New evidence shows how booster shots offer robust protection against long COVID, emphasizing their importance in battling Omicron-era health challenges.

Study: The impact of vaccination on preventing long COVID in the Omicron era: a systematic review and meta-analysis. Image Credit: p.ill.i / Shutterstock

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

In a recent preprint* study posted to the medRxiv server, an international team of researchers evaluated the effectiveness of vaccination, particularly booster doses, in reducing the risk of long coronavirus disease (COVID) during the Omicron era through a systematic review and meta-analysis of observational studies.

Background

Long COVID, also known as post-acute sequelae of COVID-19 (PASC), affects an estimated 2-7% of individuals recovering from Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection, with symptoms lasting at least three months.

This condition impairs physical and mental health, reducing quality of life and productivity while imposing economic and healthcare burdens globally, with an estimated annual cost of $1 trillion.

Symptoms such as fatigue, cognitive dysfunction, and insomnia are prevalent and challenging to manage due to the lack of effective treatments.

Vaccination, particularly booster doses, has shown promise in reducing long COVID risk by mitigating severe infections and potentially limiting viral persistence and inflammation. Further research is needed to address evolving Omicron variants.

About the study

The present study adhered to the guidelines of the Meta-analysis of Observational Studies in Epidemiology and Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA).

Literature searches spanned databases such as Embase, MEDLINE, PubMed, Europe PubMed Central (PMC), Latin American and Caribbean Health Sciences Literature (LILACS), the Cochrane COVID-19 Study Register, and the World Health Organization (WHO) COVID-19 Database, covering publications from January 1, 2022, to March 1, 2024.

Eligible studies included participants with confirmed Omicron variant SARS-CoV-2 infections, examining COVID-19 vaccines (e.g., BioNTech 162b2 (BNT162b2), messenger Ribonucleic Acid (mRNA)-1273, Adenovirus 26 Coronavirus Vaccine 2 Spike (Ad26.CoV2.S), Chimpanzee Adenovirus Oxford 1 (ChAdOx1)) compared to unvaccinated or partially vaccinated individuals.

Outcomes included prevalence, severity, and risk of long COVID, defined per Centers for Disease Control and Prevention (CDC) guidelines as symptoms persisting four weeks post-infection.

Independent reviewers screened titles and abstracts, resolved discrepancies, and assessed the risk of bias using the Newcastle-Ottawa Scale and Joanna Briggs Institute tools.

Meta-analyses assessed relative risks (RRs) of long COVID using random-effects models, with sensitivity analyses confirming robustness. The study also noted significant heterogeneity across studies, which was assessed using Cochran’s Q and I² statistics. Funnel plots and Egger’s tests assessed publication bias. Statistical analyses were conducted using R version 4.1.1 with the meta package.

Study results

A total of 9,107 records were initially identified through systematic searches. After removing duplicates, 5,360 studies were screened based on their titles and abstracts.

Following this, 368 full-text articles were assessed for eligibility, and 31 studies were ultimately included in the review. This total included two additional studies identified through hand searching. These studies spanned 16 countries, including Europe, Asia, North America, and Australia, and utilized various data sources, such as medical records, registries, and online surveys.

The studies included 11 retrospective, 17 prospective, and three cross-sectional designs. While most studies focused on adults, one included adolescents and adults, and three focused solely on children and adolescents.

Adult participants had a mean age range of 36.1 to 61.4 years and a median range of 37 to 66 years. The percentage of female participants ranged from 12.7% to 82%.

Study populations ranged from 80 to nearly 8 million participants infected with Omicron variants, with infection periods spanning 13 days to 15 months. Only seven studies reported specific Omicron subvariants, including BA.1, BA.2, BA.4, BA.5, and XBB.

The studies varied in vaccine types. Four studies exclusively examined BNT162b2 recipients, three focused on mRNA vaccines, and 10 included a mix of European Union (EU)- authorized vaccines.

Twelve studies did not specify vaccine types but were assumed to include EU-authorized vaccines based on their locations.

Vaccination statuses were categorized into unvaccinated, primary course vaccinated, and booster vaccinated.

Most studies defined primary vaccination as two doses, with booster vaccination typically indicating three or more doses. An exception was noted for Ad26.COV2.S, where one dose was considered primary, and subsequent doses were classified as boosters.

The review revealed that vaccination reduced the prevalence, symptom burden, and risk of long COVID compared with unvaccinated or partially vaccinated individuals.

Ten studies were included in a meta-analysis assessing the risk of long COVID after vaccination compared with no vaccination. Separate analyses for primary and booster vaccination showed significantly reduced risks of long COVID.

Primary vaccination reduced the risk by 22%, while booster vaccination reduced it by 29%. Booster vaccination also demonstrated additional benefits compared to primary vaccination alone, with a 23% lower risk.

Despite variability in study designs and populations, vaccination, especially booster doses, was consistently associated with reduced long COVID risks.

However, the study noted substantial statistical heterogeneity across analyses, reflecting variability in definitions, follow-up periods, and methodologies used by the included studies.

Conclusions

To summarize, vaccination reduced long COVID risk by 22–29% compared to unvaccinated individuals, with primary vaccination lowering risk by 19% and booster doses providing an additional 26% reduction.

Booster doses further reduced risk by 23% compared to primary vaccination. These findings highlight vaccination’s role in reducing severe disease, inflammation, and viral persistence linked to long COVID.

Future studies should investigate the effects of hybrid immunity from seasonal boosters and repeat infections and explore the cost-effectiveness of vaccination programs, particularly given the significant healthcare burdens of long COVID.

*Important notice: medRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.