SHIELD Trial Advances Combination Antiviral for Long COVID

PridCor Therapeutics is advancing its phase 2 SHIELD trial (NCT07597902) toward enrollment, testing whether a combination antiviral regimen can relieve the persistent fatigue, cognitive, and autonomic symptoms of long COVID. The randomized, placebo-controlled study adds a short course of nirmatrelvir/ritonavir (Paxlovid) to an antiviral and anti-inflammatory regimen already used for the condition.¹

SHIELD (SARS-CoV-2 and Herpesvirus Inhibition for Ending Long COVID Dysfunction) is a randomized, double-blind, placebo-controlled phase 2 trial enrolling approximately 150 adults aged 18 to 65 with long COVID. Participants will receive valacyclovir and celecoxib twice daily for 14 weeks, with a 25-day course of nirmatrelvir/ritonavir added partway through and the valacyclovir dose reduced during that period; assessments occur at weeks 4, 8, 12, 16, and 20.^1,2

The primary endpoint is change in the EQ-5D-5L visual analogue scale, a self-rated measure of overall health; secondary endpoints include the EQ-5D-5L descriptive system, PROMIS-29, the 30-item General Symptom Questionnaire, and the Neuro-QoL Cognitive Function scale, along with mood, anxiety, and sleep assessments. PridCor said preliminary screening has begun and full enrollment is expected once study drug supply arrives at trial sites, including Mount Sinai's Cohen Center for Recovery from Complex Chronic Illness.

“SHIELD is moving from planning to execution,” William "Skip" Pridgen, MD, co-founder and chief executive officer of PridCor Therapeutics, said in a statement.¹ “Our case series was small and open-label, and the paper itself concluded that a randomized, placebo-controlled trial had to come next.”

David Putrino, PhD, professor of rehabilitation and human performance at the Icahn School of Medicine at Mount Sinai and Nash Family Director of the Cohen Center, is serving as principal investigator; Amy Proal, PhD, co-founder and president of the PolyBio Research Foundation and scientific director of the Cohen Center, is a co-investigator.

The SHIELD design builds directly on a case series by Pridgen and Putrino, published January 5, 2026, in Frontiers in Immunology.³ The single-center, open-label study, conducted at an Alabama clinic between April 2022 and February 2024, followed 24 patients with long COVID who received either valacyclovir plus celecoxib alone for 120 days (IO protocol, n = 12) or the same regimen with a 15-day course of Paxlovid added on days 13 through 28 (IP protocol, n = 12); 3 additional patients crossed over from IO to IP.

At day 120, patients on the IP regimen reported a mean fatigue Patient Global Impression of Change (PGIC) score of 6.8 versus 4.8 for those on IO alone, a difference of 2 points (P <.0001; Cohen's d, 1.8). The IP group also showed significantly greater improvement on dysautonomia (6.9 vs 4.1; P <.001) and brain fog (6.4 vs 4.2; P <.001) PGIC scores, and a 55.3% greater reduction in fatigue on a visual analog scale compared with the IO group (P <.0001).³

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Among the 15 IP-protocol participants followed to 731 days, symptom ratings showed no statistically significant change across the 120-, 305-, and 731-day follow-up points, indicating the improvement was sustained rather than transient. The IO regimen produced no reported adverse events (AEs); the addition of Paxlovid was associated with dysgeusia (86.7%) and transient increased fatigue (40%) that resolved after the antiviral course ended, with no serious AEs or treatment discontinuations in either group.

The authors proposed that persistent SARS-CoV-2 and reactivated latent herpesviruses jointly drive long COVID symptoms, reasoning that valacyclovir suppresses herpesvirus replication, celecoxib blunts the COX-2 upregulation herpesviruses induce, and nirmatrelvir/ritonavir targets the SARS-CoV-2 protease, a combination they argued addresses 2 distinct pathophysiologic drivers rather than one. Noting that prior Paxlovid monotherapy trials of 15 to 30 days had failed to show benefit in long COVID, Pridgen and Putrino concluded that “a larger, controlled trial of IMC-2 paired with Paxlovid is recommended.”³

No treatment is currently approved specifically for long COVID, and SHIELD joins a small number of randomized trials testing distinct mechanistic approaches to the condition. In September 2026, BioVie reported that its phase 2 ADDRESS-LC trial of bezisterim, an oral insulin sensitizer with anti-inflammatory activity, showed subgroup benefit in patients with more severe baseline fatigue, post-exertional malaise, and cognitive impairment, even though none of 22 endpoints reached significance across the full study population.⁴

“These results are among the most promising we have seen in this field so far," said Michael Peluso, MD, MHS, of the University of California, San Francisco, on the bezisterim findings.⁴ Unlike ADDRESS-LC, which targets neuroinflammation broadly, SHIELD is built around a specific virological hypothesis, testing whether directly suppressing viral persistence and reactivation can relieve long COVID symptoms.

REFERENCES
1. PridCor Therapeutics advances phase 2 SHIELD study of a combination antiviral regimen for long COVID toward enrollment. News release. PridCor Therapeutics, LLC. Published September 24, 2026. Accessed September 25, 2026. https://www.globenewswire.com/news-release/2026/09/24/3368192/0/en/pridcor-therapeutics-advances-phase-2-shield-study-of-a-combination-antiviral-regimen-for-long-covid-toward-enrollment.html
2. SHIELD: SARS-CoV-2 and herpesvirus inhibition for ending long COVID dysfunction. ClinicalTrials.gov identifier: NCT07597902. Accessed September 25, 2026. https://clinicaltrials.gov/study/NCT07597902
3. Pridgen WL, Putrino D. Patient-reported improvements from use of IMC-2 alone and IMC-2 and Paxlovid in a long COVID cohort: a case series. Front Immunol. Published online January 5, 2026. doi:10.3389/fimmu.2025.1698271
4. BioVie announces topline results from phase 2 ADDRESS-LC trial evaluating bezisterim for the treatment of neurological symptoms associated with long COVID. News release. Published September 15, 2026. Accessed September 25, 2026. https://www.globenewswire.com/news-release/2026/09/15/3361943/0/en/biovie-announces-topline-results-from-phase-2-address-lc-trial-evaluating-bezisterim-for-the-treatment-of-neurological-symptoms-associated-with-long-covid.html