Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination for Paediatric Patients With Inflammatory Bowel Diseases

Abstract

In this communication, the members of the Porto group (the European Society for Paediatric Gastroenterology, Hepatology and Nutrition [ESPGHAN], inflammatory bowel diseases [IBD] working group) provide the current available evidence regarding vaccination of children and young adolescents with IBD against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Our intent is to help provide meaningful answers to the concerns that parents and adolescents may have.

Vaccination in adults against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is progressing worldwide. On 27 May 2021, the American Centers for Disease Control and Prevention (CDC) issued a recommendation to vaccinate all children over 12 years of age (yoa) with the Pfizer/BioNtech vaccine ⁽¹⁾. The next day, the European Medicine Agency (EMA) published that the indication for the Pfizer/BioNtech vaccine was extended from 16 yoa to 12 yoa ⁽²⁾. These recommendations are based on data from 2260 subjects who were vaccinated with the Pfizer/BioNtech vaccine. Pfizer issued a press release claiming 100% efficacy in this group of 12–15 yoa in a pivotal trial, an extension of their adult trial ⁽³⁾.

Since vaccination in children over 12 yoa will be initiated shortly, the authors and the Paediatric inflammatory bowel diseases (IBD) Porto Group of ESPGHAN, wish to underline some specific aspects relating to SARS-CoV-2 vaccination in children and adolescents with IBD. Most young patients with IBD are treated with immunosuppression and questions regarding their risk, due to both the underlying disease and the treatment and thus possible need for priority is very real. Our intent is to provide the available evidence regarding SARS-CoV-2 in children and adolescents with IBD so that our colleagues can address concerns that patients and their parents bring to the clinics.

In January 2021, the International Organization For the Study of IBD (IOIBD) published consensus-based recommendations on SARS-CoV-2 vaccination for adult patients with IBD ⁽⁴⁾. Among 64 voting respondents, there were 4 (6%) paediatric IBD experts. From our point of view, out of 44 statements that were finally accepted, none is generally controversial for the paediatric IBD community.

So far, marketing authorization in EU and USA was granted to four vaccines ⁽⁵⁾ produced by Pfizer/BioNtech, Astra Zeneca, Janssen and Moderna. Children were not studied as a separate group in the published vaccination studies. As stated earlier, an extension was granted to 12 yoa for the Pfizer/BioNtech vaccine.

The first publication by Pfizer/BioNtech ⁽⁶⁾ led to authorization of the vaccine ‘Comirnaty’. A deferral for the Paediatric Investigation Plan (PIP) was authorized 27 November 2020, thereby releasing the company from their obligation to submit to the regulatory authorities a clinical research proposal involving patients under 18 yoa.

In the Pfizer study ⁽⁷⁾, the population was divided into two age groups: the youngest: 16–55 yoa: n = 10,889 (57.7%) for intervention and n = 10,896 (57.8%) for placebo and the older group: >55 yoa, n = 7971 (42.3%) for intervention and n = 7950 (42.2%) for placebo. The median age at vaccination was 52 yoa. with a range 16–89. The authors state that the study was not powered to assess efficacy by subgroup and the exact number of patients between 16 and 18 yoa is unknown.

On 19 May, the acceptance of a modification of the PIP dated 23 April was published. This led to a press release stating 100% efficacy in a group of 12–15 yoa ⁽³⁾. There is no peer reviewed publication to date. Adverse events of the Pfizer/BioNtech vaccine in children are similar to the previously described: pain at the injection site, tiredness, headache, muscle and joint pain, chills and fever. These effects are usually mild or moderate and improve within a few days from the vaccination; however, myocarditis and pericarditis have been increasingly reported in adolescents and young adults but the agencies concludes that the benefits of the vaccination outweigh the risks ^(8,9).

For the second vaccine by Astra Zeneca ⁽¹⁰⁾, again a deferral for the PIP was granted 5 January 2021 and all patients studied were over 18 yoa.

For the third, recombinant vaccine by Janssen ⁽¹¹⁾ a deferral for the PIP was granted 5 February 2021 and all patients studied were over 18 yoa. The fourth mRNA vaccine produced by Moderna, was granted a deferral for the PIP 30 November 2020 and patients were over at least 18 yoa ⁽¹²⁾.

From the ongoing paediatric studies listed on Clinical trials.gov, the earliest conclusions can be expected in September 2021, from a Chinese paediatric study using an inactivated vaccine from Sinovac in children 3–17 yoa ⁽¹³⁾. The youngest group are children 6 months–12 yoa, receiving the Moderna vaccine (NCTO4796896) ⁽¹⁴⁾. Results are expected in June 2023. Four more studies are planned in children over 10 yoa ⁽¹⁵⁾, one of these uses the Moderna vaccine in children ages 12–18 yoa (NCTO4649151) and the estimated completion date is June 2022 ⁽¹⁶⁾. Table 1 lists the paediatric vaccine studies that can be identified on clinicaltrials.gov.

TABLE 1 - Paediatric vaccine studies

Commercial studies of COVID-19 vaccines that include paediatrics
Project	Sponsor	Trial	Age	Enrolment
Comirnaty (BNT162b2)	Biontech/Pfizer	NCT04368728	12-adult	43,998
			Extension in 12–15 y	2260
Comirnaty (BNT162b2)	Biontech/Pfizer	NCT04713553	12-adult	1530
Comirnaty (BNT162b2)	Biontech/Pfizer	NCT04816643	6 mo–11 y	4644
mRNA-1273	Moderna/Barda	TeenCove, NCT04649151	12–17 y	3000
mRNA-1273	Moderna/NIAID/Barda	KidCove, NCT04796896	6 mo–12 y	6750
Nanocovax	Nanogen	NCT04683484	12-adult	620
SARS-CoV-2 vaccine	Sinovac	NCT04551547	3–7 y	552
Covaxin (BBV152)	Bharat Biotech	NCT04471519	12-adult	755
Vaxzevria (AZD1222)	Astrazeneca/Oxford Uni	COV006	6–17 y	300

Evaluate Pharma & clinicaltrials.gov.COVID-19 = coronavirus disease 2019; SARS-COV-2 = severe acute respiratory syndrome coronavirus 2.

The publication by Siegel et al ⁽⁴⁾ on behalf of the IOIBD is a comprehensive and useful document. Agreement was unanimous that ‘ once SARS-CoV-2 vaccinations are authorised for children, guidance for vaccination of children with IBD will be the same as for children without IBD’.

However, some specific aspects relating to children and adolescents that merit attention and that we propose are:

Specific Aspects of Paediatric Inflammatory Bowel Disease

There are several differences in therapeutic approach in paediatric versus adult IBD patients. There is a trend to steroid-sparing strategies in paediatric IBD by using exclusive enteral nutrition (EEN) for induction of remission in Crohn's disease (CD) or using accelerated step up or first-line infliximab approach ^(17,18). Thus, the need for counselling on vaccine efficacy when receiving systemic corticosteroids may be less relevant for paediatric populations where EEN can be offered (which unfortunately is not the case in all countries). Moreover, EEN induction therapy period is a usual window-of-opportunity for completing missing vaccinations before the onset of immune modulator and/or biological therapy ⁽¹⁹⁾ and may also be applicable for SARS-CoV-2 vaccine in the future. The recommendations are to postpone the initiation of immune modulatory therapy (IM) for 3 weeks after a live vaccine. If the patient is on IM and IM has to be stopped, the recommendation is to wait for 3 months before administrating a live vaccine ⁽¹⁹⁾. Fortunately, the majority of vaccines (including Sars-CoV2 that are now permitted) are non-live, thus they can be administered along with IM. If more vaccine types become available in the future, we recommend to use the non-live ones for IBD children under IM treatment. In addition, it is known that IM may dampen the serological response to vaccination as was demonstrated for influenza vaccine ⁽²⁰⁾. Therefore, if a patient responds well to EEN or another nutritional therapy, the initiation of IM may be postponed following vaccination; however, the decision will have to be taken for each individual patient depending on disease activity, response and compliance to nutritional therapy.

In the case of anti-tumour necrosis factor (TNF) treatment, higher doses per kg of body weight may be needed in children under 10 yoa ⁽²¹⁾; however, anti-TNF is known to be associated with suboptimal vaccine response ⁽²²⁾ as was recently demonstrated in adult IBD patients for SARS-CoV-2 vaccine ⁽²³⁾. Therefore, post vaccination surveillance should be carefully applied in order to monitor vaccine efficacy, especially in younger children receiving high dose anti-TNF.

On the other hand, the experience with other therapies not yet approved for children (such as anti-integrins, anti-IL12/23, Janus Kinase inhibitors inhibitors and sphingosine-1-phosphate receptor agonists) is limited and relevant data concerning vaccination response, efficacy and safety in children treated with these drugs will probably not be available in near future; however, this does not justify us to deviate from current IOIBD recommendation on vaccination of patients receiving the above-mentioned treatment.

There is a paediatric IBD subpopulation that deserves special attention. These are children with suspected monogenic IBD-like diseases (usually generated from high risk groups, such as very early onset IBD (<6 yoa), with positive family history of IBD, autoimmune comorbidities, refractory to therapy etc.) ⁽²⁴⁾. These children usually suffer from genetically determined immune dysregulation or deficiency and should not follow general recommendation for vaccination of IBD patients. An individual approach in line with the different possible aetiologies in these patients is strongly encouraged and passive immunisation with immune globulins considered.

Specific Aspects of Coronavirus Disease 2019 Disease Course in Children

The course of coronavirus disease 2019 (COVID-19) disease is generally milder in children than in adults ⁽²⁵⁾. Children also rarely suffer from other comorbidities that were associated with unfavourable disease course ⁽²⁶⁾; however, young children may be asymptomatic carriers ⁽²⁷⁾ spreading the infection to adult population. It is not clear if vaccination would prevent this, however, when vaccination of the adult population is performed efficiently, this question will become less relevant.

There is also a subgroup of paediatric patients that develop an inflammatory multisystem syndrome, that is temporally associated with SARS-CoV-2 (paediatric multisystem inflammatory syndrome temporally associated with COVID-19 [PIMS-TS] or Multisystem Inflammatory Syndrome in Children [MIS-C])—a condition sharing similarities to Kawasaki disease ⁽²⁸⁾. A post-infectious immune dysregulation is a suggested pathophysiological mechanism rather than direct effect of SARS-CoV-2. With respect to this fact, Kawasaki disease was previously discussed as potential post-vaccination condition, but its incidence was not proven to be increased post-vaccination ⁽²⁹⁾. At the moment, there are no safety signals in SARS-CoV-2 vaccines pointing to this direction. Nevertheless, post-vaccination surveillance data should be carefully collected in a prospective manner including the occurrence of PIMS as a possibility as well as side effects, duration of immunisation and possible influence of the course of IBD itself.

General Considerations and Conclusions

As mentioned above, we agree that IOIBD statements are applicable to the paediatric population. Children should receive SARS-CoV-2 vaccine as soon as it is available and approved for paediatric population and in accordance with local rules for SARS-CoV-2 vaccination for healthy children and adolescents. Guidance for vaccination of children with IBD will be the same as for children without IBD and at the moment, there are no data supporting prioritisation of vaccination in paediatric IBD patients ^(30–33). Thus, we strongly suggest post vaccination surveillance of children with IBD. Tight follow-up of the vaccines’ efficacy in paediatric patients receiving immunomodulators, biologics or small molecules should not only include post vaccination titres but also side effects and disease course. Serological evaluations should be compared to adult data that demonstrate increased transmissibility and insufficient coverage against the delta B.1.617.2 strain ⁽³⁴⁾. An individual vaccination plan should be applied in children with suspected monogenic IBD. Finally, children with IBD should be included in prospective post-vaccination safety registries. Ideally, the competent authorities should quickly work with the scientific societies to implement such registries.