New Treatments for Long COVID: Targeting Spike Protein and Beyond in 2025

As of August 2025, Long COVID—also known as post-COVID-19 condition—continues to affect millions worldwide, with symptoms ranging from fatigue and brain fog to cardiovascular issues and respiratory problems that persist for months or years after the initial SARS-CoV-2 infection. While no FDA-approved treatments specifically for Long COVID exist yet, significant progress has been made in 2025 through research initiatives like the NIH's RECOVER program, which has completed enrollment for several observational studies and is actively testing interventions in clinical trials. This article reviews emerging treatments, with a focus on those targeting the SARS-CoV-2 spike protein—a key suspect in viral persistence and ongoing symptoms—and broader approaches addressing inflammation, immune dysregulation, and symptom management. Data from recent studies, including preclinical models and human trials, highlight promising avenues, though many remain investigational.

Understanding the Role of the Spike Protein in Long COVID

The SARS-CoV-2 spike protein, which enables the virus to enter cells, has been implicated in Long COVID pathophysiology. Research in 2025 shows that spike protein fragments can persist in tissues like the brain's meninges and skull bone marrow for up to four years post-infection, potentially triggering chronic inflammation, autoimmunity, and symptoms such as fatigue and cognitive impairment. This persistence may lead to "abzymes"—rogue antibodies that mistakenly target the spike protein but cause collateral damage to host tissues. Additionally, viral reservoirs in the body could sustain low-level replication, exacerbating symptoms. Targeting the spike protein aims to neutralize these remnants, clear reservoirs, and halt downstream effects. Preclinical studies in mice have demonstrated success: a novel antiviral compound targeting a viral enzyme prevented Long COVID-like symptoms by reducing spike protein accumulation and inflammation. Human applications are emerging, with therapies focusing on monoclonal antibodies and small-molecule inhibitors.

Treatments Targeting the Spike Protein

Several 2025 developments center on directly addressing spike protein persistence:

• Monoclonal Antibodies (mAbs): AstraZeneca's sipavibart, a long-acting mAb designed to bind and neutralize the SARS-CoV-2 spike protein, is in clinical trials for preventing and treating Long COVID symptoms. Early data suggest it could reduce viral reservoirs and alleviate symptoms in high-risk patients. Another SARS-CoV-2-specific mAb is being tested in trials to combat inflammation linked to spike protein in post-COVID cases. The SPEAR Study Group, formed by Invivyd and researchers, is guiding trials on broadly neutralizing anti-spike mAbs to evaluate their impact on Long COVID. 
• Small-Molecule Inhibitors: A new compound targeting the SARS-CoV-2 membrane (M) protein, which interacts with the spike, has shown promise in inhibiting viral assembly and persistence. Published in Nature in March 2025, this inhibitor could serve as a standalone treatment for coronaviruses, including Long COVID manifestations. Preclinical work also explores drugs that clear spike antigens in children, leading to augmented recovery.

These approaches are supported by biomarkers: 2025 studies identified plasma signatures linking spike persistence to apoptotic inflammatory networks, enabling more precise targeting.

Repurposed and Emerging Therapies

Several non-antiviral treatments show potential based on recent clinical evidence (6):

• Metformin: Large phase 3 trials demonstrated a 42% to 63% reduction in Long COVID incidence when used early, making it a leading candidate for prevention.
• Low-Dose Naltrexone (LDN): Shows significant improvements in fatigue, post-exertional malaise, and pain.
• Dexamethasone: Reduces fatigue and shortens symptom duration by about 33%.
• Omega-3 Fatty Acids: Moderate benefits for mental health and musculoskeletal symptoms.
• L-Arginine with Vitamin C: High rates of symptom relief, especially fatigue and shortness of breath.
• A multicenter trial (REVITALIZE) is testing repurposed drugs in Long COVID patients. 
• Tirzepatide (Zepbound) is in trials for symptom reduction, potentially aiding weight management and inflammation.
• The COVit-2 trial, was designed to assess whether oral nicotinamide supplementation could influence recovery in newly diagnosed COVID-19 patients. Conducted across multiple centers in Germany, the study enrolled a total of 900 individuals who had recently tested positive for SARS-CoV-2. They were randomly assigned to take either nicotinamide or a placebo for four weeks, and their symptoms and progress were tracked for six months. Nicotinamide modulates gut microbial metabolic potential and accelerates recovery in mild-to-moderate COVID-19. Patients who had taken nicotinamide during the initial infection were less likely to report persistent long COVID symptoms, such as fatigue or difficulty concentrating. (7)

Other treatments under investigation include therapeutic apheresis, intravenous immunoglobulin (IVIg), N-acetylcysteine (NAC), and immunomodulators like anakinra (IL-1 receptor antagonist), fluvoxamine (SSRI with anti-inflammatory effects), and infliximab (TNF inhibitor).

The RECOVER-VITAL platform is flexibly testing these in diverse settings.

How to Order Your Own Spike Antibody Test

You can now order a Spike protein antibody test from Labcorp Labs On Demand and get the results within a few days.

Here is a quick guide of interpretation of your results:

• <1000 U/ml very low level past exposure, negligible risks
• 1000-5000 U/ml symptoms or problem could be related to Spike protein
• >5000 U/ml Spike protein likely circulating in your bloodstream
• 10,000-25,000 U/ml very high risk for cardiac damage, blood clots, neurologic problems, autoimmunity, and potentially cancer

Remember the antibodies are an indirect reflection of Spike protein and do not change quickly. Dr Peter McCullough's advice is not to check the test again for a year. Below is one of my patients who has resolved his Spike syndrome with detoxification and you can see he has had a substantial drop in his Spike antibodies. (source)

Other Options

You can also order a Spike antibody (Covid-19 antibody) test from healthlabs.com to assess your risk and establish a baseline before and after starting any anti-spike protein protocol.

Another option is Attomarker's COVID Antibody Spectrum Test. Although the test is now available for sample collection in the US, the actual testing is still performed in the UK (United Kingdom). Please note that the test report takes about 2 to 3 weeks to arrive (X.com). The COVID Antibody Spectrum Test measures antibody levels & quality to Spike variants. Mapped with variant prevalence & your medical history, it offers insights into your immune profile, and has helped people with long COVID explore treatment pathways.

Ongoing Clinical Trials and Research Gaps

As of mid-2025, over a dozen trials on ClinicalTrials.gov focus on Long COVID, including AT1001 (Larazotide) for gut-related symptoms and multi-arm studies like RECOVER-TLC for idea generation. Biomarker research has identified blood signatures and immune networks linked to symptoms, aiding personalized therapies. However, challenges remain: No single treatment works for all, and pain as a new-onset symptom affects ~50% of patients.

Future Outlook

The complexity of Long COVID, with its multi-system involvement and varied symptoms, requires continued research and a multi-pronged treatment approach. Biomarkers like IL-6 and genetic factors may soon help identify at-risk individuals early, enabling preventive strategies. Meanwhile, ongoing clinical trials and real-world data analyses are expanding the arsenal of therapeutic options, bringing hope to millions affected worldwide.

If you or someone you know is experiencing persistent symptoms after COVID-19 infection, consult healthcare professionals for evaluation and management. Early recognition and tailored treatment can improve outcomes.