A Randomized Controlled Clinical Trial of Nasal Immunization with Live Virulence Attenuated Streptococcus pneumoniae Strains Using Human Infection Challenge.

Rationale: Pneumococcal pneumonia remains a global health problem. Pneumococcal colonization increases local and systemic protective immunity, suggesting that nasal administration of live attenuated Streptococcus pneumoniae (Spn) strains could help prevent infections. Objectives: We used a controlled human infection model to investigate whether nasopharyngeal colonization with attenuated S. pneumoniae strains protected against recolonization with wild-type (WT) Spn (SpnWT). Methods: Healthy adults aged 18-50 years were randomized (1:1:1:1) for nasal administration twice (at a 2-wk interval) with saline solution, WT Spn6B (BHN418), or one of two genetically modified Spn6B strains, SpnA1 (Δfhs/piaA) or SpnA3 (ΔproABC/piaA) (Stage I). After 6 months, participants were challenged with SpnWT to assess protection against the homologous serotype (Stage II). Measurements and Main Results: 125 participants completed both study stages per intention to treat. No serious adverse events were reported. In Stage I, colonization rates were similar among groups: SpnWT, 58.1% (18 of 31); SpnA1, 60% (18 of 30); and SpnA3, 59.4% (19 of 32). Anti-Spn nasal IgG levels after colonization were similar in all groups, whereas serum IgG responses were higher in the SpnWT and SpnA1 groups than in the SpnA3 group. In colonized individuals, increases in IgG responses were identified against 197 Spn protein antigens and serotype 6 capsular polysaccharide using a pangenome array. Participants given SpnWT or SpnA1 in Stage I were partially protected against homologous challenge with SpnWT (29% and 30% recolonization rates, respectively) at stage II, whereas those exposed to SpnA3 achieved a recolonization rate similar to that in the control group (50% vs. 47%, respectively). Conclusions: Nasal colonization with genetically modified live attenuated Spn was safe and induced protection against recolonization, suggesting that nasal administration of live attenuated Spn could be an effective strategy for preventing pneumococcal infections. Clinical trial registered with the ISRCTN registry (ISRCTN22467293).

Brain imaging in lung cancer staging: A real-world, multi-centre study of prevalence of brain metastases, impact on treatment and re-modelling of the NICE health economic analysis.

INTRODUCTION: In 2019, the National Institute for Health and Care Excellence (NICE) updated their recommendations with respect to brain imaging in the staging of non-small cell lung cancer (NSCLC) based on an analytic cost-effectiveness model using published data and modelling assumptions from committee experts. In this study, we aimed to re-run this model using real-world multi-centre UK data. MATERIALS AND METHODS: Retrospective data was collected on consecutive patients with radically treatable clinical stage II and III lung cancer from eleven acute NHS Trusts during the calendar year 01/01/2018 to 31/12/2018. Following a written application to the NICE lung cancer guideline committee, we were granted access to the NG122 brain imaging economic model for the purpose of updating the input parameters in line with the real-world findings from this study. RESULTS: A total of 444 patients had data for analysis. The combined prevalence of occult brain metastases was 6.2% (10/165) in stage II and 6% (17/283) in stage III, compared to 9.5% and 9.3% used in the NICE economic model. 30% of patients with clinical stage III NSCLC and occult BMs on pre-treatment imaging went onto complete the planned curative intent treatment of extracranial disease, 60% completed SRS to the brain and 30% completed WBRT. This compares to 0%, 10% and 0% in the NICE assumptions. The health economic analysis concluded that brain imaging was no longer cost-effective in stage II disease (ICERs £50,023-£115,785) whilst brain imaging remained cost-effective for stage III patients (ICERs 17,000-£22,173), with MRI being the most cost-effective strategy. CONCLUSION: This re-running of the NICE health economic model with real-world data strongly supports the NICE guideline recommendation for brain imaging prior to curative-intent treatment in stage III lung cancer but questions the cost-effectiveness of CT brain imaging prior to curative-intent treatment in stage II lung cancer.