In March 2020, the World Health Organization (WHO) declared a pandemic of coronavirus disease 2019 (COVID-19), due to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)1. With rapidly accumulating cases and deaths reported globally2, a vaccine is urgently needed. We report the available safety, tolerability, and immunogenicity data from an ongoing placebo-controlled, observer-blinded dose escalation study among 45 healthy adults, 18 to 55 years of age, randomized to receive 2 doses, separated by 21 days, of 10 µg, 30 µg, or 100 µg of BNT162b1, a lipid nanoparticle-formulated, nucleoside-modified mRNA vaccine that encodes trimerized SARS-CoV-2 spike glycoprotein receptor-binding domain (RBD). Local reactions and systemic events were dose-dependent, generally mild to moderate, and transient. A second vaccination with 100 µg was not administered due to increased reactogenicity and a lack of meaningfully increased immunogenicity after a single dose compared to the 30 μg dose. RBD-binding IgG concentrations and SARS-CoV-2 neutralizing titers in sera increased with dose level and after a second dose. Geometric mean neutralizing titers reached 1.9- to 4.6-fold that of a panel of COVID-19 convalescent human sera at least 14 days after a positive SARS-CoV-2 PCR. These results support further evaluation of this mRNA vaccine candidate. (ClinicalTrials.gov identifier: NCT04368728).
In recent decades, the Greenland Ice Sheet has been a major contributor to global sea-level rise1,2, and it is expected to be so in the future3. Although increases in glacier flow4-6 and surface melting7-9 have been driven by oceanic10-12 and atmospheric13,14 warming, the degree and trajectory of today’s imbalance remain uncertain. Here we compare and combine 26 individual satellite measurements of changes in the ice sheet’s volume, flow and gravitational potential to produce a reconciled estimate of its mass balance. Although the ice sheet was close to a state of balance in the 1990s, annual losses have risen since then, peaking at 335 ± 62 billion tonnes per year in 2011. In all, Greenland lost 3,800 ± 339 billion tonnes of ice between 1992 and 2018, causing the mean sea level to rise by 10.6 ± 0.9 millimetres. Using three regional climate models, we show that reduced surface mass balance has driven 1,971 ± 555 billion tonnes (52%) of the ice loss owing to increased meltwater runoff. The remaining 1,827 ± 538 billion tonnes (48%) of ice loss was due to increased glacier discharge, which rose from 41 ± 37 billion tonnes per year in the 1990s to 87 ± 25 billion tonnes per year since then. Between 2013 and 2017, the total rate of ice loss slowed to 217 ± 32 billion tonnes per year, on average, as atmospheric circulation favoured cooler conditions15 and as ocean temperatures fell at the terminus of Jakobshavn Isbræ16. Cumulative ice losses from Greenland as a whole have been close to the IPCC’s predicted rates for their high-end climate warming scenario17, which forecast an additional 50 to 120 millimetres of global sea-level rise by 2100 when compared to their central estimate.
Data analysis workflows in many scientific domains have become increasingly complex and flexible. Here we assess the effect of this flexibility on the results of functional magnetic resonance imaging by asking 70 independent teams to analyse the same dataset, testing the same 9 ex-ante hypotheses1. The flexibility of analytical approaches is exemplified by the fact that no two teams chose identical workflows to analyse the data. This flexibility resulted in sizeable variation in the results of hypothesis tests, even for teams whose statistical maps were highly correlated at intermediate stages of the analysis pipeline. Variation in reported results was related to several aspects of analysis methodology. Notably, a meta-analytical approach that aggregated information across teams yielded a significant consensus in activated regions. Furthermore, prediction markets of researchers in the field revealed an overestimation of the likelihood of significant findings, even by researchers with direct knowledge of the dataset2-5. Our findings show that analytical flexibility can have substantial effects on scientific conclusions, and identify factors that may be related to variability in the analysis of functional magnetic resonance imaging. The results emphasize the importance of validating and sharing complex analysis workflows, and demonstrate the need for performing and reporting multiple analyses of the same data. Potential approaches that could be used to mitigate issues related to analytical variability are discussed.
Since 2000, many countries have achieved considerable success in improving child survival, but localized progress remains unclear. To inform efforts towards United Nations Sustainable Development Goal 3.2-to end preventable child deaths by 2030-we need consistently estimated data at the subnational level regarding child mortality rates and trends. Here we quantified, for the period 2000-2017, the subnational variation in mortality rates and number of deaths of neonates, infants and children under 5 years of age within 99 low- and middle-income countries using a geostatistical survival model. We estimated that 32% of children under 5 in these countries lived in districts that had attained rates of 25 or fewer child deaths per 1,000 live births by 2017, and that 58% of child deaths between 2000 and 2017 in these countries could have been averted in the absence of geographical inequality. This study enables the identification of high-mortality clusters, patterns of progress and geographical inequalities to inform appropriate investments and implementations that will help to improve the health of all populations.
Highly pathogenic avian H5N1 influenza A viruses occasionally infect humans, but currently do not transmit efficiently among humans. The viral haemagglutinin (HA) protein is a known host-range determinant as it mediates virus binding to host-specific cellular receptors. Here we assess the molecular changes in HA that would allow a virus possessing subtype H5 HA to be transmissible among mammals. We identified a reassortant H5 HA/H1N1 virus-comprising H5 HA (from an H5N1 virus) with four mutations and the remaining seven gene segments from a 2009 pandemic H1N1 virus-that was capable of droplet transmission in a ferret model. The transmissible H5 reassortant virus preferentially recognized human-type receptors, replicated efficiently in ferrets, caused lung lesions and weight loss, but was not highly pathogenic and did not cause mortality. These results indicate that H5 HA can convert to an HA that supports efficient viral transmission in mammals; however, we do not know whether the four mutations in the H5 HA identified here would render a wholly avian H5N1 virus transmissible. The genetic origin of the remaining seven viral gene segments may also critically contribute to transmissibility in mammals. Nevertheless, as H5N1 viruses continue to evolve and infect humans, receptor-binding variants of H5N1 viruses with pandemic potential, including avian-human reassortant viruses as tested here, may emerge. Our findings emphasize the need to prepare for potential pandemics caused by influenza viruses possessing H5 HA, and will help individuals conducting surveillance in regions with circulating H5N1 viruses to recognize key residues that predict the pandemic potential of isolates, which will inform the development, production and distribution of effective countermeasures.
Memory T cells induced by previous pathogens can shape the susceptibility to, and clinical severity of, subsequent infections1. Little is known about the presence of pre-existing memory T cells in humans with the potential to recognize SARS-CoV-2. Here, we first studied T cell responses to structural (nucleocapsid protein, NP) and non-structural (NSP-7 and NSP13 of ORF1) regions of SARS-CoV-2 in COVID-19 convalescents (n=36). In all of them we demonstrated the presence of CD4 and CD8 T cells recognizing multiple regions of the NP protein. We then showed that SARS-recovered patients (n=23) still possess long-lasting memory T cells reactive to SARS-NP 17 years after the 2003 outbreak, which displayed robust cross-reactivity to SARS-CoV-2 NP. Surprisingly, we also frequently detected SARS-CoV-2 specific T cells in individuals with no history of SARS, COVID-19 or contact with SARS/COVID-19 patients (n=37). SARS-CoV-2 T cells in uninfected donors exhibited a different pattern of immunodominance, frequently targeting the ORF-1-coded proteins NSP7 and 13 as well as the NP structural protein. Epitope characterization of NSP7-specific T cells showed recognition of protein fragments with low homology to “common cold” human coronaviruses but conserved amongst animal betacoranaviruses. Thus, infection with betacoronaviruses induces multispecific and long-lasting T cell immunity to the structural protein NP. Understanding how pre-existing NP- and ORF-1-specific T cells present in the general population impact susceptibility and pathogenesis of SARS-CoV-2 infection is of paramount importance for the management of the current COVID-19 pandemic.
A specific memory is thought to be encoded by a sparse population of neurons. These neurons can be tagged during learning for subsequent identification and manipulation. Moreover, their ablation or inactivation results in reduced memory expression, suggesting their necessity in mnemonic processes. However, the question of sufficiency remains: it is unclear whether it is possible to elicit the behavioural output of a specific memory by directly activating a population of neurons that was active during learning. Here we show in mice that optogenetic reactivation of hippocampal neurons activated during fear conditioning is sufficient to induce freezing behaviour. We labelled a population of hippocampal dentate gyrus neurons activated during fear learning with channelrhodopsin-2 (ChR2) and later optically reactivated these neurons in a different context. The mice showed increased freezing only upon light stimulation, indicating light-induced fear memory recall. This freezing was not detected in non-fear-conditioned mice expressing ChR2 in a similar proportion of cells, nor in fear-conditioned mice with cells labelled by enhanced yellow fluorescent protein instead of ChR2. Finally, activation of cells labelled in a context not associated with fear did not evoke freezing in mice that were previously fear conditioned in a different context, suggesting that light-induced fear memory recall is context specific. Together, our findings indicate that activating a sparse but specific ensemble of hippocampal neurons that contribute to a memory engram is sufficient for the recall of that memory. Moreover, our experimental approach offers a general method of mapping cellular populations bearing memory engrams.
The COVID-19 pandemic dramatically changed human mobility patterns, necessitating epidemiological models which capture the effects of changes in mobility on virus spread1. We introduce a metapopulation SEIR model that integrates fine-grained, dynamic mobility networks to simulate the spread of SARS-CoV-2 in 10 of the largest US metropolitan statistical areas. Derived from cell phone data, our mobility networks map the hourly movements of 98 million people from neighborhoods (census block groups, or CBGs) to points of interest (POIs) such as restaurants and religious establishments, connecting 57k CBGs to 553k POIs with 5.4 billion hourly edges. We show that by integrating these networks, a relatively simple SEIR model can accurately fit the real case trajectory, despite substantial changes in population behavior over time. Our model predicts that a small minority of “superspreader” POIs account for a large majority of infections and that restricting maximum occupancy at each POI is more effective than uniformly reducing mobility. Our model also correctly predicts higher infection rates among disadvantaged racial and socioeconomic groups2-8 solely from differences in mobility: we find that disadvantaged groups have not been able to reduce mobility as sharply, and that the POIs they visit are more crowded and therefore higher-risk. By capturing who is infected at which locations, our model supports detailed analyses that can inform more effective and equitable policy responses to COVID-19.
The extreme astrophysical processes and conditions that characterize the early Universe are expected to result in young galaxies that are dynamically different from those observed today1-5. This is because the strong effects associated with galaxy mergers and supernova explosions would lead to most young star-forming galaxies being dynamically hot, chaotic and strongly unstable1,2. Here we report the presence of a dynamically cold, but highly star-forming, rotating disk in a galaxy at redshift6 z = 4.2, when the Universe was just 1.4 billion years old. Galaxy SPT-S J041839-4751.9 is strongly gravitationally lensed by a foreground galaxy at z = 0.263, and it is a typical dusty starburst, with global star-forming7 and dust properties8 that are in agreement with current numerical simulations9 and observations10. Interferometric imaging at a spatial resolution of about 60 parsecs reveals a ratio of rotational to random motions of 9.7 ± 0.4, which is at least four times larger than that expected from any galaxy evolution model at this epoch1-5 but similar to the ratios of spiral galaxies in the local Universe11. We derive a rotation curve with the typical shape of nearby massive spiral galaxies, which demonstrates that at least some young galaxies are dynamically akin to those observed in the local Universe, and only weakly affected by extreme physical processes.
Coronavirus disease 2019 (COVID-19) is an acute respiratory tract infection that emerged in late 20191,2. Initial outbreaks in China involved 13.8% cases with severe, and 6.1% with critical courses3. This severe presentation corresponds to the usage of a virus receptor that is expressed predominantly in the lung2,4. By causing an early onset of severe symptoms, this same receptor tropism is thought to have determined pathogenicity, but also aided the control, of severe acute respiratory syndrome (SARS) in 20035. However, there are reports of COVID-19 cases with mild upper respiratory tract symptoms, suggesting the potential for pre- or oligosymptomatic transmission6-8. There is an urgent need for information on body site-specific virus replication, immunity, and infectivity. Here we provide a detailed virological analysis of nine cases, providing proof of active virus replication in upper respiratory tract tissues. Pharyngeal virus shedding was very high during the first week of symptoms (peak at 7.11 × 108 RNA copies per throat swab, day 4). Infectious virus was readily isolated from throat- and lung-derived samples, but not from stool samples, in spite of high virus RNA concentration. Blood and urine never yielded virus. Active replication in the throat was confirmed by viral replicative RNA intermediates in throat samples. Sequence-distinct virus populations were consistently detected in throat and lung samples from the same patient, proving independent replication. Shedding of viral RNA from sputum outlasted the end of symptoms. Seroconversion occurred after 7 days in 50% of patients (14 days in all), but was not followed by a rapid decline in viral load. COVID-19 can present as a mild upper respiratory tract illness. Active virus replication in the upper respiratory tract puts the prospects of COVID-19 containment in perspective.