Functional and antigenic landscape of the Nipah virus receptor binding protein.

Nipah virus recurrently spills over to humans, causing fatal infections. The viral receptor-binding protein (RBP or G) attaches to host receptors and is a major target of neutralizing antibodies. Here we use deep mutational scanning to measure how all amino-acid mutations to the RBP affect cell entry, receptor binding, and escape from neutralizing antibodies. We identify functionally constrained regions of the RBP, including sites involved in oligomerization, along with mutations that differentially modulate RBP binding to its two ephrin receptors. We map escape mutations for six anti-RBP antibodies, and find that few antigenic mutations are present in natural Nipah strains. Our findings offer insights into the potential for functional and antigenic evolution of the RBP that can inform the development of antibody therapies and vaccines.

Broadly neutralizing antibodies against emerging delta-coronaviruses.

Porcine deltacoronavirus (PDCoV) spillovers were recently detected in children with acute undifferentiated febrile illness, underscoring recurrent zoonoses of divergent coronaviruses. To date, no vaccines or specific therapeutics are approved for use in humans against PDCoV. To prepare for possible future PDCoV epidemics, we isolated human spike (S)-directed monoclonal antibodies from transgenic mice and found that two of them, designated PD33 and PD41, broadly neutralized a panel of PDCoV variants. Cryo-electron microscopy structures of PD33 and PD41 in complex with the PDCoV receptor-binding domain and S ectodomain trimer provide a blueprint of the epitopes recognized by these mAbs, rationalizing their broad inhibitory activity. We show that both mAbs inhibit PDCoV by competitively interfering with host APN binding to the PDCoV receptor-binding loops, explaining the mechanism of viral neutralization. PD33 and PD41 are candidates for clinical advancement, which could be stockpiled to prepare for possible future PDCoV outbreaks.

Protein nanoparticle vaccines induce potent neutralizing antibody responses against MERS-CoV.

Middle East respiratory syndrome coronavirus (MERS-CoV) is a zoonotic betacoronavirus that causes severe and often lethal respiratory illness in humans. The MERS-CoV spike (S) protein is the viral fusogen and the target of neutralizing antibodies, and has therefore been the focus of vaccine design efforts. Currently there are no licensed vaccines against MERS-CoV and only a few candidates have advanced to Phase I clinical trials. Here we developed MERS-CoV vaccines utilizing a computationally designed protein nanoparticle platform that has generated safe and immunogenic vaccines against various enveloped viruses, including a licensed vaccine for SARS-CoV-2. Two-component protein nanoparticles displaying MERS-CoV S-derived antigens induced robust neutralizing antibody responses and protected mice against challenge with mouse-adapted MERS-CoV. Electron microscopy polyclonal epitope mapping and serum competition assays revealed the specificities of the dominant antibody responses elicited by immunogens displaying the prefusion-stabilized S-2P trimer, receptor binding domain (RBD), or N-terminal domain (NTD). An RBD nanoparticle vaccine elicited antibodies targeting multiple non-overlapping epitopes in the RBD, whereas anti-NTD antibodies elicited by the S-2P- and NTD-based immunogens converged on a single antigenic site. Our findings demonstrate the potential of two-component nanoparticle vaccine candidates for MERS-CoV and suggest that this platform technology could be broadly applicable to betacoronavirus vaccine development.

Mpox Diagnosis, Behavioral Risk Modification, and Vaccination Uptake among Gay, Bisexual, and Other Men Who Have Sex with Men, United Kingdom, 2022.

During the 2022 multicountry mpox outbreak, the United Kingdom identified cases beginning in May. UK cases increased in June, peaked in July, then rapidly declined after September 2022. Public health responses included community-supported messaging and targeted mpox vaccination among eligible gay, bisexual, and other men who have sex with men (GBMSM). Using data from an online survey of GBMSM during November-December 2022, we examined self-reported mpox diagnoses, behavioral risk modification, and mpox vaccination offer and uptake. Among 1,333 participants, only 35 (2.6%) ever tested mpox-positive, but 707 (53%) reported behavior modification to avoid mpox. Among vaccine-eligible GBMSM, uptake was 69% (95% CI 65%-72%; 601/875) and was 92% (95% CI 89%-94%; 601/655) among those offered vaccine. GBMSM self-identifying as bisexual, reporting lower educational qualifications, or identifying as unemployed were less likely to be vaccinated. Equitable offer and provision of mpox vaccine are needed to minimize the risk for future outbreaks and mpox-related health inequalities.

Persistent immune imprinting occurs after vaccination with the COVID-19 XBB.1.5 mRNA booster in humans.

Immune imprinting describes how the first exposure to a virus shapes immunological outcomes of subsequent exposures to antigenically related strains. Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) Omicron breakthrough infections and bivalent COVID-19 vaccination primarily recall cross-reactive memory B cells induced by prior Wuhan-Hu-1 spike mRNA vaccination rather than priming Omicron-specific naive B cells. These findings indicate that immune imprinting occurs after repeated Wuhan-Hu-1 spike exposures, but whether it can be overcome remains unclear. To understand the persistence of immune imprinting, we investigated memory and plasma antibody responses after administration of the updated XBB.1.5 COVID-19 mRNA vaccine booster. We showed that the XBB.1.5 booster elicited neutralizing antibody responses against current variants that were dominated by recall of pre-existing memory B cells previously induced by the Wuhan-Hu-1 spike. Therefore, immune imprinting persists after multiple exposures to Omicron spikes through vaccination and infection, including post XBB.1.5 booster vaccination, which will need to be considered to guide future vaccination.

Human coronavirus HKU1 recognition of the TMPRSS2 host receptor.

The human coronavirus HKU1 spike (S) glycoprotein engages host cell surface sialoglycans and transmembrane protease serine 2 (TMPRSS2) to initiate infection. The molecular basis of HKU1 binding to TMPRSS2 and determinants of host receptor tropism remain elusive. Here, we designed an active human TMPRSS2 construct enabling high-yield recombinant production in human cells of this key therapeutic target. We determined a cryo-electron microscopy structure of the HKU1 RBD bound to human TMPRSS2 providing a blueprint of the interactions supporting viral entry and explaining the specificity for TMPRSS2 among human type 2 transmembrane serine proteases. We found that human, rat, hamster and camel TMPRSS2 promote HKU1 S-mediated entry into cells and identified key residues governing host receptor usage. Our data show that serum antibodies targeting the HKU1 RBD TMPRSS2 binding-site are key for neutralization and that HKU1 uses conformational masking and glycan shielding to balance immune evasion and receptor engagement.

Persistent immune imprinting after XBB.1.5 COVID vaccination in humans.

Immune imprinting - also known as 'original antigenic sin' - describes how the first exposure to a virus shapes the immunological outcome of subsequent exposures to antigenically related strains. SARS-CoV-2 Omicron breakthrough infections and bivalent COVID-19 vaccination were shown to primarily recall cross-reactive memory B cells and antibodies induced by prior mRNA vaccination with the Wuhan-Hu-1 spike rather than priming naive B cells that recognize Omicron-specific epitopes. These findings underscored a strong immune imprinting resulting from repeated Wuhan-Hu-1 spike exposures. To understand if immune imprinting can be overcome, we investigated memory and plasma antibody responses after administration of the updated XBB.1.5 COVID mRNA vaccine booster. Our data show that the XBB.1.5 booster elicits neutralizing antibody responses against current variants that are dominated by recall of pre-existing memory B cells previously induced by the Wuhan-Hu-1 spike. These results indicate that immune imprinting persists even after multiple exposures to Omicron spikes through vaccination and infection, including post XBB.1.5 spike booster mRNA vaccination, which will need to be considered to guide the design of future vaccine boosters.

Full-spike deep mutational scanning helps predict the evolutionary success of SARS-CoV-2 clades.

SARS-CoV-2 variants acquire mutations in spike that promote immune evasion and impact other properties that contribute to viral fitness such as ACE2 receptor binding and cell entry. Knowledge of how mutations affect these spike phenotypes can provide insight into the current and potential future evolution of the virus. Here we use pseudovirus deep mutational scanning to measure how >9,000 mutations across the full XBB.1.5 and BA.2 spikes affect ACE2 binding, cell entry, or escape from human sera. We find that mutations outside the receptor-binding domain (RBD) have meaningfully impacted ACE2 binding during SARS-CoV-2 evolution. We also measure how mutations to the XBB.1.5 spike affect neutralization by serum from individuals who recently had SARS-CoV-2 infections. The strongest serum escape mutations are in the RBD at sites 357, 420, 440, 456, and 473-however, the antigenic impacts of these mutations vary across individuals. We also identify strong escape mutations outside the RBD; however many of them decrease ACE2 binding, suggesting they act by modulating RBD conformation. Notably, the growth rates of human SARS-CoV-2 clades can be explained in substantial part by the measured effects of mutations on spike phenotypes, suggesting our data could enable better prediction of viral evolution.

COVID-19 infection and vaccination uptake in men and gender-diverse people who have sex with men in the UK: analyses of a large, online community cross-sectional survey (RiiSH-COVID) undertaken November-December 2021.

BACKGROUND: Men and gender-diverse people who have sex with men are disproportionately affected by health conditions associated with increased risk of severe illness due to COVID-19 infection. METHODS: An online cross-sectional survey of men and gender-diverse people who have sex with men in the UK recruited via social networking and dating applications from 22 November-12 December 2021. Eligible participants included self-identifying men, transgender women, or gender-diverse individuals assigned male at birth (AMAB), aged ≥ 16, who were UK residents, and self-reported having had sex with an individual AMAB in the last year. We calculated self-reported COVID-19 test-positivity, proportion reporting long COVID, and COVID-19 vaccination uptake anytime from pandemic start to survey completion (November/December 2021). Logistic regression was used to assess sociodemographic, clinical, and behavioural characteristics associated with SARS-CoV-2 (COVID-19) test positivity and complete vaccination (≥ 2 vaccine doses). RESULTS: Among 1,039 participants (88.1% white, median age 41 years [interquartile range: 31-51]), 18.6% (95% CI: 16.3%-21.1%) reported COVID-19 test positivity, 8.3% (95% CI: 6.7%-10.1%) long COVID, and 94.5% (95% CI: 93.3%-96.1%) complete COVID-19 vaccination through late 2021. In multivariable models, COVID-19 test positivity was associated with UK country of residence (aOR: 2.22 [95% CI: 1.26-3.92], England vs outside England) and employment (aOR: 1.55 [95% CI: 1.01-2.38], current employment vs not employed). Complete COVID-19 vaccination was associated with age (aOR: 1.04 [95% CI: 1.01-1.06], per increasing year), gender (aOR: 0.26 [95% CI: 0.09-0.72], gender minority vs cisgender), education (aOR: 2.11 [95% CI: 1.12-3.98], degree-level or higher vs below degree-level), employment (aOR: 2.07 [95% CI: 1.08-3.94], current employment vs not employed), relationship status (aOR: 0.50 [95% CI: 0.25-1.00], single vs in a relationship), COVID-19 infection history (aOR: 0.47 [95% CI: 0.25-0.88], test positivity or self-perceived infection vs no history), known HPV vaccination (aOR: 3.32 [95% CI: 1.43-7.75]), and low self-worth (aOR: 0.29 [95% CI: 0.15-0.54]). CONCLUSIONS: In this community sample, COVID-19 vaccine uptake was high overall, though lower among younger age-groups, gender minorities, and those with poorer well-being. Efforts are needed to limit COVID-19 related exacerbation of health inequalities in groups who already experience a greater burden of poor health relative to other men who have sex with men.

Sexual behaviour, STI and HIV testing and testing need among gay, bisexual and other men who have sex with men recruited for online surveys pre/post-COVID-19 restrictions in the UK.

OBJECTIVES: We examined sexual behaviour, sexually transmitted infection (STI) and HIV testing and testing need, and identified associated factors, among gay, bisexual and other men who have sex with men (GBMSM) in the UK after COVID-19 restrictions ended, and compared these with 'pre-pandemic' estimates. METHODS: We analysed survey data from GBMSM (N=1039) recruited via social media and Grindr in November-December 2021. We then compared Grindr-recruited 2021 participants (N=437) with those from an equivalent survey fielded in March-May 2017 (N=1902). Questions on sexual behaviour and service use had lookback periods of 3-4 months in both surveys. Unmet testing need was defined as reporting any new male and/or multiple condomless anal sex (CAS) partners without recent STI/HIV testing. Participants were UK residents, GBMSM, aged ≥16 years who reported sex with men in the last year. Multivariable logistic regression identified associated sociodemographic and health-related factors with unmet STI/HIV testing need in 2021, and then for 2017/2021 comparative analyses, adjusting for demographic differences. RESULTS: In 2021, unmet STI and HIV testing need were greater among older GBMSM (aged ≥45 years vs 16-29 years; adjusted OR (aOR): 1.45 and aOR: 1.77, respectively), and lower for pre-exposure prophylaxis (PrEP) users (vs non-PrEP users; aOR: 0.32 and aOR: 0.23, respectively). Less unmet STI testing need was observed among HIV-positive participants (vs HIV-negative/unknown; aOR: 0.63), and trans and non-binary participants (vs cisgender male; aOR: 0.34). Between 2017 (reference) and 2021, reported sexual risk behaviours increased: ≥1 recent new male sex partner (72.1%-81.1%, aOR: 1.71) and ≥2 recent CAS partners (30.2%-48.5%, aOR: 2.22). Reporting recent STI testing was greater in 2021 (37.5%-42.6%, aOR: 1.34) but not recent HIV testing, and there was no significant change over time in unmet STI (39.2% vs 43.7%) and HIV (32.9% vs 39.0%) testing need. DISCUSSION: Comparable community surveys suggest that UK resident GBMSM may have engaged in more sexual risk behaviours in late 2021 than pre-pandemic. While there was no evidence of reduced STI/HIV service access during this time, there remained considerable unmet STI/HIV testing need.

Difficulty accessing condoms because of the COVID-19 pandemic reported by gay, bisexual and other men who have sex with men in the UK: findings from a large, cross-sectional, online survey.

BACKGROUND: COVID-19 restrictions severely reduced face-to-face sexual health services, an important access point for condoms. We examine whether gay, bisexual and other men who have sex with men (GBMSM) in the UK had difficulty accessing condoms during the first year of the pandemic, and if so, which groups were most affected. METHODS: Questions about difficulty accessing condoms were asked as part of a short, online cross-sectional survey of GBMSM undertaken November/December 2021, recruited via social media and Grindr. Eligible participants were UK-resident GBMSM (cis/trans/gender-diverse person assigned male at birth [AMAB]), aged ≥16 years who were sexually active (reported sex with men in the last year). Multivariable logistic regression was used to examine if and how reporting this outcome varied by key sociodemographic, health and behavioural factors independent of the potential confounding effect of numbers of new male sex partners. RESULTS: Of all participants (N = 1039), 7.4% (n = 77) reported difficulty accessing condoms due to the pandemic. This was higher among younger GBMSM (aged 16-29 years vs. ≥45; 12.8% vs. 4.9%; aOR: 2.78); trans/gender-diverse AMAB participants (vs. cis gender males; 24.4% vs. 6.6%; aOR = 4.86); bisexually-identifying participants (vs. gay-identifying; 11.1% vs. 6.5%; aOR = 1.78); and those without degree level education (vs. having a degree; 9.8% vs. 5.6%; aOR = 2.01). CONCLUSIONS: A minority of sexually active GBMSM reported difficulty accessing condoms because of the pandemic, however, this was more common amongst those who already experience a disproportionate burden of poor sexual health. Interventions are needed to address these inequalities in accessing this important primary STI/HIV prevention measure.

SARS-CoV-2 spike conformation determines plasma neutralizing activity elicited by a wide panel of human vaccines.

Numerous safe and effective coronavirus disease 2019 vaccines have been developed worldwide that use various delivery technologies and engineering strategies. We show here that vaccines containing prefusion-stabilizing S mutations elicit antibody responses in humans with enhanced recognition of S and the S1 subunit relative to postfusion S as compared with vaccines lacking these mutations or natural infection. Prefusion S and S1 antibody binding titers positively and equivalently correlated with neutralizing activity, and depletion of S1-directed antibodies completely abrogated plasma neutralizing activity. We show that neutralizing activity is almost entirely directed to the S1 subunit and that variant cross-neutralization is mediated solely by receptor binding domain-specific antibodies. Our data provide a quantitative framework for guiding future S engineering efforts to develop vaccines with higher resilience to the emergence of variants than current technologies.

Omicron spike function and neutralizing activity elicited by a comprehensive panel of vaccines.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant of concern comprises several sublineages, with BA.2 and BA.2.12.1 having replaced the previously dominant BA.1 and with BA.4 and BA.5 increasing in prevalence worldwide. We show that the large number of Omicron sublineage spike mutations leads to enhanced angiotensin-converting enzyme 2 (ACE2) binding, reduced fusogenicity, and severe dampening of plasma neutralizing activity elicited by infection or seven clinical vaccines relative to the ancestral virus. Administration of a homologous or heterologous booster based on the Wuhan-Hu-1 spike sequence markedly increased neutralizing antibody titers and breadth against BA.1, BA.2, BA.2.12.1, BA.4, and BA.5 across all vaccines evaluated. Our data suggest that although Omicron sublineages evade polyclonal neutralizing antibody responses elicited by primary vaccine series, vaccine boosters may provide sufficient protection against Omicron-induced severe disease.

Changes in STI and HIV testing and testing need among men who have sex with men during the UK's COVID-19 pandemic response.

OBJECTIVES: We examined the impact of COVID-19-related restrictions on sexual behaviours, STI and HIV testing and testing need among men who have sex with men (MSM) in the UK. METHODS: We used social media and dating applications to recruit to three cross-sectional surveys (S1-S3) during the UK's pandemic response (S1: 23 June-14 July 2020; S2: 23 November-12 December 2020; S3: 23 March-14 April 2021). Surveys included lookback periods of around 3-4 months (P1-P3, respectively). Eligible participants were UK resident men (cisgender/transgender) and gender-diverse people assigned male at birth (low numbers of trans and gender-diverse participants meant restricting these analyses to cisgender men), aged ≥16 years who reported sex with men (cisgender/transgender) in the last year (S1: N=1950; S2: N=1463; S3: N=1487). Outcomes were: recent STI/HIV testing and unmet testing need (new male and/or multiple condomless anal sex partners without a recent STI/HIV test). Crude and adjusted associations with each outcome were assessed using logistic regression. RESULTS: Participants' sociodemographic characteristics were similar across surveys. The proportion reporting a recent STI and/or HIV test increased between P1 and P2 (25.0% to 37.2% (p<0.001) and 29.7% to 39.4% (p<0.001), respectively), then stabilised in P3 (40.5% reporting HIV testing). Unmet STI testing need increased across P1 and P2 (26.0% to 32.4%; p<0.001), but trends differed between groups, for example, unmet STI testing need was higher in bisexually-identifying (vs gay-identifying) MSM across periods (adjusted OR (aOR): P1=1.64; P2=1.42), but declined in HIV-positive (vs HIV-negative/unknown) MSM (aOR: P1=2.06; P2=0.68). Unmet HIV testing need increased across P1 and P2 (22.9% to 31.0%; p<0.001) and declined in P3 (25.1%; p=0.001). During P3, MSM reporting a low life-satisfaction level (vs medium-very high) had greater unmet need (aOR: 1.44), while from P2 onwards HIV pre-exposure prophylaxis users (vs non-users) had lower unmet need (aOR: P2=0.32; P3=0.50). CONCLUSION: Considerable unmet STI/HIV testing need occurred among MSM during COVID-19-related restrictions, especially in bisexually-identifying men and those reporting low life satisfaction. Improving access to STI/HIV testing in MSM is essential to prevent inequalities being exacerbated.

Facile and Scalable Methodology for the Pyrrolo[2,1-f][1,2,4]triazine of Remdesivir.

Pyrrolo[2,1-f][1,2,4]triazine (1) is an important regulatory starting material in the production of the antiviral drug remdesivir. Compound 1 was produced through a newly developed synthetic methodology utilizing simple building blocks such as pyrrole, chloramine, and formamidine acetate by examining the mechanistic pathway for the process optimization exercise. Triazine 1 was obtained in 55% overall yield in a two-vessel-operated process. This work describes the safety of the process, impurity profiles and control, and efforts toward the scale-up of triazine for the preparation of kilogram quantity.

A randomized study of the safety and pharmacokinetics of GSK3358699, a mononuclear myeloid-targeted bromodomain and extra-terminal domain inhibitor.

AIMS: GSK3358699 is a mononuclear myeloid-targeted bromodomain and extra-terminal domain (BET) family inhibitor which demonstrates immunomodulatory effects in vitro. This phase 1, randomized, first-in-human study evaluated the safety, pharmacokinetics, and pharmacodynamics of GSK3358699 in healthy male participants (NCT03426995). METHODS: Part A (N = 23) included three dose-escalating periods of 1-40 mg of GSK3358699 or placebo in two cohorts in a single ascending-dose crossover design. Part C (N = 25) was planned as an initial dose of 10 mg of GSK3358699 or placebo daily for 14 days followed by selected doses in four sequential cohorts. RESULTS: In part A, exposure to GSK3358699 and its metabolite GSK3206944 generally increased with increasing doses. The median initial half-life ranged from 0.7 to 1.1 (GSK3358699) and 2.1 to 2.9 (GSK3206944) hours after a single dose of 1-40 mg. GSK3206944 concentrations in monocytes were quantifiable at 1-hour post-dose following 10 mg of GSK3358699 and 1 and 4 hours post-dose following 20-40 mg. Mean predicted percentage inhibition of ex vivo lipopolysaccharide-induced monocyte chemoattractant protein (MCP)-1 reached 75% with 40 mg of GSK3358699. GSK3358699 did not inhibit interleukin (IL)-6 and tumour necrosis factor (TNF). The most common adverse event (AE) was headache. Four AEs of nonsustained ventricular tachycardia were observed across parts A and C. One serious AE of atrial fibrillation (part C) required hospitalization. CONCLUSIONS: Single doses of GSK3358699 are generally well tolerated with significant metabolite concentrations detected in target cells. A complete assessment of pharmacodynamics was limited by assay variability. A causal relationship could not be excluded for cardiac-related AEs, resulting in an inability to identify a suitable repeat-dose regimen and study termination.

Systems analysis of miRNA biomarkers to inform drug safety.

microRNAs (miRNAs or miRs) are short non-coding RNA molecules which have been shown to be dysregulated and released into the extracellular milieu as a result of many drug and non-drug-induced pathologies in different organ systems. Consequently, circulating miRs have been proposed as useful biomarkers of many disease states, including drug-induced tissue injury. miRs have shown potential to support or even replace the existing traditional biomarkers of drug-induced toxicity in terms of sensitivity and specificity, and there is some evidence for their improved diagnostic and prognostic value. However, several pre-analytical and analytical challenges, mainly associated with assay standardization, require solutions before circulating miRs can be successfully translated into the clinic. This review will consider the value and potential for the use of circulating miRs in drug-safety assessment and describe a systems approach to the analysis of the miRNAome in the discovery setting, as well as highlighting standardization issues that at this stage prevent their clinical use as biomarkers. Highlighting these challenges will hopefully drive future research into finding appropriate solutions, and eventually circulating miRs may be translated to the clinic where their undoubted biomarker potential can be used to benefit patients in rapid, easy to use, point-of-care test systems.

An Evaluation of a Kansas Open Streets Event's Impact on Businesses.

INTRODUCTION: Open Streets is an event that promotes physical activity among populations by encouraging city residents to walk and bicycle in streets blocked from motor vehicles. Engagement of businesses is a critical component of Open Streets. This study sought to evaluate the Open Streets ICT 2019 event's impact on adjacent businesses. METHODS: A 12-item novel survey was developed for this study. Businesses eligible for study participation included retail and non-retail (e.g., non-profits, churches) sites along the Open Streets ICT route in Wichita, Kansas. To understand how Open Streets ICT impacted businesses, the survey used Likert scale questions to prompt respondents to report sales and visitors experiences during the event. Additionally, respondents reported a percent difference in sales compared to a typical Sunday. A phenomenological approach was used to convey the experiences among study participants during Open Streets ICT. RESULTS: A total of 102 surveys were completed, a 42% response rate. Most businesses (56%, n = 56) reported being open during Open Streets ICT. Many businesses (72%) reported having "more" visitors compared to a typical Sunday. More than half reported they experienced new and regular visitors (54%, n = 30) from the event. Most businesses (64%, n = 36) reported a positive financial impact, and (52%, n = 29) having more sales than a typical Sunday. CONCLUSIONS: Open Streets ICT increased sales and the number of visitors among businesses. Respondents reported they plan to participate in the 2020 Open Streets ICT, and if Open Streets ICT was offered twice a year. Finally, most participating businesses reported they recommend that other businesses participate in Open Streets ICT.

Cystic fibrosis improves COVID-19 survival and provides clues for treatment of SARS-CoV-2.

Systemic pools of ATP are elevated in individuals homozygous for cystic fibrosis (CF) as evidenced by elevated blood and plasma ATP levels. This elevated ATP level seems to provide benefit in the presence of advanced solid tumors (Abraham et al., Nature Medicine 2(5):593-596, 1996). We published in this journal a paper showing that IV ATP can elevate the depleted ATP pools of advanced cancer patients up to levels found in CF patients with subsequent clinical, biochemical, and quality of life (QOL) improvements (Rapaport et al., Purinergic Signalling 11(2): 251-262, 2015). We hypothesize that the elevated ATP levels seen in CF patients may be benefiting CF patients in another way: by improving their survival after contracting COVID-19. We discuss here the reasoning behind this hypothesis and suggest how these findings might be applied clinically in the general population.