key: cord-0881977-0aik5i71
authors: Brosh-Nissimov, Tal; Orenbuch-Harroch, Efrat; Chowers, Michal; Elbaz, Meital; Nesher, Lior; Stein, Michal; Maor, Yasmin; Cohen, Regev; Hussein, Khetam; Weinberger, Miriam; Zimhony, Oren; Chazan, Bibiana; Najjar, Ronza; Zayyad, Hiba; Rahav, Galia; Wiener-Well, Yonit
title: BNT162b2 vaccine breakthrough: clinical characteristics of 152 fully-vaccinated hospitalized COVID-19 patients in Israel
date: 2021-07-07
journal: Clin Microbiol Infect
DOI: 10.1016/j.cmi.2021.06.036
sha: 9b69a76152169af5a32283f212735c98990da20e
doc_id: 881977
cord_uid: 0aik5i71

OBJECTIVES: mRNA COVID-19 vaccines have shown high effectiveness in the prevention of symptomatic COVID-19, hospitalization, severe disease, and death. Nevertheless, a minority of vaccinated individuals might get infected and suffer significant morbidity. Characteristics of vaccine breakthrough infections have not been studied. We sought to portray the population of Israeli patients, who were hospitalized with COVID-19 despite full vaccination. METHODS: A retrospective multicenter cohort study of 17 hospitals included Pfizer/BioNTech's BNT162b2 fully-vaccinated patients who developed COVID-19 more than 7 days after the second vaccine dose and required hospitalization. The risk for poor outcome, defined as a composite of mechanical ventilation or death, was assessed. RESULTS: 152 patients were included, accounting for half of hospitalized fully-vaccinated patients in Israel. Poor outcome was noted in 38 patients and mortality rate reached 22% (34/152). Notable, the cohort was characterized by a high rate of comorbidities predisposing to severe COVID-19, including hypertension (108, 71%), diabetes (73, 48%), CHF (41, 27%), chronic kidney and lung diseases (37, 24% each), dementia (29, 19%), and cancer (36, 24%), and only 6 (%) had no comorbidities. Sixty (40%) of the patients were immunocompromised. Higher SARS-CoV-2 viral-load was associated with a significant risk for poor outcome. Risk also appeared higher in patients receiving anti-CD20 treatment and in patients with low titers of anti-spike IgG, but these differences did not reach statistical significance. CONCLUSIONS: We found that severe COVID-19 infection, associated with a high mortality rate, might develop in a minority of fully-vaccinated individuals with multiple comorbidities. Our patients had a higher rate of comorbidities and immunosuppression compared to previously reported non-vaccinated hospitalized COVID-19 patients. Further characterization of this vulnerable population may help to develop guidance to augment their protection, either by continued social-distancing, or by additional active or passive vaccinations.

The mRNA COVID-19 vaccines, Pfizer/BioNTech's BNT162b2 and Moderna's mRNA-1273

were 94-95% effective in preventing symptomatic COVID-19 in phase III studies, showing similar efficacy in different age groups, including persons older than 75, and persons with comorbidities [1, 2] . In Israel 839,162 cumulative COVID-19 cases (9,269/100,000) and 6, 396 deaths (70/100,000) were reported due to COVID-19 by 20.5.2021 [3] . The Israeli vaccination campaign began on 19.12.2020 and relied exclusively on BNT162b2. By 20.5.2021, more than 5.4 millions received two doses, reaching a coverage of 55% of the population, and about 88% for people older than 50y [3] . The real-life vaccine effectiveness (VE) of BNT162b2 was similar to the efficacy reported in the phase III studies [4, 5] , and had a significant impact on the local dynamics of COVID-19 [6] , with cases declining to 30 new cases/week (0.3/100,000) by May 20 th . VE was shown to be somewhat lower in people older than 70 and in those with multiple comorbidities [7] . The VE for the prevention of hospitalization due to COVID-19 was found to be 87% after the second dose in an early casecontrol study [4] , and 96% in a later comparison of person-time incidence rates from a national registry in Israel [5] . Currently, reports from other countries include a US study showing 94% effectiveness after two doses of any mRNA vaccine [8] , and two UK studies which measured an 80%-91% effectiveness for prevention of hospitalization of a single dose of BNT162b2 [9, 10] .

Data is lacking on the nature of breakthrough infections with COVID-19 vaccines. No data was published on the clinical characteristics and serologic correlates of protection of study participants who were hospitalized with COVID-19 after vaccination. Immunocompromised individuals were not included in those pivotal studies. Recent studies measured the immunogenicity of BNT162b2 in immunocompromised patients, showing significantly lower seroconversion rates and lower anti-S-IgG titers in kidney and liver transplant recipients [11, 12] and in patients with chronic lymphocytic leukemia [13] , and lower antibody titers in hemodialysis patients [14, 15] . Using a sample of hospitalized patients, we aimed to characterize vaccinated patients with breakthrough COVID-19 requiring hospitalization and define the main risk factors associated with poor outcomes in this group.

This was a multi-center cohort study of patients admitted to any of the seventeen participating hospitals. Included were patients who received two doses of BNT162b2, had a PCR-confirmed diagnosis of SARS-CoV-2 infection and were hospitalized in a COVID-19dedicated unit. As effectiveness of BNT162b2 was studied in patients more than 7 days after the second dose in most clinical studies [2, 4, 5] , either symptom-onset, the first positive PCR test or the date of admission, whichever happened first, had to be more than seven days following the second dose. Women in labor admitted to maternity wards were excluded.

Clinical data were retrieved from patients' records according to a predefined questionnaire and were entered into a de-identified database. SARS-CoV-2 PCR testing was done using various assays at participating centers, and Cycle threshold (Ct) values were reported according to specific gene-targets but were analyzed together with the lowest Ct value of any gene-target chosen to represent a surrogate for the viral load. Anti-spike antibody tests were performed locally using two available commercial kits: The Liaison SARS-CoV-2-S1/S2-IgG (Diasorin, Saluggia, Italy), with a positive cutoff of >15units/mL; and the Architect AdviseDx SARS-CoV-2-IgG-II (Abbot, Lake Forest, Illinois, USA), with a positive cutoff of >50u/mL. Viral genomic sequencing was done to identify variants of concern (VOC) on available samples, with results categorized as wildtype, B.1.1.7, B.1.351 or other VOC. COVID-19 severity was categorized according to the US National Institute of Health criteria [16] .

The primary outcome was a composite of mechanical ventilation or in-hospital death, referred to as poor outcome. Favorable outcome was defined as patients who were either discharged or were still hospitalized and not ventilated at the end of the study.

Statistical analysis: Categorical variables were compared between patients with favorable and poor outcomes using chi-square and Fisher's exact tests, and continuous variables were The study was approved by the institutional research ethics boards of each participating hospital. Due to the retrospective design, informed consent was not required.

During the study period (18.1.2021-20.4 .2021) data was reported for 152 patients from 17 general hospitals across Israel. The epidemic curve of new cases is shown in the online supplement and figure S1. The clinical data of the patients are shown in Table 1 . The median time elapsed from the 2 nd dose to admission was 39.5 days (range 8-97), and 125/152 (82%) of patients were admitted 21 days or more after vaccination, supporting the assumption that they were not infected before vaccination. The median age was 71.1 (range 22-98), most were males (107, 70%) and 38 (25%) were residents of a long-term care facility (LTCF).

Only six patients (4%) had no comorbidity. Immunosuppression was present in 60 patients (40%). Common causes of immunosuppression were chronic corticosteroid treatment, chemotherapy or anti-metabolite treatment, solid organ transplantation and anti-CD20 treatment.

In most cases the source of the patient's infection was unknown. Sixteen patients (12%) were exposed to an infected household member, 15 (11%) were exposed in healthcare settings to another patient (most in LCTF), and 1 (1%) was exposed to an infected healthcare worker.

For most patients, the indication for admission was severe COVID-19 (97, 64%). For 24 (16%) patients the severity of COVID-19 did not necessitate admission, and the patients were admitted to provide means of isolation (e.g., need for dialysis in a COVID-19 patient that could not be arranged outside of the hospital; a resident of a LTCF with no isolation capacity). In 29 patients (19%) there was a medical problem unrelated to COVID-19 that risk-factors between the groups did not identify any statistically-significant differences. Some nonsignificant differences of-note between favorable and poor outcome included a higher rate of anti-CD20 treatment (13% vs. 4%, p=0.12), cancer (32% vs. 22%, p=0.23), CHF (34% vs. 25%, p=0.25) and dementia (26% vs. 17%, p=0. 19) in the poor outcome group.

Measurement of anti-S-IgG titers after admission were available for 69 patients, using two different kits. In both, the median titer was lower for patients with a poor outcome: Liaison - Six patients had no comorbidities. Their average age was 60 years (range 42-85), and none were LTCF residents. Three of them presented with severe COVID-19 but had a good outcome after treatment with oxygen and corticosteroids. Two were admitted due to vestibular neuritis, and one due to chest pain. Viral sequencing was performed on 5 of them, with B.1.1.7 detected.

A repeat comparative analysis between favorable and poor outcome groups including only patients that were admitted with severe COVID-19, excluding other reasons for hospitalization, yielded similar findings (Table 1) .

This study includes a detailed description of 152 mRNA COVID-19-vaccinated individuals who presented with a significant breakthrough infection leading to hospitalization. All these patients had their disease onset 8 days or more after their 2 nd vaccine dose, and in most much later, with a median time to admission exceeding one month.

The clinical profile of the patients is typical of other COVID-19 hospitalized patients, being elderly males and having high rates of comorbidities linked to COVID-19 severity. Nevertheless, comorbidities were more common in patients with vaccine breakthrough infections compared to large case-series on unvaccinated hospitalized patients (see Table 2 ), including diabetes (48% vs. 27.9-34.7%), hypertension (71% vs. 43.5-62%), heart failure (28% vs. 5.8-12.8%), chronic lung diseases (24% vs. 7.4-16.5%), chronic kidney disease (32% vs. 12.7-22.8%), and cancer (24% vs. 4.8-10.8%) [17] [18] [19] . Furthermore, 96% of the patients had at least one comorbidity. Of six patients with no comorbidity, only three had severe COVID-19, with a favorable outcome. The high rate of comorbidities might be explained by a lower VE in patients with comorbidities, by the risk of comorbidities exacerbation after breakthrough infection, or by both. Immunosuppression in our cohort was common, with 40% of patients having any type, including a corticosteroid, chemotherapy and anti-CD20 treatments, and recipients of organ transplants. This fact is both expected, and in agreement with the lower immunogenicity findings of immunocompromised individuals after vaccination. Immunosuppression was not associated with a worse outcome, except for anti-CD20 treatment, which had a threefold higher odds-ratio to be in the poor outcome group (13% vs. 4%, p=0. 12) , but the small number of patients could preclude significant comparison of subgroups.

The mortality rate in the cohort was similar to unvaccinated hospitalized COVID-19 patients [20] . We could not find a statistically-significant risk-factor for a poor outcome, defined as mechanical ventilation or in-hospital death, except for a higher upper-respiratory viral load, as represented by a lower Ct value. As our cohort included patients who were admitted due to different reasons, an analysis including only patients whose reason for admission was severe COVID-19 was also performed, with similar findings.

Anti-S-IgG assays were developed and validated for the diagnosis of SARS-CoV-2 infection.

They can be used to measure the serological response to vaccination, although no correlate of protection has been identified so far. The two assays used in our cohort have a good correlation with neutralizing antibody titers [21, 22] . Results of anti-S-IgG were available for 69 patients, with two assays. These results do not represent titers achieved postvaccination, as they were measured after SARS-CoV-2 infection, with a median of seven days after symptom onset. Therefore, they might represent the host ability for an early serological response to infection. Overall, results were variable, with titers ranging from below threshold to high titers beyond the assay's upper reporting limit. Patients with poor outcomes had a lower median titer in both assays, but these differences did not reach statistical significance. protection. The number of patients in the cohort was too small for some of the comparisons between favorable and poor outcomes, specifically for some risk factors that seemed to be more common in patients with poor outcome such as different comorbidities, types of immunosuppression and antibody titers. In view of the impact of the successful Israeli vaccination campaign, it is not expected that a significant additional number of vaccinated patients with similar severe breakthrough infection will be available for analysis soon. More data from countries with ongoing COVID-19 might be needed. poor outcomes: (a) Diasorin's Liaison SARS-CoV-2 S1/S2 IgG (cutoff for positivity of >15u/mL). One result was omitted from the chart as an outlier, of a patient with a favorable outcome, whose antibody titer was estimated to be 2650u/mL using dilutions, as the upper limit of reporting for the assay is 400u/mL. (b) Abbott's Architect AdviseDx SARS-CoV-2 IgG II, (cutoff for positivity of 50u/mL).

For both charts the horizontal line and box represent the median and the interquartile range, respectively. The width of the curved shape represents the proportion of patients.

J o u r n a l P r e -p r o o f 

Karagiannidis et al. [17] Myers et al. [18] Petrilli et al. [19] Number of patients J o u r n a l P r e -p r o o f 

Online supplement

Patients with breakthrough COVID-19 that were not included in this cohort study

Not included in the cohort were patients admitted to non-participating hospitals, patients admitted to LTCF's that are considered as hospitals by the IMOH, and patients hospitalized with COVID-19 without knowledge of their vaccination status at time the of admission.

The incidence of new admissions reflected the national epidemic curve for COVID-19 ( Figure   S1 ). As the vaccination campaign began in the middle of December 2020, fully-vaccinated individuals increased in numbers from the 3rd week of January 2021, followed by an increase in the number of hospitalized vaccinees. Cases declined with the national decline in incidence. The orange area represents the weekly number of new PCR-proven COVID-19 patients in

Efficacy and Safety of the mRNA-1273 SARS-CoV-2 Vaccine

Safety and Efficacy of the BNT162b2 mRNA Covid-19 Vaccine

BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting

Nationwide vaccination campaign with BNT162b2 in Israel demonstrates high vaccine effectiveness and marked declines in incidence of SARS-CoV-2 infections and COVID-19 cases, hospitalisations, and deaths

COVID-19 dynamics after a national immunization program in Israel

Correspondence: BNT162b2 mRNA Covid-19 Vaccine in a Nationwide Mass Vaccination Setting

Effectiveness of Pfizer-BioNTech and Moderna Vaccines Against COVID-19 Among Hospitalized Adults Aged ≥ 65 Years -United States

Interim findings from first-dose mass COVID-19 vaccination roll-out and COVID-19 hospital admissions in Scotland: a national prospective cohort study

Early J o u r n a l P r e -p r o o f CLM-21-21243 effectiveness of COVID-19 vaccination with BNT162b2 mRNA vaccine and ChAdOx1 adenovirus vector vaccine on symptomatic disease, hospitalisations and mortality in older adults in England

Reduced humoral response to mRNA SARS-Cov-2 BNT162b2 vaccine in kidney transplant recipients without prior exposure to the virus

Low immunogenicity to SARS-CoV-2 vaccination among liver transplant recipients

Efficacy of the BNT162b2 mRNA COVID-19 Vaccine in Patients with Chronic Lymphocytic Leukemia

Antibody response to mRNA SARS-CoV-2 vaccine among dialysis patients -a prospectivecohort study

Humoral Response to the Pfizer BNT162b2 Vaccine in Patients Undergoing Maintenance Hemodialysis

19 treatment guidelines: Clinical Spectrum of SARS-CoV-2 Infection

Case characteristics, resource use, and outcomes of 10 021 patients with COVID-19 admitted to 920 German hospitals: an observational study

Characteristics of Hospitalized Adults With COVID-19 in an Integrated Health Care System in California

Factors associated with hospital admission and critical illness among 5279 people with

coronavirus disease 2019 in New York City: prospective cohort study

Factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in New York City: prospective cohort study

LIAISON ® SARS-CoV-2 S1/S2 IgG Factsheet n

SARS-CoV-2 seroprevalence and neutralizing activity in donor and patient blood from the San Francisco Bay Area

Emerging sars-cov-2 variants and impact in global vaccination programs against sars-cov-2/covid-19

Novavax COVID-19 Vaccine Demonstrates 89.3% Efficacy in UK Phase 3 Trial

Evidence for increased breakthrough rates of SARS-CoV-2 variants of concern in BNT162b2 mRNA vaccinated individuals

South African Variant Found in About 1% of All Positive Tests