Vitamin D and the hepatitis B vaccine response: a prospective cohort study and a randomized, placebo-controlled oral vitamin D3 and simulated sunlight supplementation trial in healthy adults

Abstract

Purpose: To determine serum 25(OH)D and 1,25(OH)₂D relationship with hepatitis B vaccination (study 1). Then, to investigate the effects on hepatitis B vaccination of achieving vitamin D sufficiency (serum 25(OH)D ≥ 50 nmol/L) by a unique comparison of simulated sunlight and oral vitamin D₃ supplementation in wintertime (study 2).

Methods: Study 1 involved 447 adults. In study 2, 3 days after the initial hepatitis B vaccination, 119 men received either placebo, simulated sunlight (1.3 × standard-erythema dose, 3 × /week for 4 weeks and then 1 × /week for 8 weeks) or oral vitamin D₃ (1000 IU/day for 4 weeks and 400 IU/day for 8 weeks). We measured hepatitis B vaccination efficacy as percentage of responders with anti-hepatitis B surface antigen immunoglobulin G ≥ 10 mIU/mL.

Results: In study 1, vaccine response was poorer in persons with low vitamin D status (25(OH)D ≤ 40 vs 41-71 nmol/L mean difference [95% confidence interval] - 15% [- 26, - 3%]; 1,25(OH)₂D ≤ 120 vs ≥ 157 pmol/L - 12% [- 24%, - 1%]). Vaccine response was also poorer in winter than summer (- 18% [- 31%, - 3%]), when serum 25(OH)D and 1,25(OH)₂D were at seasonal nadirs, and 81% of persons had serum 25(OH)D < 50 nmol/L. In study 2, vitamin D supplementation strategies were similarly effective in achieving vitamin D sufficiency from the winter vitamin D nadir in almost all (~ 95%); however, the supplementation beginning 3 days after the initial vaccination did not effect the vaccine response (vitamin D vs placebo 4% [- 21%, 14%]).

Conclusion: Low vitamin D status at initial vaccination was associated with poorer hepatitis B vaccine response (study 1); however, vitamin D supplementation commencing 3 days after vaccination (study 2) did not influence the vaccination response.

Clinical trial registry number: Study 1 NCT02416895; https://clinicaltrials.gov/ct2/show/study/NCT02416895 ; Study 2 NCT03132103; https://clinicaltrials.gov/ct2/show/NCT03132103 .

Keywords: 25-Hydroxyvitamin D; Cholecalciferol; Hepatitis B; UVB; Vaccination; Vitamin D.

Fig. 1

Schematic of study 1 and 2 procedures. Study 1 investigated the influence of vitamin D status at the time of the initial hepatitis B vaccination on the secondary antibody response to hepatitis B vaccination. Study 2 investigated the effect of vitamin D supplementation by solar-simulated radiation (SSR), oral vitamin D₃ (ORAL), or placebo (SSR-P or ORAL-P) after the initial hepatitis B vaccination on secondary hepatitis B vaccine response. Needle and bottle icon represents hepatitis B vaccination doses. Blood tube icon represents when blood samples were obtained for serum 25(OH)D, 1,25(OH)₂D and hepatitis B antibody titer measurements

Fig. 2

Flow diagram indicating the numbers of participants assessed for eligibility, recruited, available at follow-up, and analyzed as part of Study 1. Anti-HBs antibodies against hepatitis B antigen

Fig. 3

Secondary hepatitis B vaccine response in those with serum 25(OH)D < 50 nmol/L (n = 194) and serum 25(OH)D ≥ 50 nmol/L (n = 253 adults, (a), and low, medium and high serum 25(OH)D (b), n = 447) and low, medium and high 1,25(OH)₂D terciles (c), n = 444). ^†P < 0.1, lower percentage of secondary hepatitis B vaccination responders (anti-HBs ≥ 10 mIU/mL) in participants with 25(OH)D < 50 nmol/L than vitamin D-sufficient participants. ^‡P < 0.05, lower percentage of secondary hepatitis B vaccination responders (anti-HBs ≥ 10 mIU/mL) in low 25(OH)D and 1,25(OH)₂D terciles compared to medium 25(OH)D and high serum 1,25(OH)₂D terciles

Fig. 4

Seasonal variation in serum 25(OH)D (a), percentage of participants categorized as vitamin D sufficient (25(OH)D ≥ 50 nmol/L; (b), serum 1, 25(OH)₂D (c), and percentage of secondary hepatitis B vaccination responders (anti-HBs ≥ 10 mIU/mL; (d) in 447 healthy, young men (n = 272) and women (n = 175) residing in the UK. a, c Data are mean ± SD. b, d Are percentages represented by vertical bars. a Lower than summer (P < 0.05). b Lower than autumn (P < 0.05). c Lower than spring (P < 0.05)

Fig. 5

CONSORT flow diagram indicating the numbers of participants assessed, recruited, randomly assigned, and analyzed as part of study 2. Anti-HBs antibodies against hepatitis B antigen, vitamin D = SSR solar-simulated radiation, ORAL oral vitamin D₃, Placebo = SSR-P solar-simulated radiation placebo, ORAL-P oral placebo

Fig. 6

Serum 25(OH)D (a, d), percentage of participants categorized as vitamin D sufficient (serum 25(OH)D ≥ 50 nmol/L, (b, e), serum 1,25(OH)₂D c, f in response to 12 weeks of vitamin D supplementation by solar-simulated radiation (SSR) and oral vitamin D₃ (ORAL). a–c Show comparisons of individual vitamin D and placebo supplementation groups (SSR, SSR-P, ORAL and ORAL-P). d–f Show combined vitamin D supplementation (SSR and ORAL) vs combined placebo (SSR-P and ORAL-P) groups. ^†P < 0.05, greater than baseline. ^‡P < 0.05, greater than week 5. *P < 0.05, greater than SSR-P. ^§P < 0.05, greater than ORAL-P. ^#P < 0.05, greater than combined SSR-P and ORAL-P. Data are mean ± SD (a, c, d f) and vertical bars represent percentages (b, e)

Fig. 7

Percentage of participants categorized as secondary hepatitis B vaccine responders (anti-HBs ≥ 10 mIU/mL, (a, b) after 12 weeks of vitamin D supplementation by solar-simulated radiation (SSR) and oral vitamin D₃ (ORAL). a Compares individual vitamin D and placebo supplementation groups (SSR, SSR-P, ORAL and ORAL-P). b Shows combined vitamin D supplementation (SSR and ORAL) vs combined placebo (SSR-P and ORAL-P) groups. There was no difference in vaccine response between individual vitamin D and placebo supplementation groups (a SSR 60%, SSR-P 57%, ORAL 56%, ORAL-P 52%, P > 0.05) or between combined vitamin D and placebo groups (b SSR and ORAL 58% vs SSR-P and ORAL-P 54%, P > 0.05)