Date of Award

January 2022

Document Type


Degree Name

Medical Doctor (MD)



First Advisor

Hyung Chun


Since the first case of coronavirus disease 2019 (COVID-19) was reported in December 2019, there have been upwards of 5.7 million deaths reported worldwide. Since then, multiple vaccinations (Pfizer-BioNTech (BNT162b2), Moderna (mRNA-1273), and Janssen(Ad.26.COV2.S)) have been brought to market and attained emergency use authorization (EUA) under the U.S. Food and Drug Administration (FDA), and two have also attained FDA approval (Pfizer-BioNTech (BNT162b2) & Moderna (mRNA-1273)). While these vaccines have shown remarkable efficacy in preventing COVID-19, there has been substantial evidence that demonstrates breakthrough infections can occur in individuals who have been fully vaccinated.The goal of this thesis is to quantify the prevalence of COVID-19 breakthrough infections and understand the clinical course/outcomes of severe COVID-19 breakthrough infections.

To understand the prevalence of breakthrough COVID-19 infections, we did a systematic review of 969 patients who were admitted to a Yale New Haven Health System hospital with a confirmed positive PCR test for SARS-CoV-2 (from 03-23-2021 to 07-01-2021). 54 of the 969 (6%) were deemed to be breakthrough cases; among these 54, we found that 25 (46%) patients were asymptomatic, four (7%) had mild disease, 11 (20%) had moderate disease, and 14 (26%) had severe or critical illness. The fact that the majority of fully vaccinated patients experienced mild or no symptoms substantiates the importance of vaccinations; the individuals who had more severe disease were older — with a median age of 80.5 — and had preexisting comorbidities, such as cardiovascular disease.

To address the second part of this thesis and classify the course of severe COVID-19 disease among vaccinated individuals, we conducted a systematic review of patients with a confirmed positive PCR test for SARS-CoV-2 at Yale New Haven Health from 08-04-2021 to 10-12-2021 - a time when the SARS-CoV-2 Delta (B.1.617.2) variant accounted for >95% of COVID-19 cases in the region. In all, there were 371 confirmed cases, and 222 (60%) patients met the criteria for being severely or critically ill. Within the 222 cases of severe COVID-19 illness, 82 (37%) were fully vaccinated. We then proceeded to compare the course of severe breakthrough cases of COVID-19 in vaccinated patients to the course of disease in unvaccinated patients. Our analysis showed that patients with severe breakthrough cases tended to be older (mean age 71.5 years vs. 55.2 in the unvaccinated cohort) and also had higher prevalence of underlying cardiovascular disease and type 2 diabetes. However, despite being older and having more comorbidities, vaccinated individuals with severe COVID-19 illness still had better clinical courses, including shorter hospitalization length, decreased use of advanced oxygen support, and tended to have lower mortality rates.


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