Influenza Vaccine Enhancement with Immunomodulating Peptide Thymosin Alpha 1 - Clinical studies have shown that treatment with thymosin alpha 1 increases response to vaccination. - BioPharm


Influenza Vaccine Enhancement with Immunomodulating Peptide Thymosin Alpha 1
Clinical studies have shown that treatment with thymosin alpha 1 increases response to vaccination.

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Thymosin Stimulation of Vaccine Responses

Immune senescence, a normal aging process, has been related to a gradual decline in thymus function and thymic peptide production. The lack of thymic factors may contribute to the decline in immune function, particularly the T-cell component. In the elderly, quantitative and qualitative analysis of a specific antibody response after vaccination has been shown to be compromised when compared with the response in young subjects.20,41 Impairment of cell-mediated immunity also has been demonstrated in hemodialysis patients.42–44

Figure 1. Thymosin alpha 1 treatment increases specific CTL response after influenza vaccination21
In two preclinical studies, administration of thymosin alpha 1 to mice was shown to increase antibody response to tetanus toxoid (TT) and influenza vaccination.19,21 In the first study, thymosin alpha 1 was administered at 0.5 ug/kg to old (23 months) and young (2–3 months) mice on the day of vaccination and for each of four additional days after vaccination. Old mice that were not treated with thymosin alpha 1 had a significantly lower antibody response than young mice. Thymosin alpha 1 treatment resulted in significantly greater (p < 0.05) anti-TT antibody in both young and old mice, and appeared to restore the antibody response in the old mice close to levels seen in the young animals. In the second study, mice were pretreated with thymosin alpha 1 (10 ug/day for five days), and virus-specific CTL response was determined after vaccination with the influenza vaccine (Figure 1). Thymosin treatment increased the vaccine response of old (24–26 months) mice to that seen in young (2–6 months) mice.

In vitro antibody synthesis by human peripheral blood lymphocytes (PBL) also has been shown to be augmented by treatment with thymosin alpha 1. In this study, Ershler and colleagues examined age-related changes in antibody response to influenza vaccine in humans, and tested the capacity of TF-5 or thymosin alpha 1 to enhance specific antibody synthesis in vitro.20 They found that the antibody response following influenza vaccination was lower in elderly subjects (>65 years) compared to young subjects (<30 years). PBLs were then isolated from immunized young and old subjects and were incubated in vitro with either TF-5 at doses of 50, 100, 200 ug/mL or thymosin alpha 1 at doses of 0.01, 0.1, or 1.0 ng/mL. In vitro augmentation of the antibody response by either TF-5 or thymosin alpha 1 was detected in PBLs from 16 of the 28 elderly volunteers, compared to seven of the 30 young volunteers. In addition, there were twice as many responders (six versus three) in the 1 ng/mL thymosin alpha 1 group compared to the 0.01 ng/mL group, indicating a possible dose response that correlates with the endogenous level of circulating thymosin alpha 1 in healthy individuals (about 1 ng/mL).

Table 1. Response to influenza vaccine
Because thymosin alpha 1 can enhance T-cell–dependent specific antibody production, the addition of thymosin alpha 1 to vaccination programs for immunocompromised individuals should be effective. Five clinical studies have been undertaken and have demonstrated effectiveness of thymosin alpha 1 in increasing vaccine response, both in elderly subjects or patients undergoing hemodialysis, and after either influenza or hepatitis vaccination, as shown in Tables 1 and 2, respectively.

Table 2. Response to hepatitis B vaccine
In a pilot trial, the effect of thymosin alpha 1 on influenza vaccination was evaluated by Gravenstein, et al., at the University of Wisconsin and Cornell Medical Center.45 Nine elderly subjects (age range 65 to 99 years) who had been nonresponsive to influenza vaccination in the previous year were given biweekly thymosin alpha 1 injections for five weeks following a single injection of seasonal influenza vaccine. A total of 67% (6/9) responded with high levels of anti-influenza antibodies, compared to a historical rate of 10% after revaccination in elderly subjects.

This pilot trial was followed by a double-blind, randomized, placebo-controlled study conducted by the same researchers, at the Wisconsin Veterans' Administration Medical Center, Madison.46 Ninety male veterans over 64 years of age (range 65 to 99 years) were randomized to receive either thymosin alpha 1 or placebo biweekly for four weeks following injection with the trivalent vaccine. Effective immunization was defined as a four-fold or greater rise in antibody titer over a period of three to six weeks as measured by ELISA. About 69% (31/45) of thymosin-treated subjects were effectively immunized, compared to 52% (21/40) with placebo (p = 0.023). The differences seen were greater in subjects older than 77 years; the relationship between antibody levels and age also was significant (p < 0.039). As seen in the mouse studies, the antibody levels seen after treatment with thymosin alpha 1 were comparable to those seen in younger subjects.

Figure 2. Thymosin alpha 1 treatment decreases influenza incidence47
In a study conducted at George Washington University, 330 elderly subjects were vaccinated with the trivalent seasonal influenza vaccine (B/Ann Arbor, A/H3N2 Leningrad, A/H1N1 Taiwan).47 Biweekly doses of thymosin alpha 1 were given for either two weeks (120 subjects) or four weeks (100 subjects) after vaccination; placebo was given for two weeks (110 subjects). In the subjects treated with thymosin for four weeks, greater antibody levels were seen compared to placebo or two weeks of thymosin (p = 0.015). In addition to the improved antibody response, the subjects treated with thymosin alpha 1 for four weeks also had a significantly decreased incidence of influenza, from 19% in patients receiving influenza vaccine with placebo to 5.5% in patients receiving the vaccine in combination with thymosin alpha 1 (p = 0.002) (Figure 2).

In a study with 97 patients immunocompromised by chronic renal failure and undergoing hemodialysis, vaccination with monovalent A/Taiwan/1/86 (H1N1) vaccine followed by biweekly injections of thymosin for four weeks also led to improved response.48 Four weeks after vaccination, 71% (34/48) of subjects treated with thymosin alpha 1 had a four-fold or higher titer of specific antibody, compared to 43% (21/49) for those treated with placebo after vaccination (p < 0.002). This effect was long-lasting: eight weeks after vaccination the thymosin-treated subjects still had a rate of 65% response, compared to only 24% in the placebo-treated patients (p < 0.001).

Finally, the effect of thymosin on increasing response to vaccination was also seen with hepatitis B vaccine. In a study with 23 hemodialysis patients, nonresponders to a previous course of Heptavax vaccination were retreated with three vaccine injections one-month apart, with five biweekly injections of thymosin given after each vaccination. When response was measured three months later, 64% (7/11) of thymosin-treated patients had clinically significant anti-HBsAg titers, compared to 17% (2/12) of placebo-treated patients. The effect of thymosin was also long-lasting: measured after 12 months, 45% of the thymosin-treated patients still had clinically significant titers, whereas none of the placebo-treated patients retained theirs (p < 0.002).

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