Specific and off-target immune responses following COVID-19 vaccination with ChAdOx1-S and BNT162b2 vaccines-an exploratory sub-study of the BRACE trial.

BACKGROUND: The COVID-19 pandemic led to the rapid development and deployment of several highly effective vaccines against SARS-CoV-2. Recent studies suggest that these vaccines may also have off-target effects on the immune system. We sought to determine and compare the off-target effects of the adenovirus vector ChAdOx1-S (Oxford-AstraZeneca) and modified mRNA BNT162b2 (Pfizer-BioNTech) vaccines on immune responses to unrelated pathogens. METHODS: Prospective sub-study within the BRACE trial. Blood samples were collected from 284 healthcare workers before and 28 days after ChAdOx1-S or BNT162b2 vaccination. SARS-CoV-2-specific antibodies were measured using ELISA, and whole blood cytokine responses to specific (SARS-CoV-2) and unrelated pathogen stimulation were measured by multiplex bead array. FINDINGS: Both vaccines induced robust SARS-CoV-2 specific antibody and cytokine responses. ChAdOx1-S vaccination increased cytokine responses to heat-killed (HK) Candida albicans and HK Staphylococcus aureus and decreased cytokine responses to HK Escherichia coli and BCG. BNT162b2 vaccination decreased cytokine response to HK E. coli and had variable effects on cytokine responses to BCG and resiquimod (R848). After the second vaccine dose, BNT162b2 recipients had greater specific and off-target cytokine responses than ChAdOx1-S recipients. INTERPRETATION: ChAdOx1-S and BNT162b2 vaccines alter cytokine responses to unrelated pathogens, indicative of potential off-target effects. The specific and off-target effects of these vaccines differ in their magnitude and breadth. The clinical relevance of these findings is uncertain and needs further study. FUNDING: Bill & Melinda Gates Foundation, National Health and Medical Research Council, Swiss National Science Foundation and the Melbourne Children's. BRACE trial funding is detailed in acknowledgements.

Off-target effects of bacillus Calmette-Guérin vaccination on immune responses to SARS-CoV-2: implications for protection against severe COVID-19.

Background and objectives: Because of its beneficial off-target effects against non-mycobacterial infectious diseases, bacillus Calmette-Guérin (BCG) vaccination might be an accessible early intervention to boost protection against novel pathogens. Multiple epidemiological studies and randomised controlled trials (RCTs) are investigating the protective effect of BCG against coronavirus disease 2019 (COVID-19). Using samples from participants in a placebo-controlled RCT aiming to determine whether BCG vaccination reduces the incidence and severity of COVID-19, we investigated the immunomodulatory effects of BCG on in vitro immune responses to SARS-CoV-2. Methods: This study used peripheral blood taken from participants in the multicentre RCT and BCG vaccination to reduce the impact of COVID-19 on healthcare workers (BRACE trial). The whole blood taken from BRACE trial participants was stimulated with γ-irradiated SARS-CoV-2-infected or mock-infected Vero cell supernatant. Cytokine responses were measured by multiplex cytokine analysis, and single-cell immunophenotyping was made by flow cytometry. Results: BCG vaccination, but not placebo vaccination, reduced SARS-CoV-2-induced secretion of cytokines known to be associated with severe COVID-19, including IL-6, TNF-α and IL-10. In addition, BCG vaccination promoted an effector memory phenotype in both CD4+ and CD8+ T cells, and an activation of eosinophils in response to SARS-CoV-2. Conclusions: The immunomodulatory signature of BCG's off-target effects on SARS-CoV-2 is consistent with a protective immune response against severe COVID-19.

Unconventional T Cell Immunity in the Lungs of Young Children with Cystic Fibrosis.

BACKGROUND: People with Cystic Fibrosis (CF) develop pulmonary inflammation, chronic infection and structural lung damage early in life, with these manifestations being prevalent among preschool children and infants. While early immune events are believed to play critical roles in shaping the progression, severity and disease burden later in life, T cells and their subsets are poorly studied in the CF lung, particularly during the formative early stages of disease. METHODS: Using flow cytometry, we analyzed Mucosal Associated Invariant T (MAIT) cells, γδ T cells, and Natural Killer T (NKT)-like cells in bronchoalveolar lavage (BAL) samples from seventeen children with CF, aged two to six years old. The effect of age, sex and lung infections on the frequencies of these cells in BAL samples was analysed (grouped data were tested for normality and compared by t-test or Kruskal-Wallis analysis). RESULTS: No difference was noted in the proportions of unconventional T cells related to the sex or age of the children. The frequency of γδ T cells and MAIT cells appeared unchanged by infection status. However, viral infections were associated with a significant increase in the proportion of NKT-like cells. CONCLUSIONS: By evaluating T cells in the lungs of children during the early formative stages of CF, this study identified potentially important interactions between these cells and viral pathogens.

Health impact of water and sanitation infrastructure reconstruction programmes in eight Central American communities affected by Hurricane Mitch.

In response to Hurricane Mitch, which struck Central America in October-November 1998, the American Red Cross (ARC) and the Centers for Disease Control and Prevention (CDC) collaborated on a 3-year evaluation of the public health impact of ARC's water, sanitation and hygiene education activities in eight study areas in Honduras, Nicaragua, El Salvador and Guatemala. The evaluation compared: 1) access to and use of water and sanitation facilities, 2) the use of hygienic behaviours, and 3) diarrhoeal prevalence in children younger than 3 years of age before (February 2000) and after (February 2002) the interventions had been implemented. The evaluation included household and key informant interviews designed to measure these three components. Water quality of community water sources and household water was evaluated by measuring levels of indicator bacteria. During the final survey, an infrastructure evaluation provided a review of the design, construction, and current operation and maintenance of the water systems and latrines. The integrated water and sanitation infrastructure interventions and hygiene education programmes implemented following Hurricane Mitch effectively decreased diarrhoea prevalence in the target communities.

Blood lead levels and risk factors for lead poisoning among children in a Mexican smelting community.

The authors evaluated mean blood lead levels (BLLs) and the prevalence of elevated BLLs in children 1-6 yr of age living in Torreón, Mexico, and assessed risk factors for lead exposure in these children. The study involved a simple random sample of households in the area around a local smelter, as well as a 2-stage cluster sample of neighborhoods and households in the remainder of Torreón. The geometric mean BLL of children in this study (N = 367) was 6.0 microg/dl (95% confidence interval [CI] = 5.2, 6.8) (0.29 microM/l [95% CI = 0.25, 0.33]). Twenty percent of the children had BLLs > or = 10 microg/dl (0.48 microM/l), and 5% had BLLs > or = 20 microg/dl (0.97 microM/l). In multivariate analyses, distance from the smelter, amount of income, and education level of the primary caregiver predicted BLLs. In the environmental risk factor subsample (n = 124), dust and soil lead levels were associated with BLLs and distance from the smelter. BLLs in this study were moderately high, but the levels were lower than those in other smelting communities prior to remediation.