After the recent announcement of COVID-19 vaccine efficacy in clinical trials by several manufacturers for protection against severe disease, a comprehensive post-efficacy strategy for the next steps ...to ensure vaccination of the global population is now required. These considerations should include how to manufacture billions of doses of high-quality vaccines, support for vaccine purchase, coordination of supply, the equitable distribution of vaccines and the logistics of global vaccine delivery, all of which are a prelude to a massive vaccination campaign targeting people of all ages. Furthermore, additional scientific questions about the vaccines remain that should be answered to improve vaccine efficacy, including questions regarding the optimization of vaccination regimens, booster doses, the correlates of protection, vaccine effectiveness, safety and enhanced surveillance. The timely and coordinated execution of these post-efficacy tasks will bring the pandemic to an effective, and efficient, close.
Epidemiology of cholera Deen, Jacqueline; Mengel, Martin A; Clemens, John D
Vaccine,
02/2020, Volume:
38
Journal Article
Peer reviewed
Open access
Cholera is an ancient disease that remains a public health problem in many impoverished locations around the world. Seven pandemics of cholera have been recorded since the first pandemic in 1817, the ...last of which is on going. Overcrowding, poverty, insufficient water and sanitation facilities increase the risk for cholera outbreaks. The epidemiology of cholera in the areas in Asia, Africa and the Americas where the disease occurs continues to evolve.
Differentiation of the continental crust begins with its partial melting. The products of crustal melting are silicic, hydrous, H2O-undersaturated, granitic liquids that are generated within matrices ...of residual crystals. Crustal differentiation requires that felsic magmas form and escape from these solid residua. An important question is whether granitic magmas collect into large batches, within or near their sources, which then give rise to ascent or, alternatively, bleed out of the sources in smaller streams or pulses. We demonstrate that the physical reality is closer to the second alternative, and thus question the validity of the concepts of magma segregation and source fertility, as they are sometimes visualised.
Granitic plutons contain chemically distinct sub-populations formed by source-level entrainment of the peritectic assemblages into the melts. Rapid evacuation at source levels and high ascent rates protect the magmas from wall-rock interactions during their tenure at source depths and during their ascent through cool upper crust. The existence of different types of granites, and hence of clearly defined chemically different magmas within plutons, dictates that felsic magmas must separate efficiently from their anatectic sources and must ascend to the sites of their emplacement with minimal chemical interaction with crust through which the magma must move. Exposed deep-crustal sections are typically lithologically diverse, with the more fertile rocks commonly forming discrete layers surrounded by rocks with contrasting compositions. If the melts were required to segregate and accumulate into large volumes within their hot sources, especially by slow, gravity-driven melt percolation, it is very likely that they would be substantially modified by reaction with diverse source rocks. Thus, the processes mooted to occur in melting, assimilation, storage and homogenisation (MASH) or deep crustal hot (DCH) zones would act to erase original compositional heterogeneities and produce larger batches of more homogeneous magma, perhaps carrying evidence of extensive magma mixing. From various lines of evidence, we conclude that MASH and DCH zones may not exist and, even if they do, they cannot form the sources of most granitic magmas. The intrinsic heterogeneity in crustal source rocks, the likely occurrence of peritectic assemblage entrainment and the inefficiency of magma mixing decree that granitic rocks will retain source-inherited chemical and isotopic heterogeneities. Rapid, semi-continuous and disequilibrium withdrawal of small magma batches from source rocks means that elements of whole-rock, trace-element chemistry and accessory mineral chemistry will be decoupled from major-element variations. This also means that a large source with low nominal fertility (due to low hydrous mineral content, for example) could still produce a substantial granitic pluton, by additions of individually small increments of magma.
Type 2 circulating vaccine-derived polioviruses (cVDPV2) from Sabin oral poliovirus vaccines (OPVs) are the leading cause of poliomyelitis. A novel type 2 OPV (nOPV2) has been developed to be more ...genetically stable with similar tolerability and immunogenicity to that of Sabin type 2 vaccines to mitigate the risk of cVDPV2. We aimed to assess these aspects of nOPV2 in poliovirus vaccine-naive newborn infants.
In this randomised, double-blind, controlled, phase 2 trial we enrolled newborn infants at the Matlab Health Research Centre, Chandpur, Bangladesh. We included infants who were healthy and were a single birth after at least 37 weeks' gestation. Infants were randomly assigned (2:1) to receive either two doses of nOPV2 or placebo, administered at age 0–3 days and at 4 weeks. Exclusion criteria included receipt of rotavirus or any other poliovirus vaccine, any infection or illness at the time of enrolment (vomiting, diarrhoea, or intolerance to liquids), diagnosis or suspicion of any immunodeficiency disorder in the infant or a close family member, or any contraindication for venipuncture. The primary safety outcome was safety and tolerability after one and two doses of nOPV2, given 4 weeks apart in poliovirus vaccine-naive newborn infants and the primary immunogenicity outcome was the seroconversion rate for neutralising antibodies against type 2 poliovirus, measured 28 days after the first and second vaccinations with nOPV2. Study staff recorded solicited and unsolicited adverse events after each dose during daily home visits for 7 days. Poliovirus neutralising antibody responses were measured in sera drawn at birth and at age 4 weeks and 8 weeks. This study is registered on ClinicalTrials.gov, NCT04693286.
Between Sept 21, 2020, and Aug 16, 2021, we screened 334 newborn infants, of whom three (<1%) were found to be ineligible and one (<1%) was withdrawn by the parents; the remaining 330 (99%) infants were assigned to receive nOPV2 (n=220 67%) or placebo (n=110 33%). nOPV2 was well tolerated; 154 (70%) of 220 newborn infants in the nOPV2 group and 78 (71%) of 110 in the placebo group had solicited adverse events, which were all mild or moderate in severity. Severe unsolicited adverse events in 11 (5%) vaccine recipients and five (5%) placebo recipients were considered unrelated to vaccination. 306 (93%) of 330 infants had seroprotective maternal antibodies against type 2 poliovirus at birth, decreasing to 58 (56%) of 104 in the placebo group at 8 weeks. In the nOPV2 group 196 (90%) of 217 infants seroconverted by week 8 after two doses, when 214 (99%) had seroprotective antibodies.
nOPV2 was well tolerated and immunogenic in newborn infants, with two doses, at birth and 4 weeks, resulting in almost 99% of infants having protective neutralising antibodies.
Bill & Melinda Gates Foundation.
Granitic magmas extracted from crustal sources can form over a wide variety of P, T and aH2O conditions. Both fluid-present and effectively fluid-absent conditions can yield granitic magmas, though ...the majority are formed through high-T, fluid-absent reactions because, in the deep crust, most available H2O within rock bodies is contained within minerals rather than in free fluids. Fluid-present partial melting generally results in the formation of migmatites (and sometimes diatexites) under upper amphibolite-facies conditions. By definition, aqueous fluid-present melting begins at temperatures very close to the relevant ‘wet’ solidus. Consequently, studying mid-crustal migmatites, and the poorly mobile and mainly small intrusions that may result from such melting, provides no guide to the temperatures and fluid conditions that are involved in the genesis of highly mobile granitic magmas that facilitate crustal differentiation. Although zircon-saturation temperatures are commonly used to infer magma temperatures, and even melting temperatures, they seldom resemble actual magmatic temperatures. Recent notions about the persistence of granite-forming melts at conditions well below the experimentally determined H2O-saturated (‘wet’) solidi for granites (i.e., generally <650°C) are commonly based on the results of TitaniQ (titanium-in-quartz) thermometry on silicic plutonic rocks. These results are problematic and inconsonant with TitaniQ thermometry on rhyolites, including those thought to represent erupted near-solidus crystal mushes. Thus, the hypothesis that low-T, aqueous fluid-fluxed granitic magmas have significance for the recycling and large-scale differentiation of the continental crust is poorly founded.
The impact of mindfulness training on stress and associated brain plasticity has been shown in adults, whereas the impact of such training in the developing brain remains unknown. To address this ...open question, 40 middle-school children were randomized to either mindfulness or coding training (active control) interventions during the school day for eight weeks. Outcome measures were ratings of self-perceived stress and right amygdala activation while viewing fearful, happy, and neutral facial expressions during functional MRI. Prior to intervention, greater stress correlated with greater right amygdala activation in response to fearful versus neutral facial expressions across all children. After intervention, children who received mindfulness training reported lower stress associated with reduced right amygdala activation to fearful faces relative to children in the control condition. Amygdala responses to happy faces were unrelated to either initial stress or mindfulness reduction of stress. Moreover, mindfulness training led to relatively stronger functional connectivity between the right amygdala and ventromedial prefrontal cortex during the viewing of fearful facial expressions. Changes in perceived stress and neuroplasticity occurred in nonmeditative states, indicating that the benefits of mindfulness training generalized beyond the active meditative state. This study provides initial evidence that mindfulness training in children reduces stress and promotes functional brain changes and that such training can be integrated into the school curriculum for entire classes. This study also reveals first evidence that a neurocognitive mechanism for both stress and its reduction by mindfulness training is related specifically to reduced amygdala responses to negative stimuli.
Cholera causes substantial morbidity and mortality in the world's poorest populations. For nearly a decade, an inactivated oral cholera vaccine (OCV) stockpile has been available to control and ...prevent outbreaks. In 2017, WHO launched a bold global initiative to reduce mortality from cholera by 90% by 2030, a cornerstone of which is deployment of OCVs from the global stockpile. The current production of OCVs for the stockpile falls well short of the doses needed to accomplish this goal. Besides efforts to enlist additional manufacturers of the current OCVs in the stockpile, inclusion of new-generation inactivated OCVs already in clinical development might offer advantages of enlarged production, improved performance, simplified logistics, and reduced costs. However, logistical, scientific, and ethical barriers make conventional, randomised, phase 3 clinical efficacy trials towards licensure of such new-generation OCVs problematic. The serum vibriocidal antibody response, the traditional immunological surrogate of protection against cholera, is imperfect for use as a standalone outcome. In this Personal View, we describe the need for new thinking on approaches for licensure and recommendations for new-generation inactivated OCVs, and suggest a pathway based on a sequential combination of immunogenicity and effectiveness observational studies.
•Ivermectin, an FDA-approved anti-parasitic agent, was found to be an inhibitor of SARS-CoV-2 replication in the laboratory.•Ivermectin may be effective for the treatment of early-onset mild COVID-19 ...in adult patients.•Early viral clearance of SARS-CoV-2 was observed in ivermectin treated patients.•Remission of fever, cough and sore throat did not differ among treatment groups. No severe adverse event was observed.•Larger trials will be needed to confirm these preliminary findings.
Ivermectin, a US Food and Drug Administration-approved anti-parasitic agent, was found to inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication in vitro. A randomized, double-blind, placebo-controlled trial was conducted to determine the rapidity of viral clearance and safety of ivermectin among adult SARS-CoV-2 patients. The trial included 72 hospitalized patients in Dhaka, Bangladesh, who were assigned to one of three groups: oral ivermectin alone (12 mg once daily for 5 days), oral ivermectin in combination with doxycycline (12 mg ivermectin single dose and 200 mg doxycycline on day 1, followed by 100 mg every 12 h for the next 4 days), and a placebo control group. Clinical symptoms of fever, cough, and sore throat were comparable among the three groups. Virological clearance was earlier in the 5-day ivermectin treatment arm when compared to the placebo group (9.7 days vs 12.7 days; p = 0.02), but this was not the case for the ivermectin + doxycycline arm (11.5 days; p = 0.27). There were no severe adverse drug events recorded in the study. A 5-day course of ivermectin was found to be safe and effective in treating adult patients with mild COVID-19. Larger trials will be needed to confirm these preliminary findings.
Vibrio cholerae is a globally important pathogen that is endemic in many areas of the world and causes 3-5 million reported cases of cholera every year. Historically, there have been seven ...acknowledged cholera pandemics; recent outbreaks in Zimbabwe and Haiti are included in the seventh and ongoing pandemic. Only isolates in serogroup O1 (consisting of two biotypes known as 'classical' and 'El Tor') and the derivative O139 can cause epidemic cholera. It is believed that the first six cholera pandemics were caused by the classical biotype, but El Tor has subsequently spread globally and replaced the classical biotype in the current pandemic. Detailed molecular epidemiological mapping of cholera has been compromised by a reliance on sub-genomic regions such as mobile elements to infer relationships, making El Tor isolates associated with the seventh pandemic seem superficially diverse. To understand the underlying phylogeny of the lineage responsible for the current pandemic, we identified high-resolution markers (single nucleotide polymorphisms; SNPs) in 154 whole-genome sequences of globally and temporally representative V. cholerae isolates. Using this phylogeny, we show here that the seventh pandemic has spread from the Bay of Bengal in at least three independent but overlapping waves with a common ancestor in the 1950s, and identify several transcontinental transmission events. Additionally, we show how the acquisition of the SXT family of antibiotic resistance elements has shaped pandemic spread, and show that this family was first acquired at least ten years before its discovery in V. cholerae.
PDF
