Extending the Vaccination Season and Reducing Long COVID With Updated COVID-19 Vaccines

To increase protection against currently circulating variants of the SARS-CoV-2 virus and associated complications, the US Food and Drug Administration (FDA) recently granted approval or emergency use authorization (EUA) for several updated COVID-19 vaccines. The 2023 to 2024 formula mRNA vaccines by Moderna and Pfizer-BioNTech were approved on September 11, 2023, for use in individuals aged 12 years and older and granted EUA for those aged 6 months to 11 years. The updated adjuvanted, protein-based COVID-19 vaccine by Novavax received EUA on October 3, 2023, for use in patients aged 12 years and older.¹ The COVID-19 vaccination can offer protection against the long-term effects of SARS-CoV-2 infection.²
 
Elie Saade, MD, MPH, is a researcher and director of infection control at University Hospitals in Cleveland, Ohio. Among other accomplishments in his clinical role, he has been honored for his work leading multidisciplinary teams in interventions aimed at reducing hospital-acquired infections. In this article, Dr Saade describes updates in the understanding and treatment of long COVID and the potential role of the updated COVID-19 vaccines in reducing the risk for related complications.

How has the understanding of long COVID changed since it was first recognized, and what are current perspectives on the underlying pathophysiology?

Since the recognition of long COVID, or postacute sequelae of SARS-CoV-2 infection (PASC), the understanding of its pathophysiology has evolved significantly. Initially, there was a lack of consensus on the definition and classification of long COVID. Many studies focused on individual symptoms rather than defined phenotypes. This approach was further complicated by a disproportionate inclusion of individuals with a history of severe acute COVID-19 illness, which may have skewed the understanding of the condition.
 
The initial focus was on the lingering effects of acute infection, with symptoms believed to be a continuation of acute COVID-19 pathology associated with the direct viral damage caused by SARS-CoV-2. However, as research progressed, a more complex picture emerged, and studies revealed a wide range of symptoms affecting multiple organ systems, indicating that the impact of the infection was systemic rather than localized to the respiratory system.³
 
Moreover, emerging evidence revealed that long COVID could affect individuals regardless of the severity of the initial infection; however, the severity and number of symptoms during acute illness are still considered risk factors for long COVID.⁴ The current perspectives on the underlying pathophysiology of long COVID suggest that it is a complex and multifaceted condition. The exact mechanisms are not yet fully understood, but several factors have been proposed. These include immune dysregulation, inflammatory states, vascular compromise through endothelial abnormality and thromboembolic events, microbiota disruption, dysfunctional neurologic signaling, and autoimmunity.³
 
Despite advancements, there are still significant gaps in understanding the specific pathophysiological mechanisms at play and the identification of risk factors predisposing certain individuals to PASC. The elucidation of these mechanisms is imperative for the formulation of targeted therapeutic interventions and prognostic assessments.

What are the current approaches to the diagnosis and management of patients with long COVID? What are some of the rehabilitation strategies that have shown efficacy with these patients?

The clinical management of long COVID is an intricate process that mirrors the condition’s complexity. Diagnoses are primarily clinical, relying on an extensive review of the patient’s medical history, symptoms, and overall function. The US Centers for Disease Control and Prevention (CDC) recommends a thorough evaluation process, emphasizing the need for a customized approach due to the diverse and multiorgan symptomatology of PASC.⁵
 
Similarly, the National Institute for Health and Care Excellence advises a structured assessment, underscoring the importance of a precise clinical case definition. Patients typically present with persistent symptoms following the resolution of acute COVID-19, which can last for more than 4 weeks and are not explained by an alternative diagnosis. The symptom profile can range broadly, with fatigue, shortness of breath, chest discomfort, cognitive issues, and more, all markedly affecting quality of life.⁶ Complementary diagnostic tools such as biomarkers and imaging studies play a supportive role in evaluating specific organ involvement and excluding alternative pathologic entities.⁷
 
Treatment for long COVID remains elusive, with no standard therapy due to its complex nature and varied subtypes. For physicians, it is crucial to adopt an interdisciplinary approach, integrating physical, cognitive, psychological, and social care components. Patient care strategies often involve symptomatic relief, functional rehabilitation, and psychological support.⁶ Treatment modalities are symptom-focused, employing methods such as cough alleviation for persistent coughs or cognitive therapy for concentration difficulties. Rehabilitation protocols aim to rebuild physical capacity and endurance gradually. Mental health interventions address the psychological ramifications of long COVID, employing therapies such as cognitive behavioral therapy.
 
Patient education is central to self-care, with emphasis on techniques for conserving energy and strategically pacing activities. Monitoring and regular follow-ups are essential to dynamically refine management plans in response to symptom evolution. Continual research feeds into this adaptive management model, with clinical trials and cohort studies enhancing the evidence base and informing regularly updated treatment guidelines. Hence, the management of long COVID is an individualized, evolving practice grounded in incremental scientific insight and patient-centered care principles.

What is the role of vaccines such as Spikevax in preventing severe COVID-19 disease and long-term COVID-related complications?

Vaccination against SARS-CoV-2 is essential for pandemic control and mitigating long-term health issues such as long COVID. Research indicates that vaccinated individuals have consistently lower odds of developing long COVID than those unvaccinated.⁸ The relationship between vaccination and long COVID symptoms appears to be significant for certain symptoms, particularly headaches and muscle pain, where vaccinated people experienced these symptoms less frequently than those who were unvaccinated.⁹
 
Overall, the data underscore the role of vaccines in reducing long COVID risk by preventing or lessening the severity of infections in breakthrough cases. Vaccines prime the immune system to recognize and fight the SARS-CoV-2 virus, which could potentially decrease the intensity of the acute phase immune response, enabling faster clearance of the virus and preventing or lessening organ damage, immune dysfunction, and exacerbation of pre-existing conditions.^3,10 Although vaccines were not explicitly designed to prevent long COVID, the evidence suggests a trend toward milder symptoms and reduced effect on patients’ quality of life in social, professional, and personal settings.¹⁰
 
From a public health perspective, widespread vaccination permits the collection of long-term data on immunity and the effectiveness of vaccines against emerging variants, which is essential for understanding and mitigating long-term complications. In summary, vaccination against COVID-19 is a foundational strategy in controlling the pandemic and its associated long-term health impacts, including long COVID. The ongoing research and surveillance continue to reinforce the importance of vaccines in public health strategy and individual protection against COVID-19.

What is the role of booster shots in protecting against the risk for long COVID, and how does the durability of response vary across vaccine types and patient characteristics?

Booster shots enhance and prolong the protective effects of the initial COVID-19 vaccination series, potentially reducing the risk for infection and, by extension, long COVID. Boosters are particularly important in maintaining immunity against emerging variants of concern, which may partially evade the immune response induced by the original vaccine series. Booster shots may prevent severe disease and limit mild infection and transmission. By decreasing the likelihood of breakthrough infections, boosters may reduce the incidence of postacute sequelae associated with COVID-19. Moreover, boosting can increase neutralizing antibody levels and broaden the immune response, which might be critical for preventing the virus from establishing the conditions that lead to long COVID.^11,12
 
Durability of response to vaccines and boosters can vary based on vaccine technology. For instance, mRNA vaccines such as Moderna’s Spikevax have shown increased antibody durability and enhanced long-term immune protection upon boosting.¹² In a study, participants who received an mRNA vaccine booster dose reported fewer symptoms at 6 months after infection compared with those who were unvaccinated or had only received the primary series. Additionally, those who received the booster vaccination had higher health-related quality of life (HRQOL) scores compared with the unvaccinated and primed groups. The study concluded that booster vaccination with an mRNA vaccine was associated with a reduced risk for long COVID symptoms and improved HRQOL.¹³ Emerging research continues to guide recommendations on booster intervals and populations at greater need for boosters. These recommendations evolve as more data become available on vaccine performance in diverse demographic groups and against new variants.

What does the available evidence suggest about the ideal dosing schedule of booster shots to optimize antibody levels against SARS-CoV-2?

The ideal dosing schedule for COVID-19 booster shots is subject to ongoing research and debate, with evidence evolving as new variants of the virus emerge and more data on vaccine durability become available. The goal of optimizing antibody levels against SARS-CoV-2 is to ensure sustained immunity and to minimize the risk for breakthrough infections and severe disease. Evidence indicates that antibody levels diminish post-primary vaccination, yet boosters significantly bolster these titers.¹⁴
 
The timing of booster shots has varied across different countries and with different vaccine platforms, but emerging consensus indicates that a booster shot is often administered around 6 months after the completion of the initial vaccine series, with adjustments being made for different population groups and vaccine types. For mRNA vaccines, such as Pfizer-BioNTech and Moderna, booster doses are recommended based on evidence showing increased immunity post-booster, which is considered robust for several months thereafter. A study that evaluated the effectiveness of mRNA-1273 and BNT162b2 booster vaccinations against SARS-CoV-2 under various schedules, using a model considering antibody waning, infection probability, and timing to breakthrough infections, found that delaying boosters past 2 years significantly increases infection risk, closely resembling the risk without boosters.¹⁵ Thus, annual or more frequent boosters may be necessary for effective risk mitigation.
 
Guidance from the CDC and World Health Organization (WHO) incorporates various factors, including age, health status, and virus strains in circulation, to inform booster recommendations. For certain immunocompromised individuals and older adults, the dosing schedule may be adjusted to earlier or additional doses to maintain optimal protection.¹⁶ Further research is needed to determine the best timing for subsequent booster doses, especially in the context of new variants and long-term immune response monitoring. The longevity of protection from boosters and the potential need for variant-specific boosters are key areas of investigation.

Are there any differences in recommendations for booster shots based on the specific COVID-19 vaccine a person initially received? How should individuals decide which booster to receive if multiple options are available?

Guidance for COVID-19 booster vaccinations is tailored according to the initial vaccine regimen and may adapt with emerging data on SARS-CoV-2 variants. For the youngest demographic aged 6 months to 4 years, unvaccinated children should receive 2 or 3 homologous doses of the updated 2023 to 2024 formula mRNA vaccine, with the exact number based on whether they receive the Moderna or Pfizer-BioNTech vaccine. Those who have started but not completed the original vaccine series should receive 1 or 2 additional doses of the updated vaccine to complete the series, while those who have completed the initial series need only 1 booster dose of the updated vaccine. An 8-week interval between the first and second mRNA COVID-19 vaccine for non-immunocompromised individuals aged 6 months to 4 years might be used. For children aged 5 to 11 years old, a single updated dose of the 2023 to 2024 formula mRNA vaccine is advised, independent of their prior vaccination history.¹⁶
 
Unvaccinated individuals aged 12 years and older are recommended to get either 1 dose of the updated mRNA vaccine or a 2-dose regimen of the updated Novavax vaccine. Those who have previously received any original COVID-19 vaccines, including monovalent, bivalent, or Janssen vaccines, should receive 1 updated dose of any COVID-19 vaccine currently available. This recommendation simplifies the booster schedule across different previous vaccination statuses for these age groups. In those aged 12 years to 64 years who are not immunocompromised, an extended 8-week interval between the first and second doses of mRNA and Novavax COVID-19 vaccines is considered beneficial for reducing the risk for myocarditis and pericarditis, which remains a rare but documented side effect of these vaccines that is particularly noted in males aged 12 to 39 years. However, for the immunocompromised, those over 65, and others needing rapid protection due to high risk, the standard interval is maintained.¹⁶
 
It is important for individuals to consult with healthcare providers for advice tailored to their personal health circumstances and the most current public health guidance. This is most important for people who are moderately or severely immunocompromised, as the vaccine guidance may differ substantially from those who are not immunocompromised.

As we approach the winter months, what unique challenges and strategies should clinicians consider to extend the vaccination season, ensuring that people continue to receive COVID-19 vaccines throughout November, December, and January? What is the role of public health campaigns in promoting vaccination during the winter season and how effective are they?

As the winter months approach, clinicians face the challenge of ensuring the continuation of COVID-19 vaccinations amid potential surges in respiratory infections such as influenza and respiratory syncytial virus (RSV), which may complicate the clinical picture. Clinicians should consider the coadministration of COVID-19 vaccines with the seasonal flu vaccine, as endorsed by the CDC, to reduce visits and increase vaccination rates. Education efforts should emphasize the enhanced risk for respiratory illnesses during winter and the benefits of vaccination. Expanding vaccine availability in clinics, hospitals, and community settings and extending hours to accommodate different schedules can improve vaccine access. Staying informed about the prevalence of SARS-CoV-2 variants allows clinicians to better advise their patients on the need for booster doses. Furthermore, identifying and reaching out to populations with lower vaccination rates with tailored messaging and resources can address gaps in vaccination coverage.
 
Public health campaigns play a critical role in promoting COVID-19 vaccination during the winter by raising awareness. Campaigns can inform the public about the increased risks of COVID-19 during the winter months when people are more likely to be indoors. Active efforts to correct misinformation can help improve vaccine acceptance. Sharing data on vaccine effectiveness in preventing severe disease, hospitalization, and death can encourage uptake. Campaigns should use a mix of traditional media, social media, and community outreach to reach diverse audiences.
 
In practice, public health campaigns, when combined with easy access to vaccines and robust education efforts, have been effective in increasing vaccination rates during the winter season. Campaigns that are culturally sensitive, easy to understand, and address specific concerns or barriers to vaccination can be more effective. Involving community leaders, health care providers, and other trusted figures can enhance the impact of these campaigns. However, their success also depends on factors such as vaccine supply, public perception of vaccine necessity, and the prevalence of competing health priorities.

Can you provide insights into the latest research on the potential long-term effects of COVID-19 on various organ systems? How should clinicians be prepared to address these complications?

Proactive management and ongoing research are critical for understanding the full impact of COVID-19 and providing the best care for those with long-term effects. The long-term effects of COVID-19 can affect multiple organ systems^2,3:
 
Respiratory system: Symptoms such as dyspnea and cough have been documented. It may be a good idea to follow up with pulmonary function tests and imaging for management and surveillance.

Cardiovascular system: There have been reports of cardiac impairment, myocardial inflammation, and postural orthostatic tachycardia syndrome post-COVID-19. Clinicians should maintain a high index of suspicion for these conditions in patients with corresponding symptoms.

Neurologic system: Neurologic manifestations, such as headaches, brain fog, changes in smell or taste, and dizziness, are under investigation. Cognitive assessments and neurologic support might be necessary for some patients.

Renal system: Adverse kidney outcomes have been observed during COVID-19, and the long-term effects of this organ damage are unknown.

Gastrointestinal system: COVID-19 may cause diarrhea. Gastroenterologists should be vigilant about these potential outcomes in recovered patients.

Endocrine system: There is emerging evidence linking COVID-19 with new-onset diabetes and potential disruptions to other hormonal pathways.

Mental health: The impact on mental health includes depression, anxiety, and post-traumatic stress disorder, necessitating psychological or psychiatric intervention for some patients.
 
The dynamic nature of the pandemic requires that clinicians remain vigilant and adaptable to new findings and treatment protocols. Clinicians should be prepared to address the complications of long COVID by collaborating across specialties to manage the multifaceted needs of patients with long COVID. Establishing or utilizing post-COVID care clinics to provide integrated support for patients with persistent symptoms can also be helpful. Clinicians should inform patients of the potential for long-term effects and the importance of follow-up care; provide access to physical therapy, occupational therapy, and other rehabilitation services to aid recovery; and keep abreast of emerging data and research on long COVID to inform clinical practice. Moreover, supporting and participating in longitudinal studies that track patient outcomes over time may help in understanding the full spectrum of long COVID. This will allow for the utilization of the latest evidence to guide treatment decisions while also considering individual patient contexts.

This Q&A was edited for clarity and length.

Disclosures

Elie Saade, MD, MPH, reported affiliations with the American Hospital Association; the Centers for Disease Control and Prevention; Envision Pharma Group; Johnson & Johnson, Inc; Protein Sciences Corporation; and Sanofi Pasteur.

References

1. Regan JJ, Moulia DL, Link-Gelles R, et al. Use of updated COVID-19 vaccines 2023-2024 formula for persons aged ≥6 months: Recommendations of the Advisory Committee on Immunization Practices – United States, September 2023. MMWR Morb Mortal Wkly Rep. 2023;72(42):1140-1146. doi:10.15585/mmwr.mm7242e1
 
2. Long COVID or post-COVID conditions. US Centers for Disease Control and Prevention. Updated July 20, 2023. Accessed November 15, 2023. https://www.cdc.gov/coronavirus/2019-ncov/long-term-effects/index.html
 
3. Davis HE, McCorkell L, Vogel JM, Topol EJ. Long COVID: major findings, mechanisms and recommendations. Nat Rev Microbiol. 2023;21(3):133-146. doi:10.1038/s41579-022-00846-2
 
4. Marjenberg Z, Leng S, Tascini C, et al. Risk of long COVID main symptoms after SARS-CoV-2 infection: a systematic review and meta-analysis. Sci Rep. 2023;13(1):15332. doi:10.1038/s41598-023-42321-9
 
5. Post-COVID conditions: information for healthcare providers. Centers for Disease Control and Prevention. Updated September 11, 2023. Accessed November 15, 2023. https://www.cdc.gov/coronavirus/2019-ncov/hcp/clinical-care/post-covid-conditions.html
 
6. National Institute for Health and Care Excellence. COVID-19 rapid guideline: managing the long-term effects of COVID-19. Updated March 11, 2022. Accessed November 15, 2023. https://www.nice.org.uk/guidance/ng188/resources/covid19-rapid-guideline-managing-the-longterm-effects-of-covid19-pdf-51035515742
 
7. Battaglini D, Lopes-Pacheco M, Castro-Faria-Neto HC, Pelosi P, Rocco PRM. Laboratory biomarkers for diagnosis and prognosis in COVID-19. Front Immunol. 2022;13:857573. doi:10.3389/fimmu.2022.857573
 
8. Brannock MD, Chew RF, Preiss AJ, et al. Long COVID risk and pre-COVID vaccination in an EHR-based cohort study from the RECOVER program. Nat Commun. 2023;14(1):2914. doi:10.1038/s41467-023-38388-7
 
9. Babicki M, Kapusta J, Pieniawska-Śmiech K, et al. Do COVID-19 vaccinations affect the most common post-COVID symptoms? Initial data from the STOP-COVID Register-12-month follow-up. Viruses. 2023;15(6):1370. doi:10.3390/v15061370
 
10. Tran VT, Perrodeau E, Saldanha J, Pane I, Ravaud P. Efficacy of first dose of covid-19 vaccine versus no vaccination on symptoms of patients with long covid: target trial emulation based on ComPaRe e-cohort. BMJ Med. 2023;2(1):e000229. doi:10.1136/bmjmed-2022-000229
 
11. Moderna COVID-19 booster may protect against variants. National Institutes of Health. Published November 2, 2021. Accessed November 16, 2023. https://www.nih.gov/news-events/nih-research-matters/moderna-covid-19-booster-may-protect-against-variants
 
12. Ailsworth SM, Keshavarz B, Richards NE, et al. Enhanced SARS-CoV-2 IgG durability following COVID-19 mRNA booster vaccination and comparison of BNT162b2 with mRNA-1273. Ann Allergy Asthma Immunol. 2023;130(1):67-73. doi:10.1016/j.anai.2022.10.003
 
13. Di Fusco M, Sun X, Moran MM, et al. Impact of COVID-19 and effects of booster vaccination with BNT162b2 on six-month long COVID symptoms, quality of life, work productivity and activity impairment during Omicron. J Patient Rep Outcomes. 2023;7(1):77. doi:10.1186/s41687-023-00616-5
 
14. Chenchula S, Karunakaran P, Sharma S, Chavan M. Current evidence on efficacy of COVID-19 booster dose vaccination against the Omicron variant: a systematic review. J Med Virol. 2022;94(7):2969-2976. doi:10.1002/jmv.27697
 
15. Townsend JP, Hassler HB, Dornburg A. Infection by SARS-CoV-2 with alternate frequencies of mRNA vaccine boosting. J Med Virol. 2023;95(2):e28461. doi:10.1002/jmv.28461
 
16. US Centers for Disease Control and Prevention. Interim clinical considerations for use of COVID-19 vaccines in the United States. Updated November 3, 2023. Accessed November 15, 2023. https://www.cdc.gov/vaccines/covid-19/clinical-considerations/interim-considerations-us.html

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