Can COVID-19 vaccines turn the tide on long-haul symptoms?

In a recent article published in the International Journal of Infectious Diseases, researchers evaluated a cohort of post-COVID-19 conditions (PCC) patients before and after coronavirus disease 2019 (COVID-19) vaccination to determine its potential role in PCC management.

Study: Vaccination after developing long COVID: impact on clinical presentation, viral persistence and immune responses. Image Credit: MuchMania / Shutterstock

Background

The prevalence of PCC or long-COVID in COVID-19-related non-hospitalized and hospitalized cases is high. Given its scale, PCC has emerged as a public health crisis, generating enormous social and economic impact.

Clinically, PCC is heterogeneous, with over 200 symptoms, but its precise underpinnings remain unclear. The World Health Organization (WHO) defines PCC as the persistence of symptoms beyond 12 weeks from diagnosis for at least two months. 

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) persistence is a key driver of PCC symptoms in adults and children. In addition, PCC patients also have persistently increased serum levels of proinflammatory cytokines/chemokines, such as interleukin-1β (IL-1β), interleukin-6 (IL-6), and tumor necrosis factor-alpha (TNF-α) compared to individuals who contracted COVID-19 but not PCC. 

Several studies have correlated increased inflammatory cytokine/chemokine levels with COVID-19 severity, poor prognosis, and recently with PCC.

Studies have demonstrated that vaccination, received before or after acute SARS-CoV-2 infection, protects against severe COVID-19. However, there is a lack of evidence that COVID-19 vaccines confer protective and therapeutic effects on PCC.

About the study

In the present prospective observational study, researchers hypothesized that COVID-19 vaccination influences the evolution of PCC symptoms, systemic immune responses, including chemokine/cytokine levels, and viral persistence in PCC patients. 

So, they set out to evaluate the number of PCC symptoms, organ systems affected by PCC, and psychological well-being of PCC patients before and after receiving the COVID-19 vaccine. In addition, they evaluated biomarkers of systemic inflammation, plasma cytokines/chemokine levels, plasma and intracellular SARS-CoV-2 antigens levels, and immunoreactivity to these antigens post-vaccination.

The study cohort comprised 83 individuals infected with SARS-CoV-2 and diagnosed with PCC per the WHO PCC case definition. Of these, 44 had not received a COVID-19 vaccine at baseline (unvaccinated), while 39 had received one to two vaccine doses. 

First, the team performed a longitudinal analysis on 44 unvaccinated participants, including 23 and 16 individuals who had received one or two vaccine doses. Next, they performed a cross-sectional evaluation to compare the results for 44 unvaccinated participants vis-a-vis 61 and 39 participants who received one or two vaccine doses, respectively.

Further, the researchers collected their sociodemographic and clinical data using a self-administered questionnaire and a case report form. At each study visit, these participants also completed the WHO-5 Well-Being Index, underwent a physical examination for body mass index (BMI) measurement, and provided information regarding their vaccination status and 49 PCC-associated symptoms with their frequencies. They also provided saliva samples for reverse-transcription-polymerase chain reaction (RT-PCR) testing and blood samples for plasma isolation and cytokine/chemokine measurements.

Furthermore, the team quantified soluble SARS-CoV-2 spike (S) and nucleocapsid (NC) proteins (SARS-CoV-2 antigens) and immunoglobulins (Ig)G and IgM levels elicited in response to these antigens.

Results

The current study data supports the hypothesis that COVID-19 vaccination post-PCC reduced the number of PCC symptoms and improved patient well-being. It also markedly down-regulated systemic markers of inflammation, regardless of several vaccine doses received, in both longitudinal and cross-sectional evaluations.

Pre-vaccination, PCC patients had elevated plasma levels of some cytokines, such as macrophage inflammatory protein-1 alpha (MIP–1α), IL-1β, and IL-12p40, reminiscent of the innate immune signature of past severe acute COVID-19 episodes. It also reflected probable inflammatory chronicity and altered immune competence in PCC patients. 

Although inflammation impaired the immunocompetence of PCC patients, post-PCC vaccination promoted anti-S IgG responses, which likely lowered persistent viral burden and reduced autoantibody titers.

Despite COVID-19 vaccination post-PCC, some viral products persisted and contributed to sustained inflammation. Peluso et al. found that viral persistence increased the risk of PCC in children, raising the need for long-term studies on viral persistence and immune dysregulation in pediatric cohorts. 

PCC participants had some immunoreactivity towards SARS-CoV-2 antigen(s), and vaccination further boosted it. Accordingly, researchers detected NC more frequently than S in PCC patients, regardless of vaccination status. SARS-CoV-2 S1 antigen also persisted in the blood of PCC participants, mostly in non-classical monocytes, regardless of vaccination. 

Conclusions

Overall, the study highlighted how COVID-19 vaccination could mitigate PCC symptoms by decreasing systemic inflammation, even though SARS-CoV-2 antigen(s) not cleared by vaccines persisted and likely perpetuated inflammation through non-classical monocytes.