Lower efficacy of COVID-19 mRNA vaccines in patients with frailty


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In a recent study published in The Lancet Healthy Longevity, researchers assessed the effectiveness of coronavirus disease 2019 (COVID-19) vaccination against hospitalization and deaths among veterans based on frailty status in the United States (US).

Study: COVID-19 mRNA vaccine effectiveness against hospitalisation and death in veterans according to frailty status during the SARS-CoV-2 delta (B.1.617.2) variant surge in the USA: a retrospective cohort study. Image Credit: adriaticfoto/Shutterstock
Study: COVID-19 mRNA vaccine effectiveness against hospitalisation and death in veterans according to frailty status during the SARS-CoV-2 delta (B.1.617.2) variant surge in the USA: a retrospective cohort study. Image Credit: adriaticfoto/Shutterstock


The COVID-19 pandemic has disproportionately affected older adults, with elevated risks of morbidity, hospitalization, admission to care homes, and mortality compared to the younger population. The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Delta variant was dominant during June – August 2021 in the US and is characterized by increased transmissibility, mortality, and severe clinical presentation in non-vaccinated people relative to SARS-CoV-2 Alpha. 

Studies have reported that COVID-19 vaccination effectively prevents infection, symptomatic disease, severe complications, and mortality in older adults, albeit the responses are much lower than in younger populations. However, evidence indicates heterogeneous responses in the older population. Although vaccine clinical trials included older adults, those with disability, frailty, and multimorbidity were excluded from most trials.

Frailty is common in older individuals and often co-exists with multimorbidity/disability. COVID-19 is a significant stressor; studies reported worse clinical outcomes during COVID-19 in older people with frailty than those without. The veteran population in the US is older, predominantly male, with a higher prevalence of chronic multimorbidity, obesity, substance abuse, and frailty, which are risk factors for poor COVID-19 outcomes.

About the study

The present study evaluated vaccine effectiveness (VE) against COVID-19-associated hospital admission and all-cause mortality in US veterans. The authors obtained data from the US Department of Veteran Affairs (VA) COVID-19 shared data resource, the national surveillance tool (NST), and the VA corporate warehouse.

Individuals aged 19 or above who tested SARS-CoV-2-positive between July 25 and September 30, 2021, were included. Subjects were excluded if partially vaccinated or received vaccines other than the mRNA vaccines (BNT162b2 or mRNA-1273). Frailty status was classified using the VA frailty index (VA-FI), and a VA-FI score was calculated for each patient on testing positive for SARS-CoV-2.

The VA-FI comprises 31 items or deficits, stratified into the following groups – 1) morbidity, 2) sensory loss, 3) function, 4) cognition and mood, and 5) others. VA-FI scores were categorized as robust, pre-frail, and frail. The primary outcomes of the investigation were hospitalizations and all-cause mortality within 30 days of SARS-CoV-2 infection. 


The authors identified 62,213 veterans during the specified period, of which 57,784 were included for analysis. This comprised 28,497 patients in the robust category, 16,737 pre-frail patients, and 12,550 frail subjects. Patients in the frail category were older and more likely to have common chronic comorbidities than those in the robust group.  

There were 4,528 (36.1%) asymptomatic patients in the frail group and 12,950 (45.4%) in the robust group. The proportion of (fully) vaccinated patients in the frail group (60.6%) was higher than in the pre-frail (38.5%) or robust (25%.) group. More than 7,850 patients were hospitalized within 30 days of infection; this included 2749 vaccinated patients and 5108 non-vaccinated patients.

Of the 2577 deaths within 30 days of infection, most (73.8%) were among the non-vaccinated subjects. VE was 51% against hospitalization and 74% against all-cause mortality. Between the two vaccines, the effectiveness of mRNA-1273 against hospitalization (but not mortality) was higher than that of the BNT162b2 vaccine.

About 9.2% of frail subjects, 12.5% of pre-frail patients, and 24.9% of individuals from the robust group were hospitalized by 30 days post-SARS-CoV-2 infection. In all, 705 patients in the robust group, 760 pre-frail subjects, and 1112 frail patients succumbed to COVID-19 by 30 days of infection. Although vaccination conferred protection against hospitalization/death, protection was lower for patients in the frail group.

VE was 65% against hospitalization for those in the robust group, 54% for pre-frail patients, and 36% for frail subjects. VE against all-cause mortality for the frail group was the lowest at 68% and identical (79%) for patients in the pre-frail and robust categories.


The study observed that more patients with frailty were vaccinated than patients in pre-frail or robust categories. The frail group had lower protection against hospitalization/death than the robust group. The reduction in VE among frail patients relative to those in the robust category was higher in younger patients (< 65 years) than older patients (> 65 years). This suggested that frailty is a distinct condition that could also occur in the younger population.

These findings underscore that frailty should be considered for vaccine design and evaluation. Potential approaches in this direction could include increasing antigen dose, optimizing adjuvants, or using recombinant antigens, which have been implemented for influenza vaccines. In summary, the researchers found that COVID-19 vaccines were less effective in patients with frailty. Future studies should recruit people with frailty and incorporate frailty assessments in their analyses.

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