Impaired antibody responses to pneumococcal polysaccharide in elderly patients with low serum vitamin B12 levels
Authors: Fata F, Herzlich B, Schiffman G, Ast A.
Source: Annals of Internal Medicine. 124:299-304. February 1, 1996.
Institutions: Maimonides Medical Center; State University of New York Health Science Center, Brooklyn, NY.
Financial support: Grant from the Maimonides Research and Development Foundation.
Approximately one quarter of immunocompetent elderly persons do not mount an adequate antibody response to the polyvalent pneumococcal polysaccharide vaccine. Methylcobalamin plays a role in DNA synthesis; low vitamin B12 levels are found in 7 to 15% of the elderly. This study was undertaken to explore a possible relationship between low cobalamin levels and inadequate response to pneumococcal vaccine.
- Subjects: hospitalized patients with vitamin B12 level less than 200 pmol/l, as determined by the routine laboratory at Maimonides Medical Center. For each patient, an age and diagnosis matched control with normal (>200) vitamin B12 level was chosen. Patients with immunocompromise, cancer, renal and hepatic disease and non-ambulatory patients were excluded.
- Intervention: Patients and controls received 0.5 ml of the 23-polyvalent pneumococcal polysaccharide vaccine subcutaneously. Serum samples from before and 4 weeks after vaccination were frozen. Serum samples were assayed for vitamin B12 level, folate level and antibody titers to 12 pneumococcal serotypes.
- Analysis: Antibody titers before vaccination, after vaccination and the change in titers were correlated with B12 and folate levels. Titers were analyzed as the geometric mean of the 12 serotypes. The response of four specific subtypes was also looked at.
- There were 15 patients in each group. Mean B12 levels were 122 and 454. There was no significant difference between the groups in terms of age (75 in the low B12 group, 71 in normal group), hematocrit (37 vs. 38), MCV (88 vs. 90), folate levels (20.1 vs. 22.6).
- Antibody titers (mean of 12 antibodies) were similar in both groups before vaccination (476 vs. 423); titers after vaccination were lower in the low B12 group than in the normal group (1111 vs. 1649). Thus, the rise in titers after vaccination was significantly higher in the normal B12 group (1226.1 vs. 634.7; p=0.005).
- When the change in titers was plotted against serum B12 levels, there was a linear association (r=0.61).
- Using multiple regression analysis, erythrocyte MCV was also found to be independently, negatively associated with a greater antibody response (higher MCV predicted lower change in antibody titers). B12 levels remained independently correlated with antibody response, however.
The authors speculate that although vaccination leads to the differentiation of antigen specific memory cells, subsequent clonal expansion and maturation into plasma cells depends in part on vitamin B12 (which is a co-factor for DNA, RNA and protein synthesis). This could explain the findings presented here.
These findings may be clinically significant, since the efficacy of the pneumococcal vaccine is only about 46-70 % in the elderly, and a significant proportion of elderly patients have subclinical vitamin B12 deficiency. The authors suggest that further studies will be needed to see if vitamin B12 supplementation will correct the low antibody response and also to see if other aspects of humoral immunity are similarly affected by vitamin B12 levels.
In an accompanying editorial, Ralph Carmel, MD from UCSF reviews the issue of subtle, sub-clinical cobalamin deficiency. He points out that this is a fairly common condition, often accompanied by elevations in serum methylmalonate and homocysteine. Subtle cobalamin deficiency may cause mild neurologic dysfunction, reversible with supplementation and now may turn out to be responsible for immunologic impairment as well.
The approach to this problem is not clear, since waiting for overt symptoms may lead to undertreatment, and empiric treatment with oral preparations may overtreat many, while inadequately treating those with pernicious anemia. Extensive biochemical testing of the elderly is another possible approach, but is costly on such a large scale. Further studies are needed.
As both the authors and the editorial point out, it has not yet been proven that low B12 levels are the cause of, rather than a concomitent of, impaired antibody response. Given the role of vitamin B12 in biosynthetic processes, it certainly seems reasonable to suspect a causal role.
It is very interesting to note that, as demonstrated by figure 3 in the study, B12 levels correlate well with antibody response across the whole spectrum of B12 levels, not just low vs. normal. This might influence what we should, in fact, call normal in the future.
Further studies to elucidate the effect of vitamin B12 supplementation on antibody response should be quite simple to design and not very costly to undertake. Since cobalamin is only a cheap, generic drug, however, I suspect these studies might take a while to find funding.
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