Thymosin alpha-1 (trade name Zadaxin, international non-proprietary name thymalfasin) is a peptide — a short chain of 28 amino acids — isolated in the late 1970s from calf thymus. The thymus is the organ where T lymphocytes mature: the immune cells that recognise infected and cancerous cells. Synthetic thymosin alpha-1 is an approved medicine in more than 35 countries, mainly for chronic hepatitis B and C and as a “booster” of vaccine responses. It is the most thoroughly studied compound in our encyclopaedia, but it also has the most instructive story: small studies promised a great deal, while the largest and best-designed trials — in sepsis and in COVID-19 — returned null results. This review explains in plain terms what thymosin alpha-1 is, how it works and what the human studies actually showed.
What thymosin alpha-1 is
Thymosin alpha-1 is one of the peptides of so-called thymosin fraction 5 — a mixture of substances extracted from the thymus and studied as a possible “thymic hormone”. In 1977 Goldstein's team isolated a single peptide from that mixture, determined the order of its amino acids and named it thymosin alpha-1. The authors described a heat-stable, highly acidic molecule of 28 amino acids that may take part in the regulation, differentiation and function of T lymphocytes. Medicines and reagents today use a synthetic version — the same sequence, made chemically rather than extracted from animal tissue.
How it works — an alarm amplifier, not an antibiotic
Thymosin alpha-1 does not kill viruses or bacteria itself. It acts on immune cells so that they “see” a threat more clearly. The key players are dendritic cells — the sentinels of the immune system, which collect fragments of microbes and present them to T lymphocytes. In the work of Romani's group (2004) thymosin alpha-1 stimulated the maturation of dendritic cells and their production of interleukin-12 — the signal that steers the response towards Th1-type lymphocytes, needed to fight viral and fungal infections. The signal ran through Toll-like receptors (TLRs), the “sensors” on a cell that detect typical microbial patterns, and through a pathway dependent on the protein MyD88. The peptide therefore behaves like an alarm amplifier — hence the idea of giving it where immunity is weakened or “exhausted”.
Regulatory history — a medicine in many countries, but not everywhere
According to Goldstein's 2009 review, thymosin alpha-1 was approved in more than 35 countries for the treatment of chronic hepatitis B and C and as an immune stimulant and adjuvant (an additive that strengthens a vaccine's effect). The same review states that in the United States and in Europe the compound was at that time still in late-stage clinical testing — in hepatitis C and in melanoma — and not on sale as a medicine. Approval means that a country's regulator judged the data sufficient; it says nothing about how strong the evidence is by today's standards.
What was studied — cells and animals
The most frequently cited mechanistic paper is the 2004 study by Romani et al. In dendritic cells exposed to the fungus Aspergillus fumigatus, thymosin alpha-1 triggered maturation and interleukin-12 production through the p38 kinase and NF-κB pathway. In mice after bone-marrow transplantation — that is, with severely weakened immunity — the peptide activated Th1-type antifungal immunity, accelerated the recovery of myeloid cells and protected the animals from aspergillosis. These observations provided the rationale for studying thymosin alpha-1 as an adjuvant and as supportive treatment in people with weakened immunity. A large share of the basic literature comes from a single centre (Perugia), and mice are not people.
Human data — chronic hepatitis B
The most recent and most rigorous summary is the Cochrane review of September 2026: 10 randomised trials, 1,349 participants, published between 1991 and 2018 in Bangladesh, China, Italy, Korea, Singapore and Taiwan. The pooled result suggests that the drug may reduce all-cause mortality (risk ratio 0.53; 3 trials, 907 people) and the number of serious adverse events (0.72; 5 trials, 1,056 people), but the certainty of the evidence was rated very low for almost all outcomes and low for serious adverse events. No effect was shown on quality of life or on the histological picture of the liver. The authors state plainly that they are not sure whether thymosin alpha-1 reduces mortality. Four of the ten trials were funded by industry.
Human data — sepsis: from hope to a large null trial
Sepsis (a severe, body-wide reaction to infection) is the area where thymosin alpha-1 was studied most intensively. In 2013 a Chinese group published the ETASS trial: 361 patients with severe sepsis in six hospitals, randomly assigned to standard treatment or standard treatment plus thymosin alpha-1. Twenty-eight-day mortality was 26.0% in the treated group and 35.0% in the control group — a difference at the edge of statistical significance (P = 0.062; relative risk 0.74, confidence interval 0.54–1.02). The trial was, however, only single-blind and relatively small.
The answer came from the TESTS trial by the same group, published in January 2025 in the BMJ: 22 centres in China, 1,106 adults with sepsis, double-blind and placebo-controlled, subcutaneous injections for seven days. Twenty-eight-day mortality: 23.4% on thymosin and 24.1% on placebo (hazard ratio 0.99). None of the secondary or safety outcomes differed between the groups. In subgroup analyses, people under 60 fared worse on the drug and patients with diabetes fared better — signals to be checked, not evidence. The trial was co-funded by the manufacturer, SciClone. The authors' conclusion: no clear evidence that thymosin alpha-1 reduces mortality in sepsis.
A 2025 meta-analysis (11 randomised trials, 1,927 patients) shows where the impression of efficacy comes from: when all trials are pooled the odds ratio for death is 0.73, but in the subgroup of high-quality trials (0.82; P = 0.09) and multicentre trials (0.86; P = 0.20) the benefit disappears. The claim that “meta-analyses show lower mortality” is therefore true only when small, lower-quality trials are added together.
Human data — COVID-19 and vaccines
In COVID-19 the first reports were enthusiastic. A retrospective analysis of 76 severely ill patients in two hospitals in Wuhan (Liu et al., 2020) described mortality of 11.1% among treated versus 30.0% among untreated patients, together with rising T-cell counts and falling markers of T-cell “exhaustion” (PD-1 and Tim-3) — this is the origin of the claim that the peptide reverses T-cell exhaustion. Those are, however, observational data, without random allocation, from a small group. A 2023 meta-analysis gathered 9 studies and 5,352 patients: the relative risk of death was 1.03 (interval 0.60–1.75) with very high heterogeneity between studies. The authors conclude that the data do not support the use of thymosin alpha-1 in hospitalised adults with COVID-19, although a signal of benefit persisted in the subgroups of older and critically ill patients.
The best-founded application is boosting the vaccine response in people who respond poorly. In a pilot study in haemodialysis patients (Carraro et al., 2012; 94 people analysed) a pandemic influenza vaccine given together with thymosin alpha-1 produced higher antibody titres after 21 days than the vaccine alone, and the European immunogenicity criteria (CHMP) were fully met in the peptide groups. No adverse event was linked to the peptide. It is a small study, but consistent with the direction in which the compound was approved.
Safety and the limits of the evidence
In the human studies cited here the safety profile was favourable: in TESTS no safety outcome differed from placebo, in ETASS no serious drug-related event was recorded, and the Cochrane review counted fewer serious adverse events in the treated groups (with low certainty). We found no studies of prolonged administration in healthy volunteers and no data on people with autoimmune diseases — the claim that an “immune-stimulating” drug may aggravate such diseases is reasoning from mechanism, not a study result. The limits of the evidence are concrete: most trials come from a single country, some were funded by the manufacturer, results are heterogeneous, and the only large double-blind trial (TESTS) was negative. A research reagent is not a medicine and has not passed the quality control of a medicinal product. We deliberately give no methods of use and no doses.
The wider context — thymic peptides
Thymosin alpha-1 belongs to the group of peptides associated with the thymus. The group includes thymulin — a nine-amino-acid thymic hormone that works only when bound to zinc — and thymosin beta-4, known in the peptide trade as TB-500. Despite the similar name, thymosin alpha-1 and thymosin beta-4 are different molecules with different actions: the first is an immune modulator, the second binds actin and is studied for healing. Thymosin alpha-1 stands out as the only member of this group to have gone through large randomised trials.
Summary
Thymosin alpha-1 is a synthetic copy of a 28-amino-acid thymic peptide that amplifies the alarm signal of immune cells through TLR receptors. It is an approved medicine in more than 35 countries, but according to the 2009 review it was not a medicine in the United States or in Europe. In chronic hepatitis B the 2026 Cochrane review sees a signal of benefit with very low certainty of evidence. In sepsis small trials suggested lower mortality, while the large TESTS trial of 2025 returned a null result. In COVID-19 a meta-analysis did not confirm any effect on deaths. The most consistent data concern boosting vaccine responses in poor responders. The state of the evidence is therefore mixed: a well-documented mechanism and safety record, but efficacy confirmed only in narrow applications — and refuted where it was tested most carefully.
Sources
- Naing C, Ni H, Aung HH, et al. Thymosin-ɑ1 for people with chronic hepatitis B. Cochrane Database of Systematic Reviews. 2026;9(9):CD014610. PMID: 42713852. DOI: 10.1002/14651858.CD014610.pub2. pubmed.ncbi.nlm.nih.gov/42713852
- Wu J, Pei F, Zhou L, et al. The efficacy and safety of thymosin α1 for sepsis (TESTS): multicentre, double blinded, randomised, placebo controlled, phase 3 trial. BMJ. 2025;388:e082583. PMID: 39814420. DOI: 10.1136/bmj-2024-082583. pubmed.ncbi.nlm.nih.gov/39814420
- Gu B, Zhou Y, Nie Y, et al. Efficacy of thymosin α1 for sepsis: a systematic review and meta-analysis of randomized controlled trials. Frontiers in Cellular and Infection Microbiology. 2025;15:1673959. PMID: 40969554. DOI: 10.3389/fcimb.2025.1673959. pubmed.ncbi.nlm.nih.gov/40969554
- Wu J, Zhou L, Liu J, et al. The efficacy of thymosin alpha 1 for severe sepsis (ETASS): a multicenter, single-blind, randomized and controlled trial. Critical Care. 2013;17(1):R8. PMID: 23327199. DOI: 10.1186/cc11932. pubmed.ncbi.nlm.nih.gov/23327199
- Shang W, Zhang B, Ren Y, et al. Thymosin alpha1 use in adult COVID-19 patients: A systematic review and meta-analysis on clinical outcomes. International Immunopharmacology. 2023;114:109584. PMID: 36527881. DOI: 10.1016/j.intimp.2022.109584. pubmed.ncbi.nlm.nih.gov/36527881
- Carraro G, Naso A, Montomoli E, et al. Thymosin-alpha 1 (Zadaxin) enhances the immunogenicity of an adjuvated pandemic H1N1v influenza vaccine (Focetria) in hemodialyzed patients: a pilot study. Vaccine. 2012;30(6):1170–1180. PMID: 22178096. DOI: 10.1016/j.vaccine.2011.12.014. pubmed.ncbi.nlm.nih.gov/22178096
- Liu Y, Pan Y, Hu Z, et al. Thymosin Alpha 1 Reduces the Mortality of Severe Coronavirus Disease 2019 by Restoration of Lymphocytopenia and Reversion of Exhausted T Cells. Clinical Infectious Diseases. 2020;71(16):2150–2157. PMID: 32442287. DOI: 10.1093/cid/ciaa630. pubmed.ncbi.nlm.nih.gov/32442287
- Romani L, Bistoni F, Gaziano R, et al. Thymosin alpha 1 activates dendritic cells for antifungal Th1 resistance through toll-like receptor signaling. Blood. 2004;103(11):4232–4239. PMID: 14982877. DOI: 10.1182/blood-2003-11-4036. pubmed.ncbi.nlm.nih.gov/14982877
- Goldstein AL, Goldstein AL From lab to bedside: emerging clinical applications of thymosin alpha 1. Expert Opinion on Biological Therapy. 2009;9(5):593–608. PMID: 19392576. DOI: 10.1517/14712590902911412. pubmed.ncbi.nlm.nih.gov/19392576
- Goldstein AL, Low TL, McAdoo M, et al. Thymosin alpha1: isolation and sequence analysis of an immunologically active thymic polypeptide. Proceedings of the National Academy of Sciences of the United States of America. 1977;74(2):725–729. PMID: 265536. DOI: 10.1073/pnas.74.2.725. pubmed.ncbi.nlm.nih.gov/265536
For in-vitro laboratory research only. It is not a human medicine and is not for treatment.