Safety of co-administration of COVID-19 and seasonal influenza vaccines in individuals with autoimmune diseases from the Canadian National Vaccine Safety Network

ABSTRACT

The Canadian National Vaccine Safety Network conducted active safety surveillance for adverse events following COVID-19 and influenza immunizations. This analysis evaluated the association between the administration of mRNA COVID-19 vaccines, influenza vaccines, or co-administration of both, and health events that prevented daily activities, caused work absenteeism, or necessitated medical consultation among individuals with autoimmune diseases. Between September and December 2022, vaccinated and unvaccinated participants from seven provinces and territories self-reported health events within 7 days post-vaccination or over a 7-day period for unvaccinated individuals. This analysis focused on individuals self-reporting autoimmune diseases. Surveys were completed by 6,506 individuals: 1,743 received co-administered vaccines, 2,986 received COVID-19 vaccines alone, 491 received influenza vaccines alone, and 1,286 were unvaccinated. Health event rates were 9.5% for co-administration, 9.3% for COVID-19 alone, 5.9% for influenza alone, and 6.1% for unvaccinated controls. Compared to unvaccinated individuals, the risk of health events was higher for COVID-19 and influenza co-administration [adjusted relative risk (aRR): 1.89, 95% confidence interval (95% CI) 1.41–2.52], and COVID-19 alone [aRR: 1.86, 95% CI, 1.40–2.47], but not for influenza alone (aRR: 1.16, 95% CI, 0.76–1.78). No significant change in emergency department visits or hospitalizations was observed in any vaccine group compared to unvaccinated controls. In individuals with autoimmune diseases, mRNA COVID-19 vaccination increases mild to moderate health events compared to unvaccinated individuals. However, the rate of these events was similar when COVID-19 vaccines were administered alone or concomitantly with influenza vaccines, indicating no additional risk associated with co-administration.

Introduction

COVID-19 and seasonal influenza vaccines are recommended for individuals with autoimmune diseases due to their increased risk of severe illness.¹ COVID-19 vaccine administered with seasonal influenza vaccines during the same healthcare visit not only enhances individuals’ immunity against both COVID-19 and influenza infections but also improves efficiency in preventive healthcare services.

In Canada, as of February 2025, individuals aged 6 months and older who are at increased risk of SARS-CoV-2 infection or severe COVID-19 disease were recommended to receive a primary COVID-19 series and at least one booster dose of an updated formulation.² Canada primarily utilizes two mRNA vaccines, mRNA-1273 and BNT162b2, for both general and specific populations, with different authorized timing and dosage regimens across various age groups.² For individuals with autoimmune conditions, the National Advisory Committee on Immunization (NACI) preferentially recommended a complete vaccine series with an mRNA COVID-19 vaccine.³ An annual seasonal influenza vaccine is also recommended for everyone aged 6 months and older, with the type of vaccine varying by age group.⁴ The high-dose (IIV-HD) formulation is recommended for adults 65 years of age and older, as it offers enhanced protection compared to the standard-dose influenza vaccines.⁴ In general, influenza vaccination campaigns in Canada start in the fall, usually around October, and continue through the winter months. Concurrent administration of COVID-19 and non-COVID-19 vaccines was recommended for individuals aged 5 and older in June 2022, and for those aged 6 months and older in December 2022.⁵

The safety of co-administering mRNA COVID-19 and seasonal influenza vaccines among the general population has been investigated through clinical trials and early post-marketing studies.^6–11 However, most studies have excluded participants with underlying conditions, resulting in limited evidence available on the safety of mRNA COVID-19 and influenza vaccines specifically for individuals with autoimmune diseases. Collecting data on the safe co-administration in this population is particularly important due to concerns regarding adverse events and vaccine induced disease flares or relapse.^12–14

In this study, we assessed the safety of co-administering the mRNA COVID-19 and seasonal influenza vaccines within the Canadian National Vaccine Safety (CANVAS) network. We aimed to profile health events occurring within seven days following both single and co-administration among individuals with autoimmune diseases and determine the health events associated with the administration of mRNA COVID-19 vaccines, influenza vaccines, and co-administration.

Material and methods

CANVAS for COVID and influenza vaccines

Established in 2009, the CANVAS network has been providing real-time safety information on pandemic and seasonal influenza vaccinations to public health authorities in Canada.^15–17 The network includes seven study sites across Canadian provinces and territories, including Alberta, British Columbia, Nova Scotia, Ontario, Prince Edward Island, Quebec, and Yukon. Since the onset of the COVID-19 vaccine rollout, CANVAS has actively participated in monitoring the safety of COVID-19 vaccines, including COVID-19 booster doses and seasonal influenza vaccines.^18,19

Study design and participants

From September to December 2022, CANVAS carried out a multicenter surveillance study focusing on the safety following administration of COVID-19 and/or influenza vaccines. The study included participants aged 15 years and older, as well as parents or guardians of children aged 6 months to 14 years, who had an active e-mail address and telephone number, were able to communicate in English or French, and resided in one of the aforementioned Canadian provinces or territories. CANVAS implemented a multi-pronged recruitment strategy to engage participants. Vaccinated individuals were recruited through auto-invitations via vaccine booking systems, auto-enrollment from vaccine registries, and outreach using posters, information cards, pamphlets, and media campaigns. Recruitment of unvaccinated controls relied mainly on traditional approaches, such as posters, information cards, pamphlets, media outreach, and invitations sent to previous CANVAS participants who had consented to future contact. Not all provinces and territories employed every method. Recruitment details have been previously published.²⁰

Participation as a unvaccinated or vaccinated individual depended on the adult participant’s or child’s COVID-19 and/or influenza vaccine status. Participants were eligible to enroll as unvaccinated individuals if they had received neither a COVID-19 nor a seasonal influenza vaccine in the preceding three months. Vaccinated participants were eligible to participate if they had received either a COVID-19 booster dose alone (third dose or beyond), any dose of a COVID-19 vaccine administered concurrently with the influenza vaccine, or the influenza vaccine alone.

Study procedure

Both unvaccinated and vaccinated participants completed a self-administered online survey, which captured the occurrence of new or worsening of preexisting health problems within 7 days following vaccination or in the 7 days prior to the survey for unvaccinated controls. All vaccinated participants were asked about injection site reactions. However, only those who reported work or school absenteeism, prevention of daily activities, or the need for medical consultation were requested to provide detailed descriptions of their health symptoms. Additionally, they were asked to specify their most severe symptom, including its onset and duration. Participants who reported medically attended health events including medical consultation or emergency care utilization received a follow-up phone call to elicit further details about the event. The survey captured demographic data (age group, sex, ethnicity, gender), general health status, previous SARS-CoV-2 infection, pregnancy and lactation status, autoimmune diseases and immunocompromised conditions, vaccine status (including vaccine product), occurrence or worsening of preexisting health events, including medical consultation and/or hospitalization related to the reported event and symptoms. All participants provided informed consent electronically, but no incentive was provided for participation. Each study site had Research Ethics Board approvals for the study.

Study samples and variables

A total of 101,590 vaccinated and 27,588 unvaccinated participants completed the survey. For this analysis, we focused on individuals, both vaccinated and unvaccinated, who reported having autoimmune diseases. Of those who completed the survey, we included 6,506 participants who met our inclusion criteria: 1) reported having autoimmune diseases and specified their diagnoses/conditions; 2) reported being male or female (intersex individuals or those who did not respond to the sex-related question (0.4%) were excluded); and 3) among vaccinated individuals, received bivalent mRNA COVID-19 vaccines, either BNT162b2 or mRNA-1273, which accounted for more than 98% of the COVID-19 vaccinated group. Regarding influenza vaccination, we included all types of influenza vaccine products used in Canada in 2022,²¹ which were Afluria Tetra^Ⓡ, Fluad^Ⓡ, Flulaval Tetra^Ⓡ, FluMist Quadrivalent^Ⓡ, Fluzone^Ⓡ, Fluzone High Dose Quadrivalent^Ⓡ, and Influvac Tetra^Ⓡ. Among vaccinated participants with autoimmune diseases, 75 (1%) reported receiving pneumococcal vaccines co-administered with either influenza or mRNA COVID-19 vaccines: 15 in the influenza-alone group, 6 in the COVID-19-alone group, and 54 in the co-administration group. Due to the small number of participants, pneumococcal vaccine data were not included in further, stratified analyses.

A variety of reported specific autoimmune conditions were grouped based on the affected system: joint disorders (e.g., ankylosing spondylitis, psoriatic arthritis), gastrointestinal conditions (e.g., inflammatory bowel diseases, celiac disease), neurologic disorders (e.g., myasthenia gravis, multiple sclerosis), and dermatologic conditions (e.g., dermatitis, psoriasis, cutaneous lupus). Participants who reported more than one autoimmune condition were categorized as having ‘more than one condition.’ Very rare autoimmune conditions, such as Goodpasture syndrome, Addison’s disease, and alopecia, were grouped under the ‘other’ category.

Data on COVID-19 and influenza vaccine products were obtained either through electronic transfers from provincial vaccination registries or directly entered by participants from their own vaccine records. The primary outcome variable was defined as a new health event or worsening of a preexisting condition that led to school/work absenteeism, a medical consultation and/or impairment of daily activities in the previous 7 days for controls or within 7 days following vaccination for vaccinated individuals. The secondary outcome variable, serious health events, was a subset of primary health events and defined as any event resulting in an emergency department (ED) visit and/or hospitalization within seven days following vaccination or the prior 7 days for controls.

Statistical analysis

Among individuals with autoimmune diseases, we estimated rates of health event, medically attended event, and serious health event, injection site reaction (vaccinated group only), common and uncommon specific symptoms, onset, and duration of most severe health symptom. The frequency of reported health events was classified as very common ( >10%), common (1% to 10%), uncommon (0.1% to 1%), rare (0.01% to 0.1%) and very rare ( <0.01%) as reported by the World Health Organization and Canadian Immunization Guide.^5,22 Further, we assessed self-reported diagnoses among autoimmune disease patients who required medical consultation, including ED visit and hospitalization. We also examined information on participants’ characteristics, medical consultation, and level of care received for those diagnosed with disease flare or exacerbation of underlying conditions.

To examine the association between mRNA-COVID and/or influenza vaccine exposure and health events within 7 days following vaccination, univariable and multivariable generalized linear regression models with a log link were built in individuals with autoimmune diseases. The exposure variable had four levels depending on vaccine status: unvaccinated, influenza vaccines alone, mRNA COVID-19 vaccines alone, and co-administered mRNA COVID-19 and influenza vaccines. Due to the limited number of individuals with autoimmune diseases, participants from certain provinces (Alberta and Nova Scotia) were combined based on their use of similar recruitment strategies.²⁰ In the multivariable models, we adjusted for potential confounders and risk factors for health events, including age group, sex, health status, province, and previous SARS-CoV-2 infection.^23,24 The estimated relative risk (RR) and 95% CIs were reported. Data cleaning was done in SAS version 9.4 (SAS Institute)²⁵ and analysis was completed in R software version 4.1.3 (R Foundation for Statistical Computing, Vienna, Austria).²⁶

Subgroup analyses were conducted to determine whether the results from the primary analysis differed by mRNA COVID-19 vaccine product (BNT162b2 or mRNA-1273) and by most commonly reported autoimmune conditions – specifically those with a combined sample size of more than 400 across both vaccinated and unvaccinated groups. These conditions included rheumatoid arthritis, inflammatory bowel disease, multiple sclerosis/myasthenia gravis, and autoimmune dermatological conditions. Univariate and multivariable regression models, adjusting for the same covariates as in the primary analyses, were repeated for each mRNA COVID-19 vaccine product and each disease condition. Due to limited sample sizes, multivariable analyses were conducted only for the primary outcome (health events) for the most common autoimmune conditions.

Results

A total of 5,220 vaccinated participants with autoimmune conditions were included in the analysis. Most (57.2%) received only bivalent mRNA COVID-19 vaccines, 33.4% received both bivalent mRNA COVID-19 and influenza vaccines concurrently, and 9.4% received only influenza vaccines. The control group consisted of 1,286 unvaccinated individuals with autoimmune conditions.

Most participants, regardless of vaccination status or product, were female and aged 40 to 79 years, and reported being in good health (Table 1). Approximately one-third of all participants reported being immunocompromised and over 40% had a history of SARS CoV-2 infection. Among those who received co-administered vaccines, BNT162b2 was more frequently used (64.4%), whereas mRNA-1273 was more frequently administered alone (64.7%). For influenza vaccines, more than 50% of recipients, regardless of mRNA COVID-19 vaccine co-administration, received Fluzone® products (Supplementary table 1). The most prevalent autoimmune conditions in both vaccinated and unvaccinated participants were rheumatoid arthritis (≥15%) and inflammatory bowel disease (≥13%) (Table 1).

Table 1.

Characteristics of unvaccinated and vaccinated individuals with autoimmune diseases.

Variable	Unvaccinated Group N = 1,286	Influenza Vaccine Alone N = 491	mRNA COVID-19 Vaccine Alone N = 2,986	mRNA COVID-19 and Influenza Vaccine Co-administered N = 1,743
Age category
6 months–19 yrs	81 (6.3%)	40 (8.1%)	71 (2.4%)	109 (6.3%)
20–29	126 (9.8%)	16 (3.3%)	89 (3%)	70 (4%)
30–39	199 (15.5%)	34 (6.9%)	247 (8.3%)	168 (9.6%)
40–49	249 (19.4%)	64 (13%)	375 (12.6%)	198 (11.4%)
50–64	306 (23.8%)	158 (32.2%)	1,003 (33.6%)	557 (32%)
65–79	258 (20.1%)	156 (31.8%)	1,091 (36.5%)	548 (31.4%)
80 and above	67 (5.2%)	23 (4.7%)	110 (3.7%)	93 (5.3%)
Sex
Male	401 (31.2%)	121 (24.6%)	747 (25%)	493 (28.3%)
Female	885 (68.8%)	370 (75.4%)	2,239 (75%)	1,250 (71.7%)
Immunocompromised
Yes	409 (31.8%)	137 (27.9%)	909 (30.4%)	573 (32.9%)
Health status
Excellent/Very good	73 (5.7%)	41 (8.4%)	217 (7.3%)	136 (7.8%)
Good	687 (53.4%)	261 (53.2%)	1,597 (53.5%)	895 (51.3%)
Fair/poor	502 (39%)	175 (35.6%)	1,106 (37%)	668 (38.3%)
Unknown	24 (1.9%)	14 (2.9%)	66 (2.2%)	44 (2.5%)
Specific autoimmune condition
Ankylosing spondylitis/Juvenile/Psoriatic arthritis	64 (5%)	25 (5.1%)	147 (4.9%)	99 (5.7%)
Celiac/Crohn/Ulcerative colitis/IBDa	238 (18.5%)	76 (15.5%)	400 (13.4%)	253 (14.5%)
Dermatitis/Psoriasis/Pemphigus/ Cutaneous lupus	85 (6.6%)	32 (6.5%)	213 (7.1%)	123 (7.1%)
Graves’ disease	29 (2.3%)	11 (2.2%)	42 (1.4%)	26 (1.5%)
Hashimoto thyroiditis	57 (4.4%)	28 (5.7%)	125 (4.2%)	63 (3.6%)
Multiple sclerosis/ Myasthenia gravis	81 (6.3%)	31 (6.3%)	229 (7.7%)	126 (7.2%)
Rheumatoid arthritis	204 (15.9%)	83 (16.9%)	567 (19%)	329 (18.9%)
Systemic lupus erythematosus	30 (2.3%)	14 (2.9%)	102 (3.4%)	57 (3.3%)
Type I diabetes	57 (4.4%)	27 (5.5%)	93 (3.1%)	71 (4.1%)
More than one condition	159 (12.4%)	49 (10%)	364 (12.2%)	202 (11.6%)
Otherb	282 (21.9%)	115 (23.4%)	704 (23.6%)	394 (22.6%)

IBD^a: Inflammatory bowel disease; ^bOther includes: Goodpasture syndrome, Addison’s disease, alopecia, idiopathic thrombocytopenic purpura, vitiligo, Sjögren’s syndrome, systemic vasculitis, autoimmune hemolytic anemia, autoimmune hepatitis/nephritis, lichen planus, cicatricial pemphigoid, polymyalgia, etc.

In the week following vaccination, the incidence of health events severe enough to prevent daily activities, miss work, or require medical consultation was higher after receiving only COVID vaccines (9.3%) or in combination with influenza vaccines (9.5%), compared to receiving only influenza vaccines (5.9%) or no vaccine (6.1%) (Table 2). This pattern held across specific mRNA COVID vaccine products (Supplementary table 2). The incidence of health events requiring an ED visit or hospitalization was 0% for those who received only influenza vaccines and ranged from 0.3 to 0.4% for those received either the COVID-19 vaccine alone or co-administered with influenza vaccines (Table 2).

Table 2.

Health event rates within seven days following vaccination or previous seven days in unvaccinated and vaccinated individuals with autoimmune diseases.

	Unvaccinated Group N = 1,286	Influenza Vaccine Alone N = 491	mRNA COVID-19 Vaccine Alone N = 2,986	mRNA COVID-19 and Influenza Vaccine Co-administered N = 1,743
Health eventa	78 (6.1%)	29 (5.9%)	277 (9.3%)	165 (9.5%)
Medically attended eventb	21 (1.6%)	7 (1.4%)	45 (1.5%)	30 (1.7%)
Serious health eventc	3 (0.2%)	0 (0%)	8 (0.3%)	7 (0.4%)
ED visit	3 (0.2%)	0 (0%)	7 (0.2%)	7 (0.4%)
Hospitalization	0 (0%)	0 (0%)	1 (0.03%)	0 (0%)

Health event^a: a new health event or worsening of a preexisting condition that led to school/work absenteeism, a medical consultation and/or prevention of daily activities in the previous 7 days for controls or within 7 days following vaccination for vaccinated individuals. Medically attended event^b: a subset of health events and defined as any event requiring medical consultation (online or in person with any medical professional) within seven days following vaccination or the prior 7 days for controls. Serious health event^c: a subset of health events and defined as any event resulting in an emergency department (ED) visit and/or hospitalization.

Individuals with autoimmune disease were more likely to experience health events following vaccination with mRNA COVID-19 alone [adjusted relative risks (aRR): 1.86, 95% confidence interval (95% CI), 1.40–2.47] and co-administration of COVID-19 and influenza vaccines [aRR: 1.89, 95% CI, 1.41–2.52] but not following administration of influenza-alone (aRR: 1.16, 95% CI, 0.76–1.78) (Figure 1) when compared to unvaccinated autoimmune participants. There was no difference in risk COVID-19 alone or COVID-19 administered with influenza vaccines (aRR: 1.01, 95% CI, 0.83–1.24). No increase in risk was observed for emergency department visits or hospitalizations and any vaccine group when compared to unvaccinated participants (Figure 1). In the subgroup analyses, covariate-adjusted models for both BNT162b2 and mRNA-1273 revealed similar patterns (Supplementary figure 1). When examining specific disease conditions, a similar pattern was observed – an increased risk of health events following administration of mRNA COVID-19 vaccines alone or in combination with influenza vaccines. However, most effect estimates were no longer statistically significant, likely due to smaller sample sizes leading to wider confidence intervals (Supplementary table 3).

Figure 1.

Adjusted relative risk of health events and serious health events within seven days following vaccination with mRNA COVID-19 and/or influenza vaccines in individuals with autoimmune conditions.

Health event: a health event preventing daily activities, resulting in school absenteeism, and/or requiring medical consultation;.

Serious health event: Any event resulting in emergency department visit and/or hospitalization.

Reference group: unvaccinated individuals with autoimmune diseases. Relative risk was not available for influenza alone group as there was no serious health events among this group. Relative risk (RR) are adjusted for age group, sex, health status, province and previous SARS-CoV infection. Circles, arrows and triangles present point estimates of adjusted RR with 95% confidence intervals. The y-axis of each graph is a log-scale.

Table 3 presents injection-site reactions, and reported specific symptoms, among vaccinated and unvaccinated participants with autoimmune diseases. Participants who received either COVID-19 alone or in combination with an influenza vaccine reported local reactions approximately 20% more frequently than those who received only the influenza vaccine. The most frequently reported common systemic symptoms included feeling unwell, headaches, fever, stomach symptoms, joint pain, dizziness, sore throat, runny nose, and cough. Other symptoms were uncommon ( <1%) and occurred at similar rates in both vaccinated and unvaccinated groups, except for chest tightness and difficulty breathing, where the rates were 1.6% and 1.3%, respectively, among those who were co-administered mRNA COVID-19 and influenza vaccines (Table 3).

Table 3.

Reported health events within seven days after vaccination or previous seven days among unvaccinated and vaccinated individuals with autoimmune diseases.

Variable	Unvaccinated Group N = 1,286	Influenza Vaccine Alone N = 491	mRNA COVID-19 Vaccine Alone N = 2,986	mRNA COVID-19 and Influenza Vaccine Co-administered N = 1,743
Local symptomsa
Injection site reaction	NA	197 (40%)	1,880 (63%)	1,025 (59%)
Common Systemic symptomsb
General
Unwellc	57 (4.4%)	21 (4.3%)	242 (8.1%)	140 (8.0%)
Fever (≥38▫C)	12 (0.9%)	7 (1.4%)	61 (2.0%)	49 (2.8%)
GI symptomsd	27 (2.1%)	9 (1.8%)	98 (3.3%)	54 (3.1%)
Joint pain/stiffness	32 (2.5%)	12 (2.4%)	127 (4.3%)	68 (3.9%)
Runny nose	33 (2.6%)	12 (2.4%)	55 (1.8%)	59 (3.4%)
Nasal congestion	52 (4.0%)	15 (3.1%)	67 (2.2%)	74 (4.2%)
Earache/pain	9 (0.7%)	4 (0.8%)	16 (0.5%)	17 (1.0%)
Sore throat	39 (3.0%)	10 (2.0%)	52 (1.7%)	47 (2.7%)
Neurological
Headache	33 (2.6%)	16 (3.3%)	179 (6.0%)	110 (6.3%)
Dizziness	15 (1.2%)	4 (0.8%)	54 (1.8%)	40 (2.3%)
Paresthesia	6 (0.5%)	0 (0%)	17 (0.6%)	12 (0.7%)
Fainting	1 (<0.1%)	1 (0.2%)	4 (0.1%)	3 (0.2%)
Difficult to walk	4 (0.3%)	1 (0.2%)	15 (0.5%)	4 (0.2%)
Loss of taste/smell	5 (0.4%)	3 (0.6%)	9 (0.3%)	8 (0.5%)
Impaired or lost vision	0 (0%)	1 (0.2%)	5 (0.2%)	3 (0.2%)
Sudden unilateral	0 (0%)	0 (0%)	1 (<0.1%)	0 (0%)
facial weakness/paralysis
Seizure or convulsion	0 (0%)	0 (0%)	1 (<0.1%)	0 (0%)
Neurological symptomse	1 (<0.1%)	2 (0.4%)	12 (0.4%)	7 (0.4%)
Cardio-respiratory
Palpitation	7 (0.5%)	1 (0.2%)	23 (0.8%)	12 (0.7%)
Breathing difficulty	9 (0.7%)	0 (0%)	22 (0.7%)	22 (1.3%)
Chest tightness	11 (0.9%)	1 (0.2%)	25 (0.8%)	28 (1.6%)
Cough	36 (2.8%)	10 (2.0%)	54 (1.8%)	58 (3.3%)
Allergic-like
Face or lip swelling	1 (<0.1%)	0 (0%)	2 (<0.1%)	0 (0%)
Eyelid swelling	3 (0.2%)	0 (0%)	6 (0.2%)	4 (0.2%)
Itchy eyes	9 (0.7%)	7 (1.4%)	23 (0.8%)	14 (0.8%)
Red eyes	2 (0.2%)	1 (0.2%)	10 (0.3%)	6 (0.3%)
Throat/tongue swelling	1 (<0.1%)	2 (0.4%)	4 (0.1%)	3 (0.2%)
Rash or hives	4 (0.3%)	0 (0%)	14 (0.5%)	4 (0.2%)
Anaphylaxis	0 (0%)	0 (0%)	1 (<0.1%)	1 (<0.1%)
Coagulation symptomsf	2 (0.2%)	1 (0.2%)	6 (0.2%)	1 (<0.1%)

^aAll participants were asked about injection site reactions (Redness, pain or swelling at injection site/above and below in the immunized arm). ^bOnly those who indicated a health event that led to school/work absenteeism, a medical consultation and/or prevention of daily activities were asked to provide details and participants could report more than one symptom. ^ctiredness, weakness, muscle aches, fatigue, or chills. ^dnausea, vomiting, diarrhea, or stomach pain. ^eweakness or paralysis of the arms or legs/confusion/change in personality/behavior or difficulty with urination or defecation; ^fSymptoms of blood clot or bleeding: swelling/pain in legs.

“Feeling unwell,” which included tiredness, weakness, muscle aches, fatigue, or chills, was the most frequently reported severe symptom among both vaccinated and unvaccinated participants (Supplementary table 4). For most vaccinated participants ( > 85%), the onset of their most severe symptom occurred within 2–3 days following vaccination (Figure 2). Additionally, among those who experienced health events, approximately 65% reported symptom resolution within 7 days post-vaccination (Figure 3).

Figure 2.

Onset of the most severe symptom within seven days post-vaccination in vaccinated individuals with autoimmune diseases.

Figure 3.

Duration of the most severe symptom within seven days post-vaccination in vaccinated individuals with autoimmune diseases.

Among the vaccinated respondents, five (0.1%) reported being diagnosed with a disease flare or exacerbation of underlying conditions within 7 days following vaccination, including two within 24 hours. These included one with ulcerative colitis, one with both rheumatoid arthritis and ulcerative colitis, two with ankylosing spondylitis, and one with multiple sclerosis. Of these, three were co-administered COVID-19 and influenza vaccines, and the remaining two received COVID-19 vaccine alone. All required medical consultation, but none needed emergency treatment or hospitalization, and their symptoms resolved within a week. No cases of disease flare or exacerbation of underlying conditions were reported in the influenza alone recipients nor in the unvaccinated individuals with autoimmune diseases.

Discussion

Our findings provide ongoing safety data for COVID-19 mRNA and influenza vaccines when used in individuals with underlying autoimmune conditions. In particular, influenza vaccines are safe, with similar or lower rates of both health events and serious health events compared to unvaccinated individuals. For mRNA COVID-19 vaccines, whether administered alone or in combination with influenza vaccines, there was an increased risk of health events compared to unvaccinated individuals. The risk in the co-administration group was similar to that in the COVID-19 only group, indicating these were attributable to COVID-19 vaccine. Most reported symptoms were consistent with expected vaccine reactogenicity observed in clinical trials and very few vaccinated participants described a disease flare. Importantly, health events requiring an ED visit or hospitalization were uncommon and similar in the vaccinated and unvaccinated groups.

Previous studies, including systematic reviews, have raised no safety concern regarding the single administration of COVID-19 primary series or booster vaccines among individuals with rheumatic or immune inflammatory diseases.^27–30 Similarly, a recent review suggests that single administration of inactivated seasonal influenza vaccines is safe and effective for patients with autoimmune diseases, including systemic lupus erythematosus, rheumatoid arthritis, and inflammatory bowel disease.³¹ Our findings provide ongoing safety data for co-administration of mRNA COVID-19 and influenza vaccines among individuals with these conditions.

In our study, most individuals reported systemic symptoms as their most severe symptom, especially following either single COVID-19 or in combination with the influenza vaccine. Very few reports of disease flares within seven days post-vaccination were noted, and those that occurred were of short duration. These findings are consistent with or lower than, the rates of flares observed in other safety studies of patients with autoimmune disease following the single administration of mRNA or other COVID vaccines.^28,32,33 A recent a systematic review and meta-analysis examining risk of flare in patients with immune-mediated diseases following SARS-CoV-2 vaccination reported that flare prevalence was highest among renal disorders, followed by hematologic, gastro-enteric, and rheumatic disorders, with the lowest prevalence observed among dermatologic and neurologic disorders.³⁴ Consistent with this evidence, we detected flares among individuals with ulcerative colitis, ankylosing spondylitis, and multiple sclerosis. To our knowledge, vaccine safety evidence for this population is limited to single administration of vaccine. Our findings expand this knowledge by demonstrating the safety of co-administration of COVID-19 and influenza vaccines among individuals with autoimmune diseases.

In our study, no disease flares were reported among influenza-only recipients or unvaccinated individuals with autoimmune diseases. Among mRNA COVID-19 vaccine recipients, with or without the influenza vaccine, five cases of provider-diagnosed disease flares were reported within seven days post-vaccination. Reported flare symptoms resembled vaccine-related adverse events, such as feeling unwell, fatigue, joint pain and gastrointestinal symptoms. These symptoms were brief, resolved quickly, and did not require emergency department visits or hospitalizations. While it is possible that some reported flares may reflect COVID-19 vaccine reactogenicity rather than disease activity, our study cannot establish causality. These patterns are consistent with a prospective study in more than 1,300 patients with rheumatic and musculoskeletal disease, which also observed mild symptoms such as injection site pain, fatigue and worsening of preexisting symptoms, with no severe flares.³³

A recent review of post-COVID-19 vaccination flares among individuals with systemic autoimmune rheumatic diseases highlighted substantial variability in how flares were defined across studies, as well as the limited number of studies that used clinical assessments to verify flares.³⁵ Nevertheless, the review concluded that there is no evidence of an increased risk of flare following COVID-19 vaccination. It also noted that individuals with prior frequent flares and active disease at the time of vaccination may be at higher risk of experiencing post-vaccination flares.³⁵ In our study, data on pre-vaccination disease activity, history of prior flares, immunomodulatory medication use (including dosing and timing), or any treatment discontinuation prior to vaccination were not collected. Despite this limitation, the very low rate of mild flare-like events in our cohort provides some reassurance and may help reduce concerns about disease flares or progression following vaccination among individuals with autoimmune diseases.

Recent literature from post-marketing studies among general population supports a combined influenza/COVID-19 vaccination campaign as a valuable and effective tool in annual vaccination campaigns for SARS-CoV-2 and influenza, demonstrating similar effectiveness in COVID-19 and influenza related outcomes.³⁶ In our study, we did not identify any unusual or unexpected pattern of adverse events following co-administration of mRNA-COVID and seasonal influenza vaccines among individuals with autoimmune diseases.

The safety of co-administration of seasonal influenza and COVID-19 vaccines was also reported in a systemic review of clinical trials and early-post marketing studies among healthy adults or health care workers.^37–41 A large population-based study in the US, utilizing a smartphone-based safety surveillance system called V-safe, evaluated the safety of concomitant administration of mRNA COVID-19 booster and influenza vaccines during the first seven days post-vaccination.¹¹ Although reactions were generally mild, individuals receiving both vaccines concurrently were slightly more likely to report systemic reactions, regardless of type of COVID-19 vaccine used [aOR for Pfizer-BioNTech 1.08 (95% CI, 1.06─1.10) and for Moderna 1.11 (95% CI, 1.08─1.14)]. The study also noted that recipients of mRNA-1273 and influenza vaccines were more likely to report health impacts, such as inability to perform normal activities, or attend work/school, or needing care from a medical professional (aOR, 1.05; 95% CI, 1.02–1.08)], compared to those who received the mRNA-1273 COVID-19 booster alone. Notably, this pattern was not observed among BNT162b2 recipients, with or without influenza vaccines.¹¹ However, our study observed similar rates of health events that prevented daily activities, led to work absenteeism, or required medical consultation between the single and combined use of COVID-19 and influenza vaccines, regardless of the mRNA vaccine product used. Care should be taken when comparing these results due to differences in study populations, sample size, and statistical measures.

This analysis has several limitations. First, participating in the CANVAS surveys was voluntary, which may limit generalizability of the findings to all individuals with autoimmune diseases receiving COVID-19 and/or influenza vaccines. Survey participation may have also been influenced by the presence of health events, potentially introducing collider stratification bias.⁴² While this bias could occur in both vaccinated and unvaccinated individuals, differences in motivations or likelihood to respond by vaccination status may differentially affect selection, which could limit internal validity. Moreover, CANVAS relies on participant-based reporting without medical record verification, which could lead to differential misclassification of autoimmune conditions between vaccinated and control groups. This could result in a higher proportion of individuals with less severe conditions being included in the vaccinated group. Additionally, self-reported data may also be subject to reporting or recall bias. Survey questionnaires for vaccinated participants were systematically sent on day 8 following vaccination, resulting in a median response time of 10 days (IQR: 8–12 days), which helped minimize recall bias. For unvaccinated participants, survey questionnaires were sent immediately upon registration. Self-reported data have been shown to be a reliable proxy for healthcare utilization and absenteeism for short recall periods of up to one month.⁴³ Furthermore, due to exposure to media reports and discussion around AEFIs with COVID-19 mRNA vaccines,⁴⁴ participants might report their experiences differently following COVID-19 vaccination compared to influenza vaccination. Additionally, the follow-up interval of seven days post-vaccination may have missed events if the onset occurred beyond this time period. This limitation is particularly significant in this population, where intermediate and long-term safety data are critical. To address this, CANVAS has extended the follow-up period up to one month in subsequent studies assessing the safety of co-administraton of COVID-19 booster and influenza vaccines.

Another significant limitation is the lack of detailed information on clinical courses of disease and current drug therapies, including specific types of immunomodulatory or immunosuppressive agents, which may influence adverse event profiles. The lack of treatment-specific data limited our ability to explore differential safety signals across various therapeutic regimens. Additionally, to simplify the analysis, we did not account for the type of influenza vaccines received. Although our models were adjusted for age, which may partially address differences in reactogenicity such as those associated with high-dose quadrivalent inactivated influenza vaccine recommended for older adults, this remains a limitation.

In addition, the comparability between vaccinated and unvaccinated groups is limited, as individuals who received vaccines may differ in many characteristics from those who did not, potentially influencing how they reported health events. Specifically, unvaccinated participants were recruited a few weeks earlier than their vaccinated participants, which may have introduced temporal biases. Despite efforts to control confounders and risk factors in our multivariable regression models, residual or unmeasured confounders may still exist. Alternative designs, such as self-controlled design and case series, can help address these limitations by accounting for stable individual characteristics. However, randomized placebo-controlled trials are not ethically feasible in this context due to the established benefits and wide availability of COVID-19 vaccines.

One strength of this study was the inclusion of a larger number of individuals with autoimmune diseases. Another strength was the recruitment of non-vaccinated individuals with similar underlying disease, which enabled the assessment of events in a comparable unvaccinated group.

In conclusion, our findings provide ongoing safety data on the co-administration of influenza and mRNA COVID-19 vaccines in individuals with autoimmune conditions. While mild to moderate health events are more common following COVID-19 mRNA vaccination than following influenza vaccination or no vaccination, the risk following co-administration is similar to that associated with the COVID vaccine alone. These insights can help inform vaccination policy strategies both in Canada and globally. They are particularly valuable for tailoring communication strategies to address the unique concerns of this vulnerable group regarding adverse events and vaccine-induced disease flares or relapses. Furthermore, these findings support the inclusion of co-administration strategies in vaccination programs, optimizing resource use and reducing the burden of multiple vaccine appointments for both patients and healthcare systems.

Biography

Julie A. Bettinger is a Professor at the Vaccine Evaluation Center in the Department of Pediatrics at the University of British Columbia. She is an infectious disease epidemiologist whose research interests include vaccine safety and vaccine preventable diseases, and attitudes and beliefs around immunization uptake and use. She is the data center director for the Canadian Immunization Monitoring Program, Active (IMPACT), an active surveillance network for vaccine preventable diseases in 14 tertiary care pediatric hospitals across Canada and the principal investigator for CIRN’s Canadian National Vaccine Safety (CANVAS) network, which monitors the safety of influenza and COVID vaccines each year.

Funding Statement

The CANVAS-COVID study was supported by the COVID-19 Vaccine Readiness funding from the Canadian Institutes of Health Research and the Public Health Agency of Canada CANVAS grant number CVV-450980. It was also supported by funding from the Public Health Agency of Canada, through the Vaccine Surveillance Reference group and the COVID-19 Immunity Task Force. PS was supported by a Doctoral Studentship Award from BC Children’s Hospital Research Institute and Canadian Immunization Research Network Trainee Award. MS is supported via salary awards from the BC Children’s Hospital Foundation and Health Research BC.

Disclosure statement

GDS, PS, HW, MN, JAB, MPM, KM and OGV have no competing interests. MS has been an investigator on projects funded by GlaxoSmithKline, Merck, Moderna, Pfizer and Sanofi-Pasteur outside the submitted work. LV reports grants from Pfizer outside the submitted work. JEI has been an investigator on projects funded by GlaxoSmithKline and Sanofi-Pasteur outside the submitted work. All funds have been paid to her institute, and she has not received any personal payment. AM reports grants to her institution from Pfizer and Sanofi-Pasteur, and personal payments for consulting from AstraZeneca, Merck, GlaxoSmithKline, Moderna, Novavax, Pfizer, and Seqirus. JDK has been an investigator on projects funded by Merck, Moderna and Pfizer, all outside the submitted work. All funds have been paid to his institute, and he has not received any personal payments.

Data availability statement

The datasets presented in this article are not readily available because we do not have permission from CANVAS participants to share the data used in our study.

Declaration of generative AI and AI-assisted technologies in the writing process

During the preparation of this work, the author (PS) used ChatGPT-4 to enhance readability and language quality. After using this tool, the author (PS) thoroughly reviewed and edited the content as necessary and takes full responsibility for the content of the publication.

Supplementary material

Supplemental data for this article can be accessed online at https://doi.org/10.1080/21645515.2025.2560172