Investigation of the Effects of Dietary Nitrate and Sex on COVID-19 Vaccine Induced Vascular Dysfunction in Healthy Men and Women (DiNOVasc-COVID-19)

NCT04889274 | Active Not Recruiting Phase 1

• 1 other identifier: 21/SC/0154
• Study Type: interventional
• Target: 98
• Locations: 1 country
• Sites: 1

Brief Summary

Inorganic nitrate can protect blood vessels from the damage that occurs during cardiovascular disease. Early experimental work suggests that nitrate-induced improvements in vascular function relate to the suppression of inflammatory pathways. Whether this protection against inflammation-induced damage to the blood vessel wall might also be functional in the setting of COVID-19 vaccination will be investigated. Vascular function will be assessed before and after the healthy participant has received their COVID-19-vaccination. Whether there might be differences in the response to the vaccine between the sexes and whether a dietary nitrate intervention impacts upon the effects of vaccination will be investigated. The study is in two parts: Part A: To assess sex differences in the vascular response to COVID-19 vaccination. Part B: To assess whether inorganic nitrate, in the form of dietary inorganic nitrate supplementation compared to placebo control, can raise circulating plasma nitrite levels and thereby prevent the systemic inflammation that causes vascular dysfunction.

Conditions

Cardiovascular Diseases; Endothelial Dysfunction

Keywords

COVID-19, endothelial dysfunction, nitrate, nitrite, sex

Outcome Measures

Primary Outcomes (3)

• Comparison of change in FMD from baseline between the sexes after COVID-19 vaccination

  A measurement of brachial artery diameter using ultrasound (FMD, flow mediated dilatation) will be conducted at visits 2 and 3 (i.e. pre- and post-vaccine). This outcome measure will compare these 2 measurements, and change in FMD will be calculated as subtracting the value collected at visit 3 from visit 2, and expressed as a percentage (%). Comparisons will then be made between the sexes (i.e. males vs females) in Part A.

  Up to 28 days

• Comparison of change in FMD from baseline after COVID-19 vaccination following inorganic nitrate versus placebo supplementation

  A measurement of brachial artery diameter using ultrasound (FMD, flow mediated dilatation) will be conducted at visits 2 and 3 (i.e. pre- and post-vaccine). This outcome measure will compare these 2 measurements, and change in FMD will be calculated as subtracting the value collected at visit 3 from visit 2, and expressed as a percentage (%). Comparisons will then be made between intervention and placebo in Part B.

  Up to 28 days

• Comparison of change in plasma [NO2-] following inorganic nitrate versus placebo supplementation

  Quantification of \[NO2-\] will be made using ozone chemiluminescence. Samples of blood, urine and saliva will be acquired at visit 2 and visit 3 (i.e. pre- and post-vaccine). Measurement of \[NO2-\] will be made in all matrices at both timepoints, and a comparison will be made (for this we plan on using 2-way ANOVA, using GraphPad Prism statistics package) to compare time and intervention.

  Up to 28 days

Secondary Outcomes (5)

• Comparison between the sexes in the systemic inflammatory response to COVID-19 vaccination

  Up to 28 days

• Comparison between nitrate and placebo with respect to inflammatory cell activation state

  Up to 28 days

• Comparison between nitrate and placebo with respect to circulating inflammatory mediators

  Up to 28 days

• Comparison between nitrate and placebo with respect to platelet function during systemic inflammation

  Up to 28 days

• Comparison between nitrate and placebo with respect to endothelium independent vasodilation of the brachial artery

  Up to 28 days

Study Arms (4)

Part A: Male healthy volunteers

EXPERIMENTAL

Biological: COVID-19 vaccine

Part A: Female healthy volunteers

EXPERIMENTAL

Biological: COVID-19 vaccine

Part B: Nitrate-rich beetroot juice

ACTIVE COMPARATOR

Dietary Supplement: Concentrate beetroot Juice (70 ml) containing \~5mmol of inorganic nitrate

Biological: COVID-19 vaccine; Biological: Concentrate beetroot Juice

Part B: Nitrate-deplete beetroot juice

PLACEBO COMPARATOR

Dietary Supplement: Concentrate beetroot Juice (70 ml) which is nitrate-depleted

Biological: COVID-19 vaccine; Biological: Nitrate-deplete beetroot juice

Interventions

COVID-19 vaccine BIOLOGICAL

COVID-19 vaccine as offered by NHS England

Part A: Female healthy volunteers; Part A: Male healthy volunteers; Part B: Nitrate-deplete beetroot juice; Part B: Nitrate-rich beetroot juice

Concentrate beetroot Juice BIOLOGICAL

Beetroot juice containing approximately 5mmol/l nitrate

Part B: Nitrate-rich beetroot juice

Nitrate-deplete beetroot juice BIOLOGICAL

Beetroot juice with nitrate removed

Part B: Nitrate-deplete beetroot juice

Eligibility Criteria

• Age: 18 Years - 60 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64)

You may qualify if:

• Healthy volunteers with a booking for COVID-19 vaccination slot as per government guidelines
• Aged 18-60
• Volunteers who are willing to sign the consent form

You may not qualify if:

• Aged \<18 or \>60 years
• Healthy subjects unwilling to consent
• Pregnant, or any possibility that a subject may be pregnant
• History of any serious illnesses, including recent infections or trauma
• Subjects taking systemic medication (other than the oral contraceptive pill)
• Subjects with self-reported use of mouthwash or tongue scrapes
• Subjects with recent (2 weeks) or current antibiotic use
• Subjects with a history, or recent treatment of (within last 3 months) any oral condition (excluding caries), including gingivitis, periodontitis and halitosis
• Subjects with a history of COVID-19 vaccination
• Subjects with any history of a blood-borne infectious

Sponsors & Collaborators

• Queen Mary University of London: lead

Study Sites (1)

The William Harvey Research Institute

London, EC1M 6BQ, United Kingdom

Location

Related Publications (4)

• Rathod KS, Kapil V, Velmurugan S, Khambata RS, Siddique U, Khan S, Van Eijl S, Gee LC, Bansal J, Pitrola K, Shaw C, D'Acquisto F, Colas RA, Marelli-Berg F, Dalli J, Ahluwalia A. Accelerated resolution of inflammation underlies sex differences in inflammatory responses in humans. J Clin Invest. 2017 Jan 3;127(1):169-182. doi: 10.1172/JCI89429. Epub 2016 Nov 28.

  PMID: 27893465 RESULT

• Kapil V, Khambata RS, Jones DA, Rathod K, Primus C, Massimo G, Fukuto JM, Ahluwalia A. The Noncanonical Pathway for In Vivo Nitric Oxide Generation: The Nitrate-Nitrite-Nitric Oxide Pathway. Pharmacol Rev. 2020 Jul;72(3):692-766. doi: 10.1124/pr.120.019240.

  PMID: 32576603 RESULT

• Shabbir A, Rathod KS, Khambata RS, Ahluwalia A. Sex Differences in the Inflammatory Response: Pharmacological Opportunities for Therapeutics for Coronary Artery Disease. Annu Rev Pharmacol Toxicol. 2021 Jan 6;61:333-359. doi: 10.1146/annurev-pharmtox-010919-023229. Epub 2020 Oct 9.

  PMID: 33035428 RESULT

• Shabbir A, Chhetri I, Khambata RS, Parakaw T, Lau C, Aubdool MABN, Massimo G, Dyson N, Kapil V, Godec T, Apea V, Flint J, Orkin C, Rathod KS, Ahluwalia A. A double-blind, randomised, placebo-controlled parallel study to investigate the effect of sex and dietary nitrate on COVID-19 vaccine-induced vascular dysfunction in healthy men and women: protocol of the DiNOVasc-COVID-19 study. Trials. 2023 Sep 16;24(1):593. doi: 10.1186/s13063-023-07616-2.

  PMID: 37715222 DERIVED

MeSH Terms

Conditions

Cardiovascular Diseases; COVID-19; Coitus

Interventions

COVID-19 Vaccines

Condition Hierarchy (Ancestors)

Pneumonia, Viral; Pneumonia; Respiratory Tract Infections; Infections; Virus Diseases; Coronavirus Infections; Coronaviridae Infections; Nidovirales Infections; RNA Virus Infections; Lung Diseases; Respiratory Tract Diseases; Sexual Behavior; Behavior

Intervention Hierarchy (Ancestors)

Viral Vaccines; Vaccines; Biological Products; Complex Mixtures

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 6, 2021
• First Posted: May 17, 2021
• Study Start: May 10, 2021
• Primary Completion: April 30, 2026
• Study Completion: April 30, 2026
• Last Updated: August 6, 2025

Record last verified: 2025-08

Locations

GB (1)