Maheshi Nirmala Ramasamy

Background: Most recent childhood invasive pneumococcal disease in the UK is caused by serotypes not included in the currently used pneumococcal conjugate vaccine (PCV13). There is potential for additional protection with newer PCVs that have wider serotype coverage but there are no data on these vaccines being given in the 1+1 schedule used in the UK. This study will determine whether the PCV13 serotype-specific antibody responses to PCV15 and PCV20 given at 3 and 12 months (1+1 schedule) are non-inferior to PCV13 serotype-specific antibody responses to PCV13 given in the same schedule. It will also determine whether PCV13 serotype-specific antibody responses to PCV20 given at 2, 4 and 12 months (2+1 schedule) are non-inferior to PCV13 serotype-specific antibody response to PCV13 given at 3 and 12 months (1+1 schedule). Methods: This will be an open-label, randomised controlled multicentre study in 600 infants. Healthy infants will be enrolled at 8 weeks and randomised 1:1:1:1 to receive 2 doses (1+1) of either PCV15, PCV20 or PCV13 at 3 and 12 months of age or 3 doses (2+1) of PCV20 at 2, 4 and 12 months. Blood and nasal samples will be collected at specified intervals to assess serum and nasal IgG levels and carriage. Postprimary and postbooster IgG levels in the PCV15 and PCV20 arms will be compared against PCV13. Ethics and dissemination: Ethical approval for this study has been obtained from the South Central—Hampshire A Research Ethics Committee (REC ref 24/SC/0222). The results will be disseminated via publication in a peer-reviewed journal and presentations at international conferences. Trial registration number: ISRCTN17673117 .

Introduction: Enteric fever, primarily caused by Salmonella enterica Typhi and Salmonella enterica Paratyphi A (SPA), is endemic mainly in South Asia, disproportionately affecting school-age children. Although typhoid conjugate vaccines (TCVs) are effective and implemented in many countries, no licensed vaccine exists against paratyphoid A. Bivalent vaccines targeting both S. Typhi and SPA may address this gap. Although field efficacy trials are not considered feasible, controlled human infection models (CHIMs) offer an alternative pathway for evaluating vaccine efficacy. This will be the first efficacy study of a bivalent vaccine against typhoid and paratyphoid A using a paratyphoid CHIM. Methods and analysis: This is a phase II multicentre, double-blind, randomised controlled trial assessing the efficacy and immunogenicity of a bivalent conjugate vaccine candidate, Serum Institute of India Typhoid Conjugate Vaccine (Bivalent) (SII-TCV(B)), against SPA using a CHIM in healthy UK adults aged 18–55 years. A total of 192 participants will be randomised 1:1 to receive either SII-TCV(B) or a licensed Vi-polysaccharide typhoid vaccine (Vi-PS). All participants will be orally challenged with S. Paratyphi A (strain NVGH308) 28 days postvaccination. Participants will be monitored closely for 14 days and treated at 14 days postchallenge or promptly on diagnosis, according to prespecified criteria. The primary objective is to evaluate vaccine efficacy of SII-TCV(B) against paratyphoid infection using a CHIM. The coprimary immunogenicity objective is to assess non-inferiority of the typhoid IgG response compared with a licensed Vi-PS control. Ethics and dissemination: The study has received ethical approval from the Berkshire Research Ethics Committee (24/SC/0309) and regulatory approval from the UK Medicines and Healthcare products Regulatory Agency. Results will be disseminated via peer-reviewed publications and scientific meetings. Trial registration number: ISRCTN65855590 .

Adenoviral (Ad) vectors and mRNA vaccines exhibit distinct patterns of immune responses and reactogenicity, but underpinning mechanisms remain unclear. We longitudinally compared homologous ChAdOx1 nCoV-19 and BNT162b2 vaccination, focusing on cytokine-responsive innate-like lymphocytes—mucosal-associated invariant T (MAIT) cells and Vδ2 ⁺ γδ T cells—which sense and tune innate-adaptive cross-talk. Ad priming elicited robust type I interferon (IFN)–mediated innate-like T cell activation, augmenting T cell responses (innate-to-adaptive signaling), which was dampened at boost by antivector immunity. Conversely, mRNA boosting enhanced innate-like responses, driven by prime-induced spike-specific memory T cell–derived IFN-γ (adaptive-to-innate signaling). Extending the dosing interval dampened inflammation at boost because of waning T cell memory. In a separate vaccine trial, preboost spike-specific T cells predicted severe mRNA reactogenicity regardless of the priming platform or interval. Overall, bidirectional innate-like and adaptive cross-talk, and IFN-γ–licensed innate-like T cells, orchestrate interval-dependent early vaccine responses, suggesting modifiable targets for safer, more effective regimens.

Vaccines protect against many infectious diseases, including some that can directly or indirectly cause nervous system damage. Serious neurological consequences of immunization are typically extremely rare, although they have the potential to jeopardize vaccination programmes, as demonstrated most recently during the COVID-19 pandemic. Neurologists have an important role in identifying safety signals at population and individual patient levels, as well as providing advice on the benefit–risk profile of vaccination in cohorts of patients with diverse neurological conditions. This article reviews the links between vaccination and neurological disease and considers how emerging signals can be evaluated and their mechanistic basis identified. We review examples of neurotropic infections with live attenuated vaccines, as well as neuroimmunological and neurovascular sequelae of other types of vaccines. We emphasize that such risks are typically dwarfed by neurological complications associated with natural infection and discuss how the risks can be further mitigated. The COVID-19 pandemic has highlighted the need to rapidly identify and minimize neurological risks of vaccination, and we review the structures that need to be developed to protect public health against these risks in the future.