Immune Dysfunction Increases Risk for COVID-19 Breakthrough Infection

Illustration of antibodies (y-shaped) responding to an infection with the new coronavirus SARS-CoV-2. The virus emerged in Wuhan, China, in December 2019, and causes a mild respiratory illness (covid-19) that can develop into pneumonia and be fatal in some cases. The coronaviruses take their name from their crown (corona) of surface proteins, which are used to attach and penetrate their host cells. Once inside the cells, the particles use the cells’ machinery to make more copies of the virus. Antibodies bind to specific antigens, for instance viral proteins, marking them for destruction by other immune cells, such as the macrophage white blood cell behind the virus.
Researchers conducted a study to determine the relationship between immune dysfunction and the risk for COVID-19 breakthrough infection following vaccination.

Although the risk for COVID-19 infection was decreased among vaccinated patients, those with immune dysfunction were found to be at increased risk for breakthrough infection, regardless of vaccination status. These findings were published in JAMA Internal Medicine.

Data were sourced from the National COVID Cohort Collaborative (N3C), a centralized repository of electronic health records of patients with COVID-19. Records from individuals (N=664,722) who received at least 1 dose of a SARS-CoV-2 vaccine between December 2020 and October 2021 were assessed for breakthrough infection rates and risk factors.

Among patients included in the study, the median age was 51 (IQR, 34-66) years, 56.9% were women, 59.3% were White, 51.6% had no comorbidities, 90.9% were fully vaccinated, and 71.1% had received the Pfizer-BioNTech COVID-19 vaccine. Immune dysfunction was identified among 5.3% of patients and was attributed to rheumatoid arthritis (RA; n=13,445), solid organ transplantation (SOT; n=8688), HIV infection (n=8536), multiple sclerosis (MS; n=2970), and bone marrow transplantation (BMT; n=1872).

Full vaccination was found to decrease the risk for breakthrough infection by 28% (adjusted incidence rate ratio [aIRR], 0.72; 95% CI, 0.68-0.76). After stratification by time period, the researchers found that the frequency of breakthrough infections was decreased prior to the emergence of the Delta variant (IR, 2.2; 95% CI, 2.2-2.2 per 1000 person-months) compared with the period after the emergence of the Delta variant (IR, 7.3; 95% CI, 7.3-7.4 per 1000 person-months).

Of note, an increased risk for breakthrough infection was observed among patients who were aged 65 years and older (aIRR, 1.40; 95% CI, 1.27-1.53), 30 to 34 years (aIRR, 1.39; 95% CI, 1.26-1.53), and 50 to 64 years (aIRR, 1.31; 95% CI, 1.20-1.42). The researchers also noted an increased risk for breakthrough infection among patients living in the Western (aIRR, 1.28; 95% CI, 1.15-1.42) and Southern regions of the US (aIRR, 1.22; 95% CI, 1.08-1.36).

Compared with N3C data from patients who contracted COVID-19 prior to vaccination (n=2,111,515), the frequency of severe outcomes was decreased among those with breakthrough infections (16.0% vs 24.4%).

For the population of patients with immune dysfunction, the IR of breakthrough infection was 9.3, 15.7, 9.1, 8.9, and 8.6 per 1000 person-months for those with RA, SOT, HIV infection, MS, and those who underwent BMT, respectively. Of note, the IR of breakthrough infection was 7.1 among patients without immune dysfunction.

An increased risk for breakthrough infection was also observed among patients with SOT (aIRR, 2.16; 95% CI, 1.96-2.38), HIV infection (aIRR, 1.33; 95% CI, 1.18-1.49), and RA (aIRR, 1.20; 95% CI, 1.09-1.32).

This study may have been limited by the use data obtained from EHRs and the lack of data on patients with other types of immune dysfunction, such as those with cancer. In addition, the risk for breakthrough infection associated with exposure to immunosuppressant regimens was not evaluated.

According to the researchers, “this cohort study provide[s] real-world evidence that patients with immune dysfunction [are at significantly increased risk] for contracting COVID-19 breakthrough infection and [have] worse outcomes compared with those without immune dysfunction.” These findings support the continued use of nonpharmacologic interventions among patients with immune dysfunction following vaccination against COVID-19, such as masking and social distancing.

Disclosure: Multiple authors declared affiliations with industry. Please refer to the original article for a full list of disclosures.


Sun J, Zheng Q, Madhira V, et al. Association between immune dysfunction and COVID-19 breakthrough infection after SARS-CoV-2 vaccination in the US. JAMA Intern Med. 2021;e217024. doi:10.1001/jamainternmed.2021.7024