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

Daniel S Kashi, Samuel J Oliver, Laurel M Wentz, Ross Roberts, Alexander T Carswell, Jonathan C Y Tang, Sarah Jackson, Rachel M Izard, Donald Allan, Lesley E Rhodes, William D Fraser, Julie P Greeves, Neil P Walsh, Daniel S Kashi, Samuel J Oliver, Laurel M Wentz, Ross Roberts, Alexander T Carswell, Jonathan C Y Tang, Sarah Jackson, Rachel M Izard, Donald Allan, Lesley E Rhodes, William D Fraser, Julie P Greeves, Neil P Walsh

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://ichgcp.net/clinical-trials-registry/NCT02416895 ; Study 2 NCT03132103; https://ichgcp.net/clinical-trials-registry/NCT03132103 .

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

Conflict of interest statement

None of the authors report a conflict of interest related to the study.

Figures

Fig. 1
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
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
Fig. 3
Secondary hepatitis B vaccine response in those with serum 25(OH)D 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
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
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
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
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)

References

    1. Chang SH, Chung Y, Dong C. Vitamin D suppresses Th17 cytokine production by inducing C/EBP homologous protein (CHOP) expression. J Biol Chem. 2010;285(50):38751–38755. doi: 10.1074/jbc.C110.185777.
    1. He CS, Handzlik M, Fraser WD, Muhamad A, Preston H, Richardson A, Gleeson M. Influence of vitamin D status on respiratory infection incidence and immune function during 4 months of winter training in endurance sport athletes. Exerc Immunol Rev. 2013;19:86–101.
    1. Wang TT, Nestel FP, Bourdeau V, Nagai Y, Wang Q, Liao J, Tavera-Mendoza L, Lin R, Hanrahan JW, Mader S, White JH. Cutting edge: 1,25-dihydroxyvitamin D3 is a direct inducer of antimicrobial peptide gene expression. J Immunol. 2004;173(5):2909–2912. doi: 10.4049/jimmunol.173.5.2909.
    1. Baeke F, Takiishi T, Korf H, Gysemans C, Mathieu C. Vitamin D: modulator of the immune system. Curr Opin Pharmacol. 2010;10(4):482–496. doi: 10.1016/j.coph.2010.04.001.
    1. Lang PO, Aspinall R. Can we translate vitamin D immunomodulating effect on innate and adaptive immunity to vaccine response? Nutrients. 2015;7(3):2044–2060. doi: 10.3390/nu7032044.
    1. Lemire JM. Immunomodulatory actions of 1,25-dihydroxyvitamin D3. J Steroid Biochem Mol Biol. 1995;53(1–6):599–602. doi: 10.1016/0960-0760(95)00106-A.
    1. Enioutina EY, Bareyan D, Daynes RA. TLR ligands that stimulate the metabolism of vitamin D3 in activated murine dendritic cells can function as effective mucosal adjuvants to subcutaneously administered vaccines. Vaccine. 2008;26(5):601–613. doi: 10.1016/j.vaccine.2007.11.084.
    1. Enioutina EY, Bareyan D, Daynes RA. TLR-induced local metabolism of vitamin D3 plays an important role in the diversification of adaptive immune responses. J Immunol. 2009;182(7):4296–4305. doi: 10.4049/jimmunol.0804344.
    1. von Essen MR, Kongsbak M, Schjerling P, Olgaard K, Odum N, Geisler C. Vitamin D controls T cell antigen receptor signaling and activation of human T cells. Nat Immunol. 2010;11(4):344–349. doi: 10.1038/ni.1851.
    1. Heine G, Drozdenko G, Lahl A, Unterwalder N, Mei H, Volk HD, Dorner T, Radbruch A, Worm M. Efficient tetanus toxoid immunization on vitamin D supplementation. Eur J Clin Nutr. 2011;65(3):329–334. doi: 10.1038/ejcn.2010.276.
    1. Zitt E, Sprenger-Mahr H, Knoll F, Neyer U, Lhotta K. Vitamin D deficiency is associated with poor response to active hepatitis B immunisation in patients with chronic kidney disease. Vaccine. 2012;30(5):931–935. doi: 10.1016/j.vaccine.2011.11.086.
    1. Jhorawat R, Jain S, Pal A, Nijhawan S, Beniwal P, Agarwal D, Malhotra V. Effect of vitamin D level on the immunogenicity to hepatitis B vaccination in dialysis patients. Indian J Gastroenterol. 2016;35(1):67–71. doi: 10.1007/s12664-016-0621-8.
    1. Averhoff F, Mahoney F, Coleman P, Schatz G, Hurwitz E, Margolis H. Immunogenicity of hepatitis B vaccines. Implications for persons at occupational risk of hepatitis B virus infection. Am J Prev Med. 1998;15(1):1–8. doi: 10.1016/S0749-3797(98)00003-8.
    1. Glaser R, Kiecolt-Glaser JK, Bonneau RH, Malarkey W, Kennedy S, Hughes J. Stress-induced modulation of the immune response to recombinant hepatitis B vaccine. Psychosom Med. 1992;54(1):22–29. doi: 10.1097/00006842-199201000-00005.
    1. Prather AA, Hall M, Fury JM, Ross DC, Muldoon MF, Cohen S, Marsland AL. Sleep and antibody response to hepatitis B vaccination. Sleep. 2012;35(8):1063–1069. doi: 10.5665/sleep.1990.
    1. Public Health England (2017) Hepatitis B: the green book, Chapter 18. vol 7.
    1. Huzly D, Schenk T, Jilg W, Neumann-Haefelin D. Comparison of nine commercially available assays for quantification of antibody response to hepatitis B virus surface antigen. J Clin Microbiol. 2008;46(4):1298–1306. doi: 10.1128/JCM.02430-07.
    1. He CS, Aw Yong XH, Walsh NP, Gleeson M. Is there an optimal vitamin D status for immunity in athletes and military personnel? Exerc Immunol Rev. 2016;22:42–64.
    1. Institute of Medicine . Dietary reference intakes for calcium and vitamin D. Washington, DC: National Academies Press; 2011.
    1. European Food Safety Authority Scientific opinion on dietary reference values for vitamin D. EFSA J. 2016;14(10):1–145. doi: 10.2903/j.efsa.2016.4611.
    1. Schillie S, Vellozzi C, Reingold A, Harris A, Haber P, Ward JW, Nelson NP. Prevention of hepatitis B virus infection in the United States: recommendations of the Advisory Committee on Immunization Practices. MMWR Recomm Rep. 2018;67(1):1–31. doi: 10.15585/mmwr.rr6701a1.
    1. Bozzola E, Spina G, Russo R, Bozzola M, Corsello G, Villani A. Mandatory vaccinations in European countries, undocumented information, false news and the impact on vaccination uptake: the position of the Italian pediatric society. Ital J Pediatr. 2018;44(1):67. doi: 10.1186/s13052-018-0504-y.
    1. Public Health England (2019) Historical vaccine development and introduction of vaccines in the UK. Vaccination timeline. Public Health England. . Retrieved 10 Dec 2019
    1. Szmuness W, Stevens CE, Harley EJ, Zang EA, Oleszko WR, William DC, Sadovsky R, Morrison JM, Kellner A. Hepatitis B vaccine: demonstration of efficacy in a controlled clinical trial in a high-risk population in the United States. N Engl J Med. 1980;303(15):833–841. doi: 10.1056/NEJM198010093031501.
    1. Holick MF. Vitamin D status: measurement, interpretation, and clinical application. Ann Epidemiol. 2009;19(2):73–78. doi: 10.1016/j.annepidem.2007.12.001.
    1. Advisory Group on Non-ionising Radiation . Ultraviolet radiation, vitamin D and health. London: Public Health England; 2017.
    1. Bischoff-Ferrari HA. Optimal serum 25-hydroxyvitamin D levels for multiple health outcomes. Adv Exp Med Biol. 2014;810:500–525.
    1. Hart PH, Gorman S, Finlay-Jones JJ. Modulation of the immune system by UV radiation: more than just the effects of vitamin D? Nat Rev Immunol. 2011;11(9):584–596. doi: 10.1038/nri3045.
    1. Hart PH, Norval M, Byrne SN, Rhodes LE. Exposure to ultraviolet radiation in the modulation of human diseases. Annu Rev Pathol. 2019;14:55–81. doi: 10.1146/annurev-pathmechdis-012418-012809.
    1. Terry PC, Lane AM, Lane HJ, Keohane L. Development and validation of a mood measure for adolescents. J Sports Sci. 1999;17(11):861–872. doi: 10.1080/026404199365425.
    1. Fitzpatrick TB. The validity and practicality of sun-reactive skin types I through VI. Arch Dermatol. 1988;124(6):869–871. doi: 10.1001/archderm.1988.01670060015008.
    1. Webb AR, Kift R, Durkin MT, O’Brien SJ, Vail A, Berry JL, Rhodes LE. The role of sunlight exposure in determining the vitamin D status of the UK white adult population. Br J Dermatol. 2010;163(5):1050–1055. doi: 10.1111/j.1365-2133.2010.09975.x.
    1. Rhodes LE, Webb AR, Fraser HI, Kift R, Durkin MT, Allan D, O’Brien SJ, Vail A, Berry JL. Recommended summer sunlight exposure levels can produce sufficient (> or = 20 ng ml−1) but not the proposed optimal (> or = 32 ng ml−1) 25(OH)D levels at UK latitudes. J Investig Dermatol. 2010;130(5):1411–1418. doi: 10.1038/jid.2009.417.
    1. Webb AR, Kift R, Berry JL, Rhodes LE. The vitamin D debate: translating controlled experiments into reality for human sun exposure times. Photochem Photobiol. 2011;87(3):741–745. doi: 10.1111/j.1751-1097.2011.00898.x.
    1. Carswell AT, Oliver SJ, Wentz LM, Kashi DS, Roberts R, Tang JCY, Izard RM, Jackson S, Allan D, Rhodes LE, Fraser WD, Greeves JP, Walsh NP. Influence of vitamin D supplementation by sunlight or oral D3 on exercise performance. Med Sci Sports Exerc. 2018;50(12):2555–2564. doi: 10.1249/MSS.0000000000001721.
    1. Cashman KD, Hill TR, Lucey AJ, Taylor N, Seamans KM, Muldowney S, Fitzgerald AP, Flynn A, Barnes MS, Horigan G, Bonham MP, Duffy EM, Strain JJ, Wallace JM, Kiely M. Estimation of the dietary requirement for vitamin D in healthy adults. Am J Clin Nutr. 2008;88(6):1535–1542. doi: 10.3945/ajcn.2008.26594.
    1. Tang JCY, Nicholls H, Piec I, Washbourne CJ, Dutton JJ, Jackson S, Greeves J, Fraser WD. Reference intervals for serum 24,25-dihydroxyvitamin D and the ratio with 25-hydroxyvitamin D established using a newly developed LC–MS/MS method. J Nutr Biochem. 2017;46:21–29. doi: 10.1016/j.jnutbio.2017.04.005.
    1. Ross AC, Manson JE, Abrams SA, Aloia JF, Brannon PM, Clinton SK, Durazo-Arvizu RA, Gallagher JC, Gallo RL, Jones G, Kovacs CS, Mayne ST, Rosen CJ, Shapses SA. The 2011 report on dietary reference intakes for calcium and vitamin D from the Institute of Medicine: what clinicians need to know. J Clin Endocrinol Metab. 2011;96(1):53–58. doi: 10.1210/jc.2010-2704.
    1. Macdonald HM. Contributions of sunlight and diet to vitamin D status. Calcif Tissue Int. 2013;92(2):163–176. doi: 10.1007/s00223-012-9634-1.
    1. Fleshner M, Watkins LR, Lockwood LL, Bellgrau D, Laudenslager ML, Maier SF. Specific changes in lymphocyte subpopulations: a potential mechanism for stress-induced immunomodulation. J Neuroimmunol. 1992;41(2):131–142. doi: 10.1016/0165-5728(92)90063-Q.
    1. Harper Smith AD, Coakley SL, Ward MD, Macfarlane AW, Friedmann PS, Walsh NP. Exercise-induced stress inhibits both the induction and elicitation phases of in vivo T-cell-mediated immune responses in humans. Brain Behav Immun. 2011;25(6):1136–1142. doi: 10.1016/j.bbi.2011.02.014.
    1. Penna G, Adorini L. 1 Alpha, 25-dihydroxyvitamin D3 inhibits differentiation, maturation, activation, and survival of dendritic cells leading to impaired alloreactive T cell activation. J Immunol. 2000;164(5):2405–2411. doi: 10.4049/jimmunol.164.5.2405.
    1. D’Ambrosio D, Cippitelli M, Cocciolo MG, Mazzeo D, Di Lucia P, Lang R, Sinigaglia F, Panina-Bordignon P. Inhibition of IL-12 production by 1,25-dihydroxyvitamin D3. Involvement of NF-kappaB downregulation in transcriptional repression of the p40 gene. J Clin Investig. 1998;101(1):252–262. doi: 10.1172/jci1050.
    1. Daynes RA, Araneo BA, Hennebold J, Enioutina E, Mu HH. Steroids as regulators of the mammalian immune response. J Investig Dermatol. 1995;105(1 Suppl):14S–19S. doi: 10.1038/jid.1995.4.
    1. Daynes RA, Araneo BA. The development of effective vaccine adjuvants employing natural regulators of T-cell lymphokine production in vivo. Ann N Y Acad Sci. 1994;730:144–161. doi: 10.1111/j.1749-6632.1994.tb44246.x.
    1. Fisman DN. Seasonality of infectious diseases. Annu Rev Public Health. 2007;28:127–143. doi: 10.1146/annurev.publhealth.28.021406.144128.
    1. Sleijffers A, Garssen J, de Gruijl FR, Boland GJ, van Hattum J, van Vloten WA, van Loveren H. Influence of ultraviolet B exposure on immune responses following hepatitis B vaccination in human volunteers. J Investig Dermatol. 2001;117(5):1144–1150. doi: 10.1046/j.0022-202x.2001.01542.x.
    1. Sleijffers A, Yucesoy B, Kashon M, Garssen J, De Gruijl FR, Boland GJ, van Hattum J, Luster MI, van Loveren H. Cytokine polymorphisms play a role in susceptibility to ultraviolet B-induced modulation of immune responses after hepatitis B vaccination. J Immunol. 2003;170(6):3423–3428. doi: 10.4049/jimmunol.170.6.3423.
    1. Roth DE, Abrams SA, Aloia J, Bergeron G, Bourassa MW, Brown KH, Calvo MS, Cashman KD, Combs G, De-Regil LM, Jefferds ME, Jones KS, Kapner H, Martineau AR, Neufeld LM, Schleicher RL, Thacher TD, Whiting SJ. Global prevalence and disease burden of vitamin D deficiency: a roadmap for action in low- and middle-income countries. Ann N Y Acad Sci. 2018;1430(1):44–79. doi: 10.1111/nyas.13968.
    1. Joines RW, Blatter M, Abraham B, Xie F, De Clercq N, Baine Y, Reisinger KS, Kuhnen A, Parenti DL. A prospective, randomized, comparative US trial of a combination hepatitis A and B vaccine (Twinrix) with corresponding monovalent vaccines (Havrix and Engerix-B) in adults. Vaccine. 2001;19(32):4710–4719. doi: 10.1016/S0264-410X(01)00240-7.
    1. Farrar MD, Kift R, Felton SJ, Berry JL, Durkin MT, Allan D, Vail A, Webb AR, Rhodes LE. Recommended summer sunlight exposure amounts fail to produce sufficient vitamin D status in UK adults of South Asian origin. Am J Clin Nutr. 2011;94(5):1219–1224. doi: 10.3945/ajcn.111.019976.
    1. Shih BB, Farrar MD, Cooke MS, Osman J, Langton AK, Kift R, Webb AR, Berry JL, Watson REB, Vail A, de Gruijl FR, Rhodes LE. Fractional sunburn threshold UVR doses generate equivalent vitamin D and DNA damage in skin types I–VI but with epidermal DNA damage gradient correlated to skin darkness. J Investig Dermatol. 2018;138(10):2244–2252. doi: 10.1016/j.jid.2018.04.015.

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