Efficacy of typhoid conjugate vaccine: final analysis of a 4-year, phase 3, randomised controlled trial in Malawian children.

BACKGROUND: Randomised controlled trials of typhoid conjugate vaccines among children in Africa and Asia have shown high short-term efficacy. Data on the durability of protection beyond 2 years are sparse. We present the final analysis of a randomised controlled trial in Malawi, encompassing more than 4 years of follow-up, with the aim of investigating vaccine efficacy over time and by age group. METHODS: In this phase 3, double-blind, randomised controlled efficacy trial in Blantyre, Malawi, healthy children aged 9 months to 12 years were randomly assigned (1:1) by an unmasked statistician to receive a single dose of Vi polysaccharide conjugated to tetanus toxoid vaccine (Vi-TT) or meningococcal capsular group A conjugate (MenA) vaccine. Children had to have no previous history of typhoid vaccination and reside in the study areas for inclusion and were recruited from government schools and health centres. Participants, their parents or guardians, and the study team were masked to vaccine allocation. Nurses administering vaccines were unmasked. We did surveillance for febrile illness from vaccination until follow-up completion. The primary outcome was first occurrence of blood culture-confirmed typhoid fever. Eligible children who were randomly assigned and vaccinated were included in the intention-to-treat analyses. This trial is registered at ClinicalTrials.gov, NCT03299426. FINDINGS: Between Feb 21, 2018, and Sept 27, 2018, 28 130 children were vaccinated; 14 069 were assigned to receive Vi-TT and 14 061 to receive MenA. After a median follow-up of 4·3 years (IQR 4·2-4·5), 24 (39·7 cases per 100 000 person-years) children in the Vi-TT group and 110 (182·7 cases per 100 000 person-years) children in the MenA group were diagnosed with a first episode of blood culture-confirmed typhoid fever. In the intention-to-treat population, efficacy of Vi-TT was 78·3% (95% CI 66·3-86·1), and 163 (129-222) children needed to be vaccinated to prevent one case. Efficacies by age group were 70·6% (6·4-93·0) for children aged 9 months to 2 years; 79·6% (45·8-93·9) for children aged 2-4 years; and 79·3% (63·5-89·0) for children aged 5-12 years. INTERPRETATION: A single dose of Vi-TT is durably efficacious for at least 4 years among children aged 9 months to 12 years and shows efficacy in all age groups, including children younger than 2 years. These results support current WHO recommendations in typhoid-endemic areas for mass campaigns among children aged 9 months to 15 years, followed by routine introduction in the first 2 years of life. FUNDING: Bill & Melinda Gates Foundation.

Prevalence of sexually transmitted infection in pregnancy and their association with adverse birth outcomes: a case-control study at Queen Elizabeth Central Hospital, Blantyre, Malawi.

BACKGROUND: There are limited data on the epidemiology of sexually transmitted infections (STI) and their contribution to adverse birth outcomes (ABO) in sub-Saharan Africa (SSA). We performed a case-control study to assess the prevalence of STI and their association with ABO among women attending Queen Elizabeth Central Hospital, Blantyre, Malawi. METHODS: A composite case definition for ABO included stillborn, preterm and low birthweight infants and infants admitted to neonatal intensive care unit within 24 hours of birth. Following recruitment of an infant with an ABO, the next born healthy infant was recruited as a control. Multiplex PCR for Neisseria gonorrhoeae (NG), Chlamydia trachomatis (CT) and Trichomonas vaginalis (TV) was performed on maternal vaginal swabs. HIV and syphilis status was determined on maternal and infant serum. For syphilis, we used combined treponemal/non-treponemal rapid point-of-care tests in parallel with rapid plasma reagin tests, PCR for Treponema pallidum and clinical parameters to diagnose and stage the infection. We compared STI positivity between cases and controls. RESULTS: We included 259 cases and 251 controls. Maternal prevalence of STI was 3.1%, 2.7% and 17.1% for NG, CT and TV, respectively. Maternal prevalence of untreated syphilis was 2.0% and 6.1% for early stage and late/unknown stage, respectively; prevalence of treated syphilis was 2.7%. The HIV prevalence was 16.5%. HIV infection significantly increased the odds for ABO (OR=3.31; 95% CI 1.10 to 9.91) as did NG positivity (OR=4.30; 95% CI 1.16 to 15.99). We observed higher rates of ABO among women with untreated maternal syphilis (early: OR=7.13; 95% CI 0.87 to 58.39, late/unknown stage: OR=1.43; 95% CI 0.65 to 3.15). Maternal TV and CT infections were not associated with ABO. CONCLUSION: STI prevalence among pregnant women in Malawi is comparable to other SSA countries. HIV, NG and untreated syphilis prevalence was higher among women with ABO compared with women with healthy infants.

Quantifying health facility service readiness for small and sick newborn care: comparing standards-based and WHO level-2 + scoring for 64 hospitals implementing with NEST360 in Kenya, Malawi, Nigeria, and Tanzania.

BACKGROUND: Service readiness tools are important for assessing hospital capacity to provide quality small and sick newborn care (SSNC). Lack of summary scoring approaches for SSNC service readiness means we are unable to track national targets such as the Every Newborn Action Plan targets. METHODS: A health facility assessment (HFA) tool was co-designed by Newborn Essential Solutions and Technologies (NEST360) and UNICEF with four African governments. Data were collected in 68 NEST360-implementing neonatal units in Kenya, Malawi, Nigeria, and Tanzania (September 2019-March 2021). Two summary scoring approaches were developed: a) standards-based, including items for SSNC service readiness by health system building block (HSBB), and scored on availability and functionality, and b) level-2 + , scoring items on readiness to provide WHO level-2 + clinical interventions. For each scoring approach, scores were aggregated and summarised as a percentage and equally weighted to obtain an overall score by hospital, HSBB, and clinical intervention. RESULTS: Of 1508 HFA items, 1043 (69%) were included in standards-based and 309 (20%) in level-2 + scoring. Sixty-eight neonatal units across four countries had median standards-based scores of 51% [IQR 48-57%] at baseline, with variation by country: 62% [IQR 59-66%] in Kenya, 49% [IQR 46-51%] in Malawi, 50% [IQR 42-58%] in Nigeria, and 55% [IQR 53-62%] in Tanzania. The lowest scoring was family-centred care [27%, IQR 18-40%] with governance highest scoring [76%, IQR 71-82%]. For level-2 + scores, the overall median score was 41% [IQR 35-51%] with variation by country: 50% [IQR 44-53%] in Kenya, 41% [IQR 35-50%] in Malawi, 33% [IQR 27-37%] in Nigeria, and 41% [IQR 32-52%] in Tanzania. Readiness to provide antibiotics by culture report was the highest-scoring intervention [58%, IQR 50-75%] and neonatal encephalopathy management was the lowest-scoring [21%, IQR 8-42%]. In both methods, overall scores were low (< 50%) for 27 neonatal units in standards-based scoring and 48 neonatal units in level-2 + scoring. No neonatal unit achieved high scores of > 75%. DISCUSSION: Two scoring approaches reveal gaps in SSNC readiness with no neonatal units achieving high scores (> 75%). Government-led quality improvement teams can use these summary scores to identify areas for health systems change. Future analyses could determine which items are most directly linked with quality SSNC and newborn outcomes.

Factors Influencing the Implementation of Infant Warming Devices Among Healthcare Workers in Malawian Hospitals.

Objectives. Preterm infants are at risk of hypothermia. This study described the available infant warming devices (IWDs) and explored the barriers and facilitators to their implementation in neonates in Malawi. Methods. A qualitative descriptive study was conducted among 19 health care workers in Malawi from January to March 2020. All interviews were digitally recorded, transcribed, and managed using NVivo and analyzed using a thematic approach. Results. The warming devices included radiant warmers, Blantyre hot-cots, wall-mounted heaters, portable warmers, and incubators. Inadequate equipment and infrastructure and gaps in staff knowledge and capacity were reported as the main challenges to optimal IWD implementation. Caregiver acceptance was described as the main facilitator. Strategies to optimize implementation of IWD included continuous practical training and adequate availability of equipment and spare parts. Conclusion. Implementation of warming devices for the management of neonatal hypothermia is effective when there are adequate human and material resources.

Improving care pathways for children with severe illness through implementation of the ASPIRE mHealth primary ETAT package in Malawi.

Providing emergency care in low resource settings relies on delivery by lower cadres of health workers (LCHW). We describe the development, implementation and mixed methods evaluation of a mobile health (mHealth) triage algorithm based on the WHO Emergency, Triage, Assessment, and Treatment (ETAT) for primary-level care. We conducted an observational study design of implementation research. Key stakeholders were engaged throughout implementation. Clinicians and LCHW at eight primary health centres in Blantyre district were trained to use an mHealth algorithm for triage. An mHealth patient surveillance system monitored patients from presentation through referral to tertiary and final outcome. A total of 209,174 children were recorded by ETAT between April 2017 and September 2018, and 155,931 had both recorded mHealth and clinician triage outcome data. Concordance between mHealth triage by lower cadres of HCW and clinician assessment was 81·6% (95% CI [81·4, 81·8]) over all outcomes (kappa: 0·535 (95% CI [0·530, 0·539]). Concordance for mHealth emergency triage was 0.31 with kappa 0.42. The most common mHealth recorded emergency sign was breathing difficulty (74·1% 95% CI [70·1, 77·9]) and priority sign was raised temperature (76·2% (95% CI [75·9, 76·6]). A total of 1,644 referrals out of 3,004 (54·7%) successfully reached the tertiary site. Both providers and carers expressed high levels of satisfaction with the mHealth ETAT pathway. An mHealth triage algorithm can be used by LCHWs with moderate concordance with clinician triage. Implementation of ETAT through an mHealth algorithm documented successful referrals from primary to tertiary, but half of referred patients did not reach the tertiary site. Potential harms of such systems, such as cases requiring referral being missed during triage, require further evaluation. The ASPIRE mHealth primary ETAT approach can be used to prioritise acute illness and support future resource planning within both district and national health system.

Clinical and nutritional correlates of bacterial diarrhoea aetiology in young children: a secondary cross-sectional analysis of the ABCD trial.

OBJECTIVE: The objective was to assess the association between nutritional and clinical characteristics and quantitative PCR (qPCR)-diagnosis of bacterial diarrhoea in a multicentre cohort of children under 2 years of age with moderate to severe diarrhoea (MSD). DESIGN: A secondary cross-sectional analysis of baseline data collected from the AntiBiotics for Children with Diarrhoea trial (NCT03130114). PATIENTS: Children with MSD (defined as >3 loose stools within 24 hours and presenting with at least one of the following: some/severe dehydration, moderate acute malnutrition (MAM) or severe stunting) enrolled in the ABCD trial and collected stool sample. STUDY PERIOD: June 2017-July 2019. INTERVENTIONS: None. MAIN OUTCOME MEASURES: Likely bacterial aetiology of diarrhoea. Secondary outcomes included specific diarrhoea aetiology. RESULTS: A total of 6692 children with MSD had qPCR results available and 28% had likely bacterial diarrhoea aetiology. Compared with children with severe stunting, children with MAM (adjusted OR (aOR) (95% CI) 1.56 (1.18 to 2.08)), some/severe dehydration (aOR (95% CI) 1.66 (1.25 to 2.22)) or both (aOR (95% CI) 2.21 (1.61 to 3.06)), had higher odds of having likely bacterial diarrhoea aetiology. Similar trends were noted for stable toxin-enterotoxigenic Escherichia coli aetiology. Clinical correlates including fever and prolonged duration of diarrhoea were not associated with likely bacterial aetiology; children with more than six stools in the previous 24 hours had higher odds of likely bacterial diarrhoea (aOR (95% CI) 1.20 (1.05 to 1.36)) compared with those with fewer stools. CONCLUSION: The presence of MAM, dehydration or high stool frequency may be helpful in identifying children with MSD who might benefit from antibiotics.

The Enterics for Global Health (EFGH) Shigella Surveillance Study in Malawi.

Background: Malawi is among 7 countries participating in the Enterics for Global Health (EFGH) Shigella surveillance study, which aims to determine the incidence of medically attended diarrhea attributed to Shigella, a leading bacterial cause of diarrhea in children in low-resource settings. Methods: We describe the EFGH study site in the densely populated informal settlement of Ndirande Township, Blantyre, Malawi. We explore the site's geographical location, demographic characteristics, and the healthcare-seeking behavior of its population, particularly for childhood diarrhea. We also describe the management of childhood diarrhea at the health facility, and the associated challenges to attaining optimum adherence to local and national guidelines at the site. Conclusions: Our overarching aim is to improve global health through understanding and mitigating the impact of diarrhea attributed to Shigella.

Genomic insights into the 2022-2023Vibrio cholerae outbreak in Malawi.

Malawi experienced its deadliest Vibrio cholerae (Vc) outbreak following devastating cyclones, with >58,000 cases and >1700 deaths reported between March 2022 and May 2023. Here, we use population genomics to investigate the attributes and origin of the Malawi 2022-2023 Vc outbreak isolates. Our results demonstrate the predominance of ST69 clone, also known as the seventh cholera pandemic El Tor (7PET) lineage, expressing O1 Ogawa (~ 80%) serotype followed by Inaba (~ 16%) and sporadic non-O1/non-7PET serogroups (~ 4%). Phylogenetic reconstruction revealed that the Malawi outbreak strains correspond to a recent importation from Asia into Africa (sublineage AFR15). These isolates harboured known antimicrobial resistance and virulence elements, notably the ICEGEN/ICEVchHai1/ICEVchind5 SXT/R391-like integrative conjugative elements and a CTXφ prophage with the ctxB7 genotype compared to historical Malawian Vc isolates. These data suggest that the devastating cyclones coupled with the recent importation of 7PET serogroup O1 strains, may explain the magnitude of the 2022-2023 cholera outbreak in Malawi.