According to the European Centre for Disease Control and Prevention, the most cited goal of COVID-19 vaccinations has been the prevention of hospitalizations and deaths due to COVID-19, but depending on the levels and type of protective immunity achieved, vaccination could also potentially prevent SARS-2 coronavirus (SARS-CoV-2) infection and interrupt disease transmission [1]European Centre for Disease Control. Objectives of vaccination strategies against COVID-19. 2021. https://www.ecdc.europa.eu/sites/default/files/documents/Objectives-of-vaccination-strategies-against-COVID-19.pdf (accessed March 22, 2022). . In addition, a more nuanced, yet vital role for vaccination could be in the prevention of the post-acute COVID-19 syndrome, often referred to as ‘long-COVID’.

The case definition of long-COVID is undergoing refinement as we learn more about the natural history of COVID-19 caused by a series of variants of concern, but it generally refers to the persistence of symptoms beyond the 3–4 week period when it is no longer routine to isolate intact, replication-competent SARS-CoV-2 [2]Nalbandian A, Sehgal K, Gupta A, et al. Post-acute COVID-19 syndrome. Nat. Med. 2021; 27, 601–15..The World Health Organization (WHO) describes long-COVID in terms of a “post COVID-19 condition” that “occurs in individuals with a history of probable or confirmed SARS-CoV-2 infection, usually three months from the onset of COVID-19 with symptoms that last two months and cannot be explained by an alternative diagnosis” [3]World Health Organisation. A clinical case definition of post COVID-19 condition by a Delphi consensus. 2021. https://www.who.int/publications/i/item/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1. Some investigators further differentiate persistent symptoms as subacute COVID-19, occurring 4–12 weeks after the acute infection, and those ascribed to a lingering and chronic post-COVID-19 syndrome that extends more than 12 weeks beyond the acute period (and which cannot be linked to an alternative diagnosis). The US Centers for Disease Control and Prevention (CDC) define a post-COVID condition as an “umbrella term” for a range of health conditions that are present four or more weeks post-infection with SARS-CoV-2. Shown in Box 1 is a list of long-COVID-defining conditions from the US CDC. Some investigators prefer to categorize these conditions by systems, including cardiopulmonary sequelae with tachycardia, dyspnea, persistent cough, and an ongoing oxygen requirement; hematological with thrombotic events; renal insufficiency; arthralgias, myalgias and other rheumatologic symptoms; and neuropsychiatric disturbances associated with ‘brain fog’, fatigue, mood disturbances, and anosmia or dysgeusia [2]Nalbandian A, Sehgal K, Gupta A, et al. Post-acute COVID-19 syndrome. Nat. Med. 2021; 27, 601–15., [4]Song W-J, Hui CKM, Hull JH, et al. Confronting COVID-19-associated cough and the post-COVID syndrome: role of viral neurotropism, neuroinflammation, and neuroimmune responses. Lancet Respir. Med. 2021; 9, 533–44., [5]Ståhlberg M, Reistam U, Fedorowski A, et al. Post-COVID-19 Tachycardia Syndrome: A Distinct Phenotype of Post-Acute COVID-19 Syndrome. Am. J. Med. 2021; 134, 1451–6., among others. Furthermore, there is the potential role of persistence of virus and/or viral antigens in many of these organs.

Brain fog

The neurologic complications linked to long-COVID may rank among the most concerning. A UK biobank of more than 40,000 brain scan images collected prior to COVID-19 pandemic made it possible to study almost 400 of those individuals who subsequently tested positive for SARS-CoV-2, together with an almost equal number of matched controls. The findings were striking and included significant gray matter degeneration and a neuroimaging pattern resembling that linked to cognitive declines seen in extreme aging or even Alzheimer’s disease [7]Douaud G, Lee S, Alfaro-Almagro F, et al. SARS-CoV-2 is associated with changes in brain structure in UK Biobank. medRxiv 2022; preprint: 2021.06.11.21258690.. The underlying mechanisms are under investigation, but so far have been attributed to viral neuroinvasion, hypoxia and oxidative stress, or neuroimmunologic phenomena including microglial cell activation, neuronophagia, microglial nodules, and autoantibodies [8]Mondelli V, Pariante CM. What can neuroimmunology teach us about the symptoms of long-COVID? Oxf. Open Immunol. 2021; 2, iqab004., [9]Thakur KT, Miller EH, Glendinning MD, et al. COVID-19 neuropathology at Columbia University Irving Medical Center/New York Presbyterian Hospital. Brain.2021; 144, 2696–708..

Such dire findings could emphasize the importance of vaccinating individuals to prevent long-COVID, especially to prevent chronic neurological complications and deterioration. A comprehensive analysis of data from electronic health records of almost 300,000 COVID-19 patients (mostly in the US), found that a third exhibit at least one feature of long-COVID in a 3–6 month window post-infection (including cognitive declines and anxiety or depression), with the highest risk in those with severe illness [10]Taquet M, Dercon Q, Luciano S, Geddes JR, Husain M, Harrison PJ. Incidence, co-occurrence, and evolution of long-COVID features: A 6-month retrospective cohort study of 273,618 survivors of COVID-19. PLOS Med. 2021; 18: e1003773.Taquet M, Dercon Q, Luciano S, Geddes JR, Husain M, Harrison PJ. Incidence, co-occurrence, and evolution of long-COVID features: A 6-month retrospective cohort study of 273,618 survivors of COVID-19. PLOS Med. 2021; 18: e1003773.. Younger long-COVID patients suffer predominantly from anxiety, depression, and headaches, as well as abdominal symptoms, compared to cognitive symptoms, fatigue, pain, and difficulties in breathing in older patients [10]Taquet M, Dercon Q, Luciano S, Geddes JR, Husain M, Harrison PJ. Incidence, co-occurrence, and evolution of long-COVID features: A 6-month retrospective cohort study of 273,618 survivors of COVID-19. PLOS Med. 2021; 18: e1003773.Taquet M, Dercon Q, Luciano S, Geddes JR, Husain M, Harrison PJ. Incidence, co-occurrence, and evolution of long-COVID features: A 6-month retrospective cohort study of 273,618 survivors of COVID-19. PLOS Med. 2021; 18: e1003773.. Data are mostly lacking for children less than 12 years of age, and there are widely divergent estimates on the health impact of long-COVID in these groups [11]Lewis D. Long COVID and kids: scientists race to find answers. Nature 2021; 595: 482–483..

Therapeutic vs preventative vaccine

Given the important health and socioeconomic consequences of long-COVID, especially those related to neurologic complications and cognitive declines, there is an urgent need to study the potential benefits of COVID-19 vaccines for long-COVID. Current COVID-19 vaccines have two potential uses in this context.

The first use is as a therapeutic vaccine. This concept is based on anecdotal evidence and a few reported non-peer-reviewed studies from the UK-based longcovidSOS [12]LongCovidSOS. longcovidsos.org (Accessed May 2022)., together with hypotheses that long-COVID may in some cases be linked to the persistence of the virus or potentially delayed clearance of virus fragments [13]Tran V-T, Perrodeau E, Saldanha J, Pane I, Ravaud P. Efficacy of COVID-19 Vaccination on the Symptoms of Patients With Long COVID: A Target Trial Emulation Using Data From the ComPaRe e-Cohort in France. SSRN. 2021. DOI:10.2139/ssrn.3932953.Tran V-T, Perrodeau E, Saldanha J, Pane I, Ravaud P. Efficacy of COVID-19 Vaccination on the Symptoms of Patients With Long COVID: A Target Trial Emulation Using Data From the ComPaRe e-Cohort in France. SSRN. 2021. DOI:10.2139/ssrn.3932953.. In such cases, boosting antivirus immunity through immunization could accelerate patient recovery. Immunizing long-COVID patients with either mRNA or adenovirus-vectored COVID-19 vaccines was shown to be safe, offering slight improvements in terms of symptom resolution [14]Arnold DT, Milne A, Samms E, Stadon L, Maskell NA, Hamilton FW. Are vaccines safe in patients with Long COVID? A prospective observational study. medRxiv 2021; preprint: 2021.03.11.21253225.. A large French study of a national cohort of patients with long COVID (known as ComPaRe) found that patients vaccinated with one of the available vaccines, including ChAdOx1 nCoV-19 (Astra Zeneca), BNT162b2 mRNA (Pfizer-BioNTech), Ad26.COV2. S (Johnson & Johnson), or mRNA-1273 (Moderna) vaccines, showed improvements relative to those unvaccinated in terms of symptoms and remission rate [13]Tran V-T, Perrodeau E, Saldanha J, Pane I, Ravaud P. Efficacy of COVID-19 Vaccination on the Symptoms of Patients With Long COVID: A Target Trial Emulation Using Data From the ComPaRe e-Cohort in France. SSRN. 2021. DOI:10.2139/ssrn.3932953.Tran V-T, Perrodeau E, Saldanha J, Pane I, Ravaud P. Efficacy of COVID-19 Vaccination on the Symptoms of Patients With Long COVID: A Target Trial Emulation Using Data From the ComPaRe e-Cohort in France. SSRN. 2021. DOI:10.2139/ssrn.3932953.. However a US-based study reported aberrant T cell memory responses following vaccination in long-COVID patients, suggesting that protection against re-infection in the long term may be impaired [15]Visvabharathy L, Hanson B, Orban Z, et al. Neuro-COVID long-haulers exhibit broad dysfunction in T cell memory generation and responses to vaccination. medRxiv 2021; preprint: 2021.08.08.21261763..

The other use for a vaccine is to prevent infection and, if infected, to prevent progression to long-COVID. In the UK, those fully vaccinated (two doses) with ChAdOx1, BNT162b2, or mRNA-1273 were found to exhibit a 50% reduction in the risk of developing long-COVID [16]Antonelli M, Penfold RS, Merino J, et al. Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study. Lancet Infect. Dis. 2022; 22: 43–55.. But, there is urgency to conduct additional studies.

Next steps

The prospect of establishing a therapeutic versus preventive vaccination indication and strategy against long-COVID is potentially attractive, but success on this front will require further clinical studies and information. Strict case-definitions of long-COVID are still lacking, as is epidemiologic information on the groups at highest risk or the extent to which younger groups, including children and adolescents, suffer from this condition. Furthermore, the healthcare community does not have consensus guidelines that can be used to treat long-COVID patients. Clinical guidelines must also be developed as the number of long-COVID patients continues to rise. Also complicating the disease burden assessments of long-COVID is the unknown frequency of this condition following mild versus severe illness. The absence of long-COVID biomarkers is yet another issue and a barrier to sorting out whether long-COVID is the consequence of host inflammatory processes – such as microglial activation in the brain – or whether it reflects active viral persistence.

Without the information outlined above, it is difficult to design the optimal studies needed to pin down or confirm an impact of vaccination on long-COVID. This is also a barrier to assessing the cost-effectiveness of long-COVID vaccinations. However, consideration of long-COVID may prove to be essential for approving future COVID-19 vaccines, including additional primary series or booster doses [17]Gardner BJ, Kilpatrick AM. Third doses of COVID-19 vaccines reduce infection and transmission of SARS-CoV-2 and could prevent future surges in some populations. medRxiv 2021; preprint: 2021.10.25.21265500.. Ultimately, preventing COVID-19 hospitalizations and deaths may not be sufficient if the disease impact of long-COVID turns out to be substantial or results in life-long impairments and disabilities. Assembling a consensus panel or charging immunization technical advisory groups such as the CDC’s Advisory Committee on Immunization Practices (ACIP) to make recommendations on this issue may represent a logical first step.

References

1. European Centre for Disease Control. Objectives of vaccination strategies against COVID-19. 2021. https://www.ecdc.europa.eu/sites/default/files/documents/Objectives-of-vaccination-strategies-against-COVID-19.pdf (accessed March 22, 2022).  Crossref

2. Nalbandian A, Sehgal K, Gupta A, et al. Post-acute COVID-19 syndrome. Nat. Med. 2021; 27, 601–15.  Crossref

3. World Health Organisation. A clinical case definition of post COVID-19 condition by a Delphi consensus. 2021. https://www.who.int/publications/i/item/WHO-2019-nCoV-Post_COVID-19_condition-Clinical_case_definition-2021.1  Crossref

4. Song W-J, Hui CKM, Hull JH, et al. Confronting COVID-19-associated cough and the post-COVID syndrome: role of viral neurotropism, neuroinflammation, and neuroimmune responses. Lancet Respir. Med. 2021; 9, 533–44.  Crossref

5. Ståhlberg M, Reistam U, Fedorowski A, et al. Post-COVID-19 Tachycardia Syndrome: A Distinct Phenotype of Post-Acute COVID-19 Syndrome. Am. J. Med. 2021; 134, 1451–6.  Crossref

6. Centers for Disease Control and Prevention. Post-COVID Conditions: Overview for Healthcare Providers. 2021. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/post-covid-conditions.html.  Crossref

7. Douaud G, Lee S, Alfaro-Almagro F, et al. SARS-CoV-2 is associated with changes in brain structure in UK Biobank. medRxiv 2022; preprint: 2021.06.11.21258690.  Crossref

8. Mondelli V, Pariante CM. What can neuroimmunology teach us about the symptoms of long-COVID? Oxf. Open Immunol. 2021; 2, iqab004.  Crossref

9. Thakur KT, Miller EH, Glendinning MD, et al. COVID-19 neuropathology at Columbia University Irving Medical Center/New York Presbyterian Hospital. Brain.2021; 144, 2696–708.  Crossref

10. Taquet M, Dercon Q, Luciano S, Geddes JR, Husain M, Harrison PJ. Incidence, co-occurrence, and evolution of long-COVID features: A 6-month retrospective cohort study of 273,618 survivors of COVID-19. PLOS Med. 2021; 18: e1003773.  Crossref

11. Lewis D. Long COVID and kids: scientists race to find answers. Nature 2021; 595: 482–483.  Crossref

12. LongCovidSOS. longcovidsos.org (Accessed May 2022).  Crossref

13. Tran V-T, Perrodeau E, Saldanha J, Pane I, Ravaud P. Efficacy of COVID-19 Vaccination on the Symptoms of Patients With Long COVID: A Target Trial Emulation Using Data From the ComPaRe e-Cohort in France. SSRN. 2021. DOI:10.2139/ssrn.3932953.  Crossref

14. Arnold DT, Milne A, Samms E, Stadon L, Maskell NA, Hamilton FW. Are vaccines safe in patients with Long COVID? A prospective observational study. medRxiv 2021; preprint: 2021.03.11.21253225.  Crossref

15. Visvabharathy L, Hanson B, Orban Z, et al. Neuro-COVID long-haulers exhibit broad dysfunction in T cell memory generation and responses to vaccination. medRxiv 2021; preprint: 2021.08.08.21261763.  Crossref

16. Antonelli M, Penfold RS, Merino J, et al. Risk factors and disease profile of post-vaccination SARS-CoV-2 infection in UK users of the COVID Symptom Study app: a prospective, community-based, nested, case-control study. Lancet Infect. Dis. 2022; 22: 43–55.  Crossref

17. Gardner BJ, Kilpatrick AM. Third doses of COVID-19 vaccines reduce infection and transmission of SARS-CoV-2 and could prevent future surges in some populations. medRxiv 2021; preprint: 2021.10.25.21265500.  Crossref

Affiliations

Peter Hotez MD, PhD
Texas Children’s Center for Vaccine Development
Baylor College of Medicine
Houston, TX, USA

Carolina Batista
Médecins Sans Frontières
Rio de Janeiro
Brazil

Yanis Ben Amor
Center for Sustainable Development
Columbia University
New York, NY, USA

Onder Ergonul
Koc University Research Center for Infectious Diseases
Istanbul, Turkey

J Peter Figueroa
University of the West Indies
Mona, Kingston, Jamaica

Mayda Gursel
Middle East Technical University
Ankara, Turkey

Mazen Hassanain
College of Medicine
King Saud University
Riyadh, Saudi Arabia

Gagandeep Kang
Christian Medical College,
Vellore, India

David C. Kaslow
PATH Essential Medicines
PATH, WA, USA

Jerome H. Kim
International Vaccine Institute
Seoul, South Korea

Bhavna Lall
University of Houston College of Medicine
Houston, TX, USA

Heidi Larson
London School of Hygiene & Tropical
Medicine
London, UK

Timothy Sheahan
University of North Carolina
Gillings School of Global Public Health
Chapel Hill, NC, USA

Shmuel Shoham
Johns Hopkins University School of
Medicine
Baltimore, MD, USA

Annelies Wilder-Smith
London School of Hygiene & Tropical
Medicine,
London, UK, Institute of Social and
Preventive Medicine,
University of Bern,
Switzerland,
Heidelberg Institute of Global Health,
University of Heidelberg,
Heidelberg, Germany

Samba O Sow
Center for Vaccine Development,
Bamako, Mali,
University of Maryland, MD, USA

Prashant Yadav
Center for Global Development,
Washington, DC, USA,
Harvard Medical School, Boston, MA, USA, INSEAD

Maria Elena Bottazzi
Texas Children’s Center for Vaccine Development, Baylor College of Medicine, Houston, TX, USA

Authorship & Conflict of Interest

Contributions: All authors contributed equally. PH provided the first draft. CB, YBA, OE, JPF, MG, MH, GK, DCK, JHK, BL, HL, TS, SS, AW-S, SOS, PY and MEB drafted and edited assigned sections of the review and provided critical feedback, reference sources, and critical revisions for intellectual content and verified the information presented here. PH and MEB managed the process of review and edits. All named authors take responsibility for the integrity of the work as a whole, and have given their approval for this version to be published.

Acknowledgements: The authors thank Jeffrey Sachs, Chair of the Lancet COVID-19 Commission for his invaluable review and feedback. 

Discaimer: The authors views and opinions in the Commentary do not necessarily represent the views, decisions, or policies of the institutions, universities, or health systems with which they are affiliated.

Disclosure and potential conflicts of interest: DK reports grants from Bill and Melinda Gates Foundation (BMGF), grants from Coalition for Epidemic Preparedness Innovatiuons and grants from CEPI. DK has received support from GSK Palio meetings, Wellcome Trust, Hilleman Labs, World Health Organization for attending meetings and/or travel. DK is also a member of SAGE Working Group on COVID-19 Vaccines and CEPI Clinical SWAT. HL reports grants and honoraria from GlaxoSmithKline for training talks and from

Merck as a member of the Merck Vaccine Confidence Advisory Board, outside the submitted work. HL received a grant from Merk to investigate Health Care Professional vaccine hesitancy in the Mid-East and Europe region. HL worked with Astra Zeneca – organize webinars in multiple European countries with HCPs to discuss, address Covid vaccine concerns with relevant experts. HL worked with the UK Cabinet office – lead academic coalition to investigate and address social media concerns/anti-vaccine trends around covid vaccine. HL worked with the Euro Commission – to map 2022 vaccine confidence in bot routine and COVID vaccines across 27 EU countries and compare to pre Covid confidence data. JPF and GK are members of the WHO SAGE Working Group on COVID-19 vaccines. GK is independent director of Hilleman Laboratories Private Limited and Vice Chair of the Board, Coalition of Epidemic Preparedness Innovations (CEPI). JHK reports personal fees from SK biosciences. JHK has participate on a Scientific Advisory Board for Everest and Vaccitech. MEB and PH are developers of COVID-19 vaccine constructs which have been licensed by Baylor College of Medicine to commercial vaccine manufacturers for scale up, production, testing and licensure. MEB and PH declare that they are developers of the RBD219-N1C1and RBD203-N1 technologies, and that Baylor College of Medicine (BCM) licensed RBD219-N1C1 to Biological E, an Indian manufacturer, for further advancement and licensure. Similar licensing agreements are also in place with other partners for both RBD219-N1C1 and RBD203-N1. The research conducted in this paper was performed in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. MG participates in one of eight SARS-CoV-2 vaccine development projects supported by The Scientific and Technological Research Council of Turkey (TÜBİTAK) since March 2020. MH is Founder and Managing Director of SaudiVax. PY received the Institutional grant for improving access to oral antivirals in LMICs from Open Philanthropy Partners and the Institutional grant for improving the supply chain for pathogen genomic sequencing in Africa from Bill & Melinda Gates Foundation. PY received consulting fees to act as Subject Matter Expert on Supply Chains and market access from Impact4Development Inc. TPS reports grants from National Institute of Allergy and Infectious Disease and Fast Grants and research contracts from GlaxoSmithKline, and ViiV Healthcare. TPS declares grants (Sheahan (P.I.) payments to UNC Chapel Hill) from ViiV, GSK, Regeneron. TPS has also received payment or honoraria from Albert Einstein School of Medicine, The Rockefeller University, Southern Society for Clinical Investigation, American College of Veterinary Pathology. SS reports grants from Ansun BioPharma, Astellas Pharma, Cidara Therapeutics, F2G, Merck, T2 Biosystems, Shire Pharmaceuticals, Shionogi, and Gilead Sciences, outside the submitted work; and personal fees from Amplyx Pharmaceuticals, Acidophil, Janssen Pharmaceuticals, Reviral, Intermountain Healthcare, Karyopharm Therapeutics, Immunome, and Celltrion, outside the submitted work. SS has participated on a Data Safety Monitoring Board or Advisory Board at Adamis, Karyopharm, Intermountain Health. SS has had roles as Governor, Washington DC Chapter and Member, Board of Governors, American College of Physicians. SS also has stock options in Immunome. CB is an elected international board member at Doctors Without Borders (Medècins Sans Frontieres). All other authors declare no conflict of interests.

Funding declaration: The authors received no financial support for the research, authorship and/or publication of this article.

Article & copyright information

Copyright: Published by Vaccine Insights under Creative Commons License Deed CC BY NC ND 4.0 which allows anyone to copy, distribute, and transmit the article provided it is properly attributed in the manner specified below. No commercial use without permission.

Attribution: Copyright © 2022 Hotez P, Batista C, Ben Amor Y, Ergonul O, Figueroa JP, Gursel M, Hassanain M, Kang G, Kaslow DC, Kim JH, Lall B, Larson H, Sheahan T, Shoham S, Wilder-Smith A, Sow SO, Yadav P, Bottazzi ME. Published by Vaccine Insights under Creative Commons License Deed CC BY NC ND 4.0.

Article source: Invited; externally peer reviewed.

Submitted for peer review: May 06 2022; Revised manuscript received: May 27 2022; Publication date: Jun 14 2022.