Exploring the Relationship Between COVID-19 Vaccination Status, SARS-CoV-2 Lineages, and Risk of Infection


Background.    The CDC recently defined being “up-to-date” on COVID-19 vaccination as having received at least one dose of a COVID-19 bivalent vaccine. The purpose of this study was to compare the risk of COVID-19 among those “up-to-date” and “not up-to-date” on COVID-19 vaccination.

Methods.          Employees of Cleveland Clinic in employment when the COVID-19 bivalent vaccine first became available, and still employed when the XBB lineages became dominant, were included.

Cumulative incidence of COVID-19 since the XBB lineages became dominant was compared across the ”up-to-date” and “not up-to-date” states, by treating COVID-19 bivalent vaccination as a time-dependent covariate whose value changed on receipt of the vaccine. Risk of COVID-19 by vaccination status was also compared using multivariable Cox proportional hazards regression adjusting for propensity to get tested for COVID-19, age, sex, and phase of most recent prior SARS-CoV-2 infection.

Results.            COVID-19 occurred in 1475 (3%) of 48 344 employees during the 100-day study period. The cumulative incidence of COVID-19 was lower in the “not up-to-date” than in the “up-to-date” state. On multivariable analysis, not being “up-to-date” with COVID-19 vaccination was associated with lower risk of COVID-19 (HR, 0.77; 95% C.I., 0.69-0.86; P-value, <0.001). Results were very similar when those 65 years and older were only considered “up-to-date” after receiving 2 doses of the bivalent vaccine.

Conclusions. Since the XBB lineages became dominant, adults “not up-to-date” by the CDC definition have a lower risk of COVID-19 than those “up-to-date” on COVID-19 vaccination, bringing into question the value of this risk classification definition.

This study aimed to examine the association between COVID-19 vaccination status, as defined by the CDC, and the risk of contracting COVID-19. Additionally, the study investigated the prevalence of the dominant XBB lineages of SARS-CoV-2 during the study period and their impact on infection risk. The findings challenge the current risk classification definition based solely on vaccination status and underscore the need to consider both prior infection and emerging viral variants when assessing COVID-19 risk.


The COVID-19 pandemic continues to pose significant challenges worldwide, with vaccination emerging as a key strategy to combat the spread of the virus and reduce the severity of illness. However, recent research conducted at the Cleveland Clinic has unveiled intriguing insights into the relationship between COVID-19 vaccination status and infection risk.

This study found that individuals who were not considered “up-to-date” on COVID-19 vaccination, according to the CDC definition, exhibited a lower risk of contracting COVID-19 compared to those who were “up-to-date.” Furthermore, the study shed light on the prevalence of the XBB lineages of SARS-CoV-2, which were the dominant strains during the study period.

Factors Contributing to Lower Risk in the “Not Up-to-Date” Group: The study identified two significant factors contributing to the lower risk of COVID-19 observed in individuals who were not “up-to-date” on COVID-19 vaccination. Firstly, the bivalent vaccine, developed based on specific strains, offered some level of protection against strains that closely resembled those used in its development. However, the bivalent vaccine demonstrated ineffectiveness against the XBB lineages of the Omicron variant, which were dominant during the study period.

Secondly, the CDC definition of being “up-to-date” did not account for the protective effect of prior infection. The study highlighted that individuals who were not considered “up-to-date” were more likely to have acquired prior infections with the BA.4/BA.5 or BQ lineages, which were prevalent when these individuals were exposed to the virus. Extensive research has shown that natural infection with SARS-CoV-2 provides robust protection compared to vaccination alone.

Strengths of the Study

The study conducted at the Cleveland Clinic possessed several notable strengths. Firstly, its large sample size enhanced the statistical power and generalizability of the findings. Moreover, the comprehensive healthcare system within the Cleveland Clinic facilitated accurate tracking of COVID-19 cases, vaccination records, and timing of these events.

The study’s methodology, treating vaccination status as a time-dependent covariate, allowed for real-time determination of vaccine effectiveness. Additionally, the study accounted for the propensity to get tested for COVID-19, mitigating potential biases associated with individuals seeking testing when symptomatic.

Limitations of the Study

While the study provided valuable insights, it is important to acknowledge its limitations. The analysis focused on all detected infections and did not differentiate between symptomatic and asymptomatic cases. Furthermore, the rarity of severe illnesses during the study period precluded an examination of the impact of vaccination status on disease severity.

The study lacked information on prior COVID-19 infections, potentially resulting in incomplete data. Moreover, the study’s focus on a healthcare population excluded children and featured a limited number of elderly subjects, potentially limiting the generalizability of the findings. Finally, the study did not consider individuals with compromised immune systems, which may have influenced the observed outcomes.

Implications of the Study’s Findings

The findings of this study call into question the current approach to COVID-19 vaccination and the definition of being “up-to-date” on vaccination. The study challenges the assumption that every individual must be uniformly considered “up-to-date” and raises concerns about the effectiveness of the bivalent vaccine, particularly against the XBB lineages of the Omicron variant.

Importantly, no study has conclusively demonstrated the vaccine’s ability to protect against severe disease or death caused by these specific variants. While individuals may still choose to receive the vaccine, assumptions regarding its ability to universally protect against severe illness and death may not be warranted based on available evidence.


In conclusion, the study conducted at the Cleveland Clinic revealed that individuals who were not considered “up-to-date” on COVID-19 vaccination, according to the CDC definition, had a lower risk of contracting COVID-19 compared to those who were considered “up-to-date.” This study underscores the challenges posed by evolving viral variants that significantly differ from those used during vaccine development, resulting in decreased vaccine effectiveness over time.

Furthermore, it highlights the importance of considering the protective effects of prior infection when assessing the risk of COVID-19. These findings prompt a reevaluation of the current risk classification definition based solely on vaccination status, particularly in light of the dominance of the XBB lineages during the study period.

Further research is necessary to enhance our understanding of COVID-19 vaccine effectiveness against emerging variants and to inform public health strategies moving forward.

reference link : https://www.medrxiv.org/content/10.1101/2023.06.09.23290893v1


Please enter your comment!
Please enter your name here

Questo sito usa Akismet per ridurre lo spam. Scopri come i tuoi dati vengono elaborati.