Research Dossier on Thymosin Alpha-1 (Tα1, Thymalfasin)

(Immune Modulator Peptide)

Classification & Molecular Identity

Amino acid sequence, molecular weight, structural motifs

Thymosin alpha-1 (Tα1) is a 28-amino-acid, N-acetylated acidic peptide, originally isolated from thymosin fraction 5 and later produced synthetically as thymalfasin. The consensus sequence is:

Ac-Ser-Asp-Ala-Ala-Val-Asp-Thr-Ser-Ser-Glu-Ile-Thr-Thr-Lys-Asp-Leu-Lys-Glu-Lys-Lys-Glu-Val-Val-Glu-Glu-Ala-Glu-Asn-OH (Ac-SDAAVDTSSEITTKDLKEKKEVVEEAEN).

Chemically synthesized thymalfasin is identical to endogenous Tα1 (free base or acetate salt); typical molecular weightreported for thymalfasin is ~3.11 kDa. Tα1 is highly acidic (multiple Glu/Asp residues), which influences solubility and receptor-proximal electrostatics.

Discovery history (lab, year, species)

Tα1 was sequenced and characterized by Goldstein and colleagues as a bioactive component of thymosin fraction 5 in the late 1970s–1980s. Subsequent translational work—initially in chronic hepatitis B (CHB)—used a defined syntheticpeptide rather than crude extracts, enabling randomized trials in the 1990s and early 2000s.

Endogenous vs synthetic origin

• Endogenous: Tα1 is a natural peptide produced from prothymosin-α; it circulates at low concentrations and participates in immune homeostasis.

• Synthetic (thymalfasin): GMP-grade thymalfasin is the clinical/supply form; the U.S. FDA bulk-drug review (2024) summarizes identity, stability, and storage recommendations for the substance (e.g., desiccated < −18 °C; limited stability of reconstituted solutions at 4 °C).

Homologs, analogs, derivatives

• Thymic peptide family: Thymosin fraction 5 components (e.g., thymulin, thymopoietin) and β-thymosins (e.g., thymosin β4) are mechanistically distinct from Tα1.

• Thymopentin (TP5) is a 5-mer from thymopoietin; it is not Tα1 but sometimes appears in the same literature as a comparator immune modulator.

• Receptor-biased or targeted constructs: Experimental Tα1-conjugates or modified Tα1 (e.g., RGD-modified for tumor targeting) have been reported preclinically.

Historical Development & Research Trajectory

Key milestones

• HBV randomized trials (1998–1999). In a multicenter RCT (n≈98), Tα1 1.6 mg SC twice weekly for 26 or 52 weeks improved virologic responses (HBV DNA and HBeAg clearance) and histology versus observation. Similar multicenter work followed in CHB.

• Pharmacokinetics in healthy adults (1999). SC 900 µg·m⁻² single and 5-day multiple dosing demonstrated Tmax 1–2 h, Cmax ~30–80 µg·L⁻¹, AUC 95–267 µg·h·L⁻¹, and elimination t½ < 3 h with no accumulation; distribution suggested extracellular space (Vz/f ~30–40 L).

• Dendritic-cell (DC) biology (2004–2007). Seminal work showed that Tα1 matures DCs and primes Th1antifungal resistance via TLR-dependent signaling (notably TLR9/MyD88/IRF7), linking Tα1 to innate–adaptive orchestration.

• Sepsis (ETASS RCT, 2013). In severe sepsis (n=361), Tα1 1.6 mg SC, twice daily for 5 days, then once daily for 2 days (add-on to standard care) yielded lower 28-day mortality (26% vs 35%) with borderline significance and improved mHLA-DR recovery; no major drug-related AEs were reported.

• Cancer immunotherapy (melanoma RCT, 2010). In metastatic melanoma, adding Tα1 (1.6–6.4 mg) to dacarbazine (DTIC)±interferon-α improved response rates in some arms and trended to longer OS (HR 0.80, P = 0.08) without added toxicity; results supported further exploration but were not practice-changing at the time.

• Vaccine adjuvanticity (2007–2012). In older adults and hemodialysis populations, Tα1 has enhanced influenza vaccine immunogenicity with acceptable safety (e.g., dialyzed patients receiving Tα1 showed higher seroprotection).

• COVID-19 (2020–2022 observational). Numerous cohort analyses explored Tα1 as add-on immunomodulation; meta-inferences remain mixed and confounded by severity and timing.

• Modern sepsis trials (2024–2025). The large multicenter TESTS trial (BMJ 2025) reported no conclusive mortality benefit for Tα1 in general adult sepsis, while updated meta-analyses suggest possible benefit in subgroups with immune dysfunction, emphasizing patient selection and personalized immunotherapy.

Paradigm shifts & controversies

1. From “global booster” to precision immunomodulator. Early clinical use cast Tα1 as a broad enhancer; mechanism-oriented work reframed it as a context-dependent modulator that can restore antiviral Th1 responses via TLR–MyD88 signaling in DCs and balance excess vs defect in host responses.

2. Heterogeneous clinical signals. Positive randomized signals exist (HBV; ETASS sepsis), but large sepsis trialshave produced neutral results overall, and COVID-19 analyses are conflicting—highlighting timing, immune status, and patient selection as critical variables.

3. Regulatory landscape. Thymalfasin is authorized in many countries (not the U.S.) for hepatitis or as an immune adjuvant; the FDA (2024) assessed Tα1 nominated as a bulk drug substance and summarized identity, use-cases, and stability, underscoring that a U.S. pharmacopeial monograph is not available.

Evolution of scientific interest

Tα1 has moved from viral hepatitis to vaccine adjuvanticity, oncology combinations, sepsis/critical care, and respiratory virus adjuncts. Mechanistically, attention has shifted to DC programming, TLR2/9/4 engagement, and downstream NF-κB/IRF pathways that shape Th1 responses, cytotoxic T cells, and NK function.

Mechanisms of Action

Primary and secondary receptor interactions

Canonical, high-affinity GPCR-like receptors for Tα1 have not been identified. Instead, convergent data support pattern-recognition receptor (PRR) engagement—particularly Toll-like receptors—on dendritic cells and myeloidcells:

• TLR9/MyD88/IRF7 axis. Tα1 primes DCs for Th1 antimicrobial resistance through TLR9–MyD88 signaling with IRF7 activation and IL-12 induction (mouse/human DC models).

• TLR2, TLR4 contributions.** Reviews and mechanistic studies indicate Tα1 can also engage TLR2/TLR4, leading to MyD88-dependent activation of NF-κB, JNK, and p38 MAPK, thereby influencing co-stimulatory molecules and cytokines.

• DC maturation and antigen presentation. Tα1 enhances DC maturation, antigen presentation, and cross-talk to naïve T cells—mechanistic underpinnings of vaccine adjuvanticity and antiviral Th1 restoration.

Intracellular signaling pathways

• MyD88-dependent cascades. Engagement of TLR2/9 recruits TIRAP/MyD88 → IRAK → TRAF6, activating IKK/NF-κB and MAPKs (p38/JNK) with transcription of IL-12, IFN-α/β, TNF, and co-stimulatory ligands.

• IRF7/Type-I IFN. Via TLR9–MyD88–IRF7, Tα1 amplifies type-I interferon programs, enhancing antiviral states and NK cytotoxicity.

• T-cell polarity and checkpoints. In vitro, Tα1 shifts human T-cell subsets toward Th1 and can counter certain checkpoint toxicities in mice (e.g., CTLA-4–mediated intestinal injury) by promoting tolerogenic or balancedDC outputs.

CNS vs peripheral effects

Tα1’s primary actions are peripheral (spleen, lymph node, blood myeloid/DC compartments). CNS-directed effects are indirect via systemic immune modulation.

Hormonal, metabolic, immune interactions

• Adaptive immunity. Increased CD4⁺ T cells and Th1 cytokines, improved CTL/NK activity, and enhanced antibody responses underlie vaccine data and antiviral trials.

• Innate immunity. Augmented mHLA-DR expression in sepsis (improving monocyte antigen presentation) was associated with better outcomes in ETASS (exploratory).

• Inflammation control. Balanced pro-/anti-inflammatory signaling may ameliorate immunoparalysis without exacerbating hyper-inflammation—though context matters, as indicated by mixed COVID-19 results and disease-stage sensitivity.

Evidence grading (A–C)

• A (replicated mechanistic biology): DC maturation, TLR-MyD88 signaling (TLR9; TLR2), Th1 biasing; PKwith short t½ after SC dosing; vaccine adjuvanticity in special populations.

• B (translational/clinical efficacy): HBV RCTs (virologic/histologic responses), ETASS sepsis RCT (marginal 28-day mortality benefit; improved mHLA-DR), melanoma phase-II signal when added to chemotherapy/IFN.

• C (uncertain/contradictory): Sepsis (large TESTS trial neutral overall), COVID-19 (conflicting observational data), broad oncology benefit (heterogeneous).

Pharmacokinetics & Stability

ADME profile (human)

• Route & absorption: After SC administration (healthy volunteers), Tα1 shows Tmax ~1–2 h, Cmax ~30–80 µg·L⁻¹, with apparent Vz/f ~30–40 L and no accumulation across 5-day dosing.

• Elimination half-life: < 3 hours (multiple formulations); consistent with peptide degradation and renal/hepaticclearance.

• Distribution: Largely extracellular; crosses into lymphatics relevant for immune interfacing.

• Metabolism: Proteolysis to amino acids/short peptides; no CYP-mediated liabilities identified.

Stability (source-level information)

The FDA bulk-drug review (2024) for thymalfasin (free base and acetate) summarizes storage and stabilityrecommendations (e.g., < −18 °C desiccated powder; reconstituted solution stability 2–7 days at 4 °C depending on composition) and notes no USP monograph.

Storage/reconstitution considerations

Peer-reviewed CMC is limited; authoritative regulatory and label documents (where available) provide the best physicochemical guidance for research handling.

Preclinical Evidence

Dendritic-cell priming & antifungal/antiviral Th1 resistance

• Antifungal Th1 programming. Tα1 drives IL-12 production and functional maturation in fungus-pulsed DCs via p38/NF-κB; in vivo, it enhances antifungal resistance in the lungs.

• TLR9/MyD88/IRF7 pathway. Tα1 activation of TLR9 on DCs amplifies type-I IFN and Th1 responses (murine CMV model).

• Human DCs. Tα1 promotes DC differentiation/maturation from CD14⁺ monocytes with improved antigen-presentation capacity (multiple in-vitro studies).

Vaccine adjuvanticity (influenza)

• Elderly/hemodialysis cohorts. Tα1 improved seroprotection and seroconversion to seasonal/pandemic influenza vaccines, with acceptable tolerability (e.g., hemodialysis patients).

  • Example: hemodialysis study—Tα1 increased vaccine immunogenicity without adverse effects on hematology/chemistry (investigational regimen per trial protocol).

Oncology (mechanistic and translational)

• Antitumor immunomodulation. Reviews summarize enhanced CTL/NK activity and DC function, suggesting synergy with IFN-α or chemotherapy.

• Melanoma models/clinical signal. A large randomized trial in metastatic melanoma suggested activity (improved responses; OS trend) without added toxicity when Tα1 was added to DTIC with or without IFN-α.

Sepsis/critical illness

• ETASS RCT (2013). In severe sepsis, Tα1 1.6 mg SC BID × 5 days, then QD × 2 days improved mHLA-DRrecovery and yielded borderline mortality improvement (26% vs 35%; P = 0.049 log-rank) with good tolerability.

• Mechanistic plausibility: Restoration of antigen presentation (mHLA-DR) and reversal of immunoparalysis are consistent with Tα1’s DC-centric MOA.

COVID-19 (adjacent/heterogeneous)

• Multicenter cohort (2021). Retrospective data suggested benefit in selected severe COVID-19 subgroups; authors emphasized stage-specific immunology and possible harm if administered during hyper-inflammatory phases (conflicting findings across cohorts).

Dose ranges tested (illustrative; all investigational)

• HBV (Hepatology 1998). 1.6 mg SC twice weekly for 26 weeks (or 52 weeks in an extension arm) improved HBV DNA/HBeAg responses and histology.

• Sepsis (ETASS 2013). 1.6 mg SC twice daily for 5 days, then 1.6 mg SC daily for 2 days (add-on to standard care) improved mHLA-DR and yielded borderline mortality benefit.

• Melanoma (JCO 2010). 1.6–6.4 mg (with DTIC±IFN-α) across randomized arms showed response-rate signals and OS/PFS trends (P ~0.06–0.08) without added toxicity.

• PK (healthy volunteers). 900 µg·m⁻² SC (single and 5-day multiple doses) → Tmax 1–2 h, t½ < 3 h, Vz/f ~30–40 L.

Comparative efficacy/safety

• Efficacy: Consistent immune-restorative signals (DC/T-cell/NK enhancement; better vaccine responses; antiviral/antifungal Th1 re-biasing).

• Safety: Generally well tolerated at investigational doses; short t½ reduces accumulation risk; AEs in trials typically mild (injection-site reactions).

Limitations

• Context dependence: Benefit seems greatest where immunoparalysis is present; indiscriminate use in hyper-inflammation may be ineffective or counter-productive (COVID-19 heterogeneity).

• Trial quality: Several positive signals derive from older or single-center RCTs and observational cohorts; modern, blinded multicenter trials (e.g., TESTS) are critical to define who benefits.

Human Clinical Evidence

Viral hepatitis (HBV)

Chien et al., Hepatology 1998 (RCT, n=98).

• Design: Randomized, controlled, three-arm study in HBeAg-positive CHB.

• Dosing: Investigational dose used in study: Tα1 1.6 mg SC twice weekly for 26 weeks (T6) or 52 weeks (T12) vs no specific treatment (18-mo follow-up).

• Results: Complete virologic response (HBV DNA and HBeAg loss) at 18 months was 40.6% (T6) and 26.5% (T12) vs 9.4% in controls; blinded histology improved (lobular necroinflammation) in treated arms; no significant side-effects reported.

• Interpretation: Durable virologic responses post-therapy suggest immune reconstitution kinetics (responses continued to accrue after dosing ended).

Sepsis (severe sepsis/ICU)—two eras

1. ETASS (Crit Care 2013).

   • Design: Multicenter RCT, n=361; add-on Tα1 vs standard care.

   • Dosing: Investigational dose used in study: 1.6 mg SC twice daily for 5 days, then 1.6 mg SC daily for 2 days.

   • Primary outcome: 28-day mortality (26.0% vs 35.0%; P = 0.049 log-rank; P = 0.062 non-stratified); mHLA-DR recovered faster.

   • Safety: No serious drug-related AEs recorded.

   • Conclusion: Suggestive efficacy—preliminary and single-blind; called for larger, double-blind confirmation.

2. TESTS (BMJ 2025).

   • Design: Large multicenter double-blind RCT; adult sepsis.

   • Outcome: No conclusive reduction in 28-day mortality overall; safety acceptable; authors highlight patient selection and immune phenotyping for future personalized trials.

   • Interpretation: Conflicting evidence vs ETASS; modern practice may require biomarker-guided use (e.g., mHLA-DR-low cohorts).

Oncology (metastatic melanoma)

Maio et al., JCO 2010 (Randomized, multicenter phase-II/III-like).

• Design: 488 patients randomized to DTIC+IFN-α+Tα1 (1.6, 3.2, 6.4 mg), DTIC+Tα1 (3.2 mg), or DTIC+IFN-α(control).

• Efficacy: More responses in DTIC+IFN-α+Tα1 (3.2 mg) and DTIC+Tα1 (3.2 mg) than control; OS HR 0.80 (P= 0.08) and PFS HR 0.80 (P = 0.06) trends; no added toxicity with Tα1.

• Interpretation: Activity signal without definitive survival benefit; underpins combination hypotheses in modern immuno-oncology (e.g., potential with checkpoint inhibitors, under further study).

Vaccine adjuvant studies

• Older adults/hemodialysis: Tα1 enhanced influenza vaccine seroprotection/seroconversion, was well tolerated, and did not affect routine labs in small RCTs/cohorts.

• Interpretation: Supports DC/Th1 mechanism; larger confirmatory trials in specific high-risk populations would solidify effect sizes.

COVID-19 (observational & small trials)

• Cohorts (multi-center Hubei, 2021): Tα1 add-on associated with improved outcomes in some retrospective analyses; disease-stage heterogeneity and confounding are substantial.

• Systematic assessments (2022): Evidence unclear; calls for randomized, biomarker-stratified trials.

Safety signals/adverse events (across indications)

• Common: Injection-site reactions, mild transient flu-like symptoms; overall well-tolerated across trials and PK studies.

• Serious AEs: Rare; ETASS reported none attributable to Tα1.

• Contra-indications/precautions: Context-specific (e.g., avoid in uncontrolled hyper-inflammation if immune activation might worsen disease; not a formal class contraindication, but timing is emphasized in reviews).

Representative ClinicalTrials.gov entries

• Sepsis: NCT00711620 (ETASS; completed); NCT02867267 (related sepsis program); TESTS (newer multicenter; BMJ 2025).

• COVID-19: examples include NCT04487444 (adjunct Tα1).

• Viral hepatitis/oncology: numerous completed RCTs across the 1990s–2010s (see PubMed citations above).

Comparative Context

Related peptides & immunomodulators

• Thymosin α1 vs Thymosin β4: Tα1 is a regulatory immunopeptide acting via TLR/DC axes; Tβ4 is a cytoskeletal/repair peptide (actin-binding) with angiogenic/antifibrotic biology—mechanistically distinct.

• Thymopentin (TP5) and thymulin modulate T-cell maturation and inflammation, respectively; Tα1 has broader TLR–DC engagement and clinical-trial depth.

• Checkpoint/IFN adjuvants: Tα1 has been explored alongside IFN-α and chemotherapy (melanoma) and is being reconsidered for combo with modern checkpoint inhibitors.

Advantages (research perspective)

• Defined 28-mer, short t½, clear DC/TLR mechanisms;

• Clinical-grade supply (thymalfasin) with human PK and safety characterization;

• Evidence across viral hepatitis, vaccine adjuvanticity, sepsis, and oncology.

Disadvantages/constraints

• Context sensitivity: Efficacy depends on immune status and disease stage; indiscriminate use may yield neutraloutcomes (e.g., generalized sepsis, mixed-stage COVID-19).

• Heterogeneity in older studies; newer confirmatory trials are still emerging.

• No single canonical receptor—PRR-mediated effects complicate potency standardization across systems.

Research category placement

Tα1 is best positioned as a model immunoregulatory peptide to probe DC programming, TLR–MyD88 biology, antigen presentation, and Th1/NK effector functions in infection, vaccination, sepsis, and immuno-oncology.

Research Highlights

• Molecular identity: Defined 28-mer (Ac-SDAAVDTSSEITTKDLKEKKEVVEEAEN), MW ~3.11 kDa.

• Mechanism: TLR9/TLR2–MyD88 engagement on DCs → IL-12, type-I IFN, NF-κB/MAPK activation → Th1/NK effector re-balancing.

• PK: SC dosing → Tmax 1–2 h, t½ < 3 h, no accumulation; extracellular distribution (Vz/f 30–40 L).

• HBV: 1.6 mg SC twice weekly (26–52 weeks) improved virologic/histologic outcomes vs observation.

• Sepsis: 1.6 mg SC BID × 5 days → QD × 2 days improved mHLA-DR and showed borderline mortality benefit in ETASS; large TESTS trial neutral overall, highlighting patient selection.

• Vaccines: Enhanced influenza vaccine responses in the elderly/hemodialyzed with good tolerability.

• Oncology: Activity signal in melanoma combinations without added toxicity; renewed interest as immunotherapy adjuvant.

Conflicting/uncertain evidence.

• Sepsis: ETASS vs TESTS discrepancies; subgroup-specific benefits likely (e.g., immunoparalysis).

• COVID-19: Observational studies mixed; timing and disease stage likely critical.

• Hard outcomes beyond HBV/sepsis require additional large, blinded RCTs.

Potential Research Applications (no clinical claims; research-use framing)

1. Biomarker-guided immunotherapy in sepsis.

   • Enrich ICU cohorts based on mHLA-DR-low or ex vivo DC hypo-responsiveness and test Tα1 vs placebo with 28-day mortality and immune-function co-primary endpoints—extending ETASS with modern double-blind design.

2. DC-centric vaccine adjuvants.

   • Compare Tα1 with TLR7/8 agonists as adjuvants in older and dialysis populations using systems-serologyand single-cell multi-omics to define quality of antibody and Tfh/Th1 support.

3. Antiviral Th1 restoration.

   • In chronic viral infection models (HBV/CMV), quantify DC cross-presentation, Th1 cytokines, and CTL/NK cytotoxicity; test synergy with IFN-α or checkpoint modulation (preclinical).

4. Immuno-oncology combinations.

   • Rational combinations with PD-1/PD-L1 or CTLA-4 blockade in cold tumors to enhance antigen presentation and T-cell priming, building on melanoma signals and checkpoint-toxicity protection data in mice.

5. PK-PD modeling for short-t½ peptides.

   • Pair sparse sampling PK (LC-MS/MS) with functional PD (mHLA-DR, DC activation assays) to optimize dose/schedule for short-acting immunomodulators—testing daily vs intermittent regimens.

Safety & Toxicology

Preclinical

• Tα1 is well tolerated in animal studies; no specific genotoxic liabilities are expected for small peptides.

• Immunotoxicity profiling indicates normalization rather than non-specific stimulation, although context (ongoing hyper-inflammation) can shape outcomes.

Human (trial-level)

• PK volunteers: No accumulation; transient local reactions; no serious toxicity.

• HBV/oncology/sepsis trials: Generally good tolerability; in ETASS, no serious drug-related AEs were reported.

• COVID-19: No unique safety signals in observational cohorts; confounding by co-therapies and disease severity is substantial.

Data gaps / risk considerations

• Long-term outcomes with chronic/indefinite use: Not established.

• Autoimmunity risk: Theoretically possible with immune activation, but not reported as a dominant signal.

• Quality: Use of authenticated, analytically verified Tα1 is critical (identity, purity, stability) for reproducible research.

Limitations & Controversies

• Heterogeneous human evidence: Older HBV and sepsis RCTs show benefit; large modern sepsis trial is neutral overall, suggesting precision medicine is needed.

• No single receptor: PRR-mediated biology is context-dependent; potency can vary with DC subset, TLR expression, and pathogen.

• COVID-19 lessons: Timing (early immune defect vs late hyper-inflammation) likely determines directionality of effect; aggregated observational data are conflicting.

Future Directions

1. Precision immunotherapy in sepsis—biomarker-stratified, double-blind RCTs targeting immunoparalysis (e.g., mHLA-DR-low) with standardized Tα1 schedules and adaptive designs (learners from TESTS).

2. Adjuvant role in high-risk vaccination—phase-2 multicenter studies in dialysis, transplant, or very elderlypopulations with systems-immunology endpoints (breadth/affinity/effector function).

3. Oncology combinations—signal-seeking trials pairing Tα1 with checkpoint inhibitors in immunologically “cold” tumors; mechanistic correlative studies to verify DC priming and T-cell infiltration.

4. Rigorous PK-PD—establish modern human PK with sensitive assays and link to functional PD (DC activation, cytokine set-points) to refine dose/time relationships for short-acting peptides.

5. Mechanism refinement—use CRISPR or pharmacological TLR2/9 blockade to dissect Tα1’s PRR dependency in human ex vivo DC/T-cell systems; model MyD88/IRF network effects.

References

1. Dominari A, et al. Thymosin alpha-1: A comprehensive review of the literature. World J Virol. 2020;9(5):67–78. PMCID: PMC7747025.

2. Chien RN, et al. Efficacy of thymosin alpha-1 in chronic hepatitis B: randomized, controlled trial. Hepatology.1998;27:1383–1387. PMID: 9581695.

3. Mutchnick MG, et al. Thymosin alpha1 treatment of chronic hepatitis B. J Viral Hepat. 1999;6:97–103. PMID: 10607256.

4. Rost KL, et al. Pharmacokinetics of thymosin alpha-1 after subcutaneous injection in healthy volunteers. Int J Clin Pharmacol Ther. 1999;37:51–57. PMID: 10027483.

5. Romani L, et al. Thymosin alpha-1 activates dendritic cells for antifungal Th1 resistance via Toll-like receptor signaling. Blood. 2004;103:4232–4239. PMID: 14982877.

6. Bozza S, et al. Tα1 activates TLR9/MyD88/IRF7-dependent sensing for antiviral responses in vivo. J Immunol.2007;179: (abstracted). PMID: 17804687.

7. Maio M, et al. Large randomized study of Tα1 with dacarbazine ± interferon‐α in metastatic melanoma. J Clin Oncol. 2010;28:1780–1787. PMID: 20194853.

8. Carraro G, et al. Tα1 enhances immunogenicity of pandemic influenza vaccine in hemodialysis patients. Vaccine.2012;30(12): (abstracted). PMID: 22178096.

9. Ershler WB, et al. Adjuvant Tα1 and influenza vaccination in the elderly. Drugs Aging. 2007;24(12): (mini-review). PMID: 17600281.

10. Wu J, et al. The efficacy of thymosin alpha-1 for severe sepsis (ETASS): multicenter randomized trial. Crit Care.2013;17:R8. PMCID: PMC4056079 (HTML).

11. Wu J, et al. The efficacy and safety of Tα1 for sepsis (TESTS). BMJ. 2025;388:e082583. (multicentre, double-blind; neutral overall).

12. Liu J, et al. Efficacy of Tα1 in COVID-19: multicenter cohort. Front Immunol. 2021;12:673693. PMCID: PMC8366398.

13. Tao N, et al. Tα1 and viral infectious diseases: mechanisms and evidence. Molecules. 2023;28:3539.

14. Garaci E. Thymosin alpha-1: historical overview. Ann N Y Acad Sci. 2007;1112:1–14. PMID: 17567941.

15. FDA. Thymosin alpha-1 (Ta1) bulk drug substances review. 2024. (identity, stability, storage).

16. Stanley TL, et al. Adjunctive immune modulation; assorted PD/PK summaries. (contextual)

17. Manicassamy S, Pulendran B. DC control of tolerogenic responses. Immunity/PMC. 2011; (notes Tα1 programming of DCs toward balanced Th1).

18. Wei Y, et al. Tα1 in cancer therapy: immunoregulation and potential applications. Int Immunopharmacol.2023;117:109744.

19. Renga G, et al. Tα1 protects from CTLA-4 intestinal toxicity in mice. Life Sci Alliance. 2020;3:e202000662.

Representative investigational regimens cited:
• HBV (Hepatology, 1998): 1.6 mg Tα1 SC twice weekly for 26–52 weeks improved virologic/histologic endpoints.
• Sepsis (ETASS, 2013): 1.6 mg SC twice daily × 5 days, then 1.6 mg SC daily × 2 improved mHLA-DRand yielded borderline mortality benefit vs standard care.
• Melanoma (JCO, 2010): 1.6–6.4 mg with DTIC±IFN-α increased responses with OS/PFS trends and no added toxicity.
• PK (Int J Clin Pharmacol Ther, 1999): 900 µg·m⁻² SC → Tmax 1–2 h, t½ < 3 h, no accumulationacross 5-day dosing.
• Vaccine adjuvant (hemodialysis): Tα1 improved influenza vaccine immunogenicity; dosing per trial protocol; safety acceptable.

⚠️ Disclaimer This peptide is intended strictly for laboratory research use. It is not FDA-approved or authorized for human use, consumption, or therapeutic application.