muhamad Hamad Said

This thesis aimed to strengthen the evidence base for vaccination as a means of protecting immunocompromised children from preventable infection by addressing key unanswered questions regarding vaccine safety, immunogenicity, and effectiveness. To achieve this, it investigated five specific clinical questions that practitioners encounter in daily practice but often cannot answer with confidence, because the available evidence is limited or absent. Together, the five studies presented in this thesis provide a body of evidence across three vaccine platforms, obtained in real-world populations and in clinical settings where these decisions are actually made, and of sufficient scope and consistency to inform individual patient care, guideline revision and future research. The most consistent finding across all five studies is that vaccination in this patient group is safer than the prevailing culture of caution has assumed. The MMR booster caused no significant change in disease activity and no serious adverse events in a large real-world cohort that included biologic-treated children, the very patients most commonly advised to avoid live attenuated vaccines. COVID-19 mRNA vaccines were safe and well tolerated too, with no disease flares and none of the feared vaccine-triggered events such as myocarditis or MIS-C. The recombinant zoster vaccine Shingrix, used off-label in selected VZV-naïve immunocompromised children, represents the first published evaluation of this approach in paediatric patients and showed an acceptable preliminary safety profile despite the vulnerability of the study population. Safety did not appear to be the barrier it has been feared to be. The findings describing immunogenicity tell a more complex story. Biologic-treated patients mounted lower antibody responses to both MMR and COVID-19 than children not on biologics, and a substantial proportion of patients had lost measles seroprotection within five years of the MMR booster. For COVID-19, however, those lower antibody levels still protected children against infection, whereas the loss of measles seroprotection leaves some children unprotected. These findings are not arguments against vaccination, rather they are arguments for more tailored and more effective vaccination strategies. A targeted approach, measuring MMR-specific IgG at an appropriate interval post-booster in biologic-treated patients and offering a booster dose to those who have lost seroprotection, is both clinically practical and directly supported by the longitudinal data generated in this thesis. One of the most clinically important findings in this work comes from chapter 5: lower antibody levels did not translate into less protection. Biologic-treated children had significantly lower anti-spike IgG concentrations after COVID-19 mRNA vaccination than children not on biologics, though in almost all cases these remained above the seroprotective threshold, and their rate of symptomatic infection was no higher. Adequate T-cell responses in 91% of tested patients likely help maintain protection when antibody levels are lower. This has direct implications for how isolated serological results in immunocompromised children should be interpreted: a lower-than-expected antibody level does not necessarily mean the vaccine has failed. The meta-analysis on the incidence of MIS-C after vaccination in chapter 4 produced clear quantitative evidence: a pooled odds ratio of 0.04 (95% CI 0.03–0.06) for MIS-C in COVID-19 vaccinated children compared with unvaccinated children, representing a 96% reduction in risk that was consistent across four independent nationwide datasets covering approximately 63 million children. The rate of MIS-C following COVID-19 vaccination itself was 2.9 per million, compared with 113.3 per million following natural infection. This finding, combined with evidence that biologic and targeted synthetic therapies are themselves associated with a lower risk of MIS-C, suggests that vaccinated children with pedAIIRDs receiving immunomodulatory treatment have multiple layers of protection against this severe complication. Chapter 6 is the first published evaluation of Shingrix in VZV-naïve immunocompromised children. The vaccine was administered off-label as part of routine clinical care in selected significantly immunocompromised patients, in the absence of any approved alternative, reflecting a real-world decision made by clinicians facing an unmet need. It provides preliminary evidence that this approach is feasible, that seroconversion is achievable in most patients despite ongoing immunosuppression, that breakthrough infections when they occur are mild and manageable, and that no safety signal emerged that would preclude a larger study. For a patient group that currently has no approved vaccination option against primary varicella when high-level immunosuppression precludes the live vaccine, this represents a clinically important first step toward filling that gap. The practical conclusions are clear. In children with pedAIIRDs, vaccination status should be systematically assessed at diagnosis and re evaluated at each significant treatment transition. Biologic-treated patients should have MMR-specific IgG levels measured at an appropriate interval after the booster dose, with a further dose offered to those who have lost seroprotection. COVID-19 vaccination can generally be administered without interruption of immunosuppressive therapy. VZV-naïve children on high-level immunosuppression should be considered for Shingrix as a non-live alternative. And in the most complex cases, children on multiple immunosuppressants or with features of primary immunodeficiency, the vaccination decision should be made jointly with clinical immunology and infectious disease colleagues, and should not be deferred indefinitely on grounds of uncertainty. The evidence is not complete, and this thesis is explicit about what remains unknown: the validity of seroprotective thresholds in immunocompromised children, the vaccine responses to newer treatments including JAK inhibitors, B-cell depleting agents, and other advanced targeted therapies, the extension of these findings beyond JIA to children with other autoimmune and inflammatory conditions such as inflammatory bowel disease, psoriasis, and primary immunodeficiency, and the long-term correlates of protection for COVID-19 and recombinant zoster vaccines in paediatric patients. These limitations do not change the overall conclusions of this thesis. Instead, they identify important priorities for future research. They simply mark the point where this thesis ends and the next phase of work begin. The children who fall outside the current evidence base deserve the same quality of evidence that this thesis has begun to generate, and each gap identified here points towards a research programme that is now within reach. What this thesis demonstrates, above all, is that the default position in the care of children with pedAIIRDs should be to vaccinate rather than to defer, and that the evidence now exists to make that position specific, defensible, and safe.