Infectious Diseases - Research Publications

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    Alignment of national COVID-19 vaccine recommendations for pregnant and lactating women
    Giles, ML ; Gunatilaka, A ; Palmer, K ; Sharma, K ; Roach, V ( 2021-10)
    The rapid development and roll-out of coronavirus disease 2019 (COVID-19) vaccines is providing hope for a way to control the pandemic. As pregnant and lactating women are generally excluded from clinical trials, the vaccination programme was launched without adequate safety and efficacy data for pregnant women. Yet many professional organizations have recognized the need for administration of COVID-19 vaccines in pregnancy and have issued their own set of recommendations. The lack of evidence, however, has often led to confused messaging, inconsistent language and differing recommendations across organizations, potentially contributing to delay or refusal to accept vaccination by pregnant women. We summarize those differences and recommend that leaders collaborate at a country level to produce joint recommendations. We use the example of Australia, where two professional authorities along with the government and partners in New Zealand worked towards one message, consistent language and a unified recommendation. The aim was to help health professionals and women who are planning pregnancy or who are currently pregnant or breastfeeding to make an informed decision about COVID-19 vaccination. National advisory groups for immunization, professional obstetric organizations and government bodies should be encouraged to coordinate their statements on COVID-19 vaccination for pregnant and lactating women and to use similar language and phrasing for greater clarity.
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    Integrated immune networks in SARS-CoV-2 infected pregnant women reveal differential NK cell and unconventional T cell activation
    Kedzierska, K ; Habel, J ; Chua, B ; Kedzierski, L ; Selva, K ; Damelang, T ; Haycroft, E ; Nguyen, T ; Koay, H-F ; Nicholson, S ; McQuilten, H ; Jia, X ; Allen, L ; Hensen, L ; Zhang, W ; de Sandt, CV ; Neil, J ; Amanat, F ; Krammer, F ; Wragg, K ; Juno, J ; Wheatley, A ; Tan, H-X ; Pell, G ; Audsley, J ; Thevarajan, I ; Denholm, J ; Subbarao, K ; Godfrey, D ; Cheng, A ; Tong, S ; Bond, K ; Williamson, D ; James, F ; Holmes, N ; Smibert, O ; Trubiona, J ; Gordon, C ; Chung, A ; Whitehead, C ; Kent, S ; Lappas, M ; Rowntree, L ( 2021)
    Although pregnancy poses a greater risk for severe COVID-19, the underlying immunological changes associated with SARS-CoV-2 infection during pregnancy are poorly understood. We defined immune responses to SARS-CoV-2 in pregnant and non-pregnant women during acute and convalescent COVID-19 up to 258 days post symptom onset, quantifying 217 immunological parameters. Additionally, matched maternal and cord blood were collected from COVID-19 convalescent pregnancies. Although serological responses to SARS-CoV-2 were similar in pregnant and non-pregnant women, cellular immune analyses revealed marked differences in key NK cell and unconventional T cell responses during COVID-19 in pregnant women. While NK, γδ T cells and MAIT cells displayed pre-activated phenotypes in healthy pregnant women when compared to non-pregnant age-matched women, activation profiles of these pre-activated NK and unconventional T cells remained unchanged at acute and convalescent COVID-19 in pregnancy. Conversely, activation dynamics of NK and unconventional T cells were prototypical in non-pregnant women in COVID-19. In contrast, activation of αβ CD4 + and CD8 + T cells, T follicular helper cells and antibody-secreting cells was similar in pregnant and non-pregnant women with COVID-19. Elevated levels of IL-1β, IFN-γ, IL-8, IL-18 and IL-33 were also found in pregnant women in their healthy state, and these cytokine levels remained elevated during acute and convalescent COVID-19. Collectively, our study provides the first comprehensive map of longitudinal immunological responses to SARS-CoV-2 infection in pregnant women, providing insights into patient management and education during COVID-19 pregnancy.
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    Reprogrammed CRISPR-Cas13b suppresses SARS-CoV-2 replication and circumvents its mutational escape through mismatch tolerance
    Fareh, M ; Zhao, W ; Hu, W ; Casan, JML ; Kumar, A ; Symons, J ; Voskoboinik, I ; Ekert, P ; Rudraraju, R ; Lewin, S ; Trapani, J ( 2020)

    ABSTRACT

    Mutation-driven evolution of SARS coronavirus-2 (SARS-CoV-2) highlights the need for innovative approaches that simultaneously suppress viral replication and circumvent viral escape routes from host immunity and antiviral therapeutics. Here, we employed genome-wide computational prediction and singlenucleotide resolution screening to reprogram CRISPR-Cas13b against SARS-CoV-2 genomic and subgenomic RNAs. Reprogrammed Cas13b effectors targeting accessible regions of Spike and Nucleocapsid transcripts achieved >98% silencing efficiency in virus free-models. Further, optimized and multiplexed gRNAs suppressed viral replication by up to 90% in mammalian cells infected with replication-competent SARS-CoV-2. Unexpectedly, the comprehensive mutagenesis of guide-target interaction demonstrated that single-nucleotide mismatches do not impair the capacity of a potent single gRNA to simultaneously suppress ancestral and mutated SARS-CoV-2 in infected mammalian cells, including the highly infectious and globally disseminated Spike D614G mutant. The specificity, efficiency and rapid deployment properties of reprogrammed Cas13b described here provide a molecular blueprint of antiviral therapeutics to simultaneously suppress a wide range of SARS-CoV-2 mutants, and is readily adaptable to other emerging pathogenic viruses.
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    Evaluation of serological tests for SARS-CoV-2: Implications for serology testing in a low-prevalence setting
    Bond, K ; Nicholson, S ; Ming Lim, S ; Karapanagiotidis, T ; Williams, E ; Johnson, D ; Hoang, T ; Sia, C ; Purcell, D ; R Lewin, S ; Catton, M ; P Howden, B ; A Williamson, D ( 2020)

    Background

    Robust serological assays are essential for long-term control of the COVID-19 pandemic. Many recently released point-of-care (PoCT) serological assays have been distributed with little pre-market validation.

    Methods

    Performance characteristics for five PoCT lateral flow devices approved for use in Australia were compared to a commercial enzyme immunoassay (ELISA) and a recently described novel surrogate virus neutralisation test (sVNT).

    Results

    Sensitivities for PoCT ranged from 51.8% (95% CI 43.1 to 60.4%) to 67.9% (95% CI 59.4–75.6%), and specificities from 95.6% (95% CI 89.2–98.8%) to 100.0% (95% CI 96.1–100.0%). Overall ELISA sensitivity for either IgA or IgG detection was 67.9% (95% CI 59.4–75.6), increasing to 93.8% (95% CI 85.0–98.3%) for samples > 14 days post symptom onset. Overall, sVNT sensitivity was 60.9% (95% CI 53.2–68.4%), rising to 91.2%% (95% CI 81.8–96.7%) for samples collected > 14 days post-symptom onset, with a specificity 94.4% (95% CI 89.2–97.5%),

    Conclusion

    Performance characteristics for COVID-19 serological assays were generally lower than those reported by manufacturers. Timing of specimen collection relative to onset of illness or infection is crucial in the reporting of performance characteristics for COVID-19 serological assays. The optimal algorithm for implementing serological testing for COVID-19 remains to be determined, particularly in low-prevalence settings.
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    Point-of-care testing and treatment of sexually transmitted infections to improve birth outcomes in high-burden, low-income settings: Study protocol for a cluster randomized crossover trial (the WANTAIM Trial, Papua New Guinea).
    Vallely, AJ ; Pomat, WS ; Homer, C ; Guy, R ; Luchters, S ; Mola, GDL ; Kariwiga, G ; Vallely, LM ; Wiseman, V ; Morgan, C ; Wand, H ; Rogerson, SJ ; Tabrizi, SN ; Whiley, DM ; Low, N ; Peeling, R ; Siba, P ; Riddell, M ; Laman, M ; Bolnga, J ; Robinson, LJ ; Morewaya, J ; Badman, SG ; Batura, N ; Kelly-Hanku, A ; Toliman, PJ ; Peter, W ; Babona, D ; Peach, E ; Garland, SM ; Kaldor, JM (F1000 Research Ltd, 2019)
    Background: Chlamydia trachomatis, Neisseria gonorrhoeae, Trichomonas vaginalis and bacterial vaginosis have been associated with preterm birth and low birth weight, and are highly prevalent among pregnant women in many low- and middle-income settings. There is conflicting evidence on the potential benefits of screening and treating these infections in pregnancy. Newly available diagnostic technologies make it possible, for the first time, to conduct definitive field trials to fill this knowledge gap. The primary aim of this study is to evaluate whether antenatal point-of-care testing and immediate treatment of these curable sexually transmitted and genital infections (STIs) leads to reduction in preterm birth and low birth weight. Methods: The Women and Newborn Trial of Antenatal Interventions and Management (WANTAIM) is a cluster-randomised crossover trial in Papua New Guinea to compare point-of-care STI testing and immediate treatment with standard antenatal care (which includes the WHO-endorsed STI 'syndromic' management strategy based on clinical features alone without laboratory confirmation). The unit of randomisation is a primary health care facility and its catchment communities. The primary outcome is a composite measure of two events: the proportion of women and their newborns in each trial arm, who experience either preterm birth (delivery <37 completed weeks of gestation as determined by ultrasound) and/or low birth weight (<2500 g measured within 72 hours of birth). The trial will also evaluate neonatal outcomes, as well as the cost-effectiveness, acceptability and health system requirements of this strategy, compared with standard care. Conclusions: WANTAIM is the first randomised trial to evaluate the effectiveness, cost-effectiveness, acceptability and health system requirements of point-of-care STI testing and treatment to improve birth outcomes in high-burden settings. If the intervention is proven to have an impact, the trial will hasten access to these technologies and could improve maternal and neonatal health in high-burden settings worldwide. Registration: ISRCTN37134032.
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    Point-of-care testing and treatment of sexually transmitted infections to improve birth outcomes in high-burden, low-income settings: Study protocol for a cluster randomized crossover trial (the WANTAIM Trial, Papua New Guinea)
    Vallely, A ; Pomat, W ; Homer, C ; Guy, R ; Luchters, S ; Mola, G ; Kariwiga, G ; Vallely, L ; Wiseman, V ; Morgan, C ; Wand, H ; Rogerson, S ; Tabrizi, S ; Whiley, D ; Low, N ; Peeling, R ; Siba, P ; Riddell, M ; Laman, M ; Bolnga, J ; Robinson, L ; Morewaya, J ; Badman, S ; Batura, N ; Kelly-Hanku, A ; Toliman, P ; Peter, W ; Babona, D ; Peach, E ; Garland, S ; Kaldor, J (F1000 Research Ltd, 2019-03-22)
    Background: Chlamydia trachomatis , Neisseria gonorrhoeae , Trichomonas vaginalis and bacterial vaginosis have been associated with preterm birth and low birth weight, and are highly prevalent among pregnant women in many low- and middle-income settings. There is conflicting evidence on the potential benefits of screening and treating these infections in pregnancy. Newly available diagnostic technologies make it possible, for the first time, to conduct definitive field trials to fill this knowledge gap. The primary aim of this study is to evaluate whether antenatal point-of-care testing and immediate treatment of these curable sexually transmitted and genital infections (STIs) leads to reduction in preterm birth and low birth weight. Methods : The Women and Newborn Trial of Antenatal Interventions and Management (WANTAIM) is a cluster-randomised crossover trial in Papua New Guinea to compare point-of-care STI testing and immediate treatment with standard antenatal care (which includes the WHO-endorsed STI ‘syndromic’ management strategy based on clinical features alone without laboratory confirmation). The unit of randomisation is a primary health care facility and its catchment communities. The primary outcome is a composite measure of two events: the proportion of women and their newborns in each trial arm, who experience either preterm birth (delivery <37 completed weeks of gestation as determined by ultrasound) and/or low birth weight (<2500 g measured within 72 hours of birth). The trial will also evaluate neonatal outcomes, as well as the cost-effectiveness, acceptability and health system requirements of this strategy, compared with standard care. Conclusions: WANTAIM is the first randomised trial to evaluate the effectiveness, cost-effectiveness, acceptability and health system requirements of point-of-care STI testing and treatment to improve birth outcomes in high-burden settings. If the intervention is proven to have an impact, the trial will hasten access to these technologies and could improve maternal and neonatal health in high-burden settings worldwide. Registration: ISRCTN37134032 .