Vaccination Hesitancy and Postacute Sequelae of SARS-CoV-2: Is It Time to Reconsider?

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the pathogen responsible for coronavirus disease 2019 (COVID-19), has caused a major pandemic with substantial morbidity and mortality worldwide (10). As of June 2021, the pandemic has exceeded 178 million cases with more than 3 million deaths worldwide (https://coronavirus.jhu.edu/map.html). Among individuals infected with the virus, ∼81% experience mild to moderate disease and 5% develop critical illness (23). Some COVID-19 survivors do not fully recover and suffer from persistent or new symptoms that can last weeks or months; this postviral syndrome is called “long COVID,” “long-haul COVID,” “post COVID syndrome,” “chronic COVID syndrome,” “post-acute COVID,” or “post-acute sequelae of SARS-CoV-2 (PASC).” We will use the term PASC in the following discussion.

Although official diagnostic criteria are currently lacking, PASC involves new or ongoing symptoms of acute COVID-19 (e.g., fatigue, myalgia, arthralgia, headache, cough, chest pain, smell or taste dysfunction, confusion, and shortness of breath) that persist for at least 4 weeks after symptom onset (8). The syndrome can occur after mild or severe illness and may involve multiple organ systems, with symptoms that can range from mild to debilitating (14). PASC resembles postinfectious syndromes that followed the SARS epidemic of 2003 and the Middle East respiratory syndrome outbreak of 2012 (1). Most individuals with PASC test negative for SARS-CoV-2 by PCR and demonstrate biochemical and radiological recovery (18). The syndrome can affect anyone, even young people and those who developed only mild disease, although the risk is higher in women, older people, and those with comorbidities (15).

The underlying pathogenesis of PASC is not well understood. Potential mechanisms include persistent viremia due to poor or absent antibody response, ongoing inflammatory damage and autoimmune response, deconditioning, and psychological factors such as post-traumatic stress (13,16,18). Given the large number of people affected in a short timeframe and PASC's resemblance to other postinfectious syndromes, PASC offers a unique opportunity to better understand and treat these long-term debilitating conditions.

Treatment of PASC is primarily supportive, although many PASC sufferers have anecdotally reported improvement in symptoms and quality of life after vaccination. Understanding the potential benefits of vaccination in individuals with PASC is only just beginning. In a prospective cohort study of 44 vaccinated PASC patients and 22 matched unvaccinated participants, available preprint, Arnold et al. reported a reduction in symptom burden in vaccinated individuals compared with matched controls (3). The study sample was admittedly small and limited to an unblinded initially hospitalized cohort.

The finding that vaccination could decrease PASC is intriguing. If these findings are repeated in larger studies (one is currently ongoing at Yale) it would suggest that there is possibly ongoing SARS-CoV-2 replication in distal sites that are not detected by testing respiratory tract (nasopharyngeal or saliva) samples. Thus, it is possible that vaccine-generated immunity has greater neutralizing ability of virus, likely through production of high avidity antibodies, in distal organs than natural immunity in these individuals and leads to the resolution of inflammatory antiviral immune responses.

Support for persistent infection comes from the findings that a high percentage of individuals infected with SARS-CoV-2 have gastrointestinal symptoms, suggesting the virus is able to infect organs other than the lung. Indeed, it has been shown that infectious SARS-CoV-2 can be isolated from feces weeks after the virus is undetectable in the respiratory tract (7,21), indicating that a standard negative SARS-CoV-2 nasal or saliva test does not always mean virus has been cleared from the body. Furthermore, others have reported detecting viral RNA in the heart (19,20), kidney (9), and nervous system (cerebrospinal fluid [CSF]) (17) suggesting that multiple organs that are not routinely tested can harbor virus.

Individuals with PASC, including those with initially mild symptoms, suffer from an abnormal inflammatory response to SARS-CoV-2 infection (11). Persistent T cell response likely drives systemic inflammation that then leads to symptoms. We and others (12) have seen increased frequencies of cytokine producing T cells, which are likely there in response to persistent virus in unknown compartments. We have found that individuals with PASC have elevated levels of tumor necrosis factor-alpha-producing SARS-CoV-2-specific T cells in their blood compared with individuals who do not have lingering symptoms, suggesting that viral replication is maintaining a pool of inflammatory T cells. Virus-specific T cells that produce inflammatory cytokines in chronic viral infection, such as HIV, have been linked to development of multiple comorbidities (lung, cardiovascular system, etc.) that are characterized by symptoms similar to those in PASC (24). Thus, vaccination, which induces high levels of neutralizing SARS-CoV-2-specific antibodies and only S-specific T cells (2), could lead to elimination of virus in distal sites leading to true clearance of SARS-CoV-2 and resolution of inflammatory immune responses, both of which have been postulated to drive postacute COVID symptoms.

Overall vaccination hesitancy in the United States has decreased, but as of March 2021, 35% were still untrustful of SARS-CoV-2 vaccines (6). PASC has been cited as a reason for delaying or forgoing vaccination in some affected persons (22) comprising a portion of those not currently planning to be vaccinated. Although initially published data indicated currently available vaccines are safe and effective against COVID-19, it did not specifically comment on the effects on PASC. New reports on the impacts of vaccination on PASC are promising (4) and reasonably explained by the potential clearing of viral enclaves in distal sites. Despite the limitations of currently published information, we find no indication individuals should not be vaccinated solely due to a history of PASC or that there should be an expectation of increased or prolonged side effects. We encourage all patients to discuss vaccination with their providers with the knowledge of the potential benefits.

There is a critical need to understand the expected duration of PASC, what treatments may be beneficial, and if there are ways to mitigate the long-term effects during acute infection. The National Institutes of Health has devoted more than $1 billion to study the causes, treatment, and prevention of PASC (5). This initiative will hopefully help fill these knowledge gaps regarding this condition.

In conclusion, PASC is a debilitating and poorly understood sequela of acute infection. Given the scale of the pandemic, these patients will require health care resources well into the foreseeable future. Preliminary reports suggest vaccination may offer improvement or complete resolution of symptoms, and understanding the role of vaccination in PASC may provide insight into the pathophysiology of this syndrome.