How Vaccines Might Improve Long Covid?

A major new NIH initiative has been announced to identify the causes and ultimately the means of prevention and treatment of "Long COVID."

Source: [2]

Long-Haul COVID-19

Large numbers of patients who have been infected with SARS-CoV-2 continue to experience a constellation of symptoms long past the time that they’ve recovered from the initial stages of COVID-19 illness. The condition involves a range of symptoms such as:

Persistent fatigue, myalgia, autonomic dysregulation manifested as postural orthostatic tachycardia syndrome, abnormal thermoregulation, intestinal disturbances and skin manifestations. [28]

An exact definition is lacking, but typically symptoms with a duration > 2 months are considered long COVID and:

• Symptoms can range from mild to incapacitating

• In some cases, new symptoms arise well after the time of infection or evolve over time.

Based on two studies, here are the statistics of how many Long COVID patients exist among hospitalized COVID-19 patients:

• A new study shows that over ⅓ of hospitalized COVID-19 patients were still experiencing various “neurological reactions” like cognitive deficits, hyposmia, and postural tremor even six months later.
• Another study from the same article shows that 87% of hospitalized patients had at least one lingering symptom.

This post-COVID syndrome bears resemblance to post-infectious syndromes that followed outbreaks of chikungunya [24] and Ebola [25], for example, and selected symptoms overlap with myalgic encephalomyelitis, a disease that is also often triggered by infection and immune activation [26] and manifests as a dysregulated autonomic nervous system and perturbed immune parameters [27].

Risk Factors

In brief, long-haul COVID-19 may be driven by long-term lung and brain damage

and unresolved inflammation from multiple sources. The associated risk factors may include:

Female sex, more than five early symptoms, early dyspnea, and specific biomarkers like D-dimer.

Video 1. First Vaccine Reaction Data for Long Covid (youtube link)

Vaccines Can Help Long COVID-19 Patients

It’s clear that vaccines have helped some people with long Covid with their symptoms (watch Video 1). While the numbers are still small, these are encouraging signs.  But for those who do experience a breakthrough infection, 

Studies suggest that vaccination might only halve the risk of long COVID — or have no effect on it at all.[33,34]

How Vaccines Might Help?

Back in June 2020, Prof. Akiko Iwasaki had proposed three possible mechanisms that might be causing Long COVID:

1. A persistent viral reservoir
2. Viral ghost
• Which are fragments of the virus (RNA, proteins) that linger after the infection has been cleared but are still capable of stimulating the immune system
3. An autoimmune response induced by the infection

Of course, other mechanisms may also contribute.

Since then, many studies have provided supports for all three of these mechanisms:

1. Viral Reservoir
• Research has shown that viral reservoirs are present in tissues
2. Viral ghost
• Viral RNA is found in non-respiratory tissues and is associated with inflammation
3. Autoimmune response
• Diverse autoantibodies are detected in some Covid patients

The three mechanisms of long Covid that Prof. Akiko Iwasaki proposed above are not mutually exclusive, and all three may benefit from the vaccines in the following ways:

1. Viral Reservoir
• If this hypothesis is true, vaccine-induced T cells (immune cells that attack and kill infected cells) and antibody responses may be able to eliminate the viral reservoir.
2. Viral ghost
• If this hypothesis is true, vaccine-induced immunity may be able to eliminate the viral ghost if such viral components are associated with the spike protein, which the virus uses to gain entry into cells.
3. Autoimmune response
• If this hypothesis is true, the vaccine might divert autoimmune cells.

How Vaccine Might Divert Autoimmune Cells?

Vaccines induce immune responses and it requires two components:

• Antigen
• The stuff detected by T and B cell receptors (TCRs and BCRs)
• It is possible that adaptive immune responses induced by vaccines divert the leukocytes causing long Covid
• For example, antibody or T cell responses directed against a new antigen, regardless of what it is, might skew the immune system to shift its attention to the new antigen — though it is not clear for how long.
• Adjuvant
• Adjuvants affect the immune response in various ways [29]
• For example, adjuvants can stimulate the immune system by mimicking features of pathogens
• Adjuvants can only induce transient inflammation (i.e., temporary and short-term)
• If the adjuvant might somehow divert the leukocytes (immune cells) causing long Covid, the beneficial impact of vaccines may not be long lasting

Note that many vaccines are simply antigen combined with added adjuvant (like alum) — mRNA vaccines do not require extra adjuvant because the RNA itself can serve as the adjuvant.

References

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2. Long-Haul COVID-19: Putative Pathophysiology, Risk Factors, and Treatments
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6. Life-Threatening COVID-19: Defective Interferons Unleash Excessive Inflammation
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• Twitter thread
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21. Assessing the human immune response to SARS-CoV-2 variants
22. How Vaccines Might Improve Long Covid
23. NIH launches new initiative to study “Long COVID”
24. Guillot, X., Ribera, A. & Gasque, P. Chikungunya-induced arthritis in Reunion Island: a long-term observational follow-up study showing frequently persistent joint symptoms, some cases of persistent chikungunya immunoglobulin M positivity, and no anticyclic citrullinated peptide seroconversion after 13 years. J. Infect. Dis. 222, 1740–1744 (2020).
25. Clark, D. V. et al. Long-term sequelae after Ebola virus disease in Bundibugyo, Uganda: a retrospective cohort study. Lancet Infect. Dis. 15, 905–912 (2015).
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27. Rodriguez, L. S. T. et al. Achieving symptom relief in patients with Myalgic encephalomyelitis by targeting the neuro-immune interface and inducing disease tolerance. Preprint at bioRxiv
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34. Taquet, M., Dercon, Q. & Harrison, P. J. Preprint at medRxiv (link)
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• Similar to treatment regimens for HIV, we believe the future approach to managing pandemics will require a drug combination cocktail.
• Here, this could include a combination of vaccines and antiviral innovations to target the virus. Specifically, combination therapy approaches to target the adaptive immune response (e.g., vaccines, antibody treatments) and another inhibiting viral innate immune antagonist proteins (e.g., Orf6 and Orf9b) or activating the innate immune response, could be the most effective. Perhaps with this approach, we may be able to get ahead of viruses before they reach pandemic levels.
38. Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis
• Impact of SARS-CoV-2 ORF6 and its variant polymorphisms on host responses and viral pathogenesis