Abstract
Introduction
In United States, health care workers have been immersed in the COVID-19 pandemic since February 2020. Since availability of COVID-19 vaccines, there is limited literature investigating the incidence of unknown COVID-19 infections in physicians and Advanced Practitioner Providers (APPs) working in emergency departments (EDs). The primary objective is to determine the incidence unknown COVID-19 infection within a cohort of emergency physicians (EPs) and APPs.
Methods
Prospective observational study at a tertiary academic center with emergency medicine residency and 64,000 annual ED visits. EPs/APPs providing care to ED patients over the prior 12 months were eligible. Serum samples were collected between May 1 and June 30, 2022. Analysis utilized Luminex xMAP® SARS-CoV-2 Multi-Antigen IgG Assay for antibodies to Nucleocapsid, Receptor-binding domain, and Spike subunit 1. Mean Fluorescent Intensity (MFI) ≥ 700 was considered positive. Subjects completed 12 question survey assessing demographics and previously confirmed COVID-19 infection. Fisher's exact test evaluated associations of demographics and clinical characteristics with confirmed COVID-19 status. Analyses performed using SAS, Version 9.4. P < 0.05 considered statistically significant.
Results
Sixty-nine of 81 eligible subjects (85.2%) participated, 58.0% were male, 97.1% white, with mean age of 37. Eighteen subjects had MFI ≥ 700 strongly suggestive of prior infection, with 17.7% unknown. No statistically significant difference between age, gender, race, children in home, or household member with previously COVID-19 infection.
Conclusion
Unknown previous COVID-19 infection was less then expected in this cohort of EPs/APPs, and no association with individual characteristics, previously infected household member, or children in the home.
Keywords: COVID-19, SARS-CoV-2, Antibodies, Infection, Emergency medicine
1. Introduction
The United States (US) COVID-19 pandemic began in February of 2020, consisting of several waves of increased infection, hospitalization, and mortality rates. Emergency department providers (EDPs) including physicians, residents, and Advanced Practice Providers (APPs) have experienced some of the highest exposure rates with individuals infected with the SARS-CoV-2 virus. Studies following the initial wave of infections suggested confirmed positive rates in physicians and APPs ranging from 5 to 40% [1,2]. Following the availability of COVID-19 vaccines in December of 2020, the incidence of infection in health care workers (HCWs) had significantly decreased. Data from a recent systematic review and meta-analysis reported confirmed rates of 9–11% amongst HCWs in general but did not specify the prevalence in EDPs [3].
Evidence consistently suggests that fully vaccinated individuals experienced good protection from severe disease and death due to the SARS-CoV-2 variants that predominated the first three waves of the pandemic (Alpha, Beta, and Delta) [4]. In December 2021, the SARS-CoV-2 B.1.1.529 (Omicron) variant emerged and overtook Delta as the predominant variant. Studies evaluating serum samples in vaccinated individuals demonstrated lower titers of neutralizing antibodies against Omicron compared to the previous three predominate variants. In addition, those previously infected with COVID-19 had low or even undetectable titers against Omicron [5,6]. This supports the much more transmissible and infectious pattern that Omicron has demonstrated [7]. Fortunately, Omicron and its variants' severity of disease and mortality rates have been less than the previous strains. In fully vaccinated individuals, breakthrough infections are comparable to minor common cold infections with symptoms lasting for 4–6 days, and numerous confirmed cases with minimal or no symptoms [8].
As of March 2022, the incidence of new COVID-19 infections declined dramatically throughout the US. At the initiation of this study, the Emergency Department (ED) had a total of 11 PCR confirmed COVID-19 infections amongst the EDP group (n = 81). Two cases occurred during the initial “Omicron wave”, while the remaining 9 within the prior 12 months. Investigators of this study hypothesize there have been many more unconfirmed COVID-19 infections amongst our EDP group.
With developments in laboratory testing, we utilized a SARS-CoV-2 multi-antigen antibody assay to distinguish between serum antibodies acquired from natural infection versus those from vaccination. Specifically, nucleocapsid (N) antibodies are a unique marker for natural infection, while the Receptor-binding domain (RBD) is the target of SARS-CoV-2 vaccines [9]. Therefore, the primary objective of this study is to determine the incidence of unknown COVID-19 infection within our cohort of EDPs by analyzing their blood for natural versus vaccine acquired immunity.
2. Materials and methods
This was a prospective observational study, evaluating human serum for the presence of SARS-CoV-2 antibodies and individual characteristics and demographics amongst a cohort of EDPs, and received approval from the local Institutional Review Board.
This study was conducted at a level I trauma center with an emergency medicine residency and approximately 64,000 annual ED patient visits. The ED consists of 44 beds with an additional 9 patient care areas in a separate low acuity area. Subjects were considered attending emergency physicians, emergency medicine residents/fellows, and APPs. All study participants provided care to COVID-19 patients on a regular basis over the 12 months prior to study enrollment. Eligible subjects were initially invited to participate via email. Those responding with interest were met on an individual basis and underwent informed written consent.
Participants underwent a 3 ml venous blood draw. In addition, subjects were asked to complete a 12-question survey including descriptive variables, vaccination status, prior PCR confirmed COVID-19 infection, known positive household members, amongst other questions displayed in Fig. 1 . Subjects were consecutively enrolled from April 21, 2022, to June 30, 2022. Samples were centrifuged for 15 min at 7000 RPM, then stored per the manufacturer's instructions until the assays were performed in July 2022.
Fig. 1.
Survey for emergency medicine providers undergoing SARS-CoV-2 serum antibody analysis.
The primary objective was to determine the incidence of unknown COVID-19 infection amongst this cohort of EDPs. Secondary analysis evaluated for significant statistical differences in the combined group with prior natural infection (known and unknown) versus those who did not, and between the known and unknown individuals previously infected with COVID-19. Variables included: age, gender, race, clinical position, vaccination status, confirmed COVID-19 in prior 12 months, presumed but unconfirmed COVID-19, household member with confirmed COVID-19 in prior 12 months, and school-age children in household.
2.1. Luminex xMAP® SARS-CoV-2 Multi-Antigen IgG Assay
The Luminex xMAP® SARS-CoV-2 Multi-Antigen IgG Assay (RUO; # 30–00127) is a multiplex, microsphere-based assay that detects the presence of IgG antibodies against three different SARS-CoV-2 antigens- N, RBD, and Spike subunit 1 (S1)) from serum or plasma. Manufacturer-designated threshold values were 700 MFI for the qualitative detection of N and RBD targets and 300 MFI for the background for all lots used. Clinical specimens that are positive for both N and RBD targets are considered positive for infection with COVID-19. A positive RBD antibody result in the absence of nucleocapsid detection is consistent with an immune response to a SARS-CoV-2 vaccine. Antibody levels detected were plotted using GraphPad Prism version 9.4.1.
2.2. Primary data analysis
Counts, and percentages were used to summarize the demographic and clinical characteristics of the providers. Fisher's exact test was used to look at the association of demographic and clinical characteristics with assay results dichotomized at 700 MFI and those ≥700 (n = 18). All analyses were done using SAS, Version 9.4. P < 0.05 was considered statistically significant.
3. Results
Ultimately, 69 of the 81 eligible subjects (85.2%) agreed to participate. Of these, 58.0% were male, 97.1% white, and mean age was 37 years. Thirty-four (49.3%) of the subjects were emergency medicine residents/fellows, 31 (44.9%) emergency medicine attendings, and 4 (5.8%) APPs (Table 1 ). Eighteen individuals displayed an MFI ≥ 700 for N, strongly suggestive of prior natural COVID-19 infection. Eleven were unknown, providing a cumulative incidence of 17.7% (11 out of 62) in which the provider was unaware of their COVID-19 infection. Of the 11 individuals with confirmed COVID-19 infection in the prior 12 months, only 7 (63.6%) had an MFI ≥ 700 for N, demonstrating their prior infection. Fifteen individuals presumed (not confirmed) they had been infected with the SARS-CoV-2 virus within the prior 12 months, where only 4 (26.7%) displayed an MFI ≥ 700 for N. When comparing those with an MFI dichotomized at 700, there was no significant difference between age, gender, race, position, children in the home, or household member with confirmed COVID-19 infection in the prior 12 months. The only statistically significant association was in those with previously confirmed COVID-19 infection (p = 0.0049; Table 1). In comparing the combined group with an MFI ≥ 700 for N, there were no significantly distinguishing demographic or clinical characteristics (Table 2 ). All individuals displayed an MFI ≥ 700 for RBD regardless of their nucleocapsid response. This suggests that those without evidence of prior COVID-19 infection (MFI < 700 for N) were still retaining a significant level of antibodies from their prior vaccinations, with a mean time of 7 months and up to 12 months since last vaccine. Of note, all subjects had received at least two vaccinations and most a third. Fig. 2 demonstrates the varying degrees of N and RBD antibody levels (MFI) for each of the subjects enrolled. In addition, it is important to note that all subjects answered “yes” to the final question of survey, asking if they felt they had access to appropriate personal protective equipment (PPE) over the prior 12 months (Fig. 1 ).
Table 1.
Comparisons of patient and clinical characteristics with assay >700 status (natural infection) and <700 (no natural infection) Status.
|
Nucleocapsid cut point 700 |
||||
|---|---|---|---|---|
|
<700 (N=51) |
≥ 700 (N=18) |
Total (N=69) |
P-value | |
| Gender, n (%) | 0.78891 | |||
| Male | 29 (56.9%) | 11 (61.1%) | 40 (58.0%) | |
| Female | 22 (43.1%) | 7 (38.9%) | 29 (42.0%) | |
| Race, n (%) | 1.00001 | |||
| White | 49 (96.1%) | 18 (100.0%) | 67 (97.1%) | |
| Latino/Hispanic | 1 (2.0%) | 0 (0.0%) | 1 (1.4%) | |
| Other | 1 (2.0%) | 0 (0.0%) | 1 (1.4%) | |
| Position, n (%) | 0.32191 | |||
| PGY1 | 8 (15.7%) | 4 (22.2%) | 12 (17.4%) | |
| PGY2 | 10 (19.6%) | 1 (5.6%) | 11 (15.9%) | |
| PGY3 | 8 (15.7%) | 3 (16.7%) | 11 (15.9%) | |
| Fellow | 0 (0.0%) | 1 (5.6%) | 1 (1.4%) | |
| APP | 4 (7.8%) | 0 (0.0%) | 4 (5.8%) | |
| Attending physician | 21 (41.2%) | 9 (50.0%) | 30 (43.5%) | |
| Vaccination Status, n (%) | 0.44601 | |||
| two mRNA-1 | 1 (2.0%) | 1 (5.9%) | 2 (3.0%) | |
| two mRNA + mRNA booster | 49 (98.0%) | 16 (94.1%) | 65 (97.0%) | |
| two mRNA + J&J booster | 0 (0.0%) | |||
| J&J with J&J booster | 0 (0.0%) | |||
| Missing | 1 | 1 | 2 | |
| Confirmed COVID w/in 12 mths, n (%) | 0.00491 | |||
| Yes | 4 (7.8%) | 7 (38.9%) | 11 (15.9%) | |
| No | 47 (92.2%) | 11 (61.1%) | 58 (84.1%) | |
| Presumed COVID w/in 12 mths, n (%) | 0.74611 | |||
| Yes | 11 (21.6%) | 5 (27.8%) | 16 (23.2%) | |
| No | 40 (78.4%) | 13 (72.2%) | 53 (76.8%) | |
| Children in home, n (%) | 0.78291 | |||
| Yes | 20 (39.2%) | 8 (44.4%) | 28 (40.6%) | |
| No | 31 (60.8%) | 10 (55.6%) | 41 (59.4%) | |
| Household member with confirmed COVID, n (%) | 0.51441 | |||
| Yes | 10 (19.6%) | 5 (27.8%) | 15 (21.7%) | |
| No | 41 (80.4%) | 13 (72.2%) | 54 (78.3%) | |
| Appropriate Access to PPE, n (%) | ||||
| Yes | 51 (100.0%) | 18 (100.0%) | 69 (100.0%) | |
Fisher Exact p-value.
Table 2.
Comparisons with Assay > 700, Natural Infection Group (previosly confirmed vs. unknown).
|
Confirmed COVID w/in 12 mths |
||||
|---|---|---|---|---|
|
Yes (N=7) |
No (N=11) |
Total (N=18) |
P-value | |
| Gender, n (%) | 1.00001 | |||
| Male | 4 (57.1%) | 7 (63.6%) | 11 (61.1%) | |
| Female | 3 (42.9%) | 4 (36.4%) | 7 (38.9%) | |
| Race, n (%) | ||||
| White | 7 (100.0%) | 11 (100.0%) | 18 (100.0%) | |
| Position, n (%) | 0.20361 | |||
| PGY1 | 0 (0.0%) | 4 (36.4%) | 4 (22.2%) | |
| PGY2 | 1 (14.3%) | 0 (0.0%) | 1 (5.6%) | |
| PGY3 | 2 (28.6%) | 1 (9.1%) | 3 (16.7%) | |
| Fellow | 0 (0.0%) | 1 (9.1%) | 1 (5.6%) | |
| Attending physician | 4 (57.1%) | 5 (45.5%) | 9 (50.0%) | |
| Vaccination Status, n (%) | 0.64051 | |||
| two mRNA-1 | 1 (14.3%) | 0 (0.0%) | 1 (5.6%) | |
| two mRNA + mRNA booster | 6 (85.7%) | 10 (90.9%) | 16 (88.9%) | |
| J&J with J&J booster | 0 | 1 (9.1%) | 1 (5.6%) | |
| Presumed COVID w/in 12 mths, n (%) | 0.59561 | |||
| Yes | 1 (14.3%) | 4 (36.4%) | 5 (27.8%) | |
| No | 6 (85.7%) | 7 (63.6%) | 13 (72.2%) | |
| Children in home, n (%) | 1.00001 | |||
| Yes | 3 (42.9%) | 5 (45.5%) | 8 (44.4%) | |
| No | 4 (57.1%) | 6 (54.5%) | 10 (55.6%) | |
| Household member with confirmed COVID, n (%) | 0.32601 | |||
| Yes | 3 (42.9%) | 2 (18.2%) | 5 (27.8%) | |
| No | 4 (57.1%) | 9 (81.8%) | 13 (72.2%) | |
| Appropriate Access to PPE, n (%) | ||||
| Yes | 7 (100.0%) | 11 (100.0%) | 18 (100.0%) | |
Fisher Exact p-value.
Fig. 2.
SARS-CoV-2 antibody levels in 69 Emergency Medicine Providers (EMP). Serum collected from EMPs was analyzed using a multi-antigen assay to determine the Mean Fluorescent Intensity (MFI) of Nucleocapsid (N; blue bar) and Receptor-Binding Domain (RBD; orange bar) levels. Nucleocapsid antibodies are a unique marker for COVID-19 infection, while RBD antibodies can be from COVID-19 infection and post-vaccination for SARS-CoV-2. Nucleocapsid levels (MFI) superimposed on RBD MFI detected; the dotted line (700 MFI) represents the threshold for a positive antibody response (GraphPad Prism version 9.4.1). (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)
4. Discussion
The primary purpose of this study was to determine the incidence of unknown COVID-19 infection amongst a cohort of EDPs, who had provided regular care in an ED to patients infected with the SARS-CoV-2 virus. With an 85.2% participation rate, the results of our serum antibody analysis suggested that 26.1% of the subjects had previously been infected, and 17.7% of those individuals had never received a COVID-19 test that resulted positive. In addition, 24.2% (15 of 62) of our study population presumed they had recently been infected, whereas only 26.7% (4 of 15) had MFI levels suggesting they truly had.
To our knowledge, this is the first study to investigate this question specifically amongst EDPs providing care to COVID-19 infected individuals post vaccination roll-outs. Early in the COVID-19 pandemic, there were several studies that evaluated for the presence of SAR-CoV-2 antibodies in HCWs, reporting a prevalence ranging from 5 to 42% [[1], [2], [3],10]. Important to note that this was a time many institutions lacked appropriate PPE. Post emergence of COVID-19 vaccinations, there were diminished studies reporting on this topic, possibly due to the lack of assays available to distinguish between antibodies from natural versus acquired immunity.
At the initiation of this study, Omicron and its subsequent variants had been the predominant SARS-CoV-2 strain in our region for the prior 4–6 months at the end of enrollment. Numerous recent studies have described the increased infectivity of Omicron subvariants, suggesting three to ten times compared to Delta and its previous variants [11,12]. Additionally, Omicron subvariants have consistently demonstrated their ability to evade neutralizing antibodies in those who had received three prior mRNA vaccines, as well as those with antibodies acquired from natural infection preceding the initial Omicron wave [6,11,[13], [14], [15]]. Fortunately, lower respiratory involvement and severity of disease had decreased, resulting in fewer hospitalizations throughout the country [11,15]. Towards the end of January 2022, our institution had over 500 hospital employees on home quarantine due to acute COVID-19 infection and our system had greater than a 99% full vaccination rate, yet our number of COVID-19 units decreased from six to two within two months.
Due to the previously described characteristics of the Omicron subvariants and the high degree of COVID-19 exposure experienced by EDPs, we hypothesized that the unknown incidence of infection would be higher than 17.7%. One explanation is that this institution fortunately never experienced a shortage of PPE, which was supported by our survey data.
More intriguing is the numerous individuals who had measurable MFIs for the nucleocapsid but did not reach the threshold of 700 MFI to accurately report they had experienced a previous COVID-19 infection. It has been previously demonstrated that it can take up to two weeks to develop antibodies following acute infection, and >90% of them by end of one month [[16], [17], [18]]. Therefore, many of our subjects may have experienced recent unknown infection, but the duration of time between their exposure and blood draw was not sufficient to surmount a significant response. An alternative explanation is that these individuals had previously been infected, but their antibody levels had diminished below the assay threshold at the time of their serum analysis.
Finally, all of our subjects had MFI levels RBD ≥ 700 regardless of reaction to the nucleocapsid. Prior studies have suggested that even following a booster, antibody levels may begin to wane as early as three and commonly by six months [15,18,19]. This is encouraging within our cohort of providers considering that the mean time since their last booster was seven months, which may have contributed to our lower-than-expected incidence of prior infection.
4.1. Limitations
Although, we did enroll 85% of the eligible subjects, data from the remaining 12 EDPs could have affected our findings. Our subjects were predominantly white with a mean age of 37, therefore our findings may not extrapolate to other cohorts of EDPs. Another limitation is the self-reporting of presumed past COVID-19 and the possibility of asymptomatic infection in a healthy cohort of HCWs. Finally, during enrollment our institution was experiencing a high patient positive rate and some subjects may have a recent COVID-19 infection but had inadequate time to mount an antibody response, therefore underrepresented our reported incidence of unknown infections.
5. Conclusion
This study demonstrated a less than expected incidence of unknown COVID-19 infection in a cohort of EDPs working at a large tertiary academic center. There was no significant correlation with subject characteristics, previous confirmed infection in household members, or presence of school age children in the home. However, these data are encouraging and support the utility of adequate access to PPE and SARS-CoV-2 vaccination in the reduction of COVID-19.
Author contributions
ANB: Study concept/design, acquisition of the data, analysis/interpretation data, drafting and revisions of manuscript.
MGW: Study concept/design, analysis/interpretation data, drafting and revisions of manuscript.
CEB: Study concept/design, acquisition of the data, analysis/interpretation data, revisions of manuscript.
BZ: Study design, acquisitions of data, drafting and revisions of manuscript.
EL: Analysis/interpretation data, statistical expertise, revisions of manuscript.
TTN: Study concept/design, acquisition of the data, analysis/interpretation data, drafting and revisions of manuscript.
AH: Acquisition of the data, analysis/interpretation data, revisions of manuscript.
SK: Study concept/design, analysis/interpretation data, revisions of manuscript.
JH: Study concept/design, analysis/interpretation data, drafting and revisions of manuscript.
WGZ: Study concept/design, analysis/interpretation data, drafting and revisions of manuscript.
MCW: Study concept/design, analysis/interpretation data, drafting and revisions of manuscript.
Conflicts of interest and funding
None.
CRediT authorship contribution statement
Aaron Nathan Barksdale: Conceptualization, Data curation, Formal analysis, Investigation, Methodology, Resources, Supervision, Writing – original draft, Writing – review & editing. Macy G. Wood: Formal analysis, Methodology, Resources, Writing – review & editing. Chad E. Branecki: Conceptualization, Data curation, Investigation, Writing – review & editing. Brooklin Zimmerman: Conceptualization, Data curation, Investigation, Writing – review & editing. Elizabeth Lyden: Conceptualization, Formal analysis, Writing – review & editing. Thang T. Nguyen: Conceptualization, Data curation, Methodology, Writing – review & editing. Andrew Hatfield: Data curation, Investigation, Methodology, Writing – review & editing. Scott Koepsell: Conceptualization, Methodology, Writing – review & editing. Jason Langenfeld: Conceptualization, Methodology, Writing – review & editing. Wesley G. Zeger: Conceptualization, Methodology, Writing – review & editing. Michael C. Wadman: Conceptualization, Methodology, Supervision, Writing – review & editing.
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