July 21, 2026 · 3 min read

Vasoactive intestinal peptide (VIP): receptors, functions and the aviptadil trials

A summary of VIP pharmacology at VPAC and PAC1 receptors and what two randomized trials of intravenous aviptadil in COVID-19 respiratory failure reported.

Vasoactive intestinal peptide (VIP) is a 28-amino-acid neuropeptide. Its synthetic form is called aviptadil, which is the name used in clinical trials. This note covers what is known about its receptors and functions, and what two randomized trials of intravenous aviptadil reported.

The VIP sequence

Sequence: Histidine, Serine, Aspartic acid, Alanine, Valine, Phenylalanine, Threonine, Aspartic acid, Asparagine, Tyrosine, Threonine, Arginine, Leucine, Arginine, Lysine, Glutamine, Methionine, Alanine, Valine, Lysine, Lysine, Tyrosine, Leucine, Asparagine, Serine, Isoleucine, Leucine, Asparagine.

  • Positively charged
  • Polar
  • Negatively charged
  • Hydrophobic
Length
28 amino acids
Average mass
3,325.8 Da
Receptors
VPAC1 and VPAC2
Residues 125 to 152 of the VIP precursor (UniProt P01282), with a C-terminal asparagine amide. The mass calculated from the amidated sequence is 3,325.8 Da. PubChem lists aviptadil, the synthetic form (CID 16132300), at 3,326.8 Da, which corresponds to the free-acid form.

Receptors and functions

VIP and PACAP belong to a superfamily of structurally related hormones that also includes glucagon, the glucagon-like peptides, secretin, gastric inhibitory peptide and GHRH. The 2012 IUPHAR review describes roles for VIP and PACAP in the central nervous system, in the control of circadian rhythms, learning and memory, anxiety and responses to stress and brain injury.

In the rest of the body the review lists control of immunity and inflammation, pancreatic insulin secretion, the release of catecholamines from the adrenal medulla, and roles as co-transmitters in autonomic and sensory neurons.

The receptors for VIP and PACAP

  1. PAC1

    Selective for pituitary adenylate cyclase-activating polypeptide (PACAP).

  2. VPAC1

    Responds to both VIP and PACAP with high affinity.

  3. VPAC2

    Responds to both VIP and PACAP with high affinity.

From the IUPHAR review by Harmar et al., British Journal of Pharmacology 2012. All three are class B G protein-coupled receptors.

Aviptadil in COVID-19 respiratory failure

Nonclinical work suggested that VIP upregulates surfactant production, inhibits cytokine synthesis and blocks replication of the SARS-CoV-2 virus in pulmonary cells, which led to trials in patients with COVID-19 respiratory failure.

A 2022 trial in Critical Care Medicine randomized 196 patients at 10 US hospitals, 2 to 1, to three days of intravenous aviptadil or placebo. The primary endpoint, being alive and free from respiratory failure at day 60, did not reach statistical significance (odds ratio 1.6; 95% CI 0.86 to 3.11). The authors report a two-fold odds of improved survival at 60 days (odds ratio 2.0; 95% CI 1.1 to 3.9; P = 0.035) and reduced interleukin-6 by day 3 (P = 0.02).

Odds ratio for the primary outcome in each trial

  • Youssef et al. (196 patients)95% CI 0.86 to 3.111.6 odds ratio
  • TESICO (461 patients)95% CI 0.80 to 1.55; P = 0.541.11 odds ratio
Odds ratio for aviptadil versus placebo (1 means no difference). Youssef et al., Crit Care Med 2022 measured being alive and free from respiratory failure at day 60. Brown et al., Lancet Respir Med 2023 (TESICO) used a six-category ordinal outcome at day 90.

The larger TESICO trial

TESICO, a randomized, placebo-controlled trial at 28 US sites reported in The Lancet Respiratory Medicine in 2023, included 461 participants in the aviptadil comparison. Their median age was 57 and 94% were in an intensive care unit at baseline. The odds ratio for a better outcome category at day 90 was 1.11 (95% CI 0.80 to 1.55; P = 0.54). The hazard ratio for death was 1.04 (95% CI 0.77 to 1.41; P = 0.78).

The primary safety outcome up to day 5, a composite of death, serious adverse events, organ failure, serious infection or grade 3 or 4 adverse events, occurred in 146 of 231 patients on aviptadil (63%) and 129 of 230 on placebo (56%; odds ratio 1.40; 95% CI 0.94 to 2.08; P = 0.10). The authors concluded that aviptadil did not significantly improve clinical outcomes up to day 90.

Deaths up to day 90 in TESICO

  • Aviptadil86 deaths38%
  • Placebo83 deaths36%
Cumulative percentage who died up to day 90 among the 461 participants in the aviptadil versus placebo comparison (Brown et al., Lancet Respir Med 2023).

Reading these results

The two trials point in different directions on survival, so how they are weighed matters.

  • Neither trial met its primary endpoint. The earlier trial reports its survival finding separately, and its own abstract notes that the primary endpoint showed no significant difference.
  • The trials differ in size and design. TESICO was larger and measured a different outcome at a later time point.
  • The setting was narrow: intravenous infusion in critically ill hospital patients with a single disease. The results say little about VIP in other settings.
  • The receptor and physiology literature is much broader than the trial record, and it describes what VIP does in the body, not whether it treats a condition.

At 28 residues, a certificate of analysis for VIP should show a mass near 3,326 Da. A database entry for the free-acid form, as in PubChem, reads about 1 Da higher than the amidated peptide, so the form being tested should be stated.

References

  1. Harmar AJ et al. Pharmacology and functions of receptors for vasoactive intestinal peptide and pituitary adenylate cyclase-activating polypeptide: IUPHAR review 1. Br J Pharmacol 2012.
  2. Youssef JG et al. The use of IV vasoactive intestinal peptide (aviptadil) in patients with critical COVID-19 respiratory failure: results of a 60-day randomized controlled trial. Crit Care Med 2022.
  3. Brown SM et al. Intravenous aviptadil and remdesivir for treatment of COVID-19-associated hypoxaemic respiratory failure in the USA (TESICO): a randomised, placebo-controlled trial. Lancet Respir Med 2023.

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