
==== Front
PLoS One
PLoS One
plos
PLOS ONE
1932-6203
Public Library of Science San Francisco, CA USA

10.1371/journal.pone.0307805
PONE-D-23-33035
Research Article
Medicine and Health Sciences
Medical Conditions
Infectious Diseases
Infectious Disease Control
Vaccines
Medicine and Health Sciences
Medical Conditions
Infectious Diseases
Viral Diseases
Covid 19
Biology and life sciences
Organisms
Viruses
RNA viruses
Coronaviruses
SARS coronavirus
SARS CoV 2
Biology and life sciences
Microbiology
Medical microbiology
Microbial pathogens
Viral pathogens
Coronaviruses
SARS coronavirus
SARS CoV 2
Medicine and health sciences
Pathology and laboratory medicine
Pathogens
Microbial pathogens
Viral pathogens
Coronaviruses
SARS coronavirus
SARS CoV 2
Biology and life sciences
Organisms
Viruses
Viral pathogens
Coronaviruses
SARS coronavirus
SARS CoV 2
Biology and Life Sciences
Immunology
Vaccination and Immunization
Medicine and Health Sciences
Immunology
Vaccination and Immunization
Medicine and Health Sciences
Public and Occupational Health
Preventive Medicine
Vaccination and Immunization
Medicine and Health Sciences
Diagnostic Medicine
Virus Testing
Medicine and Health Sciences
Medical Conditions
Infectious Diseases
Infectious Disease Control
Vaccines
Booster Doses
Medicine and Health Sciences
Pathology and Laboratory Medicine
Serology
Biology and Life Sciences
Physiology
Immune Physiology
Antibodies
Biology and Life Sciences
Immunology
Immune System Proteins
Antibodies
Medicine and Health Sciences
Immunology
Immune System Proteins
Antibodies
Biology and Life Sciences
Biochemistry
Proteins
Immune System Proteins
Antibodies
Primary series COVID-19 vaccine effectiveness among health care workers in the country of Georgia, March–December 2021
Primary series COVID-19 vaccine effectiveness among health care workers in Georgia, March–December 2021
https://orcid.org/0000-0002-5532-7276
Katz Mark A. Conceptualization Funding acquisition Investigation Methodology Project administration Resources Supervision Visualization Writing – original draft Writing – review & editing 1 *
https://orcid.org/0000-0001-7006-7946
Rojas Castro Madelyn Yiseth Conceptualization Data curation Formal analysis Methodology Validation Visualization Writing – review & editing 2
Chakhunashvili Giorgi Conceptualization Data curation Investigation Methodology Project administration Supervision Validation Visualization Writing – review & editing 3
Chitadze Nazibrola Investigation Methodology Project administration Writing – review & editing 3
Ward Caleb L. Data curation Investigation Project administration Validation Writing – review & editing 4
McKnight C. Jason Conceptualization Methodology Validation Writing – review & editing 5
https://orcid.org/0000-0003-3080-9794
Lucaccioni Héloïse Conceptualization Investigation Methodology Project administration Validation Writing – review & editing 6
Finci Iris Data curation Methodology Project administration Supervision Validation Writing – review & editing 1
Zardiashvili Tamila Conceptualization Funding acquisition Project administration Writing – review & editing 7
Pebody Richard Conceptualization Funding acquisition Methodology Supervision Writing – review & editing 1
Kissling Esther Conceptualization Data curation Formal analysis Methodology Supervision Validation Writing – review & editing 2
Sanodze Lia Conceptualization Data curation Funding acquisition Investigation Methodology Project administration Resources Supervision Validation Writing – review & editing 3
1 World Health Organization Regional Office for Europe, Copenhagen, Denmark
2 Epiconcept, Paris, France
3 National Center for Disease Control and Public Health, Tbilisi, Georgia
4 Public Health Institute, Tbilisi, Georgia
5 South Caucasus Hub, World Health Organization Regional Office for Europe, Tbilisi, Georgia
6 European Programme for Intervention Epidemiology Training, European Centre for Disease Prevention and Control, Stockholm, Sweden
7 WHO Country Office in Georgia, Tbilisi, Georgia
Lau Eric HY Editor
The University of Hong Kong, CHINA
Competing Interests: None of the authors report any conflicts of interest.

* E-mail: katzm@who.int
6 9 2024
2024
19 9 e030780527 10 2023
12 7 2024
© 2024 Katz et al
2024
Katz et al
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Background

Healthcare workers (HCWs) have suffered considerable morbidity and mortality during the COVID-19 pandemic. Few data on COVID-19 vaccine effectiveness (VE) are available from middle-income countries in the WHO European Region. We evaluated primary series COVID-19 VE against laboratory-confirmed COVID-19 among HCWs in Georgia.

Methods

HCWs in six hospitals in Georgia were invited to enroll in a prospective cohort study conducted during March 19–December 5, 2021. Participants completed weekly symptom questionnaires. Symptomatic HCWs were tested by RT-PCR and/or rapid antigen test (RAT), and participants were routinely tested for SARS-CoV-2 by RT-PCR or RAT, regardless of symptoms. Serology was collected at enrolment, and quarterly thereafter, and tested by electrochemiluminescence immunoassay for SARS-CoV-2 antibodies. We defined primary series vaccination as two doses of COVID-19 vaccine received ≥14 days before symptom onset. We estimated VE as (1-hazard ratio)*100 using a Cox proportional hazards model with vaccination status as a time-varying covariate. Estimates were adjusted by potential confounders that changed the VE estimate by more than 5%, according to the change-in-estimate approach.

Results

Overall, 1561/3849 (41%) eligible HCWs enrolled and were included in the analysis. The median age was 40 (IQR: 30–53), 1318 (84%) were female, and 1003 (64%) had laboratory evidence of prior SARS-Cov-2 infection. At enrolment, 1300 (83%) were unvaccinated; By study end, 1082 (62%) had completed a primary vaccine series (69% BNT162b2 (Pfizer-BioNTech); 22% BBIBP-CorV (Sinopharm); 9% other). During the study period, 191(12%) participants had a new PCR- or RAT-confirmed symptomatic SARS-CoV-2 infection. VE against PCR- or RAT- confirmed symptomatic SARS-CoV-2 infection was 58% (95%CI: 41; 70) for all primary series vaccinations, 68% (95%CI: 51; 79) for BNT162b2, and 40% (95%CI: 1; 64) for BBIBP-CorV vaccines. Among previously infected HCWs, VE was 58% (95%CI: 11; 80). VE against medically attended COVID-19 was 52% (95%CI: 28; 68), and VE against hospitalization was 69% (95% CI: 36; 85). During the period of predominant Delta variant circulation (July-December 2021), VE against symptomatic COVID-19 was 52% (95%CI: 30; 66).

Conclusions

Primary series vaccination with BNT162b2 and BBIBP-CorV was effective at preventing COVID-19 among HCWs, most of whom had previous infection, during a period of mainly Delta circulation. Our results support the utility of COVID-19 primary vaccine series, and the importance of increasing coverage, even among previously infected individuals.

http://dx.doi.org/10.13039/100004423 World Health Organization https://orcid.org/0000-0002-5532-7276
Katz Mark A. http://dx.doi.org/10.13039/100000030 Centers for Disease Control and Prevention Cooperative Agreement No.: NU2GGH002093) https://orcid.org/0000-0002-5532-7276
Katz Mark A. Public Health Institute https://orcid.org/0000-0002-5532-7276
Katz Mark A. This study was supported by funding from the World Health Organization/European Regional Office, the US Centers for Disease Control and Prevention (Cooperative Agreement No.: NU2GGH002093), and the Public Health Institute. WHO/European Regional office staff were involved in study design, data collection and analysis, decision to publish, and preparation of the manuscript. The US CDC and the Public Health Institute had no role in in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Three authors (GC, NC, and LS) received stipends from the funding institutions in order to carry out the study in Georgia. Data AvailabilityAll relevant data are within the manuscript and its Supporting information files. Data beyond what is included in the manuscript cannot be shared publicly because public deposition would breach compliance with the protocol, and the informed consent form, approved by the two research ethics boards that reviewed the protocol.
OutbreaksCOVID-19
Data Availability

All relevant data are within the manuscript and its Supporting information files. Data beyond what is included in the manuscript cannot be shared publicly because public deposition would breach compliance with the protocol, and the informed consent form, approved by the two research ethics boards that reviewed the protocol.
==== Body
pmcIntroduction

Health care workers (HCWs) have suffered high rates of morbidity and mortality during the COVID-19 pandemic [1]. During the COVID pandemic and all pandemics, it is critical to protect the health of HCWs for a number of reasons; [2–4] first, in order to ensure the continuous functioning of the healthcare system, a critical essential service in the pandemic response, and one which is particularly challenging in resource-poor healthcare systems in low- and middle-income countries (LMICs). [5]; second, HCWs may have greater likelihood of getting infected with SARS-CoV-2 and other pathogens compared to the general population because of their close contact with infected patients; third, infected HCWs in healthcare settings risk transmitting viruses to vulnerable patients; finally, protecting HCWs is important because of the principle of reciprocity; through their vital front-line role in the pandemic response, HCWs put themselves at risk and also potentially put their households at higher risk for the sake of others [4].

In addition, HCWs play a vital role in the planning, coordination and execution of vaccination campaigns in high-income countries and LMICs. Population-wide COVID-19 vaccination campaigns have been shown to reduce pressure on the healthcare systems [6].

COVID-19 vaccine has been a critical intervention to reduce both morbidity and mortality during the pandemic. Since late 2020, when global vaccine distribution began, nearly 13.5 billion COVID-19 vaccine doses have been administered worldwide [7]. In the first year after their introduction, COVID-19 vaccines were estimated to have saved nearly 20 million lives globally [8], and over 440,000 lives among persons ≥ 60 years old in Europe [9].

Understanding COVID-19 vaccine effectiveness is critical to inform national and international vaccination guidelines. However, despite the extensive use of COVID-19 vaccines in LMICs, few VE studies have been conducted in LMICs. In the WHO European Region, where 17 of the 53 member countries are middle-income countries (MICs) [10], most VE studies to date have been conducted in high-income countries (HICs) [11]. Differences in population-level demographics and comorbidities in MICs compared to HICs could potentially lead to differences in overall vaccine performance. In addition, MICs in the WHO European Region have used a broader variety of COVID -19 vaccine products compared to HICs, including inactivated virus vaccines [12]. In the WHO European Region, primary series COVID -19 vaccine coverage has been considerably lower in MICs compared to HICs; as of 4 August 2023, primary series COVID -19 vaccine coverage was 73.8% and booster dose coverage was 48.4% in HICs compared to 55.3% and 15.9%, respectively, in upper MICs [13]. Having local data on COVID-19 VE from MICs in the WHO European Region could provide the additional advantage of promoting increased vaccine uptake.

In Georgia, an upper-middle income country of 3.7 million people, the COVID-19 vaccine rollout began on 15 March 2021 [14]. For the initial vaccine rollout, both ChAdOx1-S vaccine (Oxford/AstraZeneca) and BNT162b2 vaccine (Pfizer-BioNTech) were procured via the COVAX facility mechanism. Later in 2021, BBIBP-CorV vaccine (Sinopharm), CoronaVac vaccine (Sinovac Life Sciences, Beijing, China), and additional BNT162b2 vaccines were procured independently by the government of Georgia. HCWs were among the initial priority groups for vaccination. In order to understand COVID-19 VE among HCWs in Georgia, we conducted a prospective cohort study of COVID-19 VE against symptomatic SARS-CoV-2 infection among HCWs in six hospitals in Georgia. Here we describe the results of the initial interim analysis (March–December, 2021).

Materials and methods

Study design

We conducted a prospective cohort study to evaluate VE against symptomatic SARS-CoV-2 infection among HCWs in six hospitals in Georgia. The study design was based on a VE guidance document published by the WHO Regional Office for Europe [15], and the study was conducted within the framework of WHO’s Unity platform [16].

Data collection and management

From 19 March–16 July 2021, we invited all HCWs ≥ 18 years old who were employed at the study hospitals and eligible to receive the COVID-19 vaccine to participate in the study, as previously described [14]. At the time of enrolment, contra-indications to the COVID-19 vaccine in Georgia included having had a SARS-CoV-2 infection in the previous 120 days, and having an acute febrile illness at the time of intended vaccination. HCWs could participate in the study regardless of their hospital role, prior infection status, or their intention to receive COVID-19 vaccine. We excluded participants who were not eligible for vaccination before their enrolment in the study due to a SARS-CoV-2infection in the previous 120 days, and we excluded participants with unknown vaccination status at the time of enrollment. All HCWs in the study received COVID-19 vaccine through the national vaccine campaign led by the Georgia Ministry of Health.

At enrolment, participants completed a questionnaire that included questions about socio-demographics, comorbidities, occupation, self-perceived health status, prior SARS-CoV-2 infection, and COVID-19 and influenza vaccination history. In addition, at enrolment, every participant provided a blood sample for serology testing.

Following enrolment, participants completed a weekly symptom questionnaire, administered by study personnel; participants who reported any symptoms included in the Georgia MoH suspected COVID-19 case definition (fever, cough, general weakness, fatigue, headache, muscle aches, sore throat, runny nose, shortness of breath, lack of appetite, nausea, vomiting, diarrhea, altered mental status, loss of taste, or loss of smell) provided a respiratory specimen, which was tested for SARS-CoV-2 by either RT-PCR or rapid antigen test (RAT), depending on availability at each facility. In addition, during the entire study period, HCWs at all six hospitals could be tested routinely for SARS-CoV-2 by RT-PCR or RATs.

RT-PCR-positive samples were sent to the Richard G. Lugar Center for Public Health Research in Tbilisi, Georgia, where they underwent whole genome sequencing. Study staff verified participants’ vaccination status through the National Immunization Registry and confirmed RT-PCR and RAT results through the national SARS-CoV-2 laboratory database. Participants who tested positive for SARS-CoV-2 by RT- PCR or RAT were administered a follow-up questionnaire 30 days after their positive test, which included additional questions about symptoms and medical care. All study data were entered securely and stored in REDCap [17].

Serology

Phlebotomists collected serology specimens from participants at enrolment, and three and six months after enrolment. Serology samples were tested for anti-nucleocapsid antibodies and anti-spike antibodies by Roche Elecsys Anti-SARS-CoV-2 S immunoassay electrochemiluminescence immunoassay (ECLIA) [18]. For both serological assays, cutoff values were determined according to instructions from the package insert. Serology test results were used to identify previous COVID-19 infections, and to identify new infections in a sensitivity analysis that included only unvaccinated HCWs and HCWs who had received mRNA vaccines, as described in the vaccine effectiveness analysis section below.

Sample size estimations

We conducted sample size estimations prior to enrolment to ensure robust estimates for the primary study objective, COVID -19 VE against symptomatic SARS-CoV-2 infection. We estimated COVID-19 vaccination coverage among HWs in Georgia of 60–90% and a varying incidence of SARS-CoV-2 infection among unvaccinated participants of 0.05–0.2 during a one-year study in order to detect VE between 50–90%. To allow for different scenarios (changes in infection rates in the community, different vaccines), analysis of secondary endpoints, and to account for likely drop-out rate of roughly 15%, 1600 participants were targeted for enrolment in the study. We did not undertake purposive sampling; all eligible HCWs were offered enrolment.

Vaccine effectiveness analysis

For our primary outcome, because RAT testing occurred frequently and was not always accompanied by a PCR test, we measured primary series VE against a combined outcome of PCR-confirmed SARS-CoV-2 infection and/or RAT-confirmed COVID-19, which we defined as a positive test result in a participant who had symptom onset from 14 days before until four days after the date of specimen collection. Participants were considered fully vaccinated with their primary series ≥14 days after receipt of their second COVID-19 vaccine.

We conducted VE analyses for all primary series vaccination and then separately for primary series BNT162b2 and primary series BBIBP-CorV against outcomes of symptomatic infection, medically attended infection, and hospitalization. We also evaluated VE separately for the period in which SARS-CoV-2 B.1.617.2 (Delta variant) was predominant (5 July 2021 -– 5 December 2021), which we defined using sequencing data from study samples along with publicly available data from Georgia in the Global Initiative on Sharing All Influenza Data (GISAID) [19].

We also evaluated the combined effect of prior SARS-CoV-2 infection and COVID-19 vaccination on VE, using unvaccinated participants without prior infection as the category of reference. For the primary analysis, participants were considered to have had prior SARS-CoV-2 infection if they reported previous PCR-confirmed and/or RAT-confirmed infection and/or were seropositive for anti-nucleocapsid antibody at enrolment. For participants who received inactivated virus vaccine more than 5 days prior to enrolment, we defined prior infection by PCR and RAT only.

In addition, we measured primary series VE against both symptomatic and asymptomatic SARS-CoV-2 infection, measured by a combined endpoint of a PCR-positive test, a RAT-positive test, and/or seroconversion, which we defined as a positive three-month or six-month anti-nucleocapsid antibody test in a participant who was previously seronegative. For participants who seroconverted during the study but did not have symptomatic illness prior to their seroconversion, we estimated the time of asymptomatic infection as halfway between the last negative serological test and the subsequent positive serological test, taking into account a 3-week lag for seroconversion among asymptomatic persons [20]. For participants who had a symptomatic illness prior to their seroconversion, but did not have a positive PCR or RAT test, we assumed that the infection occurred on the date of onset of their symptomatic illness. For this analysis we only evaluated BNT162b2 vaccine effectiveness; we excluded participants who received BBIBP-CorV, as inactivated vaccines can generate the production of anti-nucleocapsid antibodies.

Further analyses and sensitivity analyses

We examined waning immunity by comparing VE in the periods from 14–89 days, 90–179 days and ≥180 days since the second vaccine dose, for both the overall period and the period of Delta circulation only.

Statistical model

VE was estimated as (1 –adjusted hazard ratio)*100. Hazard ratios (HRs) comparing vaccinated and unvaccinated were estimated using Cox proportional hazards models with vaccination as a time-varying exposure (vaccination status of some individuals changed over time from unvaccinated to vaccinated, and from one to two doses), which allowed participants to contribute person-time to more than one exposure category. Calendar time was used as the underlying time in the Cox regression.

We calculated unadjusted HR and used adjusted HR to estimate VE. Both estimates included hospital as a fixed effect. We adjusted the multivariable regression model using a priori fixed covariates (hospital, age, sex, prior SARS-CoV-2 infection) and considered potential confounders (role in hospital, hands-on care, face-to-face patient contact, smoking, household size, any comorbidity, body mass index [BMI] category, and self-perceived health status) that changed the VE estimate by more than 5%, according to the change-in-estimate approach. We used stratification to address violations of the proportional hazards assumption. All results presented in the results section reflect adjusted VE.

Participants with a SARS-CoV-2 infection prior to enrollment started contributing person-time when they were considered “at risk” of reinfection, which we defined as 90 days after their most recent positive PCR or RAT test or, for participants without who were seropositive at enrolment but did not have a history of a PCR- or RAT-positive test, four weeks after their positive enrolment serology.

Participants contributed person-time from enrolment, or from the start of time at risk for those with prior SARS-CoV-2 infection, until whichever of the following endpoints came first: 1) the day of the first SARS-CoV-2 infection, 2) the day of receipt of a third vaccine dose, or 3) the day of withdrawal from the study, or censor date for the analysis period (5 December 2021). Person-time of persons vaccinated with only one dose was excluded from all analyses from the day they received their first dose.

For all of the proposed analyses above, we only considered results from models that had achieved convergence and had a minimum of 5 events per category of vaccine status, ensuring our ability to construct reliable models.

Ethics and study registration

The study was approved by the NCDC and WHO Research Ethics Review Committees (reference numbers IRB 2021–014 and CERC.0097C, respectively). The CDC humans review determined the activity to be a public health evaluation. All participants provided written informed consent. The study is also registered at clinicaltrials.gov (Identifier NCT04868448).

Results

Of 3,849 HCWs working in the six hospitals, we enrolled 1592 (41%) participants, of whom 31 were excluded from the analysis for various reasons (Fig 1). Of the 1,561 HCWs included in the analysis, the median age was 40 (IQR: 30–53) and 1318 (84%) were female. Overall, 390 (25%) participants reported having at least one underlying chronic condition. Most HCWs were nurses or midwives [604 (39%)] and physicians [306 (20%)] (Table 1). Overall, 816 (52%) participants reported providing “hands-on care” to patients. Age and sex distribution, comorbid conditions, and occupation were similar across sites. Of the 1475 participants who were either unvaccinated at enrolment or received their first COVID-19 dose no more than 5 days prior to enrolment, 937 (63%) had evidence of prior infection by seropositivity for either anti-spike antibodies or anti-nucleocapsid antibodies.

10.1371/journal.pone.0307805.g001 Fig 1 Flowchart illustrating the enrolment of healthcare workers in COVID-19 vaccine effectiveness study, Georgia, 2021.

10.1371/journal.pone.0307805.t001 Table 1 Demographic, occupational and health characteristics, prior infection status of participants in COVID-19 vaccine effectiveness study, by vaccination status at enrolment, Georgia, 2021.

Characteristic/Category	All Participants, n = 1561	Unvaccinated, n = 1300	Partially vaccinated (1 dose), n = 224	Vaccinated with primary series (2 doses), n = 37	
Age, n = 1561	
Median (IQR)	40 (30–53)	40 (28.8–52)	47 (35–56.2)	40 (31–52)	
Age group, n = 1561	
<20, n (%)	16 (1)	15 (1)	1 (<1)	0 (0)	
20–29, n (%)	373 (24)	335 (26)	31 (14)	7 (19)	
30–39, n (%)	343 (22)	291 (22)	42 (19)	10 (27)	
40–49, n (%)	330 (21)	270 (21)	51 (23)	9 (24)	
50–59, n (%)	314 (20)	248 (19)	60 (27)	6 (16)	
60+, n (%)	185 (12)	141 (11)	39 (17)	5 (14)	
Sex, n = 1561	
female, n (%)	1318 (84)	1105 (85)	189 (84)	24 (65)	
male, n (%)	243 (16)	195 (15)	35 (16)	13 (35)	
Hospital, n = 1561	
Acad. K Central University Hosp., n (%)	300 (19)	240 (18)	49 (22)	11 (30)	
Batumi Republican Hospital, n (%)	276 (18)	216 (17)	52 (23)	8 (22)	
Bochorishvili Clinic, n (%)	194 (12)	178 (14)	14 (6)	2 (5)	
Bokeria Tbilisi Referral Hospital, n (%)	309 (20)	266 (20)	37 (17)	6 (16)	
Caucasus Medical Centre, n (%)	299 (19)	251 (19)	40 (18)	8 (22)	
Infectious Disease Hospital, n (%)	183 (12)	149 (11)	32 (14)	2 (5)	
Occupation/Role in hospital, n = 1561	
Nurse or Midwife, n (%)	604 (39)	537 (41)	58 (26)	9 (24)	
Medical Doctor, n (%)	306 (20)	181 (14)	108 (48)	17 (46)	
Other, n (%)	651 (42)	582 (45)	58 (26)	11 (30)	
Household size, n = 1561	
1–3, n (%)	703 (45)	579 (45)	107 (48)	17 (46)	
4–5, n (%)	622 (40)	526 (40)	83 (37)	13 (35)	
6+, n (%)	236 (15)	195 (15)	34 (15)	7 (19)	
Any chronic condition, n = 1561	
No, n (%)	1171 (75)	988 (76)	155 (69)	28 (76)	
Yes, n (%)	390 (25)	312 (24)	69 (31)	9 (24)	
Number of chronic conditions, n = 1561	
0, n (%)	1171 (75)	988 (76)	155 (69)	28 (76)	
1, n (%)	307 (20)	252 (19)	48 (21)	7 (19)	
≥2, n (%)	83 (5)	60 (5)	21 (9)	2 (5)	
Body mass index, n = 1561	
Underweight or normal, n (%)	721 (46)	607 (47)	101 (45)	13 (35)	
Overweight, n (%)	481 (31)	394 (30)	74 (33)	13 (35)	
Obese, n (%)	359 (23)	299 (23)	49 (22)	11 (30)	
Smoking, n = 1560	
Currently smokes, n (%)	388 (25)	323 (25)	48 (21)	17 (46)	
Never smokes, n (%)	1030 (66)	865 (67)	148 (66)	17 (46)	
Previously smokes, n (%)	142 (9)	111 (9)	28 (12)	3 (8)	
Self-assessed health status, n = 1561	
Excellent, n (%)	127 (8)	104 (8)	17 (8)	6 (16)	
Very good, n (%)	252 (16)	206 (16)	37 (17)	9 (24)	
Good, n (%)	521 (33)	438 (34)	68 (30)	15 (41)	
Fair, n (%)	641 (41)	533 (41)	101 (45)	7 (19)	
Poor, n (%)	20 (1)	19 (1)	1 (<1)	0 (0)	
Hands on care, n = 1561	
No, n (%)	745 (48)	639 (49)	91 (41)	15 (41)	
Yes, n (%)	816 (52)	661 (51)	133 (59)	22 (59)	
Received influenza vaccine during 2020–2021 influenza season, n = 1561	
No, n (%)	1068 (68)	944 (73)	105 (47)	19 (51)	
Yes, n (%)	492 (32)	355 (27)	119 (53)	18 (49)	
Face-to-face patient contact, n = 1561	
No, n (%)	336 (22)	292(22)	37 (17)	7 (19)	
Yes, n (%)	1125 (78)	1008 (78)	187 (81)	30 (81)	
Previous SARS-CoV-2 infection (before enrollment) confirmed by PCR or RAT, n = 1561	
0, n (%)	814 (52)	645 (50)	136 (61)	33 (89)	
1, n (%)	747 (48)	655 (50)	88 (39)	4 (11)	
Previous SARS-CoV-2 infection (before enrollment) confirmed by any test: PCR, RAT or serology, n = 1561	
0, n (%)	558 (36)	437 (34)	120 (54)	1 (3)	
1, n (%)	1003 (64)	863 (66)	104 (46)	36 (97)	
Seropositive at enrolment (AntiS+ or AntiN+), n = 1555	
0, n (%)	569 (37)	446 (34)	122 (55)	1 (3)	
1, n (%)	986 (63)	850 (66)	100 (45)	36 (97)	
Anti-S+, n = 1558	
0, n (%)	589 (38)	460 (35)	124 (56)	5 (14)	
1, n (%)	969 (62)	838 (65)	99 (44)	32 (86)	
Anti-N+, n = 1552	
0, n (%)	639 (41)	502 (39)	130 (59)	7 (19)	
1, n (%)	913 (59)	791 (61)	92 (41)	30 (81)	
Delay between first dose and start of person-time contribution, in days (n = 261)	
Median (IQR)	2 (1–4)	_	2 (1–3)	30 (29–31)	
Delay between second dose and start of person-time contribution, in days (n = 37)	
)Median (IQR)	7 (3–9)	_	_	7 (3–9)	
COVID-19 Vaccine product received prior to start of person-time contribution, n = 1561	
Unvaccinated, n (%)	1300 (83)	1300 (100)	0 (0)	0 (0)	
ChAdOx1-S—2 doses, n (%)	3 (<1)	0 (0)	0 (0)	3 (8)	
BNT162b2—1 dose, n (%)	145 (9)	0 (0)	145 (65)	0 (0)	
BNT162b2—2 dose, n (%)	26 (2)	0 (0)	0 (0)	26 (70)	
BBIBP-CorV—1 dose, n (%)	33 (2)	0 (0)	33 (15)	0 (0)	
BBIBP-CorV—2 dose, n (%)	4 (<1)	0 (0)	0 (0)	4 (11)	
CoronaVac—1 dose, n (%)	28 (2)	0 (0)	28 (12)	0 (0)	
CoronaVac—2 doses, n (%)	4 (<1)	0 (0)	0 (0)	4 (11)	

At enrolment, 224 (14%) participants had already received one dose of COVID-19 vaccine, 37 (2%) participants had received two doses, and 1,300 (83%) participants were unvaccinated (Table 1). At the end of the follow-up period, 1082 (69%) participants had received two doses, and 479 (31%) participants remained unvaccinated (S1 Table in S1 File). Of the 1,082 participants who had received two vaccine doses by the end of the follow-up period, most [745 (69%)] received BNT162b2, while 238 (22%) received BBIBP-CorV, 58 (5%) received CoronaVac, 26 (2%) received ChAdOx1-S and 14 (1%) received heterologous vaccination (S1 Table in S1 File and Fig 2). At the end of the analysis period, compared to participants who had received two doses of vaccine, unvaccinated participants were more likely to be doctors (24% vs. 10%) and were slightly younger (38 years (IQR = 28–52) vs. 41 years (IQR = 30–53)) but otherwise demographic, health, and occupation characteristics were similar between vaccinated and unvaccinated participants (S1 Table in S1 File).

10.1371/journal.pone.0307805.g002 Fig 2 COVID-19 vaccine coverage in the study population, by epidemiological week, Georgia, 2021.

During the study period, specimens were collected and tested from 686/796 (86%) reported symptomatic events. There were 124 symptomatic SARS-CoV-2 infections among unvaccinated participants (90 by PCR and 34 by RAT), and 67 symptomatic infections (52 by PCR and 15 by RAT) among participants who had completed a primary series (Table 2). Of the 191 symptomatic infections that occurred during the study period, 163 (85%) occurred between 1 July– 5 December 2021, a period during which the Delta variant predominated (Fig 3 and S1 Fig).

10.1371/journal.pone.0307805.g003 Fig 3 Number of symptomatic COVID-19 cases by vaccination status in the study population and national COVID-19 incidence in Georgia, by epidemiologic week, 2021.

10.1371/journal.pone.0307805.t002 Table 2 Vaccine effectiveness against symptomatic PCR and rapid antigen test confirmed SARS-CoV-2 infection for full cohort, and stratified by previous infection, vaccine brand and variant of interest.

		N participants	Total person-time (days)	PCR-confirmed symptomatic SARS-CoV-2 infection	RAT- confirmed symptomatic SARS-CoV-2 infection	All symptomatic SARS-CoV-2 infections	Unadjusted HR	(95% CI)	Unadjusted VE	(95%CI)	Adjusted VE	(95%CI)	
Overall study period	Two doses—any vaccine	
Total cohort	1561											
Unvaccinated	1300	112050	90	34	124							
≥14d from 2nd dose	1054	105080	52	15	67	0.56	(0.40; 0.80)	44	(20; 60)	58	(41; 70)	
 Without Prior Infection											
 Unvaccinated	437	36109	63	25	88							
 ≥14d from 2nd dose	357	37683	40	14	54	0.48	(0.32; 0.70)	52	(30; 68)	56	(35; 70)	
 With Prior Infection											
 Unvaccinated	863	75941	27	9	36							
 ≥14d from 2nd dose	697	67397	12	1	13	0.41	(0.20; 0.84)	59	(16; 80)	58	(11; 80)	
Two doses—BNT162b2 vaccine	
Total cohort	1470											
Unvaccinated	1300	112050	90	34	124							
≥14d from 2nd dose	732	72695	25	6	31	0.40	(0.26; 0.63)	60	(37; 74)	68	(51; 79)	
 Without Prior Infection											
 Unvaccinated	437	36109	63	25	88							
 ≥14d from 2nd dose	239	25763	22	6	28	0.37	(0.24; 0.60)	63	(40; 76)	63	(43; 77)	
Two doses—BBIBP-CorV vaccine	
Total cohort	1337											
Unvaccinated	1300	112050	90	34	124							
≥14d from 2nd dose	227	21136	18	6	24	0.87	(0.52; 1.45)	13	(-45; 48)	40	(1; 64)	
 Without Prior Infection											
 Unvaccinated	437	36109	63	25	88							
 ≥14d from 2nd dose	91	8977	15	5	20	0.74	(0.41; 1.33)	26	(-33; 59)	31	(-26; 62)	
Delta period	Two doses—any vaccine	
Total cohort	1556											
Unvaccinated	1162	72917	67	25	92							
≥14d from 2nd dose	1068	96751	49	15	64	0.60	(0.41; 0.86)	40	(14; 59)	52	(30; 66)	
 Without Prior Infection											
 Unvaccinated	378	21896	45	19	64							
 ≥14d from 2nd dose	339	30932	36	12	48	0.53	(0.35; 0.80)	47	(20; 65)	52	(26; 69)	
 With Prior Infection											
 Unvaccinated	784	51021	22	6	28							
 ≥14d from 2nd dose	729	65819	13	3	16	0.49	(0.25; 0.98)	51	(2; 75)	47	(-10; 74)	
Two doses—BNT162b2 vaccine	
Total cohort	1371											
Unvaccinated	1162	72917	67	25	92							
≥14d from 2nd dose	733	64109	23	6	29	0.46	(0.28; 0.73)	54	(27; 72)	61	(38; 75)	
 Without Prior Infection											
 Unvaccinated	378	21896	45	19	64							
 ≥14d from 2nd dose	222	19615	19	5	24	0.46	(0.28; 0.77)	54	(23; 72)	55	(26; 73)	
Two doses—BBIBP-CorV vaccine	
Total cohort	1250											
Unvaccinated	1161	72906	67	25	92							
≥14d from 2nd dose	227	20221	18	6	24	0.88	(0.52; 1.5)	12	(-50; 48)	37	(-9; 63)	
 Without Prior Infection											
 Unvaccinated	378	21896	45	19	64							
 ≥14d from 2nd dose	91	8474	15	5	20	0.72	(0.39; 1.31)	28	(-31; 61)	34	(-23; 64)	
* due to the small number of events, brand-specific VE in participants with previous infection could not be estimated

All participants who were infected during the study period completed the 30-day follow up questionnaire after their positive PCR or RAT test; 132/191 (69%) sought medical care, 26/188 (14%) sought care at an emergency department, 44/191 (23%) were hospitalized, 12/191 were admitted to the ICU and no one died.

Primary series VE against the combined outcome of symptomatic PCR-confirmed and RAT-confirmed infections was 58% (95% CI: 41, 70). Among participants without prior infection, VE was 56% (95% CI: 35, 70), and among those with prior SARS-CoV-2 infection, VE was 58% (95% CI: 11, 80) (Table 2). For participants who received primary series BNT162b2 vaccine, overall VE was 68% (95% CI: 51, 79). In those without prior infection, primary series BNT162b2 VE was 63% (95% CI: 43, 77) (Table 2 and Fig 4). For participants who received primary series BBIBP-CorV vaccine, overall VE was 40% (95% CI: 1, 64). In those without prior infection, VE for primary series BBIBP-CorV was 31% (95%CI: -26, 62) (Table 2).

10.1371/journal.pone.0307805.g004 Fig 4 COVID-19 vaccine effectiveness against symptomatic infection and medically attended cohort for total study cohort, and stratified by previous infection status, for overall study period, and for Delta-predominant period, Georgia, 2021.

Overall VE against medically attended PCR- and RAT-confirmed COVID-19 was 52% (95% CI: 28, 67), and VE against PCR- and RAT-confirmed hospitalizations was 69% (95% CI: 36; 85) (Table 3 and Fig 4). During the Delta-predominant period, VE against medically attended COVID-19 was 41% (95% CI: 10, 61), and VE against hospitalization was 61% (95% CI: 13, 81). Overall, for BNT162b2, VE against medically attended COVID-19 was 63% (95% CI: 39; 78). Because of the low number of events, BNT162b2 VE against hospitalization could not be calculated, and BBIBP-CorV Ve against medically attended COVID-19 and hospitalization could not be calculated.

10.1371/journal.pone.0307805.t003 Table 3 Vaccine effectiveness against medically attended COVID-19 and COVID-19 hospitalization, for full cohort, and stratified by previous infection, vaccine product, for overall study period and for Delta-predominant period, Georgia, 2021.

		N participants	Total person-time (days)	PCR-confirmed symptomatic SARS-CoV-2 infection	RAT-confirmed symptomatic SARS-CoV-2 infection	All symptomatic SARS-CoV-2 infections	Unadjusted HR	(95% CI)	Unadjusted VE	(95%CI)	Adjusted VE	(95%CI)	
Overall period	Medically attended SARS-CoV-2 infection	
Two doses—any vaccine	
Total cohort	1561											
Unvaccinated	1300	112050	64	22	86							
≥14d from 2nd dose	1054	105080	37	9	46	0.64	(0.43; 0.95)	36	(5; 57)	52	(28; 67)	
 Without Prior Infection											
 Unvaccinated	437	36109	47	15	62							
 ≥14d from 2nd dose	357	37683	30	8	38	0.55	(0.35; 0.85)	45	(15; 65)	51	(21; 70)	
 With Prior Infection											
 Unvaccinated	863	75941	17	7	24							
 ≥14d from 2nd dose	697	67397	7	1	8	0.42	(0.18; 0.98)	58	(2; 82)	56	(-2; 81)	
Two doses—BNT162b2	
Total cohort	1470											
Unvaccinated	1300	112050	64	22	86							
≥14d from 2nd dose	732	72695	18	5	23	0.49	(0.30; 0.81)	51	(19; 70)	63	(39; 78)	
 Without Prior Infection											
 Unvaccinated	437	36109	47	15	62							
 ≥14d from 2nd dose	239	25763	16	5	21	0.44	(0.26; 0.75)	56	(25; 74)	54	(24; 72)	
Delta period	Two doses—any vaccine	
Total cohort	1556											
Unvaccinated	1162	72917	45	13	58							
≥14d from 2nd dose	1068	96751	35	9	44	0.69	(0.45; 1.08)	31	(-8; 55)	41	(10; 61)	
 Without Prior Infection											
 Unvaccinated	378	21896	31	9	40							
 ≥14d from 2nd dose	339	30932	28	7	35	0.68	(0.42; 1.11)	32	(-11; 58)	35	(-6; 60)	
 With Prior Infection											
 Unvaccinated	784	51021	14	4	18							
 ≥14d from 2nd dose	729	65819	7	2	9	0.44	(0.19; 1.02)	56	(-2; 81)	53	(-13; 80)	
Overall period	Hospitalization due to SARS-CoV-2 infection	
Two doses—any vaccine	
Total cohort	1561											
Unvaccinated	1300	112050	25	8	33							
≥14d from 2nd dose	1054	105080	9	2	11	0.46	(0.22; 0.96)	54	(4; 78)	69	(36; 85)	
 Without Prior Infection											
 Unvaccinated	437	36109	21	6	27							
 ≥14d from 2nd dose	357	37683	8	2	10	0.37	(0.18; 0.78)	63	(22; 82)	66	(29; 84)	
Delta period	Two doses—any vaccine	
Total cohort	1556											
Unvaccinated	1162	72917	13	3	16							
≥14d from 2nd dose	1068	96751	8	2	10	0.5	(0.21; 1.17)	50	(-17; 79)	61	(13; 81)	
 Without Prior Infection											
 Unvaccinated	378	21896	10	2	12							
 ≥14d from 2nd dose	339	30932	7	2	9	0.46	(0.19; 1.11)	54	(-11; 81)	53	(-13; 81)	
* due to small number of events, brand specific VE in participants with previous infection could not be estimated

**Because of the low number of events, BNT162b2 vaccine effectiveness against hospitalization could not be calculated, and BBIBP-CorV vaccine effectiveness against medically attended COVID-19 and hospitalization could not be calculated.

Primary series VE estimates against symptomatic, PCR-confirmed SARS-CoV-2 infection, medically attended infection, and hospitalization were similar to VE estimates for the combined PCR/RAT endpoint. (S2 Table in S1 File).

Compared to unvaccinated participants with no evidence of prior SARS-CoV-2 infection, VE against symptomatic PCR- and RAT-confirmed infection was 56% (95% CI: 35; 70) for vaccinated participants without evidence of prior infection, and 95% (95% CI: 90; –98) for vaccinated participants who had prior infection. Protection against symptomatic, PCR- and RAT-confirmed infection was 85% (95%CI: 77; –90) for unvaccinated participants who had been previously infected. Trends were similar when we limited this analysis to BNT162b2-only, BBIBP-CorV-only, and for all vaccines for the Delta period (Table 4).

10.1371/journal.pone.0307805.t004 Table 4 Combined effect of previous infection and primary series vaccination in protecting against symptomatic PCR and/or RAT-confirmed SARS-CoV-2 infection, overall, by vaccine product, and for Delta-predominant period only, Georgia, 2021.

		N participants	Total person-time (days)	PCR-confirmed symptomatic SARS-CoV-2 infection	RAT-confirmed symptomatic SARS-CoV-2 infection	All symptomatic SARS-CoV-2 infections	Unadjusted HR	(95% CI)	Unadjusted VE	(95%CI)	Adjusted VE	(95%CI)	
Overall period	Two doses (all vaccines)	1561											
 Unvaccinated without previous infection [ref]	437	36109	63	25	88							
 Unvaccinated with previous infection	863	75941	27	9	36	0.17	(0.11; 0.25)	83	(75; 89)	85	(77; 90)	
 ≥14d from 2nd dose without previous infection	357	37683	40	14	54	0.48	(0.32; 0.70)	52	(30; 68)	56	(35; 70)	
 ≥14d from 2nd dose with previous infection	697	67397	12	1	13	0.06	(0.03; 0.13)	94	(87; 97)	95	(90; 98)	
Two doses (BNT162b2)	1470											
 Unvaccinated without previous infection [ref]	437	36109	63	25	88							
 Unvaccinated with previous infection	863	75941	27	9	36	0.17	(0.11; 0.25)	83	(75; 89)	85	(77; 90)	
 ≥14d from 2nd dose without previous infection	239	25763	22	6	28	0.37	(0.24; 0.60)	63	(40; 76)	64	(43; 77)	
Two doses (BBIBP-CorV)	1337											
 Unvaccinated without previous infection [ref]	437	36109	63	25	88							
 Unvaccinated with previous infection	863	75941	27	9	36	0.17	(0.11; 0.25)	83	(75; 89)	85	(77; 90)	
 ≥14d from 2nd dose without previous infection	91	8977	15	5	20	0.74	(0.41; 1.33)	26	(-33; 59)	31	(-26; 62)	
Delta period	Two doses (all vaccines)	1556											
 Unvaccinated without previous infection [ref]	378	21896	45	19	64							
 Unvaccinated with previous infection	784	51021	22	6	28	0.17	(0.11; 0.27)	83	(73; 89)	86	(77; 91)	
 ≥14d from 2nd dose without previous infection	339	30932	36	12	48	0.53	(0.35; 0.80)	47	(20; 65)	52	(26; 69)	
 ≥14d from 2nd dose with previous infection	729	65819	13	3	16	0.08	(0.04; 0.16)	92	(84; 96)	93	(86; 96)	
Two doses (BNT162b2)/Previous infection status	1371											
 Unvaccinated without previous infection [ref]	378	21896	45	19	64							
 Unvaccinated with previous infection	784	51021	22	6	28	0.17	(0.11; 0.27)	83	(73; 89)	86	(77; 91)	
 ≥14d from 2nd dose without previous infection	222	19615	19	5	24	0.46	(0.28; 0.77)	54	(23; 72)	55	(26; 73)	
Two doses (BBIBP-CorV)	1250											
 Unvaccinated without previous infection [ref]	378	21896	45	19	64							
 Unvaccinated with previous infection	783	51010	22	6	28	0.17	(0.11; 0.27)	83	(73; 89)	86	(77; 91)	
 ≥14d from 2nd dose without previous infection	91	8474	15	5	20	0.72	(0.39; 1.31)	28	(-31; 61)	34	(-23; 64)	

In our evaluation of protection against the more inclusive outcome of infection confirmed by PCR, RAT, or seroconversion, which was limited to primary series BNT162b2 vaccination, we found similar trends. VE was 32% (95% CI: 0, 53) overall, 15% (95% CI: -31, –44) for those without previous infection, and 69% (95%CI: 26, 87) for those with previous infection (S3 Table in S1 File). Compared to unvaccinated participants who had not been previously infected, VE was 15% (95%CI: –31; 44) for primary series vaccination without previous infection, and 96% (95% CI: 92–98) for primary series vaccination among participants with prior infection. Unvaccinated participants who had been previous infected had 90% (95% CI: 87; 93) protection from re-infection (S4 Table in S1 File).

In our evaluation of VE against symptomatic PCR- and RAT-confirmed SARS-CoV-2 infection stratified by time since vaccination, for the overall analysis, (Table 5 and Fig 5), VE was 60% (95% CI: 39, –74) for participants 14–89 days after their second vaccine dose, 48% (95% CI: 18, 66) for participants who were 90–179 days after their second vaccine dose, and 14% (95%CI: -134, 68) for those ≥180 days. When we restricted the time-since-vaccination analysis to vaccine product and the Delta-predominant period, the trends were similar (Table 5. Fig 5).

10.1371/journal.pone.0307805.g005 Fig 5 COVID-19 primary series vaccine effectiveness by days since vaccination against symptomatic infection for overall cohort during entire study period, overall cohort during the Delta-predominant period, and for BNT162b2 and BBIBP CorV during the Delta-predominant period, Georgia, 2021.

10.1371/journal.pone.0307805.t005 Table 5 Effect of time since vaccination on COVID-19 primary vaccine series effectiveness against symptomatic PCR- and RAT-confirmed infection, for full cohort, by vaccine product, and for Delta-predominant period, Georgia, 2021.

		N participants	Total person-time (days)	PCR-confirmed symptomatic SARS-CoV-2 infection	RAT-confirmed symptomatic SARS-CoV-2 infection	All symptomatic SARS-CoV-2 infections	Unadjusted HR	(95% CI)	Unadjusted VE	(95%CI)	Adjusted VE	(95%CI)	
Overall period	Time since two doses (all vaccines)	1561											
 Unvaccinated [ref]	1300	112050	90	34	124							
 14d–89d from 2nd dose	1054	71373	28	7	35	0.47	(0.30; 0.72)	53	(28; 70)	60	(39; 74)	
 90d-179d from 2nd dose	697	29150	19	7	26	0.73	(0.46; 1.16)	27	(-16; 54)	48	(18; 66)	
 ≥180d from 2nd dose	186	4557	5	1	6	0.92	(0.36; 2.38)	8	(-138; 64)	14	(-134; 68)	
Time since two doses (BNT162b2)	1470											
 Unvaccinated [ref]	1300	112050	90	34	124							
 14d–89d from 2nd dose	732	49837	9	1	10	0.21	(0.1; 0.44)	79	(56; 90)	82	(63; 91)	
 90d-179d from 2nd dose	485	18572	11	4	15	0.71	(0.40; 1.24)	29	(-24; 60)	52	(13; 73)	
 ≥180d from 2nd dose	151	4286	5	1	6	0.95	(0.37; 2.48)	5	(-148; 63)	40	(-55; 77)	
Time since two doses (BBIBP-CorV)	1337											
 Unvaccinated [ref]	1300	112050	90	34	124							
 14d–89d from 2nd dose	227	14894	13	5	18	0.85	(0.49; 1.50)	15	(-50; 51)	36	(-10; 63)	
 90d-179d from 2nd dose	132	6108	5	1	6	0.76	(0.30; 1.91)	24	(-91; 70)	57	(-9; 83)	
Delta period	Time since two doses (all vaccines)	1556											
 Unvaccinated [ref]	1162	72917	67	25	92							
 14d–89d from 2nd dose	1043	61860	25	7	32	0.47	(0.30; 0.75)	53	(25; 70)	54	(28; 71)	
 90d-179d from 2nd dose	715	30230	19	7	26	0.74	(0.46; 1.21)	26	(-21; 54)	40	(4; 62)	
 ≥180d from 2nd dose	189	4661	5	1	6	1	(0.38; 2.60)	-0	(-160; 62)	14	(-130; 68)	
Time since two doses (BNT162b2)	1371											
 Unvaccinated [ref]	1162	72917	67	25	92							
 14d–89d from 2nd dose	708	41088	7	1	8	0.21	(0.09; 0.49)	79	(51; 91)	81	(56; 91)	
 90d-179d from 2nd dose	489	18631	11	4	15	0.77	(0.44; 1.37)	23	(-37; 56)	38	(-9; 65)	
 ≥180d from 2nd dose	154	4390	5	1	6	1.03	(0.39; 2.72)	-3	(-172; 61)	6	(-151;65)	
Time since two doses (BBIBP-CorV)	1250											
 Unvaccinated [ref]	1161	72906	67	25	92							
 14d–89d from 2nd dose	227	13979	13	5	18	0.91	(0.52; 1.59)	9	(-59; 48)	32	(-21; 61)	
 90d-179d from 2nd dose	132	6108	5	1	6	0.75	(0.30; 1.91)	25	(-91; 70)	57	(-12; 83)	

S5 Table in S1 File presents the identified confounders for each model.

Discussion

We found that primary series COVID-19 vaccination was nearly 60% effective in preventing symptomatic SARS-CoV-2 illness among Georgian HCWs, most of whom had been previously infected with SARS-CoV-2, during a period of mostly Delta variant circulation. Both primary series BNT162b2 vaccination and primary series BBIBP-CorV vaccination conferred similarly high VE against symptomatic infection. Our findings support the current recommendations of Georgia that HCWs, and all adults over 18 years old, should receive primary series COVID-19 vaccination. The results from this study, which to our knowledge is the first study to describe COVID-19 VE in Georgia, could be used to promote increased COVID-19 vaccination in the country, which has one of the lowest COVID-19 vaccination rates in the WHO European region; as of the week of 4 June 2023 only 57% of Georgian HCWs had received primary series COVID-19 vaccination, and only 18% had received a booster dose. As of the same date, only 32% of the general population in Georgia had received primary series COVID-19 vaccination, and only 6% had received a booster dose [12].

Our findings of primary series BNT162b2 VE against symptomatic SARS-CoV-2 infection are similar to other previously published studies that evaluated VE against COVID-19 during periods of Delta circulation. A living active VE literature review and associated systematic review [21] described point estimates for studies that evaluated primary series BNT162b2 VE against symptomatic disease during Delta ranging from 80–95% in the 14 days to <3 months following completion of the primary series; VE dropped to 45–80% after 3–6 months [11]. Studies from other regions of the world have demonstrated a consistently relatively high VE (70%) of primary series BNT162b2 against severe disease, which has increased following booster doses [11].

Although well over 1.5 billion doses of BBIBP-CorV have been used globally [22], very few post-marketing studies have evaluated its effectiveness [11]. Our study is one of few studies globally to evaluate VE of primary series BBIBP-CorV against symptomatic infection during the Delta period [11]. Our finding of 40% VE was in the range of primary series BBIBP-CorV VE against symptomatic infection during Delta described in two studies from China, which found adjusted VE of 50% (95%CI: 4; –74) [23] and 75 (95%CI: 6; –94) [24], and one study from Egypt, that found VE of 67% (95%CI: 43; 80) [25]. Studies of BBIBP-CoRV against more severe outcomes have shown mixed results, but have consistently shown the added benefit of booster doses, mostly against Delta but also against Omicron; a study of primary series BBIBP-CorV VE against hospitalization among people aged 18–64 years old in Hungary during Delta found a VE of 54% (44; 62) in the 14–120 days following the second dose that decreased over time, but increased to 77–95% following homologous or heterologous booster [26]; for 65–100 year-olds, the same study found slightly lower VE against hospitalization with similar trends following booster doses. A study during a period of primarily Delta circulation in Iran found that primary series BBIBP-CorV VE peaked at 85% (95%CI: 77; 91%) against hospitalization ≥ 151 days after receipt of the second dose and 56% (95% CI 33; 71%) against death 91–120 days after receipt of the second dose [27]. A study from Thailand found BBIBP-CorV primary series VE against pneumonia requiring invasive ventilation during Omicron of 66% (95%CI: 39; 81%) that had a non-statistically significant increase to 81% (95%CI: 36; 95%) following a booster dose [28].

In our study, nearly two-thirds of participants (64%) had been previously infected with SARS-CoV-2 at the time of their enrolment into the study. Nevertheless, we found clear benefit to COVID-19 vaccination; among participants with prior infection, primary series VE with any vaccine was 58%. The benefits of hybrid immunity–immunity conferred by the combination of vaccination and infection–have been widely described globally and within the WHO European region [29–31]. The added benefit of vaccination after infection is becoming an increasingly important public message as more of the world’s population has experienced at least one SARS-CoV-2 infection [32].

Our findings of that COVID-19 vaccine prevented nearly two-thirds of symptomatic infections has positive implications for the role of vaccine in protecting the health of HCWs, the health of the patients and improving the resilience of the Georgian healthcare system. These findings underscore the importance of tailored messaging to highlight these points, and health policies to encourage increased COVID-19 vaccine uptake among HCWs.

Our study had a number of strengths. By using PCR-confirmed infection and serology to define prior infection, and by using these two diagnostic tools and RAT to estimate VE against all infections, we were able to more comprehensively identify infections among participants in our study. In addition, by collecting quarterly serology samples, we were able to identify asymptomatic infections and symptomatic infections that may have been missed by PCR on one-time swab collection. Very few participants [3/1592 (0.2%)] withdrew from the study during the follow-up period. In addition, 85% of participants who reported a symptomatic illness on their weekly questionnaire had a specimen collected for PCR testing.

Our study also has limitations. First, while we evaluated COVID-19 VE against symptomatic and asymptomatic infections, endpoints that are particularly relevant for HCWs, who need to be healthy in order to provide clinical care and infection-free so that they do not pass on the virus to their patients, our study was not powered to estimate VE against severe outcomes such as hospitalization and death. In addition, our study evaluated primary series VE during a period of Delta circulation, and could not evaluate VE of booster doses; both will be evaluated in future analyses of this ongoing cohort study. Our study may suffer from selection bias; enrolment in the study was voluntary, HCWs in our study may not fully represent HCWs in Georgia. However, we did enroll over 40% of eligible HCWs in the six hospitals.

Additionally, while serology was a strength of our study in identifying previous infections and new infections (in those participants who were not vaccinated with inactivated virus vaccines), our anti-nucleocapsid antibody likely did not capture all previous infections, due to a combination of antibody waning, imperfect sensitivity of the assay, and potentially variable production of anti-nucleocapsid antibodies in vaccinated individuals [33]. Furthermore, we were not able to use serology test results to identify previous infections in 86 (5.5%) HCWs who had received their first COVID-19 vaccine more than five days prior to enrolment; however, we believe that by defining previous by a composite of documented PCR and RAT results, combined with serology test results, we captured the nearly all previous infections, and the amount of missed previous infections would be very unlikely to meaningfully impact our results. While the Georgian government encouraged routine testing of all HCWs during the study period, not all HCWs in our study were tested routinely with the same frequency, which may have introduced bias. In our study the unvaccinated group at the end of the study period was slightly younger and included more physicians; however, in order to address these differences, we controlled for age and occupation in our final adjusted models.

Conclusions

In conclusion, we found that a primary series COVID-19 vaccination, which included mainly BNT162b2 vaccine and, to a lesser extent, BBIBP-CorV, was effective in preventing symptomatic infection in hospital-based HCWs in Georgia. Our findings support current vaccine policy and underscore the need to promote vaccine uptake in Georgia both in HCWs and the general population, where uptake has lagged in comparison to most other countries in the European region of WHO. Our findings also add to the growing literature on the added benefit of COVID-19 vaccination in individuals who have been previously infected with SARS-CoV-2.

Supporting information

S1 Fig Whole genome sequencing results of samples from SARS-CoV-2 positive cases in Georgia by week during the study analysis period, 2021*.

(DOCX)

S1 File (DOCX)

We are grateful to the study team at the Georgia National Centers for Disease Control and at all the participating study hospitals. In addition we would like to thank the following colleagues: Pernille Jorgensen and Diogo Simao Lemos (WHO Regional Office for Europe), Irina Begiashvilli (WHO Country Office in Georgia), Lindsey Duca (US CDC), Marta Valenciano and Alain Moren (Epiconcept). This study has been conducted within the framework of the WHO Strategic Preparedness and Response plan and WHO/European Regional Office Response for COVID-19.

Disclaimer: The authors affiliated with the World Health Organization (WHO) are alone responsible for the views expressed in this publication, and they do not necessarily represent the decisions or the policies of the WHO.

10.1371/journal.pone.0307805.r001
Decision Letter 0
Lau Eric HY Academic Editor
© 2024 Eric HY Lau
2024
Eric HY Lau
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submission Version0
15 Nov 2023

PONE-D-23-33035Primary Series COVID-19 Vaccine Effectiveness among Health Care Workers in the country of Georgia, March–December 2021PLOS ONE

Dear Dr. Katz,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

The Authors are expected to address all the criticisms by all Reviewers. In particular, please clarify if there’s overlap in the first sample and key informant, reassess quantitative statements (Reviewer #1), and further explain and assess the impact of the recruitment procedure, and consider the use of some basic statistics to strengthen the conclusion (Reviewer #2). In additional to the above comments, please address,

Could the authors provide the number of potential respondents invited and the number who refused the interview? This will help understand indirectly how potential respondents perceived the interview as voluntary. The authors are encouraged to provide other relevant information.

The authors considered that the answers may be shorter for those who may feel uncomfortable to be interviewed, what would be the expected bias arising from this situation and how it will affect the main findings?

Please provide more description and assessment on the interview process and further assess the potential direction and extent of bias due to the recruitment.

Please submit your revised manuscript by Dec 30 2023 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Eric HY Lau, Ph.D.

Academic Editor

PLOS ONE

Journal Requirements:

When submitting your revision, we need you to address these additional requirements.

1. Please ensure that your manuscript meets PLOS ONE's style requirements, including those for file naming. The PLOS ONE style templates can be found at 

https://journals.plos.org/plosone/s/file?id=wjVg/PLOSOne_formatting_sample_main_body.pdf and 

https://journals.plos.org/plosone/s/file?id=ba62/PLOSOne_formatting_sample_title_authors_affiliations.pdf

2. PLOS requires an ORCID iD for the corresponding author in Editorial Manager on papers submitted after December 6th, 2016. Please ensure that you have an ORCID iD and that it is validated in Editorial Manager. To do this, go to ‘Update my Information’ (in the upper left-hand corner of the main menu), and click on the Fetch/Validate link next to the ORCID field. This will take you to the ORCID site and allow you to create a new iD or authenticate a pre-existing iD in Editorial Manager. Please see the following video for instructions on linking an ORCID iD to your Editorial Manager account: https://www.youtube.com/watch?v=_xcclfuvtxQ

3. We note that the grant information you provided in the ‘Funding Information’ and ‘Financial Disclosure’ sections do not match. 

When you resubmit, please ensure that you provide the correct grant numbers for the awards you received for your study in the ‘Funding Information’ section.

4. Thank you for stating the following financial disclosure: 

"The author(s) received no specific funding for this work." 

Please state what role the funders took in the study.  If the funders had no role, please state: ""The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript."" 

If this statement is not correct you must amend it as needed. 

Please include this amended Role of Funder statement in your cover letter; we will change the online submission form on your behalf.

5. In your Data Availability statement, you have not specified where the minimal data set underlying the results described in your manuscript can be found. PLOS defines a study's minimal data set as the underlying data used to reach the conclusions drawn in the manuscript and any additional data required to replicate the reported study findings in their entirety. All PLOS journals require that the minimal data set be made fully available. For more information about our data policy, please see http://journals.plos.org/plosone/s/data-availability.

""Upon re-submitting your revised manuscript, please upload your study’s minimal underlying data set as either Supporting Information files or to a stable, public repository and include the relevant URLs, DOIs, or accession numbers within your revised cover letter. For a list of acceptable repositories, please see http://journals.plos.org/plosone/s/data-availability#loc-recommended-repositories. Any potentially identifying patient information must be fully anonymized.

Important: If there are ethical or legal restrictions to sharing your data publicly, please explain these restrictions in detail. Please see our guidelines for more information on what we consider unacceptable restrictions to publicly sharing data: http://journals.plos.org/plosone/s/data-availability#loc-unacceptable-data-access-restrictions. Note that it is not acceptable for the authors to be the sole named individuals responsible for ensuring data access.

We will update your Data Availability statement to reflect the information you provide in your cover letter.

6. We note that you have stated that you will provide repository information for your data at acceptance. Should your manuscript be accepted for publication, we will hold it until you provide the relevant accession numbers or DOIs necessary to access your data. If you wish to make changes to your Data Availability statement, please describe these changes in your cover letter and we will update your Data Availability statement to reflect the information you provide.

7. We notice that your supplementary figures are uploaded with the file type 'Figure'. Please amend the file type to 'Supporting Information'. Please ensure that each Supporting Information file has a legend listed in the manuscript after the references list.

Additional Editor Comments:

The Authors are expected to address all the criticisms by all Reviewers. In particular, please clarify if there’s overlap in the first sample and key informant, reassess quantitative statements (Reviewer #1), and further explain and assess the impact of the recruitment procedure, and consider the use of some basic statistics to strengthen the conclusion (Reviewer #2). In additional to the above comments, please address,

1. Could the authors provide the number of potential respondents invited and the number who refused the interview? This will help understand indirectly how potential respondents perceived the interview as voluntary. The authors are encouraged to provide other relevant information.

2. The authors considered that the answers may be shorter for those who may feel uncomfortable to be interviewed, what would be the expected bias arising from this situation and how it will affect the main findings?

3. Please provide more description and assessment on the interview process and further assess the potential direction and extent of bias due to the recruitment.

[Note: HTML markup is below. Please do not edit.]

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

10.1371/journal.pone.0307805.r002
Author response to Decision Letter 0
Submission Version1
29 Jan 2024

N/A

Attachment Submitted filename: Georgia VERespRevcover letter_29Jan2024_POne.docx

10.1371/journal.pone.0307805.r003
Decision Letter 1
Lau Eric HY Academic Editor
© 2024 Eric HY Lau
2024
Eric HY Lau
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submission Version1
23 Apr 2024

PONE-D-23-33035R1Primary Series COVID-19 Vaccine Effectiveness among Health Care Workers in the country of Georgia, March–December 2021PLOS ONE

Dear Dr. Katz,

Thank you for submitting your manuscript to PLOS ONE. After careful consideration, we feel that it has merit but does not fully meet PLOS ONE’s publication criteria as it currently stands. Therefore, we invite you to submit a revised version of the manuscript that addresses the points raised during the review process.

The Authors are expected to address all the criticisms by the Reviewer. In particular, please state the study objective clearly and add sample size considerations (Reviewer #1). In additional to the above comments, please address,

Serology, please make a clear statement about the ability of and how the serological tests were used to differentiate between SARS-CoV-2 infection, previous COVID-19 vaccination with mRNA and inactivated vaccines.

Please make an assessment on how the above will affect the main study results especially for inactivated vaccine BBIBP-CorV.

Results, the abbreviations VE and aVE were used interchangeably. Please harmonize and confirm that adjusted estimates are always presented.

Line 276, there are some typos in the 95% CIs, for example remove “– “ in “(95%CI: 90; –98)” (Line 276), also in lines 277, 283, 292, 328 and others

Please submit your revised manuscript by Jun 07 2024 11:59PM. If you will need more time than this to complete your revisions, please reply to this message or contact the journal office at plosone@plos.org. When you're ready to submit your revision, log on to https://www.editorialmanager.com/pone/ and select the 'Submissions Needing Revision' folder to locate your manuscript file.

Please include the following items when submitting your revised manuscript:A rebuttal letter that responds to each point raised by the academic editor and reviewer(s). You should upload this letter as a separate file labeled 'Response to Reviewers'.

A marked-up copy of your manuscript that highlights changes made to the original version. You should upload this as a separate file labeled 'Revised Manuscript with Track Changes'.

An unmarked version of your revised paper without tracked changes. You should upload this as a separate file labeled 'Manuscript'.

If you would like to make changes to your financial disclosure, please include your updated statement in your cover letter. Guidelines for resubmitting your figure files are available below the reviewer comments at the end of this letter.

If applicable, we recommend that you deposit your laboratory protocols in protocols.io to enhance the reproducibility of your results. Protocols.io assigns your protocol its own identifier (DOI) so that it can be cited independently in the future. For instructions see: https://journals.plos.org/plosone/s/submission-guidelines#loc-laboratory-protocols. Additionally, PLOS ONE offers an option for publishing peer-reviewed Lab Protocol articles, which describe protocols hosted on protocols.io. Read more information on sharing protocols at https://plos.org/protocols?utm_medium=editorial-email&utm_source=authorletters&utm_campaign=protocols.

We look forward to receiving your revised manuscript.

Kind regards,

Eric HY Lau, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments:

The Authors are expected to address all the criticisms by the Reviewer. In particular, please state the study objective clearly and add sample size considerations (Reviewer #1). In additional to the above comments, please address,

1. Serology, please make a clear statement about the ability of and how the serological tests were used to differentiate between SARS-CoV-2 infection, previous COVID-19 vaccination with mRNA and inactivated vaccines.

2. Please make an assessment on how the above will affect the main study results especially for inactivated vaccine BBIBP-CorV.

3. Results, the abbreviations VE and aVE were used interchangeably. Please harmonize and confirm that adjusted estimates are always presented.

4. Line 276, there are some typos in the 95% CIs, for example remove “– “ in “(95%CI: 90; –98)” (Line 276), also in lines 277, 283, 292, 328 and others

[Note: HTML markup is below. Please do not edit.]

Reviewers' comments:

Reviewer's Responses to Questions

Comments to the Author

1. If the authors have adequately addressed your comments raised in a previous round of review and you feel that this manuscript is now acceptable for publication, you may indicate that here to bypass the “Comments to the Author” section, enter your conflict of interest statement in the “Confidential to Editor” section, and submit your "Accept" recommendation.

Reviewer #1: (No Response)

**********

2. Is the manuscript technically sound, and do the data support the conclusions?

The manuscript must describe a technically sound piece of scientific research with data that supports the conclusions. Experiments must have been conducted rigorously, with appropriate controls, replication, and sample sizes. The conclusions must be drawn appropriately based on the data presented.

Reviewer #1: Partly

**********

3. Has the statistical analysis been performed appropriately and rigorously?

Reviewer #1: Yes

**********

4. Have the authors made all data underlying the findings in their manuscript fully available?

The PLOS Data policy requires authors to make all data underlying the findings described in their manuscript fully available without restriction, with rare exception (please refer to the Data Availability Statement in the manuscript PDF file). The data should be provided as part of the manuscript or its supporting information, or deposited to a public repository. For example, in addition to summary statistics, the data points behind means, medians and variance measures should be available. If there are restrictions on publicly sharing data—e.g. participant privacy or use of data from a third party—those must be specified.

Reviewer #1: Yes

**********

5. Is the manuscript presented in an intelligible fashion and written in standard English?

PLOS ONE does not copyedit accepted manuscripts, so the language in submitted articles must be clear, correct, and unambiguous. Any typographical or grammatical errors should be corrected at revision, so please note any specific errors here.

Reviewer #1: Yes

**********

6. Review Comments to the Author

Please use the space provided to explain your answers to the questions above. You may also include additional comments for the author, including concerns about dual publication, research ethics, or publication ethics. (Please upload your review as an attachment if it exceeds 20,000 characters)

Reviewer #1: Introduction

Given tha rationale of the study, the introduction section lacks of a brief paragraph describing the precious role of health care workers in tackling COVID-19 pandemic. Moreoever, a further paragraph pointing out the importance of planning, coordinating and carrying out vaccination campaigns, in high-, middle-, and lower-income countries, should be anticipated in this section too.

Doing so, would allow the possibility to briefly state the benefits on the healthcare system (e.g., reduction of the pressure on the health care facilities, reduciton of the infections and overall mortality).

See some examples of references:

[Pascucci D, Nurchis MC, Sapienza M, et al. Evaluation of the Effectiveness and Safety of the BNT162b2 COVID-19 Vaccine in the Vaccination Campaign among the Health Workers of Fondazione Policlinico Universitario Agostino Gemelli IRCCS. Int J Environ Res Public Health. 2021;18(21):11098. Published 2021 Oct 22. doi:10.3390/ijerph182111098]

[Gaio V, Santos AJ, Amaral P, et al. COVID-19 vaccine effectiveness among healthcare workers: a hospital-based cohort study. BMJ Open. 2023;13(5):e068996. Published 2023 May 2. doi:10.1136/bmjopen-2022-068996]

[Arriola CS, Soto G, Westercamp M, Bollinger S, Espinoza A, Grogl M, Llanos-Cuentas A, Matos E, Romero C, Silva M, Smith R, Olson N, Prouty M, Azziz-Baumgartner E, Lessa FC. Effectiveness of Whole-Virus COVID-19 Vaccine among Healthcare Personnel, Lima, Peru. Emerg Infect Dis. 2022 Dec;28(13):S238-S243. doi: 10.3201/eid2813.212477. PMID: 36502444; PMCID: PMC9745240]

Lastly, it is of paramount importance to clearly describe what is the primary aim of the study at the end of the introduction section.

Materials and methods

It should be useful to better explicit, alongside the inclusion criteria, the exclusion ones.

There is no mention about sample size estimation. How was the sample size computed? Is it a purposive sampling? Please, specify these issues.

Discussion

It would be useful to discuss few main implications associated with vaccinating HCWs in light of the results about VE. This could have a significant impact on health systems, thus promoting tailored and targeted health policies should be clearly pointed out.

**********

7. PLOS authors have the option to publish the peer review history of their article (what does this mean?). If published, this will include your full peer review and any attached files.

If you choose “no”, your identity will remain anonymous but your review may still be made public.

Do you want your identity to be public for this peer review? For information about this choice, including consent withdrawal, please see our Privacy Policy.

Reviewer #1: No

**********

[NOTE: If reviewer comments were submitted as an attachment file, they will be attached to this email and accessible via the submission site. Please log into your account, locate the manuscript record, and check for the action link "View Attachments". If this link does not appear, there are no attachment files.]

While revising your submission, please upload your figure files to the Preflight Analysis and Conversion Engine (PACE) digital diagnostic tool, https://pacev2.apexcovantage.com/. PACE helps ensure that figures meet PLOS requirements. To use PACE, you must first register as a user. Registration is free. Then, login and navigate to the UPLOAD tab, where you will find detailed instructions on how to use the tool. If you encounter any issues or have any questions when using PACE, please email PLOS at figures@plos.org. Please note that Supporting Information files do not need this step.

10.1371/journal.pone.0307805.r004
Author response to Decision Letter 1
Submission Version2
14 Jun 2024

Dear Dr. Lau,

Thank you and thanks to the reviewers for the opportunity to respond to the reviewer's comments and your comments and revise our manuscript.

We have included a detailed response to reviewers in the attached Response to Reviewers document.

Sincerely,

Mark Katz

Attachment Submitted filename: POne Reviewer Response Georgia HW Delta_12June2024.docx

10.1371/journal.pone.0307805.r005
Decision Letter 2
Lau Eric HY Academic Editor
© 2024 Eric HY Lau
2024
Eric HY Lau
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Submission Version2
12 Jul 2024

Primary Series COVID-19 Vaccine Effectiveness among Health Care Workers in the country of Georgia, March–December 2021

PONE-D-23-33035R2

Dear Dr. Katz,

We’re pleased to inform you that your manuscript has been judged scientifically suitable for publication and will be formally accepted for publication once it meets all outstanding technical requirements.

Within one week, you’ll receive an e-mail detailing the required amendments. When these have been addressed, you’ll receive a formal acceptance letter and your manuscript will be scheduled for publication.

An invoice will be generated when your article is formally accepted. Please note, if your institution has a publishing partnership with PLOS and your article meets the relevant criteria, all or part of your publication costs will be covered. Please make sure your user information is up-to-date by logging into Editorial Manager at Editorial Manager® and clicking the ‘Update My Information' link at the top of the page. If you have any questions relating to publication charges, please contact our Author Billing department directly at authorbilling@plos.org.

If your institution or institutions have a press office, please notify them about your upcoming paper to help maximize its impact. If they’ll be preparing press materials, please inform our press team as soon as possible -- no later than 48 hours after receiving the formal acceptance. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

Kind regards,

Eric HY Lau, Ph.D.

Academic Editor

PLOS ONE

Additional Editor Comments (optional):

Thanks for addressing all the editor’s and reviewers' comments. Congratulations on the excellent work!

Reviewers' comments:

10.1371/journal.pone.0307805.r006
Acceptance letter
Lau Eric HY Academic Editor
© 2024 Eric HY Lau
2024
Eric HY Lau
https://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
25 Jul 2024

PONE-D-23-33035R2

PLOS ONE

Dear Dr. Katz,

I'm pleased to inform you that your manuscript has been deemed suitable for publication in PLOS ONE. Congratulations! Your manuscript is now being handed over to our production team.

At this stage, our production department will prepare your paper for publication. This includes ensuring the following:

* All references, tables, and figures are properly cited

* All relevant supporting information is included in the manuscript submission,

* There are no issues that prevent the paper from being properly typeset

If revisions are needed, the production department will contact you directly to resolve them. If no revisions are needed, you will receive an email when the publication date has been set. At this time, we do not offer pre-publication proofs to authors during production of the accepted work. Please keep in mind that we are working through a large volume of accepted articles, so please give us a few weeks to review your paper and let you know the next and final steps.

Lastly, if your institution or institutions have a press office, please let them know about your upcoming paper now to help maximize its impact. If they'll be preparing press materials, please inform our press team within the next 48 hours. Your manuscript will remain under strict press embargo until 2 pm Eastern Time on the date of publication. For more information, please contact onepress@plos.org.

If we can help with anything else, please email us at customercare@plos.org.

Thank you for submitting your work to PLOS ONE and supporting open access.

Kind regards,

PLOS ONE Editorial Office Staff

on behalf of

Dr. Eric HY Lau

Academic Editor

PLOS ONE
==== Refs
References

1 Bandyopadhyay S. et al ., “Infection and mortality of healthcare workers worldwide from COVID-19: a systematic review,” BMJ Glob Health, vol. 5 , no. 12 , Dec. 2020, doi: 10.1136/bmjgh-2020-003097 33277297
2 Pascucci D. et al ., “Evaluation of the Effectiveness and Safety of the BNT162b2 COVID-19 Vaccine in the Vaccination Campaign among the Health Workers of Fondazione Policlinico Universitario Agostino Gemelli IRCCS,” Int J Environ Res Public Health, vol. 18 , no. 21 , Nov. 2021, doi: 10.3390/ijerph182111098 34769618
3 Gaio V. et al ., “COVID-19 vaccine effectiveness among healthcare workers: a hospital-based cohort study,” BMJ Open, vol. 13 , no. 5 , p. e068996, May 2023, doi: 10.1136/bmjopen-2022-068996 37130692
4 “WHO SAGE ROADMAP FOR PRIORITIZING USES OF COVID-19 VACCINES IN THE CONTEXT OF LIMITED SUPPLY,” 2020.
5 Hamid H. , Abid Z. , Amir A. , Rehman T. U. , Akram W. , and Mehboob T. , “Current burden on healthcare systems in low- and middle-income countries: recommendations for emergency care of COVID-19,” Drugs & Therapy Perspectives, vol. 36 , no. 10 , p. 466, Oct. 2020, doi: 10.1007/s40267-020-00766-2 32837195
6 Grøsland M. , Larsen V. B. , Telle K. , and Gjefsen H. M. , “Has vaccination alleviated the strain on hospitals due to COVID-19? A combined difference-in-difference and simulation approach,” BMC Health Serv Res, vol. 22 , no. 1 , pp. 1–11, Dec. 2022, doi: 10.1186/S12913-022-08541-X/TABLES/4 34974828
7 World Health Organization, “WHO Coronavirus (COVID-19) Dashboard,” https://covid19.who.int/. Accessed: Jun. 30, 2022. [Online].
8 Watson O. J. , Barnsley G. , Toor J. , Hogan A. B. , Winskill P. , and Ghani A. C. , “Global impact of the first year of COVID-19 vaccination: a mathematical modelling study,” Lancet Infect Dis, vol. 22 , no. 9 , pp. 1293–1302, Sep. 2022, doi: 10.1016/S1473-3099(22)00320-6 35753318
9 Meslé M. M. I. et al ., “Estimated number of deaths directly averted in people 60 years and older as a result of COVID-19 vaccination in the WHO European Region, December 2020 to November 2021,” Eurosurveillance, vol. 26 , no. 47 , p. 2101021, Nov. 2021, doi: 10.2807/1560-7917.ES.2021.26.47.2101021 34823641
10 “WDI—The World by Income and Region.” Accessed: Oct. 03, 2023. [Online]. https://datatopics.worldbank.org/world-development-indicators/the-world-by-income-and-region.html
11 “Effectiveness Studies | ViewHub.” Accessed: Sep. 12, 2022. [Online]. https://view-hub.org/covid-19/effectiveness-studies
12 “WHO/Europe Covid-19 vaccine programme monitor.” Accessed: Oct. 17, 2022. [Online]. https://worldhealthorg.shinyapps.io/EURO_COVID-19_vaccine_monitor/
13 WHO Europe, “WHO/Europe COVID-19 Vaccine Programme Monitor.” Accessed: Jul. 11, 2022. [Online]. https://worldhealthorg.shinyapps.io/EURO_COVID-19_vaccine_monitor/
14 Lucaccioni H. et al ., “Sociodemographic and Occupational Factors Associated with Low Early Uptake of COVID-19 Vaccine in Hospital-Based Healthcare Workers, Georgia, March–July 2021,” Vaccines (Basel), vol. 10 , no. 8 , p. 1197, Aug. 2022, doi: 10.3390/vaccines10081197 36016084
15 World Health Organization. Regional Office for Europe., “Cohort study to measure COVID-19 vaccine effectiveness among healthcare workers in the WHO European Region: guidance document.,” 2021.
16 World Health Organization, “Coronavirus disease (COVID-19) technical guidance: The Unity Studies: Early Investigation Protocols.” Accessed: Nov. 08, 2021. [Online]. https://www.who.int/emergencies/diseases/novel-coronavirus-2019/technical-guidance/early-investigations
17 Harris P. A. , Taylor R. , Thielke R. , Payne J. , Gonzalez N. , and Conde J. G. , “Research electronic data capture (REDCap)—A metadata-driven methodology and workflow process for providing translational research informatics support,” J Biomed Inform, vol. 42 , no. 2 , Apr. 2009, doi: 10.1016/j.jbi.2008.08.010 18929686
18 Riester E. et al ., “Performance evaluation of the Roche Elecsys Anti-SARS-CoV-2 S immunoassay,” J Virol Methods, vol. 297 , p. 114271, Nov. 2021, doi: 10.1016/j.jviromet.2021.114271 34461153
19 Khare S. et al ., “GISAID’s Role in Pandemic Response,” China CDC Wkly, vol. 3 , no. 49 , pp. 1049–1051, 2021, doi: 10.46234/ccdcw2021.255 34934514
20 Wajnberg A. et al ., “Humoral response and PCR positivity in patients with COVID-19 in the New York City region, USA: an observational study,” Lancet Microbe, vol. 1 , no. 7 , pp. e283–e289, Nov. 2020, doi: 10.1016/S2666-5247(20)30120-8 33015652
21 Higdon M. M. et al ., “A Systematic Review of Coronavirus Disease 2019 Vaccine Efficacy and Effectiveness Against Severe Acute Respiratory Syndrome Coronavirus 2 Infection and Disease,” Open Forum Infect Dis, vol. 9 , no. 6 , Jun. 2022, doi: 10.1093/ofid/ofac138 35611346
22 Mallapaty S. , “China’s COVID vaccines have been crucial—now immunity is waning,” Nature, vol. 598 , no. 7881 , pp. 398–399, Oct. 2021, doi: 10.1038/d41586-021-02796-w 34650240
23 Wu D. et al ., “Effectiveness of Inactivated COVID-19 Vaccines Against Symptomatic, Pneumonia, and Severe Disease Caused by the Delta Variant: Real World Study and Evidence—China, 2021,” China CDC Weekly, 2022, Vol. 4, Issue 4, Pages: 57–65, vol. 4 , no. 4 , pp. 57–65, Jan. 2022, doi: 10.46234/CCDCW2022.009 35186369
24 Ma C. et al ., “Effectiveness of adenovirus type 5 vectored and inactivated COVID-19 vaccines against symptomatic COVID-19, COVID-19 pneumonia, and severe COVID-19 caused by the B.1.617.2 (Delta) variant: Evidence from an outbreak in Yunnan, China, 2021,” Vaccine, vol. 40 , no. 20 , pp. 2869–2874, May 2022, doi: 10.1016/j.vaccine.2022.03.067 35400561
25 O. Fahmy Esmail, E. Drug Authority, and E. Samar Kabeel, “Effectiveness and safety of inactivated SARS-CoV2 vaccine (BBIBP-CorV) among healthcare workers: A seven-month follow-up study at fifteen hospitals,” Mar. 2022.
26 Vokó Z. et al ., “Effectiveness and Waning of Protection With Different SARS-CoV-2 Primary and Booster Vaccines During the Delta Pandemic Wave in 2021 in Hungary (HUN-VE 3 Study),” Front Immunol, vol. 13 , p. 3609, Jul. 2022, doi: 10.3389/fimmu.2022.919408 35935993
27 Heidarzadeh A. , Amini Moridani M. , Khoshmanesh S. , Kazemi S. , Hajiaghabozorgi M. , and Karami M. , “Effectiveness of COVID-19 vaccines on hospitalization and death in Guilan, Iran: a test-negative case-control study,” International Journal of Infectious Diseases, vol. 128 , pp. 212–222, Mar. 2023, doi: 10.1016/j.ijid.2022.12.024 36572376
28 Nittayasoot N. et al ., “Real-World Effectiveness of COVID-19 Vaccines against Severe Outcomes during the Period of Omicron Predominance in Thailand: A Test-Negative Nationwide Case–Control Study,” Vaccines 2022, Vol. 10, Page 2123, vol. 10 , no. 12 , p. 2123, Dec. 2022, doi: 10.3390/vaccines10122123 36560533
29 The Lancet Infectious Diseases, “Why hybrid immunity is so triggering,” Lancet Infect Dis, vol. 22 , no. 12 , p. 1649, Dec. 2022, doi: 10.1016/S1473-3099(22)00746-0 36372089
30 Hall V. et al ., “Protection against SARS-CoV-2 after Covid-19 Vaccination and Previous Infection,” New England Journal of Medicine, vol. 386 , no. 13 , pp. 1207–1220, Mar. 2022, doi: 10.1056/NEJMoa2118691 35172051
31 Rubin-Smith J. et al ., “Primary Series COVID-19 Vaccine Effectiveness Among Health Care Workers in Albania, February–December 2021,” SSRN Electronic Journal, 2022, doi: 10.2139/SSRN.4282932
32 “Interim statement on hybrid immunity and increasing population seroprevalence rates.” Accessed: Jan. 02, 2023. [Online]. https://www.who.int/news/item/01-06-2022-interim-statement-on-hybrid-immunity-and-increasing-population-seroprevalence-rates
33 Dhakal S. et al ., “Reconsideration of anti-nucleocapsid IgG antibody as a marker of SARS-CoV-2 infection post-vaccination for mild COVID-19 patients,” Open Forum Infect Dis, Dec. 2022, doi: 10.1093/OFID/OFAC677 36655185
