COVID-19 vaccine breakthrough infections among immunocompromised individuals

A Pfizer-funded large study of breakthrough infections in immunocompromised people following two doses of the Pfizer/BioNTech vaccine against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) concluded that the vaccine largely prevented such infections, but that immunocompromised people would be best served with a third dose of the vaccine for better protection.

Study: Evaluation of COVID-19 vaccine breakthrough infections among immunocompromised patients fully vaccinated with BNT162b2. Image Credit: Flowersandtraveling/ ShutterstockStudy: Evaluation of COVID-19 vaccine breakthrough infections among immunocompromised patients fully vaccinated with BNT162b2. Image Credit: Flowersandtraveling/ Shutterstock


Over 43 million coronavirus disease 2019 (COVID-19) cases arose in the USA by September 2021, of which almost 700,000 were fatal. Conversely, over 173 million people had received two doses of the Pfizer vaccine BNT162b2, which was reported to be 94% effective in preventing symptomatic illness, hospitalizations, and deaths related to COVID-19.

The current study, which appears as a preprint on the medRxiv* server, focuses on the incidence of breakthrough infections among the immunocompromised, specifically those on active immunosuppressive treatment. These groups have not been included in the randomized controlled trials of the nucleic acid vaccines that provided data for their emergency approval.

Earlier studies showed a lower vaccine efficacy (VE) among the immunocompromised, at 63% to 90%. As a result, the US Food and Drug Administration (FDA) allowed a third booster dose to be given for immunocompromised people who might not mount an adequate immune response with only two doses. This includes those with solid organ transplants or with conditions that lead to a similarly immunocompromised state.

The Centers for Disease Control and Prevention (CDC) guidelines added more groups to this list, including those on active therapy for blood cancers or those with a stem cell transplant on immunosuppressive medications, advanced HIV infections, or congenital immunodeficiency syndromes.

What did the study show?

Of about 1.2 million fully vaccinated individuals, about 18% were immunocompromised (IC), with a median age of 58 years, vs. 45 in the non-IC cohort. Almost 63% of the former had more than one condition putting them at high risk of severe COVID-19, but less than a fifth of the latter.

The highest proportion of active immunosuppressive treatment was among those with organ transplants, rheumatologic, or other inflammatory diseases. Over 75% had taken the first vaccine dose before the end of March, vs. 62% in the non-IC group.

From December 2020 to July 8, 2021, there were approximately a thousand breakthrough infections. The median age of these individuals was 61 and 51 years in the IC and non-IC cohorts, respectively. The risk of breakthrough infection was three times higher in the former compared to the non-IC group.

The incidence of vaccine breakthrough infection is thus about 0.9 and 0.34 per 100 person-years for IC vs. non-IC participants, thus indicating a 2.4-fold increase in the former.

Of the breakthrough infections, about 13% required hospitalization, and two people died altogether. In the IC cohort, one in five were hospitalized, with 2% and 6% required invasive mechanical ventilation and intensive care unit admission, respectively. Both deaths were in this cohort.

Though the IC cohort made up less than a fifth of the vaccinated group, they comprised 38% of breakthrough infections and 60% of hospitalizations. The shortest duration of protection was with organ transplant recipients, with breakthrough infections at 16 days (median) from the second dose, vs. 94 days for those with HIV/AIDS and those on antimetabolite therapy.

Meanwhile, those below 65 years in the IC group were responsible for over 60% of breakthrough infections, for an incidence of 0.71 per 100 person-years (PY). For IC patients aged 65 years or more, however, the incidence was 1.5 per 100 PY, highest among those with cancers and inflammatory conditions or chronic kidney disease compared to those without such illnesses.

Conversely, 80% of non-IC vaccine recipients with breakthrough infection were below 65 years, with an incidence of 0.31 per 100 PY, vs. 0.65 per 100 PY in those aged 65 or more. Organ transplant recipients who had received two doses of the vaccine were at the highest risk of breakthrough at all ages, at 3.64-3.75 per 100 PY, with the shortest median time to infection of 16 days compared to 35 for the whole cohort.

If the whole IC cohort is considered rather than those on active immunosuppressive drugs, the number of breakthrough infections rose by 22.

What are the implications?

This is the largest study of breakthrough infections following full vaccination with the Pfizer vaccine. It shows a reduced VE among IC individuals, varying with the exact condition. Thus, about 60% of COVID-19-related hospitalizations in this study of breakthrough infections were in IC individuals, with over 2.5-fold the incidence of infection.

These findings support FDA authorization and CDC recommendations to offer a 3rd vaccine dose to increase protection among IC individuals,” say the researchers of this study, the largest to date of fully vaccinated IC individuals with breakthrough infections.  

Even though breakthrough infections remain uncommon, their incidence is significantly higher in those with IC and has more severe outcomes. This supports the need to ensure adequate vaccine-mediated immunity among this group, especially with evidence that antibody titers wane over time and render the individual vulnerable to newer virus variants.

*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.

Journal reference:
Dr. Liji Thomas

Written by

Dr. Liji Thomas

Dr. Liji Thomas is an OB-GYN, who graduated from the Government Medical College, University of Calicut, Kerala, in 2001. Liji practiced as a full-time consultant in obstetrics/gynecology in a private hospital for a few years following her graduation. She has counseled hundreds of patients facing issues from pregnancy-related problems and infertility, and has been in charge of over 2,000 deliveries, striving always to achieve a normal delivery rather than operative.


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