Effectiveness of mRNA COVID-19 Vaccines as First Booster Doses in England: An Observational Study in OpenSAFELY-TPP.

BACKGROUND: The UK delivered its first "booster" COVID-19 vaccine doses in September 2021, initially to individuals at high risk of severe disease, then to all adults. The BNT162b2 Pfizer-BioNTech vaccine was used initially, then also Moderna mRNA-1273. METHODS: With the approval of the National Health Service England, we used routine clinical data to estimate the effectiveness of boosting with BNT162b2 or mRNA-1273 compared with no boosting in eligible adults who had received two primary course vaccine doses. We matched each booster recipient with an unboosted control on factors relating to booster priority status and prior COVID-19 immunization. We adjusted for additional factors in Cox models, estimating hazard ratios up to 182 days (6 months) following booster dose. We estimated hazard ratios overall and within the following periods: 1-14, 15-42, 43-69, 70-97, 98-126, 127-152, and 155-182 days. Outcomes included a positive SARS-CoV-2 test, COVID-19 hospitalization, COVID-19 death, non-COVID-19 death, and fracture. RESULTS: We matched 8,198,643 booster recipients with unboosted controls. Adjusted hazard ratios over 6-month follow-up were: positive SARS-CoV-2 test 0.75 (0.74, 0.75); COVID-19 hospitalization 0.30 (0.29, 0.31); COVID-19 death 0.11 (0.10, 0.14); non-COVID-19 death 0.22 (0.21, 0.23); and fracture 0.77 (0.75, 0.78). Estimated effectiveness of booster vaccines against severe COVID-19-related outcomes peaked during the first 3 months following the booster dose. By 6 months, the cumulative incidence of positive SARS-CoV-2 test was higher in boosted than unboosted individuals. CONCLUSIONS: We estimate that COVID-19 booster vaccination, compared with no booster vaccination, provided substantial protection against COVID-19 hospitalization and COVID-19 death but only limited protection against positive SARS-CoV-2 test. Lower rates of fracture in boosted than unboosted individuals may suggest unmeasured confounding. Observational studies should report estimated vaccine effectiveness against nontarget and negative control outcomes.

Association Between Maternal Breastmilk Microbiota Composition and Rotavirus Vaccine Response in African, Asian, and European Infants: A Prospective Cohort Study.

BACKGROUND: Maternal breastmilk is a source of pre- and pro-biotics that impact neonatal gut microbiota colonization. Because oral rotavirus vaccines (ORVs) are administered at a time when infants are often breastfed, breastmilk microbiota composition may have a direct or indirect influence on vaccine take and immunogenicity. METHODS: Using standardized methods across sites, we compared breastmilk microbiota composition in relation to geographic location and ORV response in cohorts prospectively followed from birth to 18 weeks of age in India (n = 307), Malawi (n = 119), and the United Kingdom ([UK] n = 60). RESULTS: Breastmilk microbiota diversity was higher in India and Malawi than the UK across 3 longitudinal samples spanning weeks of life 1 to 13. Dominant taxa such as Streptococcus and Staphylococcus were consistent across cohorts; however, significant geographic differences were observed in the prevalence and abundance of common and rare genera throughout follow up. No consistent associations were identified between breastmilk microbiota composition and ORV outcomes including seroconversion, vaccine shedding after dose 1, and postvaccination rotavirus-specific immunoglobulin A level. CONCLUSIONS: Our findings suggest that breastmilk microbiota composition may not be a key factor in shaping trends in ORV response within or between countries.

Isocitrate dehydrogenase 3b is required for spermiogenesis but dispensable for retinal viability.

Isocitrate dehydrogenase 3 (IDH3) is a key enzyme in the mitochondrial tricarboxylic acid (TCA) cycle, which catalyzes the decarboxylation of isocitrate into α-ketoglutarate and concurrently converts NAD+ into NADH. Dysfunction of IDH3B, the ß subunit of IDH3, has been previously correlated with retinal degeneration and male infertility in humans, but tissue-specific effects of IDH3 dysfunction are unclear. Here, we generated Idh3b-KO mice and found that IDH3B is essential for IDH3 activity in multiple tissues. We determined that loss of Idh3b in mice causes substantial accumulation of isocitrate and its precursors in the TCA cycle, particularly in the testes, whereas the levels of the downstream metabolites remain unchanged or slightly increased. However, the Idh3b-KO mice did not fully recapitulate the defects observed in humans. Global deletion of Idh3b only causes male infertility but not retinal degeneration in mice. Our investigation showed that loss of Idh3b causes an energetic deficit and disrupts the biogenesis of acrosome and flagellum, resulting in spermiogenesis arrestment in sperm cells. Together, we demonstrate that IDH3B controls its substrate levels in the TCA cycle, and it is required for sperm mitochondrial metabolism and spermiogenesis, highlighting the importance of the tissue-specific function of the ubiquitous TCA cycle.

Increased bacterial taxonomic and functional diversity is associated with impaired rotavirus vaccine immunogenicity in infants from India and Malawi.

The immunogenicity and effectiveness of oral rotavirus vaccines (ORVs) against severe rotavirus-associated gastroenteritis are impaired in low- and middle-income countries (LMICs) where the burden of disease is highest. Determining risk factors for impaired ORV response may help identify strategies to enhance vaccine effectiveness. In this study, we use metagenomic sequencing to provide a high-resolution taxonomic analysis of stool samples collected at 6 weeks of age (coinciding with the first ORV dose) during a prospective study of ORV immunogenicity in India and Malawi. We then analyse the functional capacity of the developing microbiome in these cohorts. Microbiome composition differed significantly between countries, although functional capacity was more similar than taxonomic composition. Our results confirm previously reported findings that the developing microbiome is more diverse in taxonomic composition in ORV non-seroconverters compared with seroconverters, and we additionally demonstrate a similar pattern in functional capacity. Although taxonomic or functional feature abundances are poor predictors of ORV response, we show that skews in the direction of associations within these microbiome data can be used to identify consistent markers of ORV response across LMIC infant cohorts. We also highlight the systemic under-representation of reference genes from LMICs that limit functional annotation in our study (7% and 13% annotation at pathway and enzyme commission level, respectively). Overall, higher microbiome diversity in early life may act as marker for impaired ORV response in India and Malawi, whilst a holistic perspective of functional capacity may be hidden in the "dark matter" of the microbiome.

Daily mitochondrial dynamics in cone photoreceptors.

Cone photoreceptors in the retina are exposed to intense daylight and have higher energy demands in darkness. Cones produce energy using a large cluster of mitochondria. Mitochondria are susceptible to oxidative damage, and healthy mitochondrial populations are maintained by regular turnover. Daily cycles of light exposure and energy consumption suggest that mitochondrial turnover is important for cone health. We investigated the three-dimensional (3D) ultrastructure and metabolic function of zebrafish cone mitochondria throughout the day. At night retinas undergo a mitochondrial biogenesis event, corresponding to an increase in the number of smaller, simpler mitochondria and increased metabolic activity in cones. In the daytime, endoplasmic reticula (ER) and autophagosomes associate more with mitochondria, and mitochondrial size distribution across the cluster changes. We also report dense material shared between cone mitochondria that is extruded from the cell at night, sometimes forming extracellular structures. Our findings reveal an elaborate set of daily changes to cone mitochondrial structure and function.

FUT2 Secretor Status Is Not Associated With Oral Poliovirus Vaccine Immunogenicity in South Indian Infants.

FUT2 determines whether histo-blood group antigens are secreted at mucosal surfaces. Secretor status influences susceptibility to enteric viruses, potentially including oral poliovirus vaccine (OPV). We performed a nested case-control study to determine the association between FUT2 genotype (single-nucleotide polymorphisms G428A, C302T, and A385T) and seroconversion among Indian infants who received a single dose of monovalent type 3 OPV. Secretor prevalence was 75% (89 of 118) in infants who seroconverted and 80% (97 of 122) in infants who did not seroconvert (odds ratio, 0.79; 95% confidence interval, .43-1.45). Our findings suggest that FUT2 genotype is not a key determinant of variation in OPV immunogenicity.

Influence of Nonpolio Enteroviruses and the Bacterial Gut Microbiota on Oral Poliovirus Vaccine Response: A Study from South India.

BACKGROUND: Oral poliovirus vaccine (OPV) is less immunogenic in low- or middle-income than in high-income countries. We tested whether bacterial and viral components of the intestinal microbiota are associated with this phenomenon. METHODS: We assessed the prevalence of enteropathogens using TaqMan array cards 14 days before and at vaccination in 704 Indian infants (aged 6-11 months) receiving monovalent type 3 OPV (CTRI/2014/05/004588). Nonpolio enterovirus (NPEV) serotypes were identified by means of VP1 sequencing. In 120 infants, the prevaccination bacterial microbiota was characterized using 16S ribosomal RNA sequencing. RESULTS: We detected 56 NPEV serotypes on the day of vaccination. Concurrent NPEVs were associated with a reduction in OPV seroconversion, consistent across species (odds ratio [95% confidence interval], 0.57 [.36-.90], 0.61 [.43-.86], and 0.69 [.41-1.16] for species A, B, and C, respectively). Recently acquired enterovirus infections, detected at vaccination but not 14 days earlier, had a greater interfering effect on monovalent type 3 OPV seroresponse than did persistent infections, with enterovirus detected at both time points (seroconversion in 44 of 127 infants [35%] vs 63 of 129 [49%]; P = .02). The abundance of specific bacterial taxa did not differ significantly according to OPV response, although the microbiota was more diverse in nonresponders at the time of vaccination. CONCLUSION: Enteric viruses have a greater impact on OPV response than the bacterial microbiota, with recent enterovirus infections having a greater inhibitory effect than persistent infections.

The microRNA bantam regulates a developmental transition in epithelial cells that restricts sensory dendrite growth.

As animals grow, many early born structures grow by cell expansion rather than cell addition; thus growth of distinct structures must be coordinated to maintain proportionality. This phenomenon is particularly widespread in the nervous system, with dendrite arbors of many neurons expanding in concert with their substrate to sustain connectivity and maintain receptive field coverage as animals grow. After rapidly growing to establish body wall coverage, dendrites of Drosophila class IV dendrite arborization (C4da) neurons grow synchronously with their substrate, the body wall epithelium, providing a system to study how proportionality is maintained during animal growth. Here, we show that the microRNA bantam (ban) ensures coordinated growth of C4da dendrites and the epithelium through regulation of epithelial endoreplication, a modified cell cycle that entails genome amplification without cell division. In Drosophila larvae, epithelial endoreplication leads to progressive changes in dendrite-extracellular matrix (ECM) and dendrite-epithelium contacts, coupling dendrite/substrate expansion and restricting dendrite growth beyond established boundaries. Moreover, changes in epithelial expression of cell adhesion molecules, including the beta-integrin myospheroid (mys), accompany this developmental transition. Finally, endoreplication and the accompanying changes in epithelial mys expression are required to constrain late-stage dendrite growth and structural plasticity. Hence, modulating epithelium-ECM attachment probably influences substrate permissivity for dendrite growth and contributes to the dendrite-substrate coupling that ensures proportional expansion of the two cell types.

The epidemiology of non-polio enteroviruses: recent advances and outstanding questions.

PURPOSE OF REVIEW: There are over 100 serotypes of human enteroviruses, which cause a spectrum of illnesses, including meningitis, encephalitis, paralysis, myocarditis and rash. Increasing incidence of hand-foot-and-mouth disease in the Asia-Pacific region and recent outbreaks of enterovirus-associated disease, such as severe respiratory illness in the United States in 2014, highlight the threat of these viruses to human health. RECENT FINDINGS: We describe recent outbreaks of human enteroviruses and summarize knowledge gaps regarding their burden, spectrum of diseases and epidemiology. SUMMARY: Reported outbreaks of respiratory, neurological, skin and eye diseases associated with human enteroviruses have increased in frequency and size in recent years. Improved molecular diagnostics and genetic sequence analysis are beginning to reveal the complex dynamics of individual serotypes and genotypes, and their contribution to these outbreaks. However, the biological mechanisms underlying their emergence and transmission dynamics remain elusive. They are likely to involve changes in the virus, such as fitness, antigenicity, virulence or tropism, and in the human population, such as levels of sanitation and of homotypic and heterotypic immunity. Improvements in surveillance, serological surveys and detailed genetic and antigenic characterization of viral populations would help to elucidate these mechanisms. This will be important for the design of outbreak control and vaccine development strategies.

Neurotransmission selectively regulates synapse formation in parallel circuits in vivo.

Activity is thought to guide the patterning of synaptic connections in the developing nervous system. Specifically, differences in the activity of converging inputs are thought to cause the elimination of synapses from less active inputs and increase connectivity with more active inputs. Here we present findings that challenge the generality of this notion and offer a new view of the role of activity in synapse development. To imbalance neurotransmission from different sets of inputs in vivo, we generated transgenic mice in which ON but not OFF types of bipolar cells in the retina express tetanus toxin (TeNT). During development, retinal ganglion cells (RGCs) select between ON and OFF bipolar cell inputs (ON or OFF RGCs) or establish a similar number of synapses with both on separate dendritic arborizations (ON-OFF RGCs). In TeNT retinas, ON RGCs correctly selected the silenced ON bipolar cell inputs over the transmitting OFF bipolar cells, but were connected with them through fewer synapses at maturity. Time-lapse imaging revealed that this was caused by a reduced rate of synapse formation rather than an increase in synapse elimination. Similarly, TeNT-expressing ON bipolar cell axons generated fewer presynaptic active zones. The remaining active zones often recruited multiple, instead of single, synaptic ribbons. ON-OFF RGCs in TeNT mice maintained convergence of ON and OFF bipolar cells inputs and had fewer synapses on their ON arbor without changes to OFF arbor synapses. Our results reveal an unexpected and remarkably selective role for activity in circuit development in vivo, regulating synapse formation but not elimination, affecting synapse number but not dendritic or axonal patterning, and mediating independently the refinement of connections from parallel (ON and OFF) processing streams even where they converge onto the same postsynaptic cell.

Influence of enteric infections on response to oral poliovirus vaccine: a systematic review and meta-analysis.

BACKGROUND: The impaired immunogenicity of oral poliovirus vaccine (OPV) in low-income countries has been apparent since the early field trials of this vaccine. Infection with enteropathogens at the time of vaccination may contribute to this phenomenon. However, the relative influence of these infections on OPV performance remains uncertain. METHODS: We conducted a systematic review to examine the impact of concurrent enteric infections on OPV response. Using random-effects models, we assessed the effects of nonpolio enteroviruses (NPEVs) and diarrhea on the odds of seroconversion and/or vaccine virus shedding. RESULTS: We identified 25 trials in which OPV outcomes were compared according to the presence or absence of enteric infections, the majority of which (n = 17) reported only on NPEVs. Concurrent NPEVs significantly reduced the odds of per-dose seroconversion for type 1 poliovirus (odds ratio [OR] 0.44, 95% confidence interval 0.23-0.84), but not type 2 (OR 0.53 [0.19-1.46]) or type 3 (OR 0.56 [0.27-1.12]). A similar reduction, significant for type 1 poliovirus (OR 0.50 [0.28-0.89]), was observed in the odds of vaccine virus shedding among NPEV-infected individuals. Concurrent diarrhea significantly inhibited per-dose seroconversion overall (OR 0.61 [0.38-0.87]). CONCLUSIONS: Our findings are consistent with an inhibitory effect of concurrent enteric infections on OPV response.

Identification of patients undergoing chronic kidney replacement therapy in primary and secondary care data: validation study based on OpenSAFELY and UK Renal Registry.

Objective: To validate primary and secondary care codes in electronic health records to identify people receiving chronic kidney replacement therapy based on gold standard registry data. Design: Validation study using data from OpenSAFELY and the UK Renal Registry, with the approval of NHS England. Setting: Primary and secondary care electronic health records from people registered at 45% of general practices in England on 1 January 2020, linked to data from the UK Renal Registry (UKRR) within the OpenSAFELY-TPP platform, part of the NHS England OpenSAFELY covid-19 service. Participants: 38 745 prevalent patients (recorded as receiving kidney replacement therapy on 1 January 2020 in UKRR data, or primary or secondary care data) and 10 730 incident patients (starting kidney replacement therapy during 2020), from a population of 19 million people alive and registered with a general practice in England on 1 January 2020. Main outcome measures: Sensitivity and positive predictive values of primary and secondary care code lists for identifying prevalent and incident kidney replacement therapy cohorts compared with the gold standard UKRR data on chronic kidney replacement therapy. Agreement across the data sources overall, and by treatment modality (transplantation or dialysis) and personal characteristics. Results: Primary and secondary care code lists were sensitive for identifying the UKRR prevalent cohort (91.2% (95% confidence interval (CI) 90.8% to 91.6%) and 92.0% (91.6% to 92.4%), respectively), but not the incident cohort (52.3% (50.3% to 54.3%) and 67.9% (66.1% to 69.7%)). Positive predictive values were low (77.7% (77.2% to 78.2%) for primary care data and 64.7% (64.1% to 65.3%) for secondary care data), particularly for chronic dialysis (53.7% (52.9% to 54.5%) for primary care data and 49.1% (48.0% to 50.2%) for secondary care data). Sensitivity decreased with age and index of multiple deprivation in primary care data, but the opposite was true in secondary care data. Agreement was lower in children, with 30% (295/980) featuring in all three datasets. Half (1165/2315) of the incident patients receiving dialysis in UKRR data had a kidney replacement therapy code in the primary care data within three months of the start date of the kidney replacement therapy. No codes existed whose exclusion would substantially improve the positive predictive value without a decrease in sensitivity. Conclusions: Codes used in primary and secondary care data failed to identify a small proportion of prevalent patients receiving kidney replacement therapy. Codes also identified many patients who were not recipients of chronic kidney replacement therapy in UKRR data, particularly dialysis codes. Linkage with UKRR kidney replacement therapy data facilitated more accurate identification of incident and prevalent kidney replacement therapy cohorts for research into this vulnerable population. Poor coding has implications for any patient care (including eligibility for vaccination, resourcing, and health policy responses in future pandemics) that relies on accurate reporting of kidney replacement therapy in primary and secondary care data.

Disruption of myelin structure and oligodendrocyte maturation in a macaque model of congenital Zika infection.

Zika virus (ZikV) infection during pregnancy can cause congenital Zika syndrome (CZS) and neurodevelopmental delay in infants, of which the pathogenesis remains poorly understood. We utilize an established female pigtail macaque maternal-to-fetal ZikV infection/exposure model to study fetal brain pathophysiology of CZS manifesting from ZikV exposure in utero. We find prenatal ZikV exposure leads to profound disruption of fetal myelin, with extensive downregulation in gene expression for key components of oligodendrocyte maturation and myelin production. Immunohistochemical analyses reveal marked decreases in myelin basic protein intensity and myelinated fiber density in ZikV-exposed animals. At the ultrastructural level, the myelin sheath in ZikV-exposed animals shows multi-focal decompaction, occurring concomitant with dysregulation of oligodendrocyte gene expression and maturation. These findings define fetal neuropathological profiles of ZikV-linked brain injury underlying CZS resulting from ZikV exposure in utero. Because myelin is critical for cortical development, ZikV-related perturbations in oligodendrocyte function may have long-term consequences on childhood neurodevelopment, even in the absence of overt microcephaly.

Mag-Net: Rapid enrichment of membrane-bound particles enables high coverage quantitative analysis of the plasma proteome.

Membrane-bound particles in plasma are composed of exosomes, microvesicles, and apoptotic bodies and represent ~1-2% of the total protein composition. Proteomic interrogation of this subset of plasma proteins augments the representation of tissue-specific proteins, representing a "liquid biopsy," while enabling the detection of proteins that would otherwise be beyond the dynamic range of liquid chromatography-tandem mass spectrometry of unfractionated plasma. We have developed an enrichment strategy (Mag-Net) using hyper-porous strong-anion exchange magnetic microparticles to sieve membrane-bound particles from plasma. The Mag-Net method is robust, reproducible, inexpensive, and requires <100 µL plasma input. Coupled to a quantitative data-independent mass spectrometry analytical strategy, we demonstrate that we can collect results for >37,000 peptides from >4,000 plasma proteins with high precision. Using this analytical pipeline on a small cohort of patients with neurodegenerative disease and healthy age-matched controls, we discovered 204 proteins that differentiate (q-value < 0.05) patients with Alzheimer's disease dementia (ADD) from those without ADD. Our method also discovered 310 proteins that were different between Parkinson's disease and those with either ADD or healthy cognitively normal individuals. Using machine learning we were able to distinguish between ADD and not ADD with a mean ROC AUC = 0.98 ± 0.06.

Evaluation of SERS labeling of CD20 on CLL cells using optical microscopy and fluorescence flow cytometry.

Immunophenotyping of lymphoproliferative disorders depends on the effective measurement of cell surface markers. The inherent light-scattering properties of plasmonic nanoparticles (NPs) combined with recent developments in NP design may confer significant advantages over traditional fluorescence probes. We report and evaluate the use of surface-enhanced Raman scattering (SERS) gold NPs (AuNPs) conjugated to therapeutic rituximab antibodies for selective targeting of CD20 molecules. SERS AuNPs were prepared by adsorbing a Raman-active dye onto the surface of 60 nm spherical AuNPs, coating the particles with 5 kDa polyethylene glycol, and conjugating rituximab to functional groups on polyethylene glycol. The effective targeting of CD20 on chronic lymphocytic leukemia cells by rituximab-conjugated SERS AuNPs was evaluated by dark-field imaging, Raman spectroscopy, and flow cytometry with both competitive binding and fluorescence detection procedures. Evidence of CD20 clustering within approximately 100 nm was observed. FROM THE CLINICAL EDITOR: This study discusses the use of surface enhancement Raman scattering (SERS)-based plasmonic gold nanoparticles, which can be used for cell specific labeling. In this example rituximab, a commercially available CD20 humanized monoclonal antibody is used. Dark field imaging, Raman spectroscopy and flow cytometry was utilized to demonstrate the sensitive labeling capability of these gold nanoparticle based hybrid nanodevices.

Cone photoreceptors transfer damaged mitochondria to Müller glia.

Mitochondria are vital organelles that require sophisticated homeostatic mechanisms for maintenance. Intercellular transfer of damaged mitochondria is a recently identified strategy broadly used to improve cellular health and viability. Here, we investigate mitochondrial homeostasis in the vertebrate cone photoreceptor, the specialized neuron that initiates our daytime and color vision. We find a generalizable response to mitochondrial stress that leads to loss of cristae, displacement of damaged mitochondria from their normal cellular location, initiation of degradation, and transfer to Müller glia cells, a key non-neuronal support cell in the retina. Our findings show transmitophagy from cones to Müller glia as a response to mitochondrial damage. Intercellular transfer of damaged mitochondria represents an outsourcing mechanism that photoreceptors use to support their specialized function.

Bias assessment of a test-negative design study of COVID-19 vaccine effectiveness used in national policymaking.

National test-negative-case-control (TNCC) studies are used to monitor COVID-19 vaccine effectiveness in the UK. A questionnaire was sent to participants from the first published TNCC COVID-19 vaccine effectiveness study conducted by the UK Health Security Agency, to assess for potential biases and changes in behaviour related to vaccination. The original study included symptomatic adults aged ≥70 years testing for COVID-19 between 08/12/2020 and 21/02/2021. A questionnaire was sent to cases and controls tested from 1-21 February 2021. In this study, 8648 individuals responded to the questionnaire (36.5% response). Using information from the questionnaire to produce a combined estimate that accounted for all potential biases decreased the original vaccine effectiveness estimate after two doses of BNT162b2 from 88% (95% CI: 79-94%) to 85% (95% CI: 68-94%). Self-reported behaviour demonstrated minimal evidence of riskier behaviour after vaccination. These findings offer reassurance to policy makers and clinicians making decisions based on COVID-19 vaccine effectiveness TNCC studies.

Disruption of myelin structure and oligodendrocyte maturation in a pigtail macaque model of congenital Zika infection.

Zika virus (ZikV) infection during pregnancy can cause congenital Zika syndrome (CZS) and neurodevelopmental delay in non-microcephalic infants, of which the pathogenesis remains poorly understood. We utilized an established pigtail macaque maternal-to-fetal ZikV infection/exposure model to study fetal brain pathophysiology of CZS manifesting from ZikV exposure in utero. We found prenatal ZikV exposure led to profound disruption of fetal myelin, with extensive downregulation in gene expression for key components of oligodendrocyte maturation and myelin production. Immunohistochemical analyses revealed marked decreases in myelin basic protein intensity and myelinated fiber density in ZikV-exposed animals. At the ultrastructural level, the myelin sheath in ZikV-exposed animals showed multi-focal decompaction consistent with perturbation or remodeling of previously formed myelin, occurring concomitant with dysregulation of oligodendrocyte gene expression and maturation. These findings define fetal neuropathological profiles of ZikV-linked brain injury underlying CZS resulting from ZikV exposure in utero. Because myelin is critical for cortical development, ZikV-related perturbations in oligodendrocyte function may have long-term consequences on childhood neurodevelopment, even in the absence of overt microcephaly.

Comparative effectiveness of two- and three-dose COVID-19 vaccination schedules involving AZD1222 and BNT162b2 in people with kidney disease: a linked OpenSAFELY and UK Renal Registry cohort study.

Background: Kidney disease is a key risk factor for COVID-19-related mortality and suboptimal vaccine response. Optimising vaccination strategies is essential to reduce the disease burden in this vulnerable population. We therefore compared the effectiveness of two- and three-dose schedules involving AZD1222 (AZ; ChAdOx1-S) and BNT162b2 (BNT) among people with kidney disease in England. Methods: With the approval of NHS England, we performed a retrospective cohort study among people with moderate-to-severe kidney disease. Using linked primary care and UK Renal Registry records in the OpenSAFELY-TPP platform, we identified adults with stage 3-5 chronic kidney disease, dialysis recipients, and kidney transplant recipients. We used Cox proportional hazards models to compare COVID-19-related outcomes and non-COVID-19 death after two-dose (AZ-AZ vs BNT-BNT) and three-dose (AZ-AZ-BNT vs BNT-BNT-BNT) schedules. Findings: After two doses, incidence during the Delta wave was higher in AZ-AZ (n = 257,580) than BNT-BNT recipients (n = 169,205; adjusted hazard ratios [95% CIs] 1.43 [1.37-1.50], 1.59 [1.43-1.77], 1.44 [1.12-1.85], and 1.09 [1.02-1.17] for SARS-CoV-2 infection, COVID-19-related hospitalisation, COVID-19-related death, and non-COVID-19 death, respectively). Findings were consistent across disease subgroups, including dialysis and transplant recipients. After three doses, there was little evidence of differences between AZ-AZ-BNT (n = 220,330) and BNT-BNT-BNT recipients (n = 157,065) for any outcome during a period of Omicron dominance. Interpretation: Among individuals with moderate-to-severe kidney disease, two doses of BNT conferred stronger protection than AZ against SARS-CoV-2 infection and severe disease. A subsequent BNT dose levelled the playing field, emphasising the value of heterologous RNA doses in vulnerable populations. Funding: National Core Studies, Wellcome Trust, MRC, and Health Data Research UK.