“Let there be light”: the role of vitamin D in the immune response to vaccines

Abstract

Vitamin D’s non-skeletal actions, including immunomodulatory role, have been increasingly recognized. Of significance, many immune cells are able to synthesize a biologically active form of vitamin D from circulating 25-hydroxyvitamin D with subsequent intracrine actions, and the vitamin D receptor is broadly distributed. In this review, we discuss vitamin D’s potent role in innate and adaptive immune responses and published studies evaluating the impact of serum vitamin D, vitamin D gene pathway polymorphisms or empiric vitamin D supplementation on vaccine immunogenicity. We highlight existing knowledge gaps and propose the steps needed to advance the science and answer the question of whether vitamin D may prove valuable as a vaccine adjuvant for certain vaccines against infectious diseases.

Keywords:

• adaptive immunity
• cellular immunity
• immunization
• innate immunity
• vaccines
• vitamin D

Financial & competing interests disclosure

Research reported in this publication was supported by the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number U01AI089859. This publication was supported by Grant Number UL1 TR000135 from the National Center for Advancing Translational Sciences (NCATS). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. G Poland is the chair of a Safety Evaluation Committee for novel investigational vaccine trials being conducted by Merck Research Laboratories. G Poland offers consultative advice on vaccine development to Merck & Co. Inc., CSL Biotherapies, Avianax, Sanofi Pasteur, Dynavax, Novartis Vaccines and Therapeutics, PAXVAX Inc, Emergent Biosolutions, Adjuvance, and Vaxess. G Poland holds two patents related to vaccinia and measles peptide research. These activities have been reviewed by the Mayo Clinic Conflict of Interest Review Board and are conducted in compliance with Mayo Clinic Conflict of Interest policies. This research has been reviewed by the Mayo Clinic Conflict of Interest Review Board and was conducted in compliance with Mayo Clinic Conflict of Interest policies. JA Whitaker receives funding for Mayo Clinic research from Pfizer Independent Grants for Learning and Change. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• Vitamin D has various immunomodulatory actions, including potent actions on the innate immune system, enhancing production of antimicrobial peptide, and biasing toward a Th2 skewed phenotype.

• The vitamin D level/threshold that is relevant to immune actions has not been defined, as current definitions of deficiency are based on effects on bone health.

• Vitamin D’s role has been examined in the immune response to vaccines in studies looking at vitamin D levels as well as vitamin D signaling pathway polymorphisms (influenza, hepatitis B, measles, rubella, BCG vaccine, pneumococcal, meningococcal, etc.), but the results have been variable, and such studies remain unreplicated to date.

• Higher hemagglutination-inhibition response to influenza vaccine was seen in vitamin D-replete patients in a small study involving prostate cancer patients. There was suggestion of dose–response relationship of improved hemagglutination-inhibition response in hemodialysis patients who were receiving calcitriol in a separate study. Similarly, vitamin D deficiency was an independent negative predictor of seroconversion to hepatitis B vaccine in patients with CKD stages 3–5. Anti-tetanus-specific IgG responses were noted to be higher in patients who received vitamin D supplementation compared with placebo, and this group had higher 25-(OH) D levels.

• Certain vitamin D receptor and retinoid X receptor α gene polymorphisms were associated with measles and rubella vaccine induced adaptive immune responses in two separate studies. A single study found an association with a particular vitamin D receptor gene polymorphism with higher odds of non-response to hepatitis B vaccine.

• Animal studies have shown superior immunogenicity with vitamin D co-administered with inactivated polio vaccine, hepatitis B, and Hemophilus influenzae vaccines.

• Elderly, obese, and chronic kidney disease patients have a higher incidence of vitamin D deficiency, and often have suboptimal vaccine responses, hence they remain important patient populations to study.

• Future studies need to include patients with a wide range of vitamin D levels and vitamin D gene polymorphisms.

• Mechanistic and systems biology-level studies are also needed, examining strategies of either boosting homeostatic levels, or co-administering vitamin D with vaccine.