Men with low vitamin A stores respond adequately to primary yellow fever and secondary tetanus toxoid vaccination

Abstract

Current recommendations for vitamin A intake and liver stores (0.07 micromol/g) are based on maintaining normal vision. Higher levels may be required for maintaining normal immune function. The objective of this study was to assess the relationship between total body vitamin A stores in adult men and measures of adaptive immune function. We conducted an 8-wk residential study among 36 healthy Bangladeshi men with low vitamin A stores. Subjects received a standard diet and were randomized in a double-blind fashion to receive vitamin A (240 mg) or placebo during wk 2 and 3. Subjects received Yellow Fever Virus (YFV) and tetanus toxoid (TT) vaccines during wk 5. Vitamin A stores were estimated by isotopic dilution during wk 8. Vaccine-specific lymphocyte proliferation, cytokine production, and serum antibody responses were evaluated before and after vaccination. Vitamin A supplementation increased YFV- and TT-specific lymphocyte proliferation and YFV-specific interleukin (IL)-5, IL-10, and tumor necrosis factor-alpha production but inhibited development of a TT-specific IL-10 response. Both groups developed protective antibody responses to both vaccines. Some responses correlated positively with vitamin A stores. These findings indicate that the currently recommended vitamin A intake is sufficient to sustain a protective response to YFV and TT vaccination. However, YFV-specific lymphocyte proliferation, some cytokine responses, and neutralizing antibody were positively associated with liver vitamin A stores > 0.084 micromol/g. Such increases may enhance vaccine protection but raise the question of whether immune-mediated chronic diseases may by exacerbated by high-level dietary vitamin A.

FIGURE 1

Immune responses to live YFV vaccination in low VA (n = 16) and high VA (n = 17) groups. (A–C) PBMC SI in 3 different levels of YFV antigen. (D–F) ³H-thymidine incorporation in PBMC in 3 different levels of YFV antigen (G). Serum YFV-specific PRNT₅₀; and (H–N) YFV-specific T-cell cytokines in PBMC. Values are means ± SE. Significance levels of the main effects (M) and interactions with time (In) are indicated. Labeled means within a group without a common letter differ, P < 0.05. ^#Groups differ at that time, P < 0.05.

FIGURE 2

Immune responses to recall TT vaccination in low VA (n = 18) and high VA (n = 18) groups. (A–C) PBMC SI in 3 different levels of TT antigen. (D) Serum anti-TT IgG responses (E) PBMC-released spontenous anti-TT IgG. (F–K) TT-specific T-cell cytokines in PBMC. Values are means ± SE. Significance levels of the main effects (M) and interactions with time (In) are indicated. Labeled means within a group without a common letter differ, P < 0.05. ^#Groups differ at that time, P < 0.05.

FIGURE 3

Spearman correlation between vaccine-specific immune responses and estimated whole body vitamin A pool size during 1 wk and 1 mo post vaccination: (A) YFV-specific responses, n = 30, and (B) TT-specific responses, n = 33. *P < 0.05.

FIGURE 4

Relationship between liver vitamin A concentrations and logical groupings of YFV vaccine responses (n = 30): (A) Th2 cytokines (IL-4, IL-5, and IL-10) at 1 wk postvaccination; and (B) 3 levels of antigen-induced PBMC SI and neutralizing antibody PRNT₅₀ titer at 1 mo postvaccination. The Z-score-normalized responses for each group were plotted and the break-point estimates obtained from the 2-phase segmental linear regression model. ^#Liver vitamin A stores were estimated from total body vitamin A pool size 1 mo after vaccination (includeding oral isotopic dose) as described in Materials and Methods.