Publications

14

Jun, 2021

A conceptual approach to the rationale for SARS-CoV-2 vaccine allocation prioritisation

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Authors: MK. Vasconcelos, C. Marazia, M. Koniordou, H. Fangerau, I. Drexler & AAA. Awuah

Published in: Taylor and Francis Online

 

Currently vaccines protecting from COVID-19 are a scarce resource. Prioritising vaccination for certain groups of society is placed in a context of uncertainty due to changing evidence on the available vaccines and changing infection dynamics. To meet accepted ethical standards of procedural justice and individual autonomy, vaccine allocation strategies need to state reasons for prioritisation explicitly while at the same time communicating the expected risks and benefits of vaccination at different times and with different vaccines transparently.

In this article, we provide a concept summarising epidemiological considerations underlying current vaccine prioritisation strategies in an accessible way. We define six priority groups (vulnerable individuals, persons in close contact with the vulnerable, key workers with direct work-related contact with the public, key workers without direct work-related contact to the public, dependents of key workers and members of groups with high interpersonal contact rates) and state vaccine priorities for them. Additionally, prioritisation may follow non-epidemiological considerations including the aim to increase intra-societal justice and reducing inequality.

While national prioritisation plans integrate many of these concepts, the international community has so far failed to guarantee equitable or procedurally just access to vaccines across settings with different levels of wealth.

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11

Jun, 2021

Young infants exhibit robust functional antibody responses and restrained IFN-γ production to SARS-CoV-2

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Authors: A. Goenka, A. Halliday, M. Gregorova, E. Milodowski, A. Thomas, MK. Williamson, H. Baum, E. Oliver, AE. Long, L. Knezevic, AJK. Williams, V. Lampasona, L. Piemonti, K. Gupta, ND. Bartolo, I. Berger, AM. Toye, B. Vipond, P. Muir, J. Bernatoniene, M. Bailey, KM. Gillespie, AD. Davidson, L. Wooldridge, L. Rivino, A. Finn

Published in: Cell Reports Medicine

 

Summary: Severe COVID-19 appears rare in children. This is unexpected, especially in young infants, who are vulnerable to severe disease caused by other respiratory viruses. We evaluate convalescent immune responses in four infants under 3 months old with confirmed COVID-19 who presented with mild febrile illness, alongside their parents, and adult controls recovered from confirmed COVID-19. Although not statistically significant, compared to seropositive adults, infants have high serum levels of IgG and IgA to SARS-CoV-2 spike protein with corresponding functional ability to block SARS-CoV-2 cellular entry. Infants also exhibit robust saliva anti-spike IgG and IgA responses. Spike-specific IFN-γ production by infant peripheral blood mononuclear cells appears restrained, but the frequency of spike-specific IFN-γ and/or TNF-ɑ producing T cells is comparable between infants and adults. On principal component analysis, infant immune responses appear distinct from their parents. Robust functional antibody responses alongside restrained IFN-γ production may help protect infants from severe COVID-19.

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3

Jun, 2021

Brain MRI and neurocognitive characteristics of children with perinatal HIV infection in Russia: a retrospective cross-sectional study

 

Authors: MB. García,  L. Okhonskaya,  E. Voronin,  V. Rozenberg,  M. Titova,  T. Kovalenko,  A. Turkova,  IJ. Collins,  S. Crichton,  C. Velo Higueras,  MI. Gonzalez-Tomé,  JT. Ramos-Amador,  AMD. Aragón, on behalf of the REACH/EPPICC research groups

Published in: ESPID

 

Abstract

Method: Retrospective cross-sectional study,  Republican Children’s Infectious Diseases Hospital (Saint Petersburg, Sept. 2013- July 2015)

39 consecutive children in routine follow up underwent Weschler Intelligence Scale for Children (WISC-III) assessment

Linked to clinical data including immune and virological status

MRI assessment were independently reviewed by 2 radiologists

  • Presence and number of focal white matter (WM) lesions
  • Diffuse WM hyperintensities
  • Global or regional atrophy

WISC III profiles 
Assess intelligence in school-age children: 12 subtests, 3 indexes: Verbal IQ (VIQ), Performance IQ (PIQ) and Full Scale IQ (FSIQ).

Conclusion: 1. Almost half of children had evidence of neuroradiological abnormalities but most had IQ scores within the average range except for few subtests scores. 2. A trend towards older age at ART initiation among children with MRI abnormalities but not statistically significant and not adjusted for other confounders. 3. These assessments may help identify children in need of developmental support and ART optimisation.

 

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1

Jun, 2021

Association of Maternal SARS-CoV-2 Infection in Pregnancy With Neonatal Outcomes

 

Authors: M. Norman, L. Navér, J. Söderling, M. Ahlberg, HH. Askling, B. Aronsson, E. Byström, MSc; J. Jonsson, V. Sengpiel, JF. Ludvigsson, S. Håkansson, O. Stephansson

Published in: JAMA Network

 

Abstract

Importance  The outcomes of newborn infants of women testing positive for SARS-CoV-2 in pregnancy is unclear.

Objective  To evaluate neonatal outcomes in relation to maternal SARS-CoV-2 test positivity in pregnancy.

Design, Setting, and Participants  Nationwide, prospective cohort study based on linkage of the Swedish Pregnancy Register, the Neonatal Quality Register, and the Register for Communicable Diseases. Ninety-two percent of all live births in Sweden between March 11, 2020, and January 31, 2021, were investigated for neonatal outcomes by March 8, 2021. Infants with malformations were excluded. Infants of women who tested positive for SARS-CoV-2 were matched, directly and using propensity scores, on maternal characteristics with up to 4 comparator infants.

Exposures  Maternal test positivity for SARS-CoV-2 in pregnancy.

Main Outcomes and Measures  In-hospital mortality; neonatal resuscitation; admission for neonatal care; respiratory, circulatory, neurologic, infectious, gastrointestinal, metabolic, and hematologic disorders and their treatments; length of hospital stay; breastfeeding; and infant test positivity for SARS-CoV-2.

Results  Of 88 159 infants (49.0% girls), 2323 (1.6%) were delivered by mothers who tested positive for SARS-CoV-2. The mean gestational age of infants of SARS-CoV-2–positive mothers was 39.2 (SD, 2.2) weeks vs 39.6 (SD, 1.8) weeks for comparator infants, and the proportions of preterm infants (gestational age <37 weeks) were 205/2323 (8.8%) among infants of SARS-CoV-2–positive mothers and 4719/85 836 (5.5%) among comparator infants. After matching on maternal characteristics, maternal SARS-CoV-2 test positivity was significantly associated with admission for neonatal care (11.7% vs 8.4%; odds ratio [OR], 1.47; 95% CI, 1.26-1.70) and with neonatal morbidities such as respiratory distress syndrome (1.2% vs 0.5%; OR, 2.40; 95% CI, 1.50-3.84), any neonatal respiratory disorder (2.8% vs 2.0%; OR, 1.42; 95% CI, 1.07-1.90), and hyperbilirubinemia (3.6% vs 2.5%; OR, 1.47; 95% CI, 1.13-1.90). Mortality (0.30% vs 0.12%; OR, 2.55; 95% CI, 0.99-6.57), breastfeeding rates at discharge (94.4% vs 95.1%; OR, 0.84; 95% CI, 0.67-1.05), and length of stay in neonatal care (median, 6 days in both groups; difference, 0 days; 95% CI, −2 to 7 days) did not differ significantly between the groups. Twenty-one infants (0.90%) of SARS-CoV-2–positive mothers tested positive for SARS-CoV-2 in the neonatal period; 12 did not have neonatal morbidity, 9 had diagnoses with unclear relation to SARS-CoV-2, and none had congenital pneumonia.

Conclusions and Relevance  In a nationwide cohort of infants in Sweden, maternal SARS-CoV-2 infection in pregnancy was significantly associated with small increases in some neonatal morbidities. Given the small numbers of events for many of the outcomes and the large number of statistical comparisons, the findings should be interpreted as exploratory.

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1

Jun, 2021

Clinical characteristics of children and young people admitted to hospital with covid-19 in United Kingdom: prospective multicentre observational cohort study

 

Authors: OV. Swann, KA. Holden, L. Turtle, L. Pollock, CJ Fairfield, TM Drake, S. Seth, C. Egan, HE. Hardwick, S. Halpin, M. Girvan, C. Donohue, M. Pritchard, LB. Patel, S. Ladhani, L. Sigfrid, IP. Sinha, PL. Olliaro, JS. Nguyen-Van-Tam, PW. Horby, L. Merson, G. Carson, J. Dunning, PJM. Openshaw, JK. Baillie, EM. Harrison, AB. Docherty, MG. Semple, On behalf of ISARIC4C Investigators

Published in: The BMJ

 

Abstract Objective: To characterise the clinical features of children and young people admitted to hospital with laboratory confirmed severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the UK and explore factors associated with admission to critical care, mortality, and development of multisystem inflammatory syndrome in children and adolescents temporarily related to coronavirus disease 2019 (covid-19) (MIS-C).

Design: Prospective observational cohort study with rapid data gathering and near real time analysis.

Setting: 260 hospitals in England, Wales, and Scotland between 17 January and 3 July 2020, with a minimum follow-up time of two weeks (to 17 July 2020).

Participants: 651 children and young people aged less than 19 years admitted to 138 hospitals and enrolled into the International Severe Acute Respiratory and emergency Infections Consortium (ISARIC) WHO Clinical Characterisation Protocol UK study with laboratory confirmed SARS-CoV-2.

Main outcome measures: Admission to critical care (high dependency or intensive care), in-hospital mortality, or meeting the WHO preliminary case definition for MIS-C.

Results: Median age was 4.6 (interquartile range 0.3-13.7) years, 35% (225/651) were under 12 months old, and 56% (367/650) were male. 57% (330/576) were white, 12% (67/576) South Asian, and 10% (56/576) black. 42% (276/651) had at least one recorded comorbidity. A systemic mucocutaneousenteric cluster of symptoms was identified, which encompassed the symptoms for the WHO MIS-C criteria. 18% (116/632) of children were admitted to critical care. On multivariable analysis, this was associated with age under 1 month (odds ratio 3.21, 95% confidence interval 1.36 to 7.66; P=0.008), age 10-14 years (3.23, 1.55 to 6.99; P=0.002), and black ethnicity (2.82, 1.41 to 5.57; P=0.003). Six (1%) of 627 patients died in hospital, all of whom had profound comorbidity. 11% (52/456) met the WHO MIS-C criteria, with the first patient developing symptoms in mid-March. Children meeting MIS-C criteria were older (median age 10.7 (8.3-14.1) v 1.6 (0.2-12.9) years; P<0.001) and more likely to be of non-white ethnicity (64% (29/45) v 42% (148/355); P=0.004). Children with MIS-C were five times more likely to be admitted to critical care (73% (38/52) v 15% (62/404); P<0.001). In addition to the WHO criteria, children with MIS-C were more likely to present with fatigue (51% (24/47) v 28% (86/302); P=0.004), headache (34% (16/47) v 10% (26/263); P<0.001), myalgia (34% (15/44) v 8% (21/270); P<0.001), sore throat (30% (14/47) v (12% (34/284); P=0.003), and lymphadenopathy (20% (9/46) v 3% (10/318); P<0.001) and to have a platelet count of less than 150 × 109 /L (32% (16/50) v 11% (38/348); P<0.001) than children who did not have MIS-C. No deaths occurred in the MIS-C group.

Conclusions: Children and young people have less severe acute covid-19 than adults. A systemic mucocutaneousenteric symptom cluster was also identified in acute cases that shares features with MIS-C. This study provides additional evidence for refining the WHO MIS-C preliminary case definition. Children meeting the MIS-C criteria have different demographic and clinical features depending on whether they have acute SARS-CoV-2 infection (polymerase chain reaction positive) or are post-acute (antibody positive).

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30

Apr, 2021

Adequate Daclatasvir exposures in children 14-35 Kg with available adult formulations

 

Authors: Cressey RT, Abbassi M, Lallemant M, Indolfi G, Al-Nahari M, Farid S, Easterbrook P, Penazzato M,  El-Sayed HM

Published in: CROI 2021

 

Abstract: World Health Organization 2018 guidelines recommend Sofosbuvir (SOF)/Daclatasvir (DCV) as a pangenotypic regimen for the treatment of adults with chronic HCV infection. SOF/DAC is widely available as low-cost generic formulation in low and middle-income countries (LMICs). Recent studies in adolescents (?12 to <18) using SOF/DCV 400/60 mg once-daily (OD) adult dose reported excellent efficacy and safety. DCV pharmacokinetic (PK) data in younger children are lacking. Within the framework of the Global Accelerator for Pediatric Formulations (GAPf), we performed a population PK analysis using data from adolescents to predict DCV exposure in children <35 kg to determine the lowest body weight children could be treated with the available DCV formulations (60 and 30 mg).

Data from HCV-infected adolescents receiving SOF/DCV (400/60 mg, OD) who participated in a PK study in Egypt were used for PK model development. Intensive PK sampling was performed pre-dose, then 0.5, 1.0, 1.5, 2, 4, 8, 12, and 24 hrs post-dose. PK parameters were estimated using a population approach (NONMEM VII). Monte Carlo simulations were run for virtual children between 10 to <35 kg receiving 60 mg or 30 mg OD and DCV exposures (AUC0-24) were compared with the expected adults range (6.15 to 20.63 µg.hr/mL).

Seventeen HCV-infected adolescents (13 males) provided 151 DCV concentrations. Median (range) age was 14 (11-18) years and weight 50 (32-63) kg. DCV plasma concentrations were best described by a 1-compartment model with transit absorption compartments. Body weight (allometrically scaled) and albumin influenced DCV PK parameters. DCV oral clearance and volume of distribution were 7.05 L/hr/70kg and 95.8 L/70kg. In adolescents using 60 mg DCV OD, mean (SD) DCV AUC0-24, Cmax, and Clast were 12,004 (4,916) ng.hr/mL, 1,182 (393) ng/mL and 194 (168) ng/mL, respectively; while predicted to be 9,808 (3,949) ng.hr/mL, 1,039 (316) ng/mL and 148 (129) ng/mL in children 17 to <35 kg receiving 30 mg OD. Simulations showed that the proportion of children with DCV exposures above expected range rapidly increased for children <30 kg using 60 mg OD; and similarly for children 10-14 kg using 30 mg (Fig 1).

DCV 30 mg OD is expected to provide exposures comparable to adult values in children 14-35 kg. Our results suggest that children could be treated using currently available low-cost DCV formulations together with approved doses of pediatric SOF formulations, thus expanding access to HCV treatment.

 

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27

Apr, 2021

COVID-19 herd immunity by immunisation: are children in the herd?

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Authors: S. Obaro

Published in: The Lancet

 

Introduction: The scourge of COVID-19 has been global, but the most affected subgroups in the population have largely been older people and individuals with comorbid conditions that predispose them to increasingly severe disease and poor outcomes. Overall, the disease burden in children has been reasonably mild, even in those with comorbidities, such as oncological conditions. Protection from severe disease in children might be related to a lower expression of host factors required for viral replication, and to differences in the magnitude and timing of innate or adaptive immune responses. Data for recorded COVID-19 cases show that only 7% of children younger than 18 years with severe disease required intensive care, whereas 53% of adults who had severe disease required intensive care.1–3 Multisystem inflammatory syndrome in children, arguably the most dreaded presentation, typically presents between 3 and 6 weeks after SARS-CoV-2 exposure.4 Most patients at presentation have a negative nasopharyngeal RT-PCR but are positive for serology.

 

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29

Mar, 2021

COVID-19 vaccine response in pregnant and lactating women: a cohort study

 

Authors: Kathryn J. Gray, MD PhD, Evan A. Bordt, PhD, Caroline Atyeo, BS, Elizabeth Deriso, PhD, Babatunde Akinwunmi, MD MPH MMSc, Nicola Young, BA, Aranxta Medina Baez, BS, Lydia L. Shook, MD, Dana Cvrk, CNM, Kaitlyn James, PhD, MPH, Rose De Guzman, PhD, Sara Brigida, BA, Khady Diouf, MD, Ilona Goldfarb, MD MPH, Lisa M. Bebell, MD, Lael M. Yonker, MD, Alessio Fasano, MD, S. Alireza Rabi, MD, Michal A. Elovitz, MD, Galit Alter, PhD, Andrea G. Edlow, MD, MSc

Published in: American journal of obstetrics and gynecology

 

Abstract

Background: Pregnant and lactating women were excluded from initial COVID-19 vaccine trials; thus, data to guide vaccine decision-making are lacking.

Objectives: To evaluate the immunogenicity and reactogenicity of COVID-19 mRNA vaccination in pregnant and lactating women compared to: (1) non-pregnant controls and (2) natural COVID-19 infection in pregnancy.

Study Design: 131 reproductive-age vaccine recipients (84 pregnant, 31 lactating, and 16 non-pregnant) were enrolled in a prospective cohort study at two academic medical centers. Titers of SARS-CoV-2 Spike and RBD IgG, IgA and IgM were quantified in participant sera (N=131) and breastmilk (N=31) at baseline, second vaccine dose, 2-6 weeks post second vaccine, and at delivery by Luminex. Umbilical cord sera (N=10) titers were assessed at delivery. Titers were compared to those of pregnant women 4-12 weeks from natural infection (N=37) by ELISA. A pseudovirus neutralization assay was used to quantify neutralizing antibody titers for the subset of women who delivered during the study period. Post-vaccination symptoms were assessed via questionnaire. Kruskal-Wallis tests and a mixed effects model, with correction for multiple comparisons, were used to assess differences between groups.

Results: Vaccine-induced antibody titers were equivalent in pregnant and lactating compared to non-pregnant women (median [IQR] 5.59 [4.68-5.89] pregnant, 5.74 [5.06-6.22] lactating, 5.62 [4.77-5.98] non-pregnant, p = 0.24). All titers were significantly higher than those induced by SARS-CoV-2 infection during pregnancy (p < 0.0001). Vaccine-generated antibodies were present in all umbilical cord blood and breastmilk samples. Neutralizing antibody titers were lower in umbilical cord compared to maternal sera, although this finding did not achieve statistical significance (median [IQR] 104.7 [61.2-188.2] maternal sera, 52.3 [11.7-69.6] cord sera, p=0.05). The second vaccine dose (boost dose) increased SARS-CoV-2-specific IgG, but not IgA, in maternal blood and breastmilk. No differences were noted in reactogenicity across the groups.

Conclusions: COVID-19 mRNA vaccines generated robust humoral immunity in pregnant and lactating women, with immunogenicity and reactogenicity similar to that observed in non-pregnant women. Vaccine-induced immune responses were significantly greater than the response to natural infection. Immune transfer to neonates occurred via placenta and breastmilk.

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24

Mar, 2021

SARS-CoV-2 infection and transmission in primary schools in England in June–December, 2020 (sKIDs): an active, prospective surveillance study

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Authors: Shamez N Ladhani, Frances Baawuah, Joanne Beckmann, Ifeanichukwu O Okike, Shazaad Ahmad, Joanna Garstang, Andrew J Brent, Bernadette Brent, Jemma Walker, Nick Andrews, Georgina Ireland, Felicity Aiano, Zahin Amin-Chowdhury, Louise Letley, Jessica Flood, Samuel E I Jones, Ray Borrow, Ezra Linley, Maria Zambon, John Poh, Vanessa Saliba, Gayatri Amirthalingam, Jamie Lopez Bernal, Kevin E Brown, Mary E Ramsay

Published in: The Lancet

 

Summary Background: Little is known about the risk of SARS-CoV-2 infection and transmission in educational settings. Public Health England initiated a study, COVID-19 Surveillance in School KIDs (sKIDs), in primary schools when they partially reopened from June 1, 2020, after the first national lockdown in England to estimate the incidence of symptomatic and asymptomatic SARS-CoV-2 infection, seroprevalence, and seroconversion in staff and students.

Methods: sKIDs, an active, prospective, surveillance study, included two groups: the weekly swabbing group and the blood sampling group. The swabbing group underwent weekly nasal swabs for at least 4 weeks after partial school reopening during the summer half-term (June to mid-July, 2020). The blood sampling group additionally underwent blood sampling for serum SARS-CoV-2 antibodies to measure previous infection at the beginning (June 1–19, 2020) and end (July 3–23, 2020) of the summer half-term, and, after full reopening in September, 2020, and at the end of the autumn term (Nov 23–Dec 18, 2020). We tested for predictors of SARS-CoV-2 antibody positivity using logistic regression. We calculated antibody seroconversion rates for participants who were seronegative in the first round and were tested in at least two rounds.

Findings: During the summer half-term, 11 966 participants (6727 students, 4628 staff, and 611 with unknown staff or student status) in 131 schools had 40 501 swabs taken. Weekly SARS-CoV-2 infection rates were 4·1 (one of 24463; 95% CI 0·1–21·8) per 100000 students and 12·5 (two of 16 038; 1·5–45·0) per 100000 staff. At recruitment, in 45 schools, 91 (11·2%; 95% CI 7·9–15·1) of 816 students and 209 (15·1%; 11·9–18·9) of 1381 staff members were positive for SARS-CoV-2 antibodies, similar to local community seroprevalence. Seropositivity was not associated with school attendance during lockdown (p=0·13 for students and p=0·20 for staff) or staff contact with students (p=0·37). At the end of the summer half-term, 603 (73·9%) of 816 students and 1015 (73·5%) of 1381 staff members were still participating in the surveillance, and five (four students, one staff member) seroconverted. By December, 2020, 55 (5·1%; 95% CI 3·8–6·5) of 1085 participants who were seronegative at recruitment (in June, 2020) had seroconverted, including 19 (5·6%; 3·4–8·6) of 340 students and 36 (4·8%; 3·4–6·6) of 745 staff members (p=0·60).

Interpretation: In England, SARS-CoV-2 infection rates were low in primary schools following their partial and full reopening in June and September, 2020.

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24

Mar, 2021

Testing for SARS-CoV-2 infection: a key strategy to keeping schools and universities open

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Authors: Archana Koirala, Nicholas Wood, Kristine Macartney

Published in: The Lancet

 

Introduction: Education has been profoundly affected by the COVID-19 pandemic. Lack of access to education has exacerbated the divide between rich and poor and left vulnerable children exposed to domestic violence and hunger. The best way of keeping educational institutions open for in-person learning is to control transmission of SARS-CoV-2 in the wider community1 and to ensure rapid identification of infected staff and students to support timely and tailored public health responses. A comprehensive testing strategy is a core tenet in control, especially as a majority (40–60%) of children and young people have asymptomatic COVID-19,2 and individuals who are pre-symptomatic also present a transmission risk. Mitigation measures such as physical distancing, use of masks, and ensuring adequate ventilation within classrooms are also key, especially when community based transmission exists.

SARS-CoV-2 infection can be diagnosed by two methods: direct testing for the viral RNA with highly sensitive SARS-CoV-2 RT-PCR tests or viral antigen detection tests, which identify active (or resolving) infection on a nasal, oropharyngeal, or salivary sample and allow early case identification to contain outbreaks. Testing for antibodies against the virus diagnose previous or recent infection (with onset of 10 or more days previously). The delayed nature of virus-specific antibody testing precludes it as tool for rapid outbreak suppression; rather, its predominant public health utility is to understand infection and transmission rates and patterns in a community or clusters.

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