Vaccination impact on long COVID sequelae; a perspective view

Dear Editor;

Now that three years from COVID-19 pandemic have passed and while SARS-CoV-2 virus remains in continuous evolution, there are several comprehensive pharmaceutical interventions, educational endeavors, mass vaccination that have been accomplished at the global scale achieving a successful reduction in COVID-19 burden and severity. However, long-COVID syndromes remain an inevitable challenge.¹ There are estimates that about 10% of individuals infected with SARS-CoV-2 virus develop post-viral COVID-19 related syndromes and complications.²

First of all, there is no consensus on the definition of COVID-19 sequelae that have been assigned various terms i.e., “post-COVID syndrome”, “long COVID”, as well as “ long-haul COVID”. In this scenario, the Centers for Disease Control and Prevention (CDC) defines long COVID as the presentation of clinical symptoms more than 4 weeks after the first onset of signs and symptoms of infection, whereas the World Health Organization (WHO) defined long COVID as the continuation or onset of clinical manifestations 3 months after the first onset or positive diagnostic test for SARS-CoV-2 infection.³ Nevertheless, the International Classification of Diseases (ICD-10) assigns a numerical code for long COVID (U09.9) and defines it as one or multiple symptoms occurring 4 weeks after the acute COVID-19 phase. Secondly, there are no set criteria for diagnosis of long COVID due to its various clinical manifestations e.g., fatigue, headache, cough, memory loss, neuropsychiatric symptoms, sleep disorder, dyspnea, brain fog, nausea, vomiting, anxiety, depression, cutaneous rash, joint pain, as well as multiple organ impairments particularly of the gastrointestinal, cardiovascular, neuropsychiatric, and pulmonary systems. Therefore, the extended clinical manifestation associated with long COVID hampers diagnosis and treatment, as well as multidisciplinary care.⁴ Recent studies reveal the wide range of long COVID prevalence in several countries including the United Kingdom with a range of 1.6 to 71%, Germany from 35 to 77%, Italy from 5 to 51%, the United States from 16 to 53%, China from 49 to 76%, Bangladesh from 16 to 46%, India as 22%, Denmark as 1%, Norway as 61% and in the African continent as a whole 68%.⁵

The mechanism underlying long COVID was also remains nebulous. According to available literature, post-viral symptoms are also reported in other viral infections including e.g. Epstein–Barr virus, human herpes virus, influenza, SARS, and Ebola viruses. In this regard, there are three factors that contribute to long COVID such as viral persistence, chronic pro-inflammatory response, and autoimmunity that combines to establish a favorable microenvironment for the development of post-COVID syndrome through pulmonary fibrosis, cardiac remodeling, neural inflammation, as well as dysautonomia.⁶ Consequently, it is obvious that long COVID mostly affects gastrointestinal, cardiovascular system, as well as respiratory organs. Indeed, the SARS-CoV2 infected individuals with comorbidities affecting these organs are more prone to develop long COVID.⁷

One important question remains unanswered with regard to long COVID: what is the critical impact of COVID-19 vaccines in both prevention and resolution of long COVID? Obviously COVID-19 vaccines reduce the risk of severity and mortality-related to COVID-19 disease. The review of literature suggests that mRNA-based COVID-19 vaccines may be more efficient than adenoviral vector-based COVID-19 vaccines in reducing the susceptibility to present severe illness.⁸ COVID-19 vaccination does not completely eradicate the circulation of SARS-CoV-2 virus variants of concern (VOCs). There are serious incomplete investigations on the clinical benefit of COVID-19 vaccines on lessening the risk of developing long-COVID in individuals who previously infected with SARS-CoV-2. However, current studies highlighted the clinical benefits of COVID-19 vaccination before SARS-CoV-2 infection and that it significantly reduced the risk of long COVID.^9,10 In this scenario, two-dose COVID-19 vaccination was associated to lower risk of long COVID compared to individuals who received one-dose vaccination. However, there is no data to support whether vaccination is effective in lowering the risk of long COVID in those immunized post- SARS-CoV-2 infection. There are also limitations as to addressing the clinical benefits of vaccination in persons with pre-existing immunosuppressive conditions and the prevention of long COVID. In addition, there is limited knowledge as to the effectiveness of heterogeneous COVID-19 vaccines in the reduction of long COVID among the proportion of population to whom these vaccines were administered. Note that these gaps in knowledge should not stop encouraging vaccination against SARS-CoV-2 to prevent COVID-19 disease.

We speculated that COVID-19 vaccines may be useful in lowering the risk of long COVID even in individuals who had been infected with SARS-CoV-2 VOC. As discussed above, there are two major factors that contribute to present long COVID, including the SARS-CoV-2 viral persistency as well as chronic inflammatory response. The COVID-19 vaccines lower the severity of acute SARS-CoV-2 virus infection through modulation of the immune response. This may translate to having a lower chance of multi-organ inflammation as well as lowering the clinical symptom duration. Thus, it could be expected that less severe COVID-19 illness guarantees a lower risk of long COVID. Furthermore, COVID-19 vaccination is associated with acceleration of viral clearance and with the reduction of viral reservoirs, it could help hinder the exaggerative systemic inflammation. In conclusion, COVID-19 vaccination may have associated with lower risk of develop to long COVID through lowering systemic inflammation by efficient viral clearance.

To sum, there are few studies regarding the clinical relevance of COVID-19 vaccines in reducing the burden of long COVID. However, present evidences highlighted the potential effectiveness of COVID-19 vaccination in the prevention of developing long COVID. The current findings should be interpreted with caution while further observational studies are carried out to further strengthen the impact COVID-19 vaccination has on preventing long COVID and its complications.