Severe acute respiratory syndrome coronavirus 2 vaccination in children with a history of multisystem inflammatory syndrome in children: an international survey

1 SARS-CoV-2 vaccination in children with a history of MIS-C: an international survey Levi Hoste MD1,2, MIS-C researchers*, Antoni Soriano-Arandes MD PhD3, Emilie Pauline Buddingh MD PhD4, Elizabeth Whittaker MD PhD5,6, Alexandre Belot MD PhD7, Rolando Ulloa-Gutierrez MD8, Peter Olbrich MD PhD9,10 °, Filomeen Haerynck MD PhD1,2° Affiliations 1 Primary Immune Deficiency Research Laboratory, Department of Internal Diseases and Pediatrics, Centre for Primary Immunodeficiency Ghent, Jeffrey Modell Diagnosis and Research Centre, Ghent University, Ghent, Belgium 2 Department of Internal Medicine and Pediatrics, Division of Pediatric Pulmonology, Infectious Diseases and Inborn Errors of Immunity, Ghent University Hospital, Ghent, Belgium 3 Pediatric Infectious Diseases and Immunodeficiencies Unit, Hospital Universitari Vall d'Hebron (HUVH), Barcelona, Spain 4 Department of Pediatrics, Leiden University Medical Centre, Leiden, The Netherlands 5 Paediatric Infectious Diseases, Imperial College Healthcare NHS Trust, London, United Kingdom 6 Section of Paediatric Infectious Diseases, Imperial College, London, United Kingdom 7 Pediatric Nephrology Rheumatology and Dermatology, CHU Lyon, Lyon, France 8 Servicio de Infectología Pediátrica, Hospital Nacional de Niños "Dr. Carlos Sáenz Herrera", Centro de Ciencias Médicas, Caja Costarricense de Seguro Social (C.C.S.S.), San José, Costa Rica 9 Pediatric Infectious Diseases, Rheumatology and Immunology Unit, Hospital Universitario Virgen del Rocío, Instituto de Biomedicina de Sevilla, IBiS/ Universidad de Sevilla/CSIC, Red de Investigación Traslacional en Infectología Pediátrica RITIP, Sevilla, Spain 10 Departamento de Farmacología, Pediatría y Radiología. Facultad de Medicina. Universidad de Sevilla, Spain *MIS-C researchers are listed in Acknowledgements ° both authors contributed equally and should be considered shared last author 2 Corresponding author: Filomeen Haerynck, Department of Pediatric Pulmonology, Infectious Diseases and Immunology, Ghent University Hospital, Corneel Heymanslaan 10, Ghent, Belgium, [email protected] Funding: LH was funded by the VIB Grand Challenge Programs and FWO-TBM (T004721N). FH is supported by Ghent University research grant (BOF-UGent), VIB Grand Challenges Programs and Jeffrey Modell Foundation. AS-A is supported by the Departments of Health and Education of the Government of Catalonia (Spain) for the COVID-19 Sentinel School Network project. PO has received funding by the Instituto de Salud Carlos III (Contrato Juan Rodés, JR18/00042), Madrid, Spain. Conflict of interest: none applicable Short title: SARS-CoV-2 vaccination after MIS-C Word count: 1988 Keywords: MIS-C, SARS-CoV-2, COVID-19, vaccination, adverse events Abbreviations AE adverse event COVID-19 coronavirus disease 2019 MIS-C multisystem inflammatory syndrome in children SAg superantigen SARS-CoV-2 severe acute respiratory syndrome coronavirus 2 Abstract The optimal SARS-CoV-2 vaccine strategy for patients with a history of MIS-C is unclear. We performed an international survey (32 countries) and found substantial variations in vaccine policies for these patients. Reassuringly, respondents were not aware of relapses of MIS-C or other severe inflammatory side effects after SARS-CoV-2 vaccination in 273 patients with a history of MIS-C. 3 Introduction In general, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes asymptomatic to mild disease in children, resulting in 1-5% of all coronavirus disease 2019 (COVID-19) hospitalizations and less than 0.25% of total deaths[1]. However, in approximately 1 in 3000 to 1 in 5000 SARS-CoV-2 infections, multisystem inflammatory syndrome in children (MIS-C) occurs with a severe and potentially lifethreatening disease course (1-2% mortality)[2–4]. MIS-C primarily affects previously healthy children between 6 and 10 years of age[4,5]. Although their initial SARS-CoV-2 infection usually is asymptomatic or mild, children develop persistent fever with multisystem involvement 2 weeks to 2 months after infection. Besides high-grade fever, the clinical spectrum especially includes gastrointestinal, cardiovascular, dermatologic and neurologic symptoms[4,6]. Multiple-organ dysfunction and hemodynamic instability requires admission to intensive care units for up to 70% of MIS-C patients. In addition to supportive care, most patients are treated with immunomodulatory therapies, including one or more of intravenous immunoglobulin, systemic corticosteroid and a biologic response modifying agent[7]. In parallel with increased SARS-CoV-2 infections in children, recent data has shown that pediatric SARS-CoV-2 related hospitalizations increased during the more recent omicron surge, both in relative (18% of hospitalizations in South-Africa were children)[8] and absolute numbers (4-5 times as many children hospitalized in the US compared with delta surge)[9]. To date, it is unclear how the incidence of MIS-C evolves with different SARS-CoV-2 variants, although a recent pre-print suggests a lower risk for MIS-C when delta and omicron were dominant compared with alpha lineage[10]. Although the pathophysiology of MIS-C remains enigmatic, recent data show activation of oligoclonally expanded T lymphocytes, reminiscent of disease driven by superantigen (SAg) exposure such as in toxic shock syndrome. In MIS-C, however, upregulated T lymphocytes associate with MIS-C harbor the TRBV11-2 gene, encoding for the T-cell receptor Vβ 21.3, which appears to be a highly sensitive and specific feature[11-14]. While the exact source of SAg in MIS-C remains unknown, persistence of viral exposure is one of the possibilities, given that widespread replication of SARS-CoV-2 has been demonstrated in 4 deceased MIS-C patients[15] and SARS-CoV-2 spike, S1, and nucleocapsid antigens have been detected in plasma of patients with MIS-C[16]. Currently approved pediatric vaccines against COVID-19 are mRNA-based and encode for the SARS-CoV-2 spike protein[17–19]. SARS-CoV-2 vaccination generally is well tolerated, even in young children[20]. Nevertheless, rare but severe inflammatory events have been documented after SARS-CoV-2 vaccination, such as myocarditis in young (male) adults[21], or broader multisystem inflammation (MIS after SARS-CoV- 2 vaccination; MIS-V) in adolescents or adults[22-28]. One could hypothesize that in children who previously experienced MIS-C, re-exposure to the viral protein could trigger a relapse of hyperinflammation, especially with a presumed SAg underlying the pathophysiology of MIS-C. Childhood vaccination programs have been implemented in many countries. However, to date, limited data are available on children receiving SARS-CoV-2 vaccination after MIS-C. Physicians, families, and other stakeholders may have substantial doubts about the best vaccine strategy for this specific population. We therefore performed an international survey among healthcare professionals to assess experience with tolerability of SARS-CoV-2 vaccine in children with a history of MIS-C. Methods A cross-sectional electronic survey was drafted directed to professionals involved with MIS-C care (Supplementary Appendix). The survey was comprised of 24 questions, covering 1) vaccination policies used for children with previous MIS-C (local, regional and/or national guidelines); 2) number of children with a history of MIS-C who were or were not (yet) vaccinated against SARS-CoV-2; and 3) identification of uncommon adverse events, codified as possible, probable, or certain, occurring after SARS-CoV-2 vaccination in these children. Respondents were asked to specify if the entered cases were counted accurately (e.g. registered as cases) or as estimated numbers. The survey link was distributed globally through personal communication by the authors and through e-mail invitations by multiple professional (inter)national societies of pediatrics, infectious diseases, intensive care medicine, inborn errors of immunity, Kawasaki disease/MIS-C networks, and clinical trials networks. Participants also were asked to distribute the survey invitation to other colleagues involved in MIS-C care. The professional background of 5 respondents was evaluated to confirm relevant roles in MIS-C patient care and/or policymaking. IP addresses were verified to ensure the uniqueness of each participant. Possible overlapping data (e.g. national data that included regional counts) were excluded after personal communication with the involved respondents. Given the study design, overall survey response rates and subsequently any comparisons between survey respondents with non-respondents could not be performed. On an individual patient level, no identifiable information was collected. Data were collected from November 1, 2021 to December 15, 2021. Results Study population One hundred and thirty-two healthcare professionals involved in the care of MIS-C patients initiated the survey. After excluding incomplete entries, we collected complete data from 83 health care professionals, from 32 different countries (Figure 1). Most respondents were clinicians (79/83) and/or clinical researchers (21/83). Medical specialties included pediatrics (53/83), pediatric infectious diseases (23/83), cardiology (13/83), immunology (8/83), intensive care and emergency medicine (8/83), rheumatology (7/83) and dermatology (1/83). Four entries were excluded because of probable or confirmed overlapping data. After excluding these cases, information from 5673 MIS-C patients was analyzed (Figure 2). 3465 of these cases were accurately counted and 2208 were reported as estimated case numbers of MIS-C patients. Almost half of the patients (44.4%) had been admitted to intensive care units (ICU) during their MIS-C episode. Patients Who Received SARS-CoV-2 Vaccine As stated by the participants at the time of the survey, 1750 MIS-C patients (30.8% of the study cohort) were eligible by age, vaccine availability and time since the episode of MIS-C for vaccination. 273 (15.6% of eligible patients) were confirmed to be vaccinated at the time of the survey. For an additional 420 cases (24.0% of eligible patients) respondents assumed vaccine administration based on the absence of formal contraindication, although no registration or follow-up was performed. This included 81 accurately counted cases and 339 based on estimate numbers. 6 Policy and Practice Fourteen of 79 (17.7%) respondents from Belgium, France, India, Italy, Mexico, Pakistan, Turkey, and the USA declared MIS-C as a contraindication for SARS-CoV-2 vaccination at the time of the survey, accounting for 1144 patients (20.2% of the cohort). Of note, not all respondents from the same country declared MIS- C as a contraindication (e.g. Belgium 7 of 12 respondents, Italy 1/6, Turkey 1/5, USA 1/7), suggesting heterogeneous policies or their knowledge on a national level. The participants affirmed that vaccination was contraindicated in their settings due to recommendations of national or regional guidelines (9/14 regions) as well as safety concerns (9/14). Furthermore, 9 participants stated deviation from the standard vaccine regimen for these children compared with previously healthy children without MIS-C or SARS-CoV-2 infection. Recommendations included a minimal interval between MIS-C and administration of the first vaccine dose ranging from 3 months (respondents from Italy, Spain, Sweden, Turkey, UK, Uruguay, and USA) up to 6 months (The Netherlands, UK). Some respondents declared intent to administer only one dose instead of the typical two-dose regimen (Italy, Spain and Switzerland). Most children with prior MIS-C were vaccinated in the same locations as healthy children according to local health authority guidelines such as vaccination centers or schools (n=45 respondents), hospitals without admission (n=3 from India, Italy and Turkey) or hospitals with admission (n=13 from Belgium, South Korea, Colombia, Indonesia, Spain, Turkey, India, Italy, USA). Only one respondent from Italy declared that vaccination in a hospital without admission was a specific procedure for MIS-C not applying to healthy children. Tolerability of SARS-CoV-2 Vaccine Most respondents (for 54 of 65 entries without contraindication for vaccination) could not provide specific data on mild or moderate AE, either because there was lack of formal registration and/or that respondents were not at all confronted with these specific AE in patients. Of registered data, mild or moderate AE were reported to a variable extent including both localized reactions (swelling, redness, pain) and systemic responses (fever, chills, nausea, fatigue, headache, lymphadenopathy). As such, frequencies of AEs for 7 individual entries ranged from 0 to 100% of patients, although importantly, all mild or moderate AEs disappeared after 1-3 days without requiring specific interventions. One 13-year-old male was reported with acute-onset facial nerve palsy (Bell palsy), one week after his second BNT162b2 (Pfizer-BioNTech) vaccine. He was hospitalized and given methylprednisolone (40mg/day) and recovered without sequelae. No other severe AE was reported by the participants. Importantly, no MIS-C relapse or any other inflammatory conditions were reported after vaccination. Discussion This international survey on SARS-CoV-2 vaccination in children with a history of MIS-C provides early experience and insights into a specific population of children who suffered from a rare but severe complication of SARS-CoV-2 infection. The survey documents heterogeneity of vaccine policy as well as limited data on vaccination after recovery from MIS-C. Questionnaires included data collected concerning over 5000 MIS-C patients and more than 30 countries. Our data suggest that vaccine recommendations or their understanding or both in the context of MIS-C not only differ between continents and healthcare systems, but also within countries. Potential harms and benefits of SARS-CoV-2 vaccination in children with a history of MIS-C may be weighted differently in each setting. Individual choices or concerns regarding vaccine safety also might exist. Although SARS-CoV-2 vaccination was not contraindicated in patients according to CDC guidelines, we observed a heterogeneous advice within respondents from the USA [29] Although in most countries adverse events of vaccines and drugs are registered centrally by healthcare agencies, the rarity of MIS-C and the absence of registries documenting follow up of vaccination episodes in affected patients leads to a lack of specific knowledge regarding tolerability of SARS-CoV-2 vaccination in these children. Our survey provides a limited but timely snapshot. Based on this survey, we found that in most regions around the world, MIS-C is not considered a contraindication for SARS-CoV-2 vaccination. In addition, respondents stated that 273 patients effectively received at least one dose of SARS-CoV-2 vaccine after MIS-C. There was no overt experience of increased 8 frequency or severity of AE and no case of MIS-C relapse or other inflammatory conditions after vaccination was reported. In this small observation, and when given in the timed manner of reporting participants, systemic re-exposure to the SARS-CoV-2 spike protein was well tolerated in these patients. Our observations are consistent with the overall good safety profile of SARS-CoV-2 vaccines in healthy children. Moreover, recent data suggest that SARS-CoV-2 vaccination is associated with a reduced risk of development of MIS-C after infection[30,31]. It should be noted that Bell palsy was reported as a severe AE in one patient although this condition is encountered rarely after vaccination (including COVID-19)[32], and generally is reversible[33]. Administration of a SARS-CoV-2 vaccine after MIS-C was assessed by participants as contraindicated in 20.2%. Furthermore, a substantial number of MIS-C patients, even if already eligible for vaccination (30% of the cohort), had not been vaccinated (of the eligible cohort only 15.6% [273/1750] were confirmed to be vaccinated, 24.0% [420/1750] were possibly vaccinated, and 60.4% were not). In addition, some respondents declared to propose longer intervals between MIS-C and vaccination or different dosing schedules than for previously healthy children, potentially exposing MIS-C patients to a higher risk of reinfection. More detailed information on safety of delayed vaccination or oneversus two-dose vaccination will be of value in order to define the optimal vaccine strategy for this specific group of patients. Of additional importance for vaccination policies, it will be of interest to document whether occurrence of MIS-C is limited to primary exposure to SARS-CoV-2 or if MIS-C, and with what frequency, following re-infection[34]. This analysis is limited by the temporary nature of its data, especially in the midst of an evolving pandemic and vaccine policies. When this survey was initiated, SARS-CoV-2 vaccines were not yet universally accessible for children 5-11 years of age, representing a substantial proportion of MIS-C patients[4]. The systematic and prospective collection of additional safety data on younger MIS-C patients is important to either support or adjust conclusions beyond the current context of predominantly adolescent MIS-C patients receiving the BNT162b2 (Pfizer-BioNTech) vaccine. A major limitation of the study design is confirmation of receipt of vaccine in only 273 cases, and potential bias related to recall or notification or 9 both of adverse events. It seems unlikely, however, that attending physicians or healthcare providers would not have been notified of important inflammatory complications or MIS-C relapses. We did not collect individual data on patients, so information on the demography of those vaccinated, the number of doses administered or the interval between MIS-C and SARS-CoV-2 vaccination was not documented. Finally, data represent a convenience sample supplied by numerous professionals involved with MIS-C patient care worldwide who chose to participate and should be interpreted as such. Much larger specific safety surveillance studies are needed to define the effect of SARS-CoV-2 vaccination in patients with a history of MIS-C.