Risk factors for acquisition of SARS-CoV-2 Omicron variant among a prospective cohort of French Healthcare Workers: impact of hybrid immunity

Abstract

Healthcare workers (HCW) have been at the frontline during the COVID-19 pandemic, with an increased risk of infection, particularly due to the emergence of the omicron variant. This study aims to assess risk factors for omicron acquisition among vaccinated HCW, comparing hybrid immunity (previous infection and vaccination) to vaccine-induced immunity alone. We took advantage of the COVID-HOP prospective cohort, which includes vaccinated HCW followed over several months, collecting detailed data on demographic characteristics, comorbidities, and professional and personal exposures to COVID-19. We analyzed factors associated with omicron acquisition after January 2022, with a focus on immunization scheme (hybrid or vaccine-induced immunity). Out of 698 HCW analyzed, 298 acquired the omicron variant. In the multivariable analysis (taking into account comorbidities, professional/personal exposure and lifestyle), the two independent factors associated with an increased risk of infection were: younger age (P = 0.005) and immunization scheme (OR associated with vaccine-induced immunity alone: 2.43 [95% Confidence Interval: 1.64–3.60]) with hybrid immunity as reference). HCW with hybrid immunity have a reduced risk of acquiring omicron compared to those with vaccine-induced immunity alone. These findings emphasize the importance of a combined vaccination strategy to better protect HCW against emerging variants, and to vaccine HCW who experienced previous COVID-19 episodes.

Supplementary Information

The online version contains supplementary material available at 10.1038/s41598-026-57971-8.

Introduction

Since the first wave of COVID-19, healthcare workers (HCW) have been in front line with higher incidence of infection, as compared to the general population, especially among HCW working in COVID-19 wards¹. It also became apparent that an important proportion of infections among HCW did not involve infected in-hospital patients but rather colleagues and, more frequently, family or relatives outside of the hospital^2–4. Considering this important risk, HCW were among the first group of people who received SARS-CoV-2 vaccination in January 2021 in France, leading to a significant decrease in contaminations⁵. Prospective cohort studies latter observed that neutralizing antibodies decreased rapidly after infection or vaccination, suggesting that HCW could experience breakthrough infections, despite history of COVID-19 or complete vaccination, especially in the context of emerging SARS-CoV-2 variants^6,7.

The omicron variant, initially described in November 2021 in South Africa, rapidly and successfully spread all over the world⁸. In France, epidemiological surveillance based on whole genome sequencing revealed that omicron variant (initially BA.1) started to spread in December 2021 and accounted for more than 90% of contaminations and hospitalizations in January 2022^9,10. This rapid spread was mostly explained by the ability of the omicron variant to escape immune response, resulting in a reduced protection offered by previous non-omicron infections or vaccination^11–13. HCW also experienced omicron breakthrough, despite an important vaccine coverage^12,14,15. Strikingly, HCW cohort studies performed in Greece and in South Africa observed that HCW with hybrid immunity (past non-omicron infection and vaccination) had a lower risk of omicron infection, as compared to those who only received vaccination^14,15. This finding was confirmed in meta-analysis demonstrating that patients with hybrid immunity had the highest and longest protection against omicron infections, as compared to patients who only received vaccination, without previous history of COVID-19^16,17. However, most of these studies did not take into account comprehensive comorbidity and SARS-CoV-2 exposure data.

In France, COVID-19 vaccination was deemed mandatory for all HCW from October 2021, few months before the emergence and spread of the omicron variant. We took advantage of a prospective cohort of HCW initiated during the first wave of COVID-19 (COVID-HOP) to measure the risk of omicron acquisition among HCW, with extensive data regarding baseline characteristics but also professional and personal exposure to SARS-CoV-2. Our main objective was to identify risk factors for acquisition of SARS-CoV-2 omicron variant among vaccinated HCW with a special focus on comparing hybrid immunity and vaccine-induced immunity, taking into account comprehensive comorbidity and exposure data.

Materials and methods

Study design and participants

The COVID-HOP cohort was initiated to create a longitudinal collection of clinical data associated with a biological collection (serum, plasma, DNA, RNA, mononuclear cells and urine collection) of medical and non-medical HCW from 6 teaching hospitals of the Assistance Publique-Hôpitaux de Paris (George Pompidou European Hospital, Cochin, Lariboisière, Bichat, Necker, La Pitié-Salpétrière), France. The cohort originally aimed at identifying clinical factors and biomarkers associated with either symptomatic or asymptomatic COVID-19 (see Appendix 1, study protocol). All adult HCW working in any of the 6 AP-HP hospitals participating in the COVID-HOP study (Paris, France) and who provided written consent could be included. HCW could be included in the COVID-HOP study by two modalities:

1-Participants with no serology available on day of inclusion were included at the Occupational Health Services between June 8, 2020 and July 8, 2021 (Fig. 1 and Supplementary Table 1). Inclusion was proposed to all HCW who came to request a blood sample to perform anti-SARS-CoV-2 antibody testing, which was proposed to all HCW from the AP-HP, after the first wave of COVID-19. After inclusion (visit #1), participants were prospectively followed and monitored at 3–9 months (+/− 6 weeks) (visit #2) and 12 months (+/− 4 weeks) (visit #3) after the initial serology (Supplementary Table 1).

Fig. 1.

Flow chart of the COVID-HOP study. Healthcare workers (HCW) could be included prospectively (n = 296, at the time of their first anti-SARS-CoV-2 antibody testing) or retrospectively (n = 892, this inclusion method concerned HCW who already had a screening serology less than 9 months before inclusion).

2-Participants who already had an anti-SARS-CoV-2 antibody testing available could also be included (Fig. 1 and Supplementary Table 1). In that case, the only inclusion criteria was to have had an anti-SARS-CoV-2 antibody testing performed less than 9 months before inclusion. In that case, visits #1 and #2 were both performed at inclusion, between June 8, 2020 and July 8, 2021. Subsequently, participants were prospectively followed at 12 months (+/− 4 weeks) after the initial serology.

At each visit, anti-SARS-CoV-2 antibody testing was performed in each inclusion site with comparable methods as well as an interview assessing the occurrence of COVID-19 since last visit, the description of clinical signs and the type of diagnostic method that was used (Supplementary Table 1). We also compared anti-N and anti-S antibodies to differentiate exposure to COVID-19 and vaccine.

An additional phone interview (visit #4) was performed between May 23, 2022 and October 12, 2022 in order to record any COVID-19 infection occurring since visit #3. It was also designed to record data regarding the exposure to SARS-CoV-2 at work and in the personal sphere. Any COVID-19 occurring after January 2, 2022 was considered to be caused by the omicron variant as it was responsible for more than 90% of infections in France at that time^9,10,18. The chronological distribution of visits #1 to #4 as well as the incidence of COVID-19 and the proportion of omicron variants in Ile-de-France are depicted on Supplementary Fig. 1.

The objective of the present study was to compare hybrid immunity and vaccine-induced immunity on the risk of acquisition of SARS-CoV-2 omicron variant. We therefore restricted our analysis to the population of HCW who received at least one dose of vaccine before January 2nd, 2022, and who had visit #4. We subsequently excluded HCW who experienced COVID-19 not caused by omicron variant between visit #3 and #4.

Data collection and definitions

At inclusion, a detailed questionnaire was fulfilled, including demographic data (age, gender), comorbidities (including immunosuppression, body mass index, smoking and alcohol consumption), treatments (including corticosteroids and immunosuppressive drugs), as well as professional and extra professional exposures to SARS-CoV-2 (see below). At each visit, we also recorded data regarding each COVID-19 infection which had occurred since the previous visit (symptoms, see below) and vaccination (number and dates of vaccine doses). Vaccination of HCW was made mandatory in France in October 2021. As of that date, HCW had to be fully immunized to continue their professional activity. Immunization was considered complete with the following schemes: either two vaccine doses or one COVID-19 episode and one vaccine dose, or two COVID-19 episodes. Most vaccinations were performed with a mRNA vaccine (BNT162b2, BioNTech-Pfizer).

On last visit (#4), the following occupational data were recorded: professional category (see below), frequency of contacts with patients and especially COVID-19 patients, contacts with infected colleagues at work, and use of personal protective equipment (surgical face mask, N95 respirator, eye protection) since the last COVID-HOP study visit. We also recorded exposure of HCW in their personal sphere including number and ages of household members, exposure to an infected person outside of work (less than 2 m, without face mask), use of public transportation, use of surgical face mask outside of the hospital⁴.

HCW were grouped as follows: i) medical staff (physicians, residents); ii) nurses and nurse’s aides; iii) medico-technic professionals including pharmacists and laboratory professionals (including clinical biologists) and iv) administrative staff.

A definite diagnosis of COVID-19 required one of the following criteria:

i) a positive SARS-CoV-2 PCR or antigenic test at any moment (PCR or antigenic tests could be performed in one of including hospitals or in pharmacy).

or ii) a positive anti-SARS-CoV-2 antibody testing (initially antibodies directed against N-protein and then against N and spike proteins, see Supplementary Table 2) before December 31, 2020 (date of the initiation of HCW vaccination in France). Therefore, after December 31, 2020, COVID-19 cases could not be diagnosed solely on positive anti-SARS-CoV-2 antibody testing.

Presumed omicron cases were those who tested positive for SARS-CoV-2 (PCR or antigenic test) after January 2, 2022, when omicron variant accounted for more than 90% of COVID-19 cases (Supplementary Fig. 1). Even if in-depth molecular analysis were rarely performed at that time, some positive PCR samples were sequenced. Therefore, some omicron cases were confirmed before the date of January 2, 2022. Those early confirmed cases were also included in our analysis of omicron cases.

In case of acquisition of COVID-19 caused by the omicron variant, we classified the severity of the disease as follows: 1—Asymptomatic; 2—Ambulatory mild disease = including both non pneumonia and pneumonia cases but that do not require hospitalization. Presence of at least one symptom among fever ≥ 38 °C, asthenia, myalgia, headache, cough, dyspnea, anosmia, ageusia; 3—Hospitalised, moderate disease: without oxygen (3A) or with oxygen ≤ 3 l/min (3B); 4- Hospitalised, severe disease: non-invasive ventilation or oxygen > 3 l/min; 5-Hospitalised, critical, requiring ICU admission.

The time since the last immunological contact was calculated between the last COVID-19 episode or vaccine dose and the beginning of the omicron wave in France (January 2nd, 2022). We chose an identical date (January 2nd, 2022) for all participants because visit #4 occurred during a wide period (between May 23, 2022 and October 12, 2022), leading to important differences in exposure for each participant. This date was chosen because omicron variant was responsible for more than 90% of infections in France at that time (Supplementary Fig. 1).

The type of immunization was based on history of COVID infection and vaccination dates and classified into three categories: hybrid immunity (COVID and vaccine), COVID only or vaccine only. For this classification, we considered COVID infection as defined above if the last episode was diagnosed before January 2nd, 2022.

As our main objective was to compare hybrid immunity and vaccine-induced immunity, we did not retain in our final analysis HCW who were classified as “COVID only” and who never received any vaccine dose.

Statistical analyses

Continuous data are presented as medians with their interquartile ranges (IQR) and categorical data as counts and proportions. A logistic regression analysis was used to determine the risk factors associated with acquiring omicron variant. A backward stepwise approach was first used to identify independent factors and selected variables (with p < 0.05) were added in the model. Multicollinearity between variables was assessed on the model using the Generalised Variance Inflation Factor (GVIF) calculated using the car package in the R software. Due to missing data, a brief comparison between patients with complete data and those with at least one missing data was performed. A sensitivity analysis was also conducted by re-estimating the model after removing the variable with the most missing data. Adjusted odds ratios (aOR) and 95% confidence intervals (95% CIs) were calculated for all variables.

As visit #4 occurred during a wide period (between May 23, 2022 and October 12, 2022), this led to important differences in exposure for each participant. We therefore also performed a Cox model analysis, taking into account the follow-up period between December 1, 2021 (this date was chosen because it was the date of the first confirmed omicron case in our cohort) and the date on which the omicron variant was detected or the last follow-up visit. Logistic regression and Cox model analysed the same study population and outcome. Statistical analyses were made using R version 4.2.2 software (R Foundation for Statistical Computing, Vienna, Austria), and p < 0.05 were considered statistically significant.

The STROBE checklist is depicted in Appendix 2.

Ethical considerations

This study was conducted in accordance with the Declaration of Helsinki and with French laws and subscribed to the principles outlined in the International Conference on Harmonization on Good Clinical Practice, 2002. A favorable opinion was delivered by the Ethics Committee CPP Sud-Ouest et Outre Mer II (Committee for the Protection of Persons- Sud-Ouest et Outre Mer II) with the reference number 2-20-047 id8221. The study was registered in ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT04418375) on June 5, 2020. All participants provided written informed consent. The data were collected by each trial-site personnel, stored in an electronic database, and monitored by an independent data monitoring board.

Results

Participants

The COVID-HOP cohort included 1201 participants between June 8, 2020 and July 8, 2021 (Fig. 1). After exclusion of 13 HCW not meeting inclusion criteria or meeting exclusion criteria, 1188 participants have been included (Supplementary Table 3). A complete follow-up reaching the visit #4 interview was obtained for 754 participants. Of note, all participants of one centre (n = 82) were excluded because that centre did not participate to the V4. Among the 754 remaining participants, 30 participants experienced COVID-19 not caused by the omicron variant and where not retained for the present analysis. We also excluded 26 participants who had no vaccination history before January 2nd, 2022. As a result, data regarding 698 HCW were analysed: 298 (42.7%) who experienced COVID-19 caused by a presumed omicron variant and 400 (57.3%) who did not (Table 1). Among 298 omicron cases, 55/298 (18.4%) were confirmed by sequencing. The first confirmed omicron case was diagnosed in December 1, 2021 and a total number of 25 confirmed cases were diagnosed up to January 2, 2022. After January 2, 2022, 30 cases were confirmed by sequencing. Other cases were presumed as being caused by omicron variant because they were diagnosed after January 2, 2022.

Table 1.

Clinical and biological characteristics at inclusion of the 698 Healthcare Workers (HCW) who reached visit #4 and univariate comparison of HCW who acquired COVID-19 caused by the omicron variant (n = 298) and those who did not (n = 400).

Variable		Whole sample (N = 698)	No infection (N = 400)	Acquisition of the omicron variant (N = 298)	OR (CI95)	P-value
Age (years), n (%)
≤ 35		151 (21.6)	77 (19.2)	74 (24.8)	ref	0.002
]35;45]		163 (23.3)	80 (20.0)	83 (27.8)	1.08 (0.69–1.68)	0.616
]45;55]		202 (28.9)	120 (30.0)	82 (27.5)	0.71 (0.46–1.09)	0.17
> 55		182 (26.1)	123 (30.7)	59 (19.8)	0.50 (0.32–0.78)	0.005
Female, n (%)		579 (82.9)	322 (80.5)	257 (86.2)	1.52 (1.01–2.29)	0.047
Born in France, n (%) (n = 697)		603 (86.5)	336 (84.2)	267 (89.6)	1.61 (1.02–2.56)	0.041
Body mass index, median (IQR) (kg/m2) (n = 691)		23.6 [21.2;27.2]	24.0 [21.2;27.5]	23.2 [21.1;26.4]	0.97 (0.93–1.00)	0.054
Tobacco consumption, n (%) (n = 692)
Former smoker		137 (19.8)	78 (19.7)	59 (19.9)
Active smoker		99 (14.3)	56 (14.1)	43 (14.5)	1.01 (0.60–1.71)	0.984
Never smoked		456 (65.9)	262 (66.2)	194 (65.5)	0.98 (0.67–1.44)
Diabetes, n (%) (n = 693)		13 (1.9)	5 (1.3)	8 (2.7)	2.95 (0.68–12.81)	0.15
Active comorbidities, n (%)
Chronic autoimmune disease (n = 691)		44 (6.4)	26 (6.6)	18 (6.1)	0.92 (0.49–1.71)	0.790
Solid organ transplantation (n = 694)		1 (0.1)	1 (0.2)	0 (0.0)	–	0.980
Haematological malignancy		1 (0.1)	1 (0.2)	0 (0.0)	–	0.980
Immunosuppressive agent, n (%)
Systemic corticosteroids (n = 691)		10 (1.4)	7 (1.8)	3 (1.0)	0.58 (0.15–2.25)	0.430
Other Immunosuppressive agents (n = 677)		4 (0.6)	3 (0.8)	1 (0.3)	0.45 (0.05–4.33)	0.488
Occupational characteristics, n (%)
HCWs professional category (n = 697)
Administrative staff		133 (19.1)	83 (20.8)	50 (16.8)	ref
Medical staff (physicians, residents)		135 (19.4)	73 (18.3)	62 (20.8)	1.41 (0.87–2.30)	0.246
Medico-technic professionals		103 (14.8)	52 (13.0)	51 (17.1)	1.63 (0.97–2.74)
Nurses and nurse’s aides		326 (46.8)	191 (47.9)	135 (45.3)	1.17 (0.77–1.78)
Recent personal exposures to COVID-19
Exposure to an infected person, n (%) (n = 586)		372 (63.5)	190 (59.2)	182 (68.7)	1.51 (1.07–2.13)	0.018
Number of household members, Median (IQR) (n = 691)		2 [2;4]	2 [2;4]	2 [2;4]	1.04 (0.94–1.17)	0.431
Age of people in the household, n (%) (n = 691)
From 0- to 4-year-old		79 (11.4)	40 (10.1)	39 (13.1)	1.34 (0.84–2.14)	0.224
From 5- to 15-year-old		162 (23.4)	82 (20.8)	80 (26.9)	1.40 (0.98–2.00)	0.061
From 16- to 70-year-old		684 (99.0)	391 (99.2)	293 (98.6)	0.56 (0.12–2.53)	0.453
More than 70-year-old		19 (2.7)	12 (3.0)	7 (2.4)	0.77 (0.30–1.98)	0.585
Use of public transportation, n (%) (n = 694)
Never		135 (19.4)	72 (18.1)	63 (21.2)	ref
Occasionally		165 (23.8)	93 (23.4)	72 (24.2)	0.88 (0.56–1.40)	0.515
Every day		394 (56.8)	232 (58.4)	162 (54.5)	0.80 (0.54–1.18)
Use of surgical face mask in closed public places, n (%) (n = 693)
Never		110 (15.9)	63 (15.9)	47 (15.8)	ref
Occasionally		280 (40.4)	154 (38.9)	126 (42.4)	1.10 (0.70–1.71)	0.610
All the time		303 (43.7)	179 (45.2)	124 (41.7)	0.93 (0.60–1.44)
Recent professional exposures to COVID-19, n (%)†
Currently working in a unit dedicated to patients with COVID-19 (n = 688)		143 (20.8)	79 (20.1)	64 (21.7)	1.10 (0.76–1.60)	0.610
Currently taking care of patients with COVID-19 (n = 679)		239 (35.2)	136 (34.9)	103 (35.6)	1.03 (0.75–1.42)	0.836
Use of N95 respirator when caring for patients with COVID-19 (n = 293)
Never		112 (38.2)	61 (37.4)	51 (39.2)	ref
Most of the time		82 (28.0)	46 (28.2)	36 (27.7)	0.94 (0.53–1.66)	0.949
Only for some acts		99 (33.8)	56 (34.4)	43 (33.1)	0.92 (0.53–1.58)
Use of eye protection (goggles or face shield) when caring for patients with COVID-19 (n = 285)
Never		169 (59.3)	93 (59.2)	76 (59.4)	ref
Most of the time		37 (13.0)	17 (10.8)	20 (15.6)	1.44 (0.70–2.94)	0.396
Only for some acts		79 (27.7)	47 (29.9)	32 (25.0)	0.83 (0.48–1.43)
Number of COVID-19 episodes before the omicron wave, n (%)
0		373 (53.4)	193 (48.2)	180 (60.4)	ref
1		309 (44.3)	197 (49.2)	112 (37.6)	0.61 (0.45–0.83)	0.006
2		16 (2.3)	10 (2.5)	6 (2.0)	0.64 (0.23–1.81)
Number of COVID-19 vaccine doses before the omicron wave, n (%)
1		91 (13.0)	61 (15.2)	30 (10.1)	ref	0.046
≥ 2		607 (87.0)	339 (84.7)	268 (89.9)	1.61 (1.01–2.56)
Time since the last immunological contact (last COVID-19 or vaccine dose), n (%)*
≤ 4 months		564 (80.8)	312 (78.0)	252 (84.6)	ref
]4–6] months		31 (4.4)	19 (4.7)	12 (4.0)	0.78 (0.37–1.64)	0.092
]6–8] months		27 (3.9)	21 (5.2)	6 (2.0)	0.354 (0.14–0.89)
> 8 months		76 (10.9)	48 (12.0)	28 (9.4)	0.72 (0.44–1.18)
Type of immunization, n (%)
	Hybrid immunity	309 (44.3)	207 (51.7)	102 (34.2)	ref
	Vaccine only	389 (55.7)	193 (48.2)	196 (65.8)	2.06 (1.51–2.81)	< 0.001

CI₉₅: Confidence interval at 95%; IQR: inter quartile range; OR : Odds-ratio ; ref: reference.

*The time since the last immunological contact was calculated between the last COVID-19 episode or vaccine dose and the beginning of the omicron wave in France (January 2nd, 2022), see “Materials and methods”.

^†Data regarding recent exposure were collected during visit #4.

Median age was 48 [37.0; 56.0] years and most of HCW were female (579/698, 83.0%) (Table 1). Description of the COVID-19 cases caused by the omicron variant are depicted in Supplementary Table 4.

Risk factors for the acquisition of the omicron variant

In univariate analysis (Table 1), younger age (≤ 35-year-old, as compared to older HCW), being a woman, being born in France, exposure to an infected person, not having had a COVID-19 before the omicron wave, being vaccinated with ≥ 2 vaccine doses and having a vaccine immunity only were significantly associated with the acquisition of COVID-19 presumed to be caused by the omicron variant.

In multivariable analysis (Table 2), young age (P = 0.005) and vaccine only-induced immunity were the only factors (P =  < 0.001) associated with the acquisition of COVID-19 presumed to be caused by the omicron variant. Even if the use of surgical face masks in closed public places was not associated with the acquisition of presumed omicron infection (p = 0.61) in univariate analysis, we forced this variable in the multivariable model and reached similar results.

Table 2.

Multivariable comparison of HCW who acquired COVID-19 caused by the omicron variant (n = 242) and those who did not (n = 293). A backward stepwise approach was first used to identify independent factors and selected variables were added in the model on complete data.

Variable	Whole sample (N = 535)	No infection (N = 293)	Acquisition of the omicron variant (N = 242)	aOR (CI95)	P-value
Age (years), n (%)
≤ 35	120 (22.4)	59 (20.1)	61 (25.2)	ref	0.005
]35;45]	128 (23.9)	59 (20.1)	69 (28.5)	1.16 (0.68–1.96)
]45;55]	146 (27.3)	82 (28.0)	64 (26.4)	0.71 (0.43–1.19)
> 55	141 (26.4)	93 (31.7)	48 (19.8)	0.48 (0.28–0.81)
Female, n (%)	448 (83.7)	235 (80.2)	213 (88.0)	1.71 (0.99–2.95)	0.055
Exposure to an infected person, n (%)	339 (63.4)	172 (58.7%)	167 (69.0)	1.47 (1.00–2.15)	0.051
Age of people in the household from 16- to 70-year-old n (%)	529 (98.9)	291 (99.3)	238 (98.3)	0.29 (0.05–1.69)	0.169
Time since the last immunological contact (last COVID-19 or vaccine dose)*, n (%)
≤ 4 months	431 (80.6)	225 (76.8)	206 (85.1)	ref	0.089
]4–6] months	22 (4.1)	14 (4.8)	8 (3.3)	0.89 (0.31–2.52)
]6–8] months	24 (4.5)	18 (6.1)	6 (2.5)	0.31 (0.12–0.84)
> 8 months	58 (10.8)	36 (12.3)	22 (9.1)	0.66 (0.35–1.24)
Type of immunization, n (%)
Hybrid immunity	236 (44.1)	154 (52.6)	82 (33.9)	ref	< 0.001
Vaccine only	299 (55.9)	139 (47.4)	160 (66.1)	2.43 (1.64–3.60)
HCWs professional category, n (%)
Administrative staff	99 (18.5)	60 (20.5)	39 (16.1)	ref	0.455
Medical staff (physicians, residents)	106 (19.8)	59 (20.1)	47 (19.4)	1.54 (0.83–2.85)
Medico-technic professionals	81 (15.1)	40 (13.6)	41 (16.9)	1.49 (0.79–2.81)
Nurses and nurse’s aides	249 (46.5)	134 (45.7)	115 (47.5)	1.43 (0.86–2.37)
Number of COVID-19 vaccine doses before the omicron wave, n (%)
1	65 (12.1)	42 (14.3)	23 (9.5)	ref	0.716
≥ 2	470 (87.8)	251 (85.7)	219 (90.5)	0.88 (0.44–1.76)

aOR: adjusted Odds-ratio; CI₉₅: Confidence interval at 95%; IQR: inter quartile range; ref: reference.

*The time since the last immunological contact was calculated between the last COVID-19 episode or vaccine dose and the beginning of the omicron wave in France (January 2nd, 2022), see “Materials and methods”.

Multicollinearity analysis using adjusted GVIF showed that all variables had values below 2, suggesting there is no substantial collinearity between the explanatory variables in the model (Supplementary Table 5). No significant differences were observed between patients with complete data and patients with at least one missing data (Supplementary Table 6). Exposure to an infected person was the variable that contains the most missing data. A sensitivity analysis excluding this variable yielded similar results.

When compared to hybrid immunity, vaccine-induced immunity alone was associated with a higher risk of acquisition of COVID-19 presumed to be caused by the omicron variant (OR:2.43 (1.64–3.60), P =  < 0.001).

Similar results were obtained after multivariable analysis with Cox model, to take into account differences in exposure for each participant (Supplementary Table 7).

Discussion

In our prospective cohort study of 698 vaccinated healthcare workers, we identified that two factors were independently associated with an increased risk of acquisition of the COVID-19 presumed to be caused by the omicron variant: young age and vaccine immunity alone. Conversely, we observed that participants with hybrid immunity (previous COVID-19 episode and vaccine) had a reduced risk to acquire the omicron variant, as compared to those with vaccine-induced immunity alone. To consider differences in exposure for each participant, we also performed multivariable analysis with Cox model that confirmed our results.

The main interest of our cohort was that 100% of our HCW were vaccinated against COVID-19 before the beginning of the omicron wave, as vaccination was deemed mandatory for all HCW in October 2021. Were therefore specifically analysed the impact of each type of immunization, considering the respective role of personal/professional exposure and use of personal protective equipment. A meta-analyse published in 2024 reported that hybrid immunity was associated with the lowest risk of reinfection by a presumed omicron variant, as compared to complete vaccination group (but no history of COVID-19), or incomplete vaccination group¹⁷. To understand this higher level of protection, different studies explored humoral and cellular responses among patients with hybrid immunity (history of COVID-19 and vaccine) and those who never experienced COVID-19 (“vaccine-only” group). In a large cohort study performed in China between December 2022 and June 2023, the authors observed that individuals with previous COVID-19 infections had a slower decline of SARS-CoV-2 IgG antibody levels after vaccination, as compared to individuals with no history of infection¹⁹. Among 111 HCW, S1-specific IgG and neutralizing antibody levels were significantly higher in individuals with hybrid immunity as compared to the “vaccine-only” group. Another group also analysed T-cell responses cross-reactivity in previously exposed individuals. They observed that responses and cross-recognition were higher when the first immunological contact was caused by COVID-19, rather than vaccination²⁰.

In our cohort, we also observed that young age (≤ 35-year-old) was associated with a higher risk of contamination by the omicron variant. This observation might be due to a reduced use of face masks: in a self-reported mask-wearing survey performed among 378 207 participants in the USA in June and July 2020, the use of face mask increased in a linear manner with age²¹. However, the use of face masks was not associated with the acquisition of presumed omicron infection after univariate analysis in our cohort, nor when forced in the multivariable model.

In univariate analyses, we observed that participants receiving a single vaccine dose had a reduced risk of acquisition of the omicron variant, as compared to those receiving at least two vaccine doses. This counterintuitive result is likely caused by the vaccine policy that was used among HCW: individuals who previously experienced COVID-19 met criteria for mandatory vaccination in October 2021 if they received a single vaccine dose. This means that in univariate analysis, receiving a single vaccine dose was likely a proxy of hybrid immunity. In line with this hypothesis, this variable was not statistically significant after multivariable analysis, suggesting that the hybrid immunity per se is associated with a reduced risk of infection and not the fact that HCW received a single vaccine dose.

The second interest of our cohort is that we collected several important data regarding participants’ lifestyle and exposure to COVID-19 during their professional or personal life. Our multivariable analysis could therefore take into account several factors that were previously demonstrated to increase the risk of COVID-19 acquisition among HCW, such as exposure to an infected person, being a nurse or a nurse’s aide (as compared to medical professions), not wearing eye protection or a gown for COVID-19 patient care⁴. We did not identify these factors in our cohort, likely suggesting the acquisition of COVID-19 in the community during the omicron wave, rather than at the hospital, and the widespread availability of personal protective equipment. However, this interpretation should be cautious because lifestyle data were collected at a single time point and may have changed over the course of follow-up, especially with possible behavioural changes (e.g., avoiding contacts, increased mask use).

Our cohort has several limitations: i) we only analysed a subset of all initially included participants. Even if baseline characteristics of included participants appear comparable to that of the overall cohort (Table 1 and Supplementary Table 3), we cannot rule out that this may have led to attrition bias ; ii) The criteria for acquisition of a presumed omicron variant was mostly based on the date of COVID-19 acquisition, since in-depth molecular analysis was rarely available. Nevertheless, national surveillance data indicate that from this date and thereafter, more than 90% of COVID-19 cases were caused by the omicron variant in France; iii) Lifestyle data were collected at one time point but could evolve along time; iv) as visit #4 was performed by telephone interview, asymptomatic infections may have been missed and it is also possible that recall bias may have reduced our ability to capture 100% of omicron cases; v) Lack of data regarding additional vaccinations (performed after January 2, 2022), is a limitation of the study. Indeed, booster vaccinations may have influenced outcomes; vi) Lastly, as we only included French HCW, our data may not be generalizable to author countries.

In our cohort, 100% of HCW received COVID-19 vaccination. Our aim was not to study the effect of vaccination but rather compare HCW who had vaccine-induced immunity to those who had hybrid immunity. It is important to remind that among HCW, vaccination has been repeatedly demonstrated to reduce the risk of COVID-19 acquisition and the risk of severe evolution of the disease^22–24.

In conclusion, our data suggest that hybrid-immunity was associated with a reduced risk of acquisition of the omicron variant, compared to vaccine-induced immunity alone while lifestyle and exposure factors appear less relevant. These data are important to guide vaccination policies.

Author contributions

David Lebeaux : Study design, Data collection, Data analysis, Writing Estelle Lu: Study design, Data collection, Data analysis, Writing Béatrice Parfait: Study design, Data collection, Data analysis, Writing Aurélie Vilfaillot: Study design, Data collection, Data analysis, Writing Cléo Bourgeois: Study design, Data collection, Data analysis, Writing Gérard Friedlander : Data collection, Data analysis, Writing Hélène Péré : Data collection, Data analysis, Writing Xavier Duval : Data collection, Data analysis, Writing Pauline Jouany: Study design, Data collection, Data analysis, Writing Juliette Djadi-Prat: Study design, Data collection, Data analysis, Writing Solen Kernéis: Study design, Data collection, Data analysis, Writing Marie Courbebaisse: Study design, Data collection, Data analysis, Writing Marie Lachatre, Nathalie Demory, Michaela Semeraro, Bénédicte Sawicki, Damien Sene Martine Louët, Bruno Pinna, Benoit Vedie, Daniela Geromin, Marie-Alexandra Alyanakian, Sarah Tubiana, Philippe Manivet, Jean-Marc Lacorte : Data collection, Writing Marie Lachatre : : Data collection, Writing Nathalie Demory: Data collection, Writing Michaela Semeraro : Data collection, Writing Bénédicte Sawicki: Data collection, Writing Damien Sene: Data collection, Writing Martine Louët: Data collection, Writing Bruno Pinna: Data collection, Writing Benoit Vedie : Data collection, Writing Daniela Geromin : Data collection, Writing Marie-Alexandra Alyanakian : Data collection, Writing Sarah Tubiana : Data collection, Writing Philippe Manivet: Data collection, Writing Jean-Marc Lacorte: Data collection, Writing.

Funding

The authors would like to thank Fondation Université de Paris, AXA research fund, Fondation Hôpitaux de Paris-Hôpitaux de France, Mécénat du GH APHP. CUP, Fondation pour la Recherche en Physiologie and DMU BioPhyGen for the funding of the COVID-HOP study.

Data availability

The datasets generated during the current study are not publicly available due regulatory reasons but are available from the corresponding author on reasonable request.

Declarations

Ethical considerations

This study was conducted in accordance with the Declaration of Helsinki and with French laws and subscribed to the principles outlined in the International Conference on Harmonization on Good Clinical Practice, 2002. A favorable opinion was delivered by the Ethics Committee CPP Sud-Ouest et Outre Mer II (Committee for the Protection of Persons- Sud-Ouest et Outre Mer II) with the reference number 2-20-047 id8221. The study was registered in ClinicalTrials.gov (ClinicalTrials.gov Identifier: NCT04418375). All participants provided written informed consent. The data were collected by each trial-site personnel, stored in an electronic database, and monitored by an independent data monitoring board.

Competing interests

The authors declare no competing interests.