2 distinct episodes of COVID-19 with B.1.617.2 (Delta) variant followed by the Omicron variant; 2 distinct episodes of COVID-19 with B.1.617.2 (Delta) variant followed by the Omicron variant; respiratory failure; This is a literature report.  Eight years ago, a 77-year-old man with bilateral LT for idiopathic pulmonary fibrosis, presented with a history of fever, cough, and malaise for 2 days. His past medical history was significant for candida tropicalis pericarditis needing pericardial wash, left hemidiaphragm paresis, Stage 4 chronic kidney disease, hepatic nodular regenerative hyperplasia with evidence of esophageal varices and portal hypertensive gastropathy, multiple skin cancers, and venous thromboembolic episodes requiring chronic anticoagulant use. He did not have any biopsy proven acute cellular or humoral rejection although he had been treated 3 times with pulse dose corticosteroids (methylprednisone 10 mg/Kg daily x 3 days) since his transplant. His immunosuppression regimen consisted of low dose prednisone (7.5 mg/day) and tacrolimus dose was maintained to target trough levels of 5-8 ng/mL. He had been on azathioprine early after transplant followed by mycophenolate 2 years posttransplant. However, he was off either cell cycle inhibitors for 6 months because of recalcitrant skin cancers. The last laboratory tests before the infection revealed a total white blood cell count of 7.1 x 103/mL with an absolute lymphocyte count of 1.4 x 103/mL and Cylex Immuknow assay value of 441 ng/mL (with a low immune cell response defined as <225 ng/mL). He had good lung functions prior to the infection with forced expiratory volume in 1 second (FEV1) of 2.46 L (75% of predicted) and forced vital capacity of 3.08 L (70% of predicted). He had received 3 doses of BNT162b2 vaccine (Pfizer-BioNTech, BioNTech) with the last dose 10 weeks ago. A nasopharyngeal swab was positive for SARS-CoV-2 virus (real-time RT-PCR assay). The whole-genome sequencing revealed infection with the Delta variant. He was treated with intravenous casirivimab and imdevimab (600 mg each). Given the multiple comorbidities, he was admitted and started on remdesivir (200 mg IV once followed by 100 mg daily), along with prednisone burst (starting with 1 mg/Kg PO) per institutional protocols. The inflammatory markers revealed mild elevation of C-reactive protein, lactate dehydrogenase, and Ddimer. Ferritin levels were normal, and chest imaging were unchanged from baseline. This was confirmed on a computed tomography chest which was also unchanged. He had an uncomplicated course and was discharged home after completing 5 days of remdesivir. He returned to the clinic 4 weeks after the diagnosis feeling well with no significant change in spirometry (FEV1 of 2.27 L, 69% of predicted and forced vital capacity of 2.98 L, 67% of predicted) from baseline. However, 2 weeks later, he developed fever with cough again. This time he had noted a concurrent drop in his home lung functions and found to be hypoxic. Chest radiograph showed new bibasilar opacities, and these were confirmed on a repeat computed tomography chest. The nasopharyngeal swab was positive for the SARS-CoV-2 virus again. Given the clinical presentation and the emergence of the Omicron variant at the time, the patient was suspected to have a re-infection. The variant testing was positive for Omicron. All the laboratory markers were abnormal during this admission, with peaks and troughs that were more severe than previously. He remained symptomatic with respiratory failure necessitating an extension of the remdesivir to 10 days. He showed slow improvement but remained with respiratory failure, necessitating discharge with home oxygen. He returned for the outpatient follow-up 4 weeks later and found to have a significant loss of lung functions (>20% decline in both FEV1 [1.79 L] and forced vital capacity [2.32 L]) and persistent oxygen needs.  The patient developed 2 episodes of COVID-19, 6 weeks apart, with the Delta (2021) confirmed as the initial variant followed by the Omicron variant (2022). The short interval between the 2 infections meant that his immunosuppressive regimen, baseline comorbidities, and risk of severe disease as well as the available therapeutics, were similar during both infections. Furthermore, both infections occurred within 4 months since the last dose of the vaccine became protective. Finally, the patient's first episode of COVID-19 led to a mild illness that did not require any potent immunosuppressives that may have had ill affects well beyond the acute illness. Given these features, the host factors can be deemed similar during both episodes of COVID-19, permitting a direct comparison of the severity of clinical disease from these 2 variants. It is evident that the Omicron variant was associated with a more severe clinical course in this patient. This encompassed the severity of symptoms at presentation, development of COVID pneumonia, new-onset respiratory failure, worse laboratory abnormalities, longer hospital stay, and finally,significant loss of lung functions. This occurred despite the patient being vaccinated with 3 doses of the mRNA vaccine and the recent recovery from the Delta variant. The course of illness from Delta was expectedly mild, a variant against that the mRNA vaccines appear to be effective in attenuating the severity of the disease. One of the noteworthy differences in the therapeutic strategy pertains to the use of monoclonal antibodies during the first episode. And while this may have favorably altered the subsequent clinical course of the Delta infection, it does not explain the significant difference in clinical presentation. Despite a similar duration of symptoms (2 days), the Omicron episode led to severe disease at diagnosis.; Sender's Comments: The vaccine efficacy varies from one patient to another and can be affected by different factors; however, a contributory role of the suspect vaccine BNT162B2 to the drug ineffective and COVID-19 cannot be ruled out. The reported respiratory failure is considered unrelated to BNT162B2. The patient's medical history including bilateral lung transplant and the concomitant medications may provide alternative predisposing conditions to the event. The impact of this report on the benefit risk profile of the Pfizer product is evaluated as part of Pfizer procedures for safety evaluation, including the review and analysis of aggregate data for adverse events. Any safety concern identified as part of this review, as well as any appropriate action in response, will be promptly notified to regulatory authorities, Ethics Committees, and Investigators, as appropriate