Vasoactive intestinal peptide, usually called VIP, is a 28-residue neuropeptide that acts through VPAC receptors in several tissues. Its synthetic form, aviptadil, has been tested in serious lung disease. A small inhaled pulmonary-hypertension pilot found lower pressure in the arteries supplying the lungs. In an earlier randomized COVID-19 respiratory-failure trial, a secondary analysis found better survival, but the main comparison was too uncertain to establish that aviptadil helped patients survive free of respiratory failure at day 60. The larger TESICO trial did not establish better recovery or survival at 90 days.
Overview
VIP was characterized as a short amidated signaling peptide. Mutt and Said’s molecular work established the 28-residue porcine sequence, while later human receptor studies directly examined VIP bound to its signaling machinery. Those experiments provide the chemical identity and receptor context for interpreting modern clinical work with synthetic VIP. Original molecular paper; human receptor study
Molecular profile
Forms and derivatives
VIP and aviptadil
Aviptadil is the synthetic VIP preparation used in the clinical literature here. IV aviptadil respiratory-failure trials and inhaled VIP pulmonary-hypertension observations delivered the peptide by different routes in different diseases.
PACAP is a separate peptide
PACAP activates shared VPAC receptors and has different activity at PAC1. The 2022 structural study resolved actual VIP-bound VPAC1 as well as PACAP-bound complexes; a PACAP–receptor structure should not be captioned as though VIP were the ligand.
VIP and aviptadil are names encountered in biological and clinical contexts. Formulation and route still matter: an inhaled pulmonary-vascular experiment does not describe exposure after intravenous administration or demonstrate the effects of an unspecified nasal product.
Uses and research areas
Research spans vascular function, secretion and neuroimmune signaling. The clinical lung studies reviewed here pursued two different problems. Pulmonary hypertension involves elevated pressure in the lung’s arterial circulation. COVID-19 respiratory failure involves severely impaired oxygenation in an acute illness, often requiring intensive-care respiratory support. Their mechanisms, comparators and outcome measures differ.
The pulmonary-hypertension pilot measured vascular pressures and related physiology during inhaled treatment. The later IV respiratory-failure trials followed recovery and survival, allowing investigators to test whether the proposed lung effects produced a clinical improvement in acutely ill patients.
Mechanism of action
VIP activates the related VPAC1 and VPAC2 receptors. These are cell-surface G protein-coupled receptors: activation can recruit Gs, which stimulates the enzyme adenylyl cyclase. That enzyme produces cAMP, an intracellular messenger that helps transmit the receptor signal. The related peptide PACAP also activates VPAC receptors but has different activity at PAC1. Receptor subtype, ligand and tissue therefore help determine the response. Piper and colleagues, 2022
Piper and colleagues combined cryo-electron microscopy, functional assays and molecular simulations, including an actual VIP–VPAC1–Gs complex. Their work showed how the peptide engages the receptor and how its interactions differ from PACAP, giving a structural explanation for differences in receptor selectivity.
VIP binds VPAC1 at the cell surface. The activated receptor engages Gs inside the cell, leading to activation of adenylyl cyclase and production of the messenger cAMP. Piper and colleagues resolved the active VIP–VPAC1–Gs complex (PDB 8E3Z) and studied its signaling in cell assays. The drawing simplifies the receptor’s seven membrane-spanning segments; the lung-disease outcomes were measured in separate clinical trials.
VIP relaxes blood vessels and influences intestinal secretion. These actions help explain why investigators monitored low blood pressure and diarrhea during IV aviptadil treatment. A molecular action can therefore be relevant both to the proposed treatment effect and to its adverse effects.
Pharmacokinetics
Domschke and colleagues studied graded intravenous VIP infusions in four healthy male volunteers, measuring circulating VIP with a radioimmunoassay. After the infusion stopped, the reported average disappearance half-time was about one minute. The experiment describes a short-lived plasma immunoreactivity signal under controlled IV conditions. Its sample was small, and it did not measure brain delivery or a nasal or subcutaneous preparation. Domschke and colleagues, 1978
The clinical trials used their own formulations, infusion periods and monitoring. Relating those interventions to the historical measurements requires the same analyte and delivery context; receptor responses and clinical outcomes can unfold over longer periods than a short circulating signal.
Research findings
An inhaled pulmonary-hypertension pilot supplied a physiological signal
Petkov and colleagues combined tissue and cell observations with an open clinical pilot in eight people with primary pulmonary hypertension. During inhaled VIP treatment, mean pulmonary arterial pressure fell from 59 ± 8 to 46 ± 7 mmHg at three months (mean ± SD). The result is a direct measured physiological observation. With no randomized placebo group, the small pilot could not isolate the contribution of treatment from patient selection, background management or time. Petkov and colleagues, 2003
The paper also included tissue and cell experiments that explored how VIP might affect pulmonary blood vessels. Those experiments and the eight-patient pilot supplied different kinds of evidence: cellular responses in the laboratory and changes in vascular physiology during treatment.
The earlier COVID-19 trial had different primary and secondary findings
Youssef and colleagues randomized 196 patients with critical COVID-19 respiratory failure at ten U.S. hospitals, in a 2:1 allocation to IV aviptadil or placebo. The primary endpoint, being alive and free of respiratory failure at day 60, did not reach statistical significance: the adjusted odds ratio was 1.6, with a 95% confidence interval of 0.86–3.11. The report also found a favorable secondary survival result, with an odds ratio of 2.0 (1.1–3.9). Youssef and colleagues, 2022
The survival result provided a reason for further study, but the trial did not establish that aviptadil increased the chance of being alive and free of respiratory failure at day 60, its main planned test. The subsequent TESICO trial supplied a larger, separate test of clinical recovery and survival.
TESICO did not confirm a clinical benefit
The larger multicenter TESICO study randomized 471 people in its aviptadil comparison. The modified intention-to-treat analysis included 461 who received at least a partial blinded infusion: 231 assigned to aviptadil and 230 to placebo. At day 90, the odds ratio for a better clinical outcome category was 1.11 (95% CI 0.80–1.55; P = 0.54). Cumulative mortality was 38% with aviptadil and 36% with placebo, with a hazard ratio of 1.04 (0.77–1.41). Brown and colleagues, 2023
TESICO found no improvement in recovery or survival. Its larger comparison did not confirm the survival advantage reported as a secondary finding in the earlier trial, leaving no demonstrated clinical benefit in the respiratory-failure populations studied.
Safety and tolerability
Intravenous aviptadil remains investigational for respiratory failure; this review identified no U.S. FDA-approved lung indication for VIP or aviptadil. The randomized trials closely monitored participants and specified how to manage reactions to the infusion. In TESICO, low blood pressure and diarrhea were more frequent during aviptadil infusion. By day 5, 63% of aviptadil participants and 56% of placebo participants had experienced at least one event in a combined safety measure covering death, organ failure, serious infection, serious adverse events or grade 3–4 events. The uncertainty around that comparison prevents a reliable estimate of how much aviptadil increased severe harm. TESICO report
The small inhaled pilot cannot establish the safety of other routes or longer use. Severe acute illness also creates substantial background risk, so an event observed during treatment is not automatically caused by the peptide. The applicable safety question concerns a defined preparation, route, population and monitored outcome.
What the research means
VIP has well-supported receptor biology and measurable vascular effects. The largest controlled respiratory-failure study did not show the hoped-for clinical improvement. That result materially limits claims for that indication even though biological reasons for investigating the peptide remain understandable.
The pulmonary-hypertension pilot concerns another disease and another route, with a much weaker comparator design. It should be treated as an early signal within that setting. A useful interpretation keeps molecular activity, physiological change and clinical benefit connected through actual experiments, while preserving where each was measured.
FAQs
Is VIP simply an anti-inflammatory peptide?
VIP is a neuropeptide with effects that depend on receptor, tissue and delivery. Vascular relaxation, secretion and immune signaling are different consequences of that biology. The lung trials directly tested clinical outcomes and did not establish a general anti-inflammatory treatment benefit.
Did aviptadil work in COVID-19 respiratory failure?
The 196-patient trial did not establish an improvement in its main outcome: being alive and free of respiratory failure at day 60. It did report better survival in a secondary analysis. The larger TESICO comparison then found no improvement in clinical outcome or survival at day 90, so the earlier survival finding was not confirmed.
Why are 471 and 461 both reported for TESICO?
The trial randomized 471 participants in the aviptadil comparison. Its modified intention-to-treat analysis included 461 who received at least some blinded infusion, split 231 and 230. Those denominators describe different stages of the same study.
Does a one-minute half-life describe every VIP preparation?
The approximately one-minute half-life describes how quickly antibody-detected VIP disappeared from plasma in four healthy men after an IV infusion stopped. That assay and route do not establish how much intact peptide reaches the brain, or the absorption and persistence of inhaled, nasal or subcutaneous preparations.
What does the pulmonary-hypertension pilot establish?
Eight patients had improved physiological measurements during inhaled treatment. Without a randomized placebo group, the study cannot isolate treatment effects from selection, background care or time. It supplied a clinical signal to test, rather than definitive efficacy.
Is aviptadil an approved lung therapy?
The IV respiratory-failure uses discussed here are investigational. No U.S. FDA-approved VIP/aviptadil lung indication was identified in the current source search. Trial registration and product development names do not confer a marketing authorization.
Comparisons and related reading
References
The source list includes original molecular and pharmacokinetic work, receptor structural research and the clinical lung reports. The two COVID-19 trials are separate studies with distinct endpoints and analysis populations.
The original molecular paper established the 28-residue amidated porcine peptide sequence; modern human/VIP receptor work supplies the corresponding human context.
Cryo-EM, signaling assays and simulations include the actual VIP–VPAC1–Gs complex, separating direct VIP structural evidence from PACAP-bound receptor structures.
A four-volunteer infusion experiment measured VIP immunoreactivity and an average one-minute disappearance half-time after infusion stopped. This describes the measured plasma signal in healthy men.
Tissue/cell findings and an eight-patient inhaled-treatment pilot connected vascular biology with hemodynamic observations. The small open pilot had no placebo control.
The 196-patient trial missed the primary recovery-plus-survival endpoint while reporting a favorable secondary survival result. Both findings are needed to interpret the study.
The larger multicenter trial found no improvement in the day-90 clinical ordinal outcome or mortality. Its modified intention-to-treat population included 461 of 471 randomized participants.
Glossary
- VPAC receptor
- A cell-surface receptor activated by VIP and PACAP; VPAC1 and VPAC2 are related subtypes.
- Gs
- A signaling G protein that couples activated receptors to adenylyl cyclase and cellular cAMP production.
- Pulmonary arterial pressure
- Pressure in the arteries carrying blood from the heart through the lungs.
- Ordinal outcome
- An outcome ranked into ordered clinical categories, such as death and degrees of recovery.
- Modified intention-to-treat
- An analysis population defined after randomization by an explicit rule; TESICO required at least a partial blinded infusion.