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Background The COVID-19 pandemic resulted in major inequalities in infection and disease burden between areas of varying socioeconomic deprivation in many countries, including England. Areas of higher deprivation tend to have a different population structure—generally younger—which can increase viral transmission due to higher contact rates in school-going children and working-age adults. Higher deprivation is also associated with a higher presence of chronic comorbidities, which were convincingly demonstrated to be risk factors for severe COVID-19 disease. These two major factors need to be combined to better understand and quantify their relative importance in the observed COVID-19 inequalities. Methods We used UK Census data on health status and demography stratified by decile of the Index of Multiple Deprivation (IMD), which is a measure of socioeconomic deprivation. We calculated epidemiological impact using an age-stratified COVID-19 transmission model, which incorporated different contact patterns and clinical health profiles by decile. To separate the contribution of each factor, we considered a scenario where the clinical health profile of all deciles was at the level of the least deprived. We also considered the effectiveness of school closures and vaccination of over 65-year-olds in each decile. Results In the modelled epidemics in urban areas, the most deprived decile experienced 9% more infections, 13% more clinical cases, and a 97% larger peak clinical size than the least deprived; we found similar inequalities in rural areas. Twenty-one per cent of clinical cases and 16% of deaths in England observed under the model assumptions would not occur if all deciles experienced the clinical health profile of the least deprived decile. We found that more deaths were prevented in more affluent areas during school closures and vaccination rollouts. Conclusions This study demonstrates that both clinical and demographic factors synergise to generate health inequalities in COVID-19, that improving the clinical health profile of populations would increase health equity, and that some interventions can increase health inequalities.

Compartmental infectious disease models are used to calculate disease transmission, estimate underlying rates, forecast future burden, and compare benefits across intervention scenarios. These models aggregate individuals into compartments, often stratified by characteristics to represent groups that might be intervention targets or otherwise of particular concern. Ideally, model calculation could occur at the most demanding resolution for the overall analysis, but this may be infeasible due to availability of computational resources or empirical data. Instead, detailed population age structure might be consolidated into broad categories such as children, working-age adults, and seniors. Researchers must then discretise key epidemic parameters, like the infection-fatality ratio, for these lower resolution groups. After estimating outcomes for those crude groups, follow-on analyses, such as calculating years of life lost (YLLs), may need to distribute or weight those low-resolution outcomes back to the high resolution. The specific calculation for these aggregation and disaggregation steps can substantially influence outcomes. To assist researchers with these tasks, we developed paramix , an R package which simplifies the transformations between high and low resolution. We demonstrate applying paramix to a common discretisation analysis: using age structured models for health economic calculations comparing YLLs. We compare how estimates vary between paramix and several alternatives for an archetypal model, including comparison to a high resolution benchmark. We consistently found that paramix yielded the most similar estimates to the high-resolution model, for the same computational burden of low-resolution models. In our illustrative analysis, the non- paramix methods estimated up to twice as many YLLs averted as the paramix approach, which would likely lead to a similarly large impact on incremental cost-effectiveness ratios used in economic evaluations.

Next-generation influenza vaccines (NGIVs) are in development and have the potential to achieve substantial reductions in influenza burden, with resulting widespread health and economic benefits. The prices at which their market can be sustained and which vaccination strategies may maximise health impact and cost-effectiveness, particularly in low- and middle-income countries, are unknown, yet such an understanding could provide a valuable tool for vaccine development and investment decision-making at a national and global level. To address this evidence gap, we projected the health and economic impact of NGIVs in 186 countries and territories. We inferred current influenza transmission parameters from World Health Organization (WHO) FluNet data in regions defined by their seasonal influenza timing and positivity, and projected 30 years of influenza epidemics, accounting for demographic changes. We considered vaccines including current seasonal vaccines, vaccines with increased efficacy, duration, and breadth of protection, and universal vaccines, defined in line with WHO Preferred Product Characteristics. We estimated cost-effectiveness of different vaccination scenarios using novel estimates of key health outcomes and costs. NGIVs have the potential to substantially reduce influenza burden: compared to no vaccination, vaccinating 50% of children aged under 18 annually prevented 1.3 (95% uncertainty range (UR): 1.2-1.5) billion infections using current vaccines, 2.6 (95% UR: 2.4-2.9) billion infections using vaccines with improved efficacy or breadth, and 3.0 (95% UR: 2.7-3.3) billion infections using universal vaccines. In many countries, NGIVs were cost-effective at higher prices than typically paid for existing seasonal vaccines. However, tiered prices may be necessary for improved vaccines to be cost-effective in lower income countries. This study is limited by the availability of accurate data on influenza incidence and influenza-associated health outcomes and costs. Furthermore, the model involves simplifying assumptions around vaccination coverage and administration, and does not account for societal costs or budget impact of NGIVs. How NGIVs will compare to the vaccine types considered in this model when developed is unknown. We conducted sensitivity analyses to investigate key model parameters. This study highlights the considerable potential health and economic benefits of NGIVs, but also the variation in cost-effectiveness between high-income and low- and middle-income countries. This work provides a framework for long-term global cost-effectiveness evaluations, and the findings can inform a pathway to developing NGIVs and rolling them out globally.

Case-fatality risk (CFR) is an important indicator of disease severity for influenza infection and an input to estimates of influenza burden and vaccination impact. However, CRF estimates based on laboratory-confirmed cases (cCFR) are more-highly sensitive to features of the local health-care system and surveillance. Estimates based on diagnosed-symptomatic cases (sCFR) are likely to be more consistent across health systems but are less commonly reported. We present a systematised review of sCFR for seasonal influenza to determine the availability of studies, variation across their sCFR estimates, and factors driving this variation. We identified 10 studies reporting sCFR, or primary data for its direct estimation, resulting in 40 location and season-specific point estimates (range 0.3–908 per 100,000 cases). There is considerable variation in sCFR across geographies, which was not linearly related to key socio-economic factors, but the variation can be even larger across seasons in a geography. The wide variation across studies and the lack of studies in many world regions point to the need for standardised protocols and more data collection.

Lethal mutagenesis has emerged as a novel potential therapeutic approach to treat viral infections. Several studies have demonstrated that increases in the high mutation rates inherent to RNA viruses lead to viral extinction in cell culture, but evidence during infections in vivo is limited. In this study, we show that the broad-range antiviral nucleoside favipiravir reduces viral load in vivo by exerting antiviral mutagenesis in a mouse model for norovirus infection. Increased mutation frequencies were observed in samples from treated mice and were accompanied with lower or in some cases undetectable levels of infectious virus in faeces and tissues. Viral RNA isolated from treated animals showed reduced infectivity, a feature of populations approaching extinction during antiviral mutagenesis. These results suggest that favipiravir can induce norovirus mutagenesis in vivo, which in some cases leads to virus extinction, providing a proof-of-principle for the use of favipiravir derivatives or mutagenic nucleosides in the clinical treatment of noroviruses. Viruses can infect, take control of and replicate themselves inside the living cells of other organisms. Some viral diseases can be treated with antiviral drugs, which stop viral infections either by making it more difficult for viruses to enter cells or by preventing the virus replicating once inside. As antiviral drugs are currently only available to treat a handful of viral infections, efforts are underway to develop and test experimental antiviral drugs. One such experimental drug is called favipiravir, which is proving to be effective against several viruses that store their genetic information in the form of RNA molecules. These viruses include those that cause diseases such as influenza, gastroenteritis, and Ebola. Along with ongoing work determining how safe and effective favipiravir is for treating viral infections, researchers are also attempting to better understand how favipiravir works. Whenever a strand of RNA is copied to allow a new virus to form, there is a risk that mistakes—or mutations—that could harm the virus are introduced into the genetic code. Previous experiments performed on cells grown in the laboratory suggested that favipiravir works against RNA viruses by increasing how often these mutations occur. RNA viruses naturally experience a large number of mutations and the ability to make mutations is in fact a benefit for viruses as it allows them to evolve rapidly and to escape immune responses. However, there is a limit to how many mutations can be tolerated in the viral genome before it can no longer replicate. Therefore, a slight increase in how often mutations occur—as thought to be caused by favipiravir—is able to stop the RNA virus replicating and halt the infection. However, favipiravir's mode of action had yet to be confirmed in living animals. Using mice, Arias et al. tested favipiravir's ability to treat a persistent infection by norovirus—the most common cause of viral gastroenteritis in humans and also responsible for life-threatening chronic diarrhoea in immunodeficient patients. Treatment increased the number of mutations that occurred when the viral RNA replicated and could reduce the amount of virus in the mice to undetectable levels. In addition, favipiravir did not show toxicity in mice after 8 weeks of treatment. This suggests that favipiravir has the potential to be used safely and effectively to treat norovirus and other RNA viruses, although further studies are required before it can be developed into a clinical treatment.

The emergence of SARS-CoV-2 variants of concern suggests viral adaptation to enhance human-to-human transmission 1 , 2 . Although much effort has focused on the characterization of changes in the spike protein in variants of concern, mutations outside of spike are likely to contribute to adaptation. Here, using unbiased abundance proteomics, phosphoproteomics, RNA sequencing and viral replication assays, we show that isolates of the Alpha (B.1.1.7) variant 3 suppress innate immune responses in airway epithelial cells more effectively than first-wave isolates. We found that the Alpha variant has markedly increased subgenomic RNA and protein levels of the nucleocapsid protein (N), Orf9b and Orf6—all known innate immune antagonists. Expression of Orf9b alone suppressed the innate immune response through interaction with TOM70, a mitochondrial protein that is required for activation of the RNA-sensing adaptor MAVS. Moreover, the activity of Orf9b and its association with TOM70 was regulated by phosphorylation. We propose that more effective innate immune suppression, through enhanced expression of specific viral antagonist proteins, increases the likelihood of successful transmission of the Alpha variant, and may increase in vivo replication and duration of infection 4 . The importance of mutations outside the spike coding region in the adaptation of SARS-CoV-2 to humans is underscored by the observation that similar mutations exist in the N and Orf9b regulatory regions of the Delta and Omicron variants. The SARS-CoV-2 Alpha variant suppresses innate immune responses more effectively than isolates of first-wave SARS-CoV-2, and this is a result of mutations outside of the spike coding region that lead to upregulation of viral innate immune antagonists.

Human noroviruses are a leading cause of gastroenteritis worldwide, yet there are no licensed antivirals. There is an urgent need for norovirus therapeutics, particularly for chronic infections in immunocompromised individuals, but also a potential need for prophylactic use in epidemics. Continued research has led to the identification of compounds that inhibit norovirus replication in vitro and, at least in some cases, are also effective in vivo against murine norovirus. Progress has included classical approaches targeting viral proteins and harnessing the antiviral action of interferon, strategies targeting essential host cell factors, and novel strategies exploiting the high mutation rate of noroviruses.

TKM-130803, a small interfering RNA lipid nanoparticle product, has been developed for the treatment of Ebola virus disease (EVD), but its efficacy and safety in humans has not been evaluated. In this single-arm phase 2 trial, adults with laboratory-confirmed EVD received 0.3 mg/kg of TKM-130803 by intravenous infusion once daily for up to 7 d. On days when trial enrolment capacity was reached, patients were enrolled into a concurrent observational cohort. The primary outcome was survival to day 14 after admission, excluding patients who died within 48 h of admission. After 14 adults with EVD had received TKM-130803, the pre-specified futility boundary was reached, indicating a probability of survival to day 14 of ≤0.55, and enrolment was stopped. Pre-treatment geometric mean Ebola virus load in the 14 TKM-130803 recipients was 2.24 × 109 RNA copies/ml plasma (95% CI 7.52 × 108, 6.66 × 109). Two of the TKM-130803 recipients died within 48 h of admission and were therefore excluded from the primary outcome analysis. Of the remaining 12 TKM-130803 recipients, nine died and three survived. The probability that a TKM-130803 recipient who survived for 48 h will subsequently survive to day 14 was estimated to be 0.27 (95% CI 0.06, 0.58). TKM-130803 infusions were well tolerated, with 56 doses administered and only one possible infusion-related reaction observed. Three patients were enrolled in the observational cohort, of whom two died. Administration of TKM-130803 at a dose of 0.3 mg/kg/d by intravenous infusion to adult patients with severe EVD was not shown to improve survival when compared to historic controls. Pan African Clinical Trials Registry PACTR201501000997429.

The Norovirus genus contains important human pathogens, but the role of host pathways in norovirus replication is largely unknown. Murine noroviruses provide the opportunity to study norovirus replication in cell culture and in small animals. The human norovirus nonstructural protein NS1/2 interacts with the host protein VAMP-associated protein A (VAPA), but the significance of the NS1/2-VAPA interaction is unexplored. Here we report decreased murine norovirus replication in VAPA- and VAPB-deficient cells. We characterized the role of VAPA in detail. VAPA was required for the efficiency of a step(s) in the viral replication cycle after entry of viral RNA into the cytoplasm but before the synthesis of viral minus-sense RNA. The interaction of VAPA with viral NS1/2 proteins is conserved between murine and human noroviruses. Murine norovirus NS1/2 directly bound the major sperm protein (MSP) domain of VAPA through its NS1 domain. Mutations within NS1 that disrupted interaction with VAPA inhibited viral replication. Structural analysis revealed that the viral NS1 domain contains a mimic of the phenylalanine–phenylalanine-acidic-tract (FFAT) motif that enables host proteins to bind to the VAPA MSP domain. The NS1/2-FFAT mimic region interacted with the VAPA-MSP domain in a manner similar to that seen with bona fide host FFAT motifs. Amino acids in the FFAT mimic region of the NS1 domain that are important for viral replication are highly conserved across murine norovirus strains. Thus, VAPA interaction with a norovirus protein that functionally mimics host FFAT motifs is important for murine norovirus replication. IMPORTANCE Human noroviruses are a leading cause of gastroenteritis worldwide, but host factors involved in norovirus replication are incompletely understood. Murine noroviruses have been studied to define mechanisms of norovirus replication. Here we defined the importance of the interaction between the hitherto poorly studied NS1/2 norovirus protein and the VAPA host protein. The NS1/2-VAPA interaction is conserved between murine and human noroviruses and was important for early steps in murine norovirus replication. Using structure-function analysis, we found that NS1/2 contains a short sequence that molecularly mimics the FFAT motif that is found in multiple host proteins that bind VAPA. This represents to our knowledge the first example of functionally important mimicry of a host FFAT motif by a microbial protein. Human noroviruses are a leading cause of gastroenteritis worldwide, but host factors involved in norovirus replication are incompletely understood. Murine noroviruses have been studied to define mechanisms of norovirus replication. Here we defined the importance of the interaction between the hitherto poorly studied NS1/2 norovirus protein and the VAPA host protein. The NS1/2-VAPA interaction is conserved between murine and human noroviruses and was important for early steps in murine norovirus replication. Using structure-function analysis, we found that NS1/2 contains a short sequence that molecularly mimics the FFAT motif that is found in multiple host proteins that bind VAPA. This represents to our knowledge the first example of functionally important mimicry of a host FFAT motif by a microbial protein.

Microbes, including viruses, influence type 1 diabetes (T1D) development, but many such influences remain undefined. Previous work on underlying immune mechanisms has focussed on cytokines and T cells. Here, we compared two nonobese diabetic (NOD) mouse colonies, NODlow and NODhigh, differing markedly in their cumulative T1D incidence (22% vs. 90% by 30 weeks in females). NODhigh mice harbored more complex intestinal microbiota, including several pathobionts; both colonies harbored segmented filamentous bacteria (SFB), thought to suppress T1D. Young NODhigh females had increased B-cell activation in their mesenteric lymph nodes. These phenotypes were transmissible. Co-housing of NODlow with NODhigh mice after weaning did not change T1D development, but T1D incidence was increased in female offspring of co-housed NODlow mice, which were exposed to the NODhigh environment both before and after weaning. These offspring also acquired microbiota and B-cell activation approaching those of NODhigh mice. In NODlow females, the low rate of T1D was unaffected by cyclophosphamide but increased by PD-L1 blockade. Thus, environmental exposures that are innocuous later in life may promote T1D progression if acquired early during immune development, possibly by altering B-cell activation and/or PD-L1 function. Moreover, T1D suppression in NOD mice by SFB may depend on the presence of other microbial influences. The complexity of microbial immune regulation revealed in this murine model may also be relevant to the environmental regulation of human T1D.