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What are alternatives to squalene in modern flu shot formulations?
Executive Summary
Modern influenza vaccines can avoid shark‑derived squalene through multiple viable alternatives: plant‑ or fermentation‑derived squalene (yeast, olive‑oil distillate, semisynthetic farnesene routes), completely different adjuvant chemistries (aluminum salts, CpG oligodeoxynucleotides, AS01‑style MPL+QS‑21 combinations), and alternative oil phases or triterpene oils developed by synthetic biology. These options are already used in cosmetics and some licensed vaccines, are the subject of peer‑reviewed studies showing comparable adjuvant activity, and are being evaluated for pharmaceutical‑grade production and regulatory acceptance [1] [2] [3] [4]. Switching away from shark squalene is technically feasible today, though manufacturers face regulatory, supply‑scaling, and formulation‑optimization tasks before broad substitution in seasonal influenza products becomes routine [1] [3] [5].
1. How biotech and plant sources change the squalene story
Biotechnology and plant extraction provide shark‑free squalene at commercial scale by two main routes: fermentation of sugars to produce farnesene followed by chemical conversion to squalene, and purification from olive‑oil refining distillate. Companies have leveraged semisynthetic fermentation pathways to produce β‑farnesene that can be converted into squalene suitable for cosmetics and are now testing pharmaceutical‑grade processes; olive‑oil distillates are already a known industrial source that can be purified to meet high‑purity specifications. These routes reduce pressure on shark populations and create traceable, renewable supply chains, but converting cosmetic‑grade outputs to licensed vaccine grade requires validated Good Manufacturing Practice (GMP) processes and regulatory dossiers to prove equivalence and safety in parenteral use [1] [2] [4].
2. Non‑squalene adjuvants already protecting people
Vaccine developers commonly use non‑squalene adjuvants that do not require any oil‑in‑water oil phase. Examples in licensed vaccines include aluminum salts (aluminum hydroxide/phosphate), CpG oligodeoxynucleotides such as CpG‑1018, and the AS01 family combining MPL with QS‑21 saponin; these adjuvants have documented safety and regulatory acceptance in multiple products. MF59 and AS03 are squalene‑based oil‑in‑water emulsions used in some flu vaccines, but the availability of aluminum and immunostimulatory adjuvants means manufacturers can design influenza formulations without squalene when the immunogenicity profile allows. Regulatory precedent exists for these alternatives, easing potential pathway choices for manufacturers wishing to omit squalene [3] [6] [7].
3. Oil alternatives and engineered triterpenes in the lab
Laboratory and preclinical studies compare alternate oil phases and engineered triterpenes—including long‑ and medium‑chain triglycerides, perfluorocarbons, botryococcene, and yeast‑produced triterpenes—to squalene emulsions. Several studies show synthetic biology‑derived triterpenes can match or exceed squalene’s adjuvant effect in animal models and in vitro assays, and that oil composition materially affects emulsion stability and immune modulation. These findings imply scientifically credible non‑shark oil substitutes exist, but they remain at different Technology Readiness Levels: some are already scalable and cosmetic‑used, while others need more clinical bridging and stability work for vaccine licensure [5] [4] [2].
4. Practical hurdles: regulation, formulation, and supply chain realities
Even with alternatives available, practical barriers slow rapid substitution. Pharmaceutical‑grade certification requires GMP production, stability and sterility demonstration, and clinical comparability studies to show equal safety and efficacy—especially for parenteral adjuvants. Manufacturers must also validate manufacturing analytics and traceability for semisynthetic or plant‑derived squalene, and some alternative adjuvants change dose, reactogenicity, or cold‑chain constraints, which affects vaccine policy and procurement. Governments and manufacturers must weigh biodiversity goals against near‑term supply reliability, because switching adjuvant platforms can trigger new regulatory reviews and affect vaccine rollout timelines [1] [3] [8].
5. What remains unresolved and why choices matter
Key open questions include the pace at which pharmaceutical‑grade non‑shark squalene can be scaled under GMP, the clinical equivalence of novel triterpene oils in humans, and whether switching to non‑oil adjuvants will meet efficacy needs across age groups. Policy tradeoffs involve conservation benefits versus costs and timing of reformulation, while scientific tradeoffs include differing immune profiles and reactogenicity between adjuvants. The evidence shows squalene is replaceable by both shark‑free squalene and non‑squalene adjuvants, but broad adoption hinges on regulatory pathways, clinical comparators, and industrial investment to ensure alternatives meet the practical demands of seasonal influenza vaccination programs [1] [2] [3].