Success of 4CMenB in preventing meningococcal disease: evidence from real-world experience

Meningococcal disease remains one of the most feared infectious diseases worldwide because of its sudden onset, rapid progression and high case fatality rates, while survivors are often left with severe long-term sequelae. Young children have the highest incidence of invasive meningococcal disease (IMD), and nearly all cases in the UK, as in most of Europe and many other industrialised countries, are due to group B meningococci (MenB). The licensure of a broad-coverage, recombinant protein-based MenB vaccine (4CMenB) in 2013 was, therefore, heralded a major breakthrough in the fight against IMD. This vaccine was, however, licensed on immunogenicity and reactogenicity studies only, raising uncertainties about field effectiveness, long-term safety and antibody persistence. In 2015, the UK became the first country to implement 4CMenB into the national infant immunisation schedule and, since then, several countries have followed suit. Seven years after licensure, a wealth of real-world data has emerged to confirm 4CMenB effectiveness, along with large-scale safety data, duration of protection in different age groups, successful strategies to reduce vaccine reactogenicity, impact on carriage in adolescents and the potential for 4CMenB to protect against other meningococcal serogroups and against gonorrhoea. A number of questions, however, remain unanswered, including the investigation and management of vaccine-associated fever in infants, as well as disease severity and assessment of breakthrough cases in immunised children. Increasing use of 4CMenB will provide answers in due course. We now have vaccines against all the major serogroups causing IMD worldwide. Next-generation and combination vaccines against multiple serogroups look very promising.</jats:p

The role of biomarkers in evaluating human health concerns from fungal contaminants in food

Mycotoxins are toxic secondary metabolites that globally contaminate an estimated 25 % of cereal crops and thus exposure is frequent in many populations. Aflatoxins, fumonisins and deoxynivalenol are amongst those mycotoxins of particular concern from a human health perspective. A number of risks to health are suggested including cancer, growth faltering, immune suppression and neural tube defects; though only the demonstrated role for aflatoxin in the aetiology of liver cancer is widely recognised. The heterogeneous distribution of mycotoxins in food restricts the usefulness of food sampling and intake estimates; instead biomarkers provide better tools for informing epidemiological investigations. Validated exposure biomarkers for aflatoxin (urinary aflatoxin M1, aflatoxin–N7-guaunine, serum aflatoxin–albumin) were established almost 20 years ago and were critical in confirming aflatoxins as potent liver carcinogens. Validation has included demonstration of assay robustness, intakev.biomarker level, and stability of stored samples. More recently, aflatoxin exposure biomarkers are revealing concerns of growth faltering and immune suppression; importantly, they are being used to assess the effectiveness of intervention strategies. For fumonisins and deoxynivalenol these steps of development and validation have significantly advanced in recent years. Such biomarkers should better inform epidemiological studies and thus improve our understanding of their potential risk to human health.</jats:p

The early impact of vaccination against SARS-CoV-2 in Region Stockholm, Sweden

AbstractVaccination against SARS-CoV-2 started in Region Stockholm, Sweden in December 2020 with those in long-term care facilities or receiving home care vaccinated first followed by those aged over 80 years. In this population-based, retrospective cohort study, we performed a Poisson regression to model the expected incidence of infections and deaths which we compared to the observed incidence and compared this to an unvaccinated control group of those aged 18-79 years. The aim of this study was to measure the early impact of the vaccination programme in Region Stockholm.Infections and deaths reduced substantially amongst the first two groups targeted for SARS-CoV-2 vaccination with an estimated total 3112 infections prevented, and 854 deaths prevented in these two groups from 4 weeks after the introduction of vaccination through to 2nd May 2021.</jats:p

Adverse pregnancy outcomes following syphilis treatment in pregnancy in the UK

Syphilis infection in pregnancy is known to cause a number of severe adverse pregnancy outcomes, including second-trimester miscarriage, stillbirth, very pre-term delivery and neonatal death, in addition to congenital syphilis. A retrospective review of women with positive syphilis serology and a pregnancy outcome between 2005 and 2012 in Leeds, UK, was performed. In all, 57 cases of positive syphilis serology in pregnancy were identified: 24 with untreated syphilis treated in the current pregnancy (Group 1); seven with reported but unconfirmed prior treatment who were retreated (Group 2); and 26 adequately treated prior to pregnancy (Group 3). The rate of severe adverse pregnancy outcomes in Group 1 at 21% was significantly higher than the 0% outcome of Group 3 ( p = 0.02). The severe adverse pregnancy outcomes were two second-trimester miscarriages, two pre-term births at 25 and 28 weeks and one stillbirth at 32 weeks. There were no cases of term congenital syphilis or term neonatal death, but we observed high rates of other adverse pregnancy outcomes despite treatment during pregnancy. Rapid referral for treatment is needed before 18 weeks in order to minimise adverse pregnancy outcomes. </jats:p

Serological follow-up of infants born to mothers with positive syphilis serology – real-world experiences

The 2008 UK syphilis guideline recommends infants born to women with any positive syphilis serology be followed up until both treponemal and nontreponemal tests are negative to exclude congenital syphilis, whereas Centers for Disease Control and Prevention guidelines recommend using only nontreponemal tests. Historically, we had low infant follow-up rates with no coherent pathways. We initiated a change in multidisciplinary team practice of infant testing for syphilis in 2011 and evaluated the results before and after by retrospective review of testing of infants born to women with positive syphilis serology between 2005 and 2012. A total of 28 infants’ mothers were treated in pregnancy (termed ‘high risk’); 26 had adequate treatment prior to pregnancy (termed ‘low risk’). There was a significant increase in serological testing after 2011 compared with before (83% versus 48%; OR 5.07 [95% CI 1.22–22.77] p = 0.01) but mainly in low risk infants with no significant improvement in high risk infants who are the priority group. Using nontreponemal tests only in the infants would have reduced the tests required by at least 50%, allowing health resources to be concentrated on achieving adequate follow-up for those infants most at risk. </jats:p

Safety and immunogenicity of the ChAdOx1 nCoV-19 vaccine against SARS-CoV-2: a preliminary report of a phase 1/2, single-blind, randomised controlled trial.

BACKGROUND: The pandemic of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) might be curtailed by vaccination. We assessed the safety, reactogenicity, and immunogenicity of a viral vectored coronavirus vaccine that expresses the spike protein of SARS-CoV-2. METHODS: We did a phase 1/2, single-blind, randomised controlled trial in five trial sites in the UK of a chimpanzee adenovirus-vectored vaccine (ChAdOx1 nCoV-19) expressing the SARS-CoV-2 spike protein compared with a meningococcal conjugate vaccine (MenACWY) as control. Healthy adults aged 18-55 years with no history of laboratory confirmed SARS-CoV-2 infection or of COVID-19-like symptoms were randomly assigned (1:1) to receive ChAdOx1 nCoV-19 at a dose of 5 × 1010 viral particles or MenACWY as a single intramuscular injection. A protocol amendment in two of the five sites allowed prophylactic paracetamol to be administered before vaccination. Ten participants assigned to a non-randomised, unblinded ChAdOx1 nCoV-19 prime-boost group received a two-dose schedule, with the booster vaccine administered 28 days after the first dose. Humoral responses at baseline and following vaccination were assessed using a standardised total IgG ELISA against trimeric SARS-CoV-2 spike protein, a muliplexed immunoassay, three live SARS-CoV-2 neutralisation assays (a 50% plaque reduction neutralisation assay [PRNT50]; a microneutralisation assay [MNA50, MNA80, and MNA90]; and Marburg VN), and a pseudovirus neutralisation assay. Cellular responses were assessed using an ex-vivo interferon-γ enzyme-linked immunospot assay. The co-primary outcomes are to assess efficacy, as measured by cases of symptomatic virologically confirmed COVID-19, and safety, as measured by the occurrence of serious adverse events. Analyses were done by group allocation in participants who received the vaccine. Safety was assessed over 28 days after vaccination. Here, we report the preliminary findings on safety, reactogenicity, and cellular and humoral immune responses. The study is ongoing, and was registered at ISRCTN, 15281137, and ClinicalTrials.gov, NCT04324606. FINDINGS: Between April 23 and May 21, 2020, 1077 participants were enrolled and assigned to receive either ChAdOx1 nCoV-19 (n=543) or MenACWY (n=534), ten of whom were enrolled in the non-randomised ChAdOx1 nCoV-19 prime-boost group. Local and systemic reactions were more common in the ChAdOx1 nCoV-19 group and many were reduced by use of prophylactic paracetamol, including pain, feeling feverish, chills, muscle ache, headache, and malaise (all p<0·05). There were no serious adverse events related to ChAdOx1 nCoV-19. In the ChAdOx1 nCoV-19 group, spike-specific T-cell responses peaked on day 14 (median 856 spot-forming cells per million peripheral blood mononuclear cells, IQR 493-1802; n=43). Anti-spike IgG responses rose by day 28 (median 157 ELISA units [EU], 96-317; n=127), and were boosted following a second dose (639 EU, 360-792; n=10). Neutralising antibody responses against SARS-CoV-2 were detected in 32 (91%) of 35 participants after a single dose when measured in MNA80 and in 35 (100%) participants when measured in PRNT50. After a booster dose, all participants had neutralising activity (nine of nine in MNA80 at day 42 and ten of ten in Marburg VN on day 56). Neutralising antibody responses correlated strongly with antibody levels measured by ELISA (R2=0·67 by Marburg VN; p<0·001). INTERPRETATION: ChAdOx1 nCoV-19 showed an acceptable safety profile, and homologous boosting increased antibody responses. These results, together with the induction of both humoral and cellular immune responses, support large-scale evaluation of this candidate vaccine in an ongoing phase 3 programme. FUNDING: UK Research and Innovation, Coalition for Epidemic Preparedness Innovations, National Institute for Health Research (NIHR), NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and the German Center for Infection Research (DZIF), Partner site Gießen-Marburg-Langen