figure 1

Flow chart of the classification of common variable immunodeficiency (CVID) patients according to clinical criteria.

Figure 2

MV130 significantly reduces the incidence of respiratory infections (A–C). (A,B) Number of respiratory tract infectious episodes scored 1 year prior to immunization (black) and in the 12 months after the initiation of immunotherapy with MV130 (green). (C) Percentage of subjects that remained free of infection (grey) or suffered recurrences (red) in the 12 months following MV130 administration. Data from 10 subjects are shown. (B) Lines link paired values. Normal distribution was evaluated using the Shapiro–Wilk test, p value was calculated using Wilcoxon signed-rank test. (C) p value was calculated using Fischer’s exact test, compared with rates prior to MV130 initiation (100% of subjects suffering infections).

Figure 3

Prophylaxis with MV130 significantly decreases the rate of healthcare resources consumption and work absenteeism. (A–C) Antibiotic consumption (A), visits to emergency unit (B) and work absenteeism (C) during the year before and after the initiation of MV130 treatment. Bars show the relative number of antibiotic courses (A), emergency unit visits (B) or days of work lost (C) in the total of subjects recorded. Data from 10 subjects are shown. Normal distribution was evaluated using the Shapiro–Wilk test. p values were calculated using Wilcoxon signed-rank test.

Figure 4

Specific anti-MV130 IgA and IgG antibodies. Prophylaxis with MV130 increases serum IgA antibody production. (A,B) Serum IgA (A) and IgG (B) antibodies against S. pneumoniae (left panels) or the bacterial mixture (right panels), collected from subjects before and after 12 months following MV130 immunotherapy analyzed by ELISA. Data from 6–10 individuals are shown. Lines show paired values. Normal distribution was evaluated using the Shapiro–Wilk test. p values were calculated using Paired Student’s t-test or Wilcoxon signed-rank test.

Figure 5

Prophylaxis with MV130 modulates serum cytokine, chemokine and growth factor secretion pattern. Cytokines (upper panels), chemokines (left bottom panel) and growth factors (right bottom panel) secreted in serum one year following MV130 administration determined by Luminex technique. Fold induction relative to basal level (before MV130 treatment) is shown. Undetectable values were found for IL-2, IL-5, IL-10, IL-12(p70), IL-15, GM-CSF, RANTES and VEGF. Data from 9–10 subjects are shown as mean ± SEM of fold increase. Outliers were identified by means of Tukey’s range test on represented values. Normal distribution was evaluated using the Shapiro–Wilk test. p values were calculated using one-sample t-test with a theoretical value of 1 (no fold induction). * p < 0.05.