Live Attenuated Influenza Vaccine in Pediatric Liver Transplant Recipients: A Retrospective Series

ABSTRACT

Background

Influenza remains a significant cause of morbidity and mortality in pediatric patients, particularly among solid organ transplant (SOT) recipients. Live attenuated influenza vaccines (LAIV) historically have been contraindicated in SOT recipients, with very limited data on the safety of administration after SOT.

Methods

We report on the general safety outcomes of a series of four pediatric liver transplant recipients who received LAIV as a part of clinical care between 2019 and 2025 due to prior severe local reaction to the inactivated influenza vaccine (IIV). All patients met specific eligibility criteria for LAIV. Electronic medical records were reviewed.

Results

Among 15 administered doses, there were no serious adverse events and only three reports of mild symptoms within the 30 days following vaccination that could not be definitively attributed to LAIV. There were four confirmed influenza infections across two patients that occurred 45 days or more postvaccination; these were mild and did not require emergency department visits or hospitalization.

Conclusions

In this cohort of four pediatric liver transplant recipients with severe localized side effects after IIV, LAIV was well‐tolerated without significant safety events, which suggests that safety and immunogenicity of LAIV should be further explored in transplant recipients.

Abbreviations

ED

emergency department

IIV

inactivated influenza vaccine

ILI

influenza‐like illness

LAIV

live attenuated influenza vaccine

MMF

mycophenolate mofetil

MMR

measles, mumps, rubella

SOT

solid organ transplant

1. Introduction

Despite available vaccinations, influenza continues to be an important source of morbidity and mortality for children around the world [1, 2]. While infection severity and vaccine efficacy vary year to year, those who are immunocompromised from solid organ transplant (SOT) are consistently shown to be at higher risk of complications from influenza [1, 2, 3, 4]. The introduction of the live attenuated influenza vaccine (LAIV) has broadened opportunities for healthy children to receive influenza vaccination. However, data on LAIV safety in immunocompromised patients, particularly pediatric SOT recipients, are limited based on the theoretical risk of infection from LAIV in this population. The most recent guidance from the American Society of Transplantation and the American Academy of Pediatrics recommends against administration of LAIV to SOT recipients [1, 5]. For patients with severe local reactions to the inactivated influenza vaccine (IIV), this limits access to an alternative means of protection against influenza and highlights a gap in knowledge surrounding vaccination with LAIV in the SOT population. We report on the general safety outcomes of four pediatric SOT patients with severe local reactions to IIV who received LAIV over a 7‐year period.

2. Methods

After Institutional Review Board approval, we conducted a retrospective review of pediatric SOT recipients who received LAIV as part of clinical care from 2019 to 2025. Patients included in this analysis had documented severe local reactions to IIV (Table 1), including significant erythema and swelling, fever, and rash. For example, Patient 1 experienced significant injection site arm swelling with movement restriction prompting presentation to the emergency department (ED). Patient 3 developed significant injection site swelling and erythema prompting treatment as suspected cellulitis with antibiotics multiple times including one hospitalization. They were later diagnosed with an allergy to polysorbate 80, a component of forms of IIV. All patients met specific immunologic criteria defined by our institution for eligibility for live viral vaccines (see Figure 1). Outside of receipt of immunosuppression for SOT, all patients had no other contraindications for LAIV administration. Families were routinely contacted by the clinical team to inquire if the patient had experienced symptoms or a reaction to LAIV. Families were also instructed to report symptoms of influenza‐like illness (ILI) that occurred post‐LAIV administration and during the subsequent influenza season. The electronic medical record was reviewed for events such as episodes of influenza, influenza‐like illness, visits for medical assessments (ED, urgent care, primary care office), or hospitalizations that occurred within 30 days of administration as well as influenza infections or ILI during the season following LAIV administration. Data was collected in a REDCap database and reported with descriptive statistics.

TABLE 1.

Patient demographics and live attenuated influenza vaccine (LAIV) administration.

Patient	Sex	Ethnicity	Age at transplant	Live viral vaccine(s) received posttransplant prior to first LAIV	Reaction to IIV	Duration of time between transplant and dose of LAIV	Immunosuppression at time of LAIV (if applicable: most recent level prior to LAIV in ng/mL)	Reported side effects/symptoms within 30 days of LAIV
1	Female	White	6 months	Varicella	Significant injection site swelling and pain—Presented to ED due to restricted arm movement	4 years	Sirolimus (4.8)	None
						6 years	Sirolimus (3.9)	Rhinorrhea—Developed prior to LAIV administration, exact date not reported
2	Female	White	3 months	None	Swelling from shoulder to elbow on injection site arm	15 years	Tacrolimus (5.3)	None
3	Female	White	31 months	MMR Varicella	Significant injection site swelling and erythema	3 years	Sirolimus (3.4)	None
					Treated with antibiotics as cellulitis twice Diagnosed with polysorbate 80 allergy	4 years	Sirolimus (4.1)	None
						5 years	Sirolimus (4.7)	None
						6 years	Sirolimus (4.2)	Fever, diarrhea—Adenoviral infection, not attributed to LAIV
						7 years	Sirolimus (3.4)	None
						8 years	Sirolimus (3.9)	None
						9 years	Sirolimus (2.9)	None
4	Female	White	6 months	MMR Varicella	Significant erythema and swelling of injection site	6 years	Tacrolimus (3.0)	None
						7 years	Tacrolimus (3.3)	None
						8 years	Tacrolimus (4.1)	None
						9 years	Tacrolimus (4.3) Mycophenolate mofetil	None
						10 years	Tacrolimus (3.1) Mycophenolate mofetil	Cough—Developed 13 days post‐LAIV, improved with amoxicillin‐clavulanic acid Congestion and rhinorrhea—Developed > 20 days post‐LAIV

FIGURE 1.

Clinical algorithm for live viral vaccination eligibility at Cincinnati Children's Hospital Medical Center. Description of the criteria that must be met by patients at Cincinnati Children's Hospital in order to be eligible for live viral vaccination.

3. Results

Four SOT recipients (Table 1) underwent liver transplantation with steroid induction at an average age of 6.45 months (range 3–27 months). All patients received at least one dose of LAIV (range 1–7 doses) for a cumulative total of 15 doses. Average age at the time of the first LAIV dose was 8.44 years (range 5.25–15.33 years), with administration occurring on average 7 years after transplant (range 3–15 years). Prior to LAIV, three of the four had received other live viral vaccines after transplant, either varicella and/or measles, mumps, rubella (MMR), with minor local or systemic reactions and no severe adverse effects. Patient 3 experienced mild injection site erythema following both varicella and MMR vaccinations. Patient 4 experienced fever following the second dose of MMR, and fever with emesis 5 days after the second dose of varicella vaccine. These vaccines were otherwise well tolerated and patients had documented serologic responses.

Of the 15 doses of LAIV given, few side effects or symptoms were reported within 30 days of vaccination (Table 1), and these symptoms could not be clearly attributed to LAIV. Patient 3 developed fever, cough, and diarrhea 9 days after LAIV administration and tested positive for adenovirus from a nasopharyngeal swab and blood sample. After LAIV in her 5th season, Patient 4 experienced a cough more than 10 days after LAIV administration that improved with amoxicillin/clavulanic acid, as well as congestion and rhinorrhea more than 20 days after LAIV. It is unknown if viral testing was obtained. After LAIV in her 2nd season, Patient 1 reported rhinorrhea 2 days after LAIV administration, but exact time of onset was not recorded. LAIV was otherwise well tolerated with no reports of serious adverse events following administration.

Four confirmed influenza events occurred among two patients during the season after LAIV administration (Table 2). Symptoms included fever, cough, congestion, headache, and sore throat. One patient developed influenza in three separate seasons (two influenza B, one influenza A). All three positive tests occurred more than 45 days after immunization. An undifferentiated influenza strain was reported in another patient and occurred more than 3 months postvaccination. These infections were all managed in outpatient clinics or an urgent care setting (for testing and assessment), and none required emergency care or hospitalization. A third patient developed ILI after exposure to influenza B 29 days post‐LAIV. Symptoms resolved with oseltamivir; however, no influenza test was obtained to confirm infection (Table 2).

TABLE 2.

Influenza infections following live attenuated influenza vaccine (LAIV) administration.

Patient	LAIV dose	Positive influenza test during influenza season after receiving LAIV	Time from vaccine to positive influenza test	Reported symptoms with influenza infection	Emergency department visit or hospitalization?
1	1	None	N/A	N/A	N/A
	2	No confirmed positive test	Symptoms developed 29 days after LAIV	Fever and vomiting after exposure to Influenza B, resolved with oseltamivir	No
2	1	None	N/A	N/A	N/A
3	1	Yes; influenza strain unknown	109–115 days a	Cough	No
	2	None	N/A	N/A	N/A
	3	None	N/A	N/A	N/A
	4	None	N/A	N/A	N/A
	5	None	N/A	N/A	N/A
	6	None	N/A	N/A	N/A
	7	None	N/A	N/A	N/A
4	1	None	N/A	N/A	N/A
	2	None	N/A	N/A	N/A
	3	Yes; Influenza B	126 days	Fever Cough Congestion Headache Sore throat	No
	4	Yes; Influenza A	161 days	No specific symptoms documented; “not feeling great” per parent EMR message	No
	5	Yes; Influenza A	51 days	No symptoms specified in chart	No

^a Test was collected in this window, exact date unreported.

4. Discussion

In a small series of pediatric liver transplant recipients with prior severe local injection‐site reactions to IIV, LAIVs were well‐tolerated with no serious adverse events related to the vaccine. Of the three reports of minor illness within 30 days after administration two cannot be clearly attributed to LAIV, with one patient testing positive for adenovirus and the other having had a cough that improved with antibiotics. While this cough could have been related to LAIV, the initial improvement with antibiotics is less consistent with vaccine‐related viral infection. LAIV seemed to be well‐received by families, with three of the four patients receiving doses over several seasons. While four confirmed influenza infections occurred, these were mild and did not require emergency care or hospitalization. Additionally, all infections occurred more than 45 days postvaccination; as the incubation period for influenza is 1–4 days [6], it is more likely that these were community‐acquired infections rather than from replication of vaccine‐strain virus, although molecular typing to identify vaccine strain was not performed. This suggests that LAIV may be a safe option for pediatric liver transplant recipients and adds to the growing literature showing that live viral vaccination can be administered safely in select immunosuppressed populations [5, 7, 8, 9]. Much of this literature evaluates varicella and MMR vaccination, which notably do not have an alternative inactivated option as is the case with influenza vaccination. While LAIV does carry a theoretical risk of vaccine‐associated influenza following administration, LAIV is cold‐adapted to decrease the risk of replication at normal body temperature which also should reduce the risk of developing symptomatic lower respiratory tract infection. For patients in whom IIV is less desirable, such as for the patients in this case series with severe local injection site reactions to IIV or for patients with anaphylaxis to IIV, it is important to consider all potential options such as LAIV administration for protection against influenza infection due to the higher risk of hospitalization and complications in immunocompromised children [1, 2, 3, 4].

There are several aspects of this study that limit generalizability to a broader population. This cohort consisted of a very small sample of only white females. Additionally, although families were instructed to report events to the medical team and had multiple contact points with clinical staff, no active surveillance was performed. Therefore, symptoms of ILI may have been underreported and influenza events missed; however, it is unlikely that a hospitalization was not reported given longitudinal care at our center. Additionally, all patients were liver transplant recipients and on stable immunosuppressive regimens consisting of sirolimus or tacrolimus with or without mycophenolate mofetil. The potential safety, tolerability, and efficacy of LAIV in recipients of other solid organs and/or who are on alternative immunosuppressive regimens cannot be assumed. Samples were not collected to assess immunogenicity as part of clinical administration of LAIV, so immune responses were not assessed. Larger studies are needed to explore the safety and immunogenicity of LAIV in SOT recipients, including timing of posttransplant LAIV and the impact of different immunosuppressive regimens on immunogenicity.

LAIVs were administered safely to a small group of pediatric liver transplant recipients. LAIVs may offer an alternative method of influenza vaccination in similar circumstances when IIV is not tolerated; additional studies evaluating the immunogenicity and safety in larger, more diverse groups of SOT recipients are needed to guide future recommendations for influenza immunization of this vulnerable population.

Data Availability Statement

The data that support the findings of this study are available from the corresponding author upon reasonable request.