Effectiveness of Monovalent Rotavirus Vaccine in Mozambique, a Country with a High Burden of Chronic Malnutrition

Funding Information: Funding: This research was funded by GAVI through the Centers for Disease Control and Prevention (CDC), Atlanta and World Health Organization, Regional Office for Africa (WHO/AFRO). African Research in Neglected Tropical Diseases (EFINTD, grant number 89539); Deutsche Forschungsge-meinschaft (DFG; grant number JO369/5-1); Fundo Nacional de Investigação (FNI); United States Agency for International Development (USAID; grant number AID-656-F-16-00002); the Calouste Gulbenkian Foundation from where A.C., F.M., and J.S. have a PhD fellowship. Publisher Copyright: © 2022 by the authors. Licensee MDPI, Basel, Switzerland.Mozambique introduced monovalent rotavirus vaccine (Rotarix® ) in September 2015. We evaluated the effectiveness of Rotarix® under conditions of routine use in Mozambican children hospitalized with acute gastroenteritis (AGE). A test negative case-control analysis was performed on data collected during 2017–2019 from children <5 years old, admitted with AGE in seven sentinel hospital sites in Mozambique. Adjusted VE was calculated for ≥1 dose of vaccine vs. zero doses using unconditional logistic regression, where VE = (1 − aOR) × 100%. VE estimates were stratified by age group, AGE severity, malnutrition, and genotype. Among 689 children eligible for analysis, 23.7% were rotavirus positive (cases) and 76.3% were negative (controls). The adjusted VE of ≥1 dose in children aged 6–11 months was 52.0% (95% CI, −11, 79), and −24.0% (95% CI, −459, 62) among children aged 12–23 months. Estimated VE was lower in stunted than non-stunted children (14% (95% CI, −138, 66) vs. 59% (95% CI, −125, 91)). Rotavirus vaccination appeared moderately effective against rotavirus gastroenteritis hospitalization in young Mozambican children. VE point estimates were lower in older and stunted children, although confidence intervals were wide and overlapped across strata. These findings provide additional evidence for other high-mortality countries considering rotavirus vaccine introduction.publishersversionpublishe

Pediatric Bacterial Meningitis Surveillance in the World Health Organization African Region Using the Invasive Bacterial Vaccine-Preventable Disease Surveillance Network, 2011-2016.

BACKGROUND: Bacterial meningitis is a major cause of morbidity and mortality in sub-Saharan Africa. We analyzed data from the World Health Organization's (WHO) Invasive Bacterial Vaccine-preventable Diseases Surveillance Network (2011-2016) to describe the epidemiology of laboratory-confirmed Streptococcus pneumoniae (Spn), Neisseria meningitidis, and Haemophilus influenzae meningitis within the WHO African Region. We also evaluated declines in vaccine-type pneumococcal meningitis following pneumococcal conjugate vaccine (PCV) introduction. METHODS: Reports of meningitis in children <5 years old from sentinel surveillance hospitals in 26 countries were classified as suspected, probable, or confirmed. Confirmed meningitis cases were analyzed by age group and subregion (South-East and West-Central). We described case fatality ratios (CFRs), pathogen distribution, and annual changes in serotype and serogroup, including changes in vaccine-type Spn meningitis following PCV introduction. RESULTS: Among 49 844 reported meningitis cases, 1670 (3.3%) were laboratory-confirmed. Spn (1007/1670 [60.3%]) was the most commonly detected pathogen; vaccine-type Spn meningitis cases declined over time. CFR was the highest for Spn meningitis: 12.9% (46/357) in the South-East subregion and 30.9% (89/288) in the West-Central subregion. Meningitis caused by N. meningitidis was more common in West-Central than South-East Africa (321/954 [33.6%] vs 110/716 [15.4%]; P < .0001). Haemophilus influenzae (232/1670 [13.9%]) was the least prevalent organism. CONCLUSIONS: Spn was the most common cause of pediatric bacterial meningitis in the African region even after reported cases declined following PCV introduction. Sustaining robust surveillance is essential to monitor changes in pathogen distribution and to inform and guide vaccination policies

Risk factors for mortality among children under 5 years of age with severe diarrhea in low- and middle-income countries: Findings from the WHO-coordinated Global Rotavirus and Pediatric Diarrhea Surveillance Networks.

BACKGROUND: Diarrhea is the second leading cause of death in children under five years of age globally. The burden of diarrheal mortality is concentrated in low-resource settings. Little is known about the risk factors for childhood death from diarrheal disease in low and middle-income countries. METHODS: Data from the WHO-coordinated Global Rotavirus and Pediatric Diarrhea Surveillance Networks, which are composed of active, sentinel, hospital-based surveillance sites, were analyzed to assess mortality in children less than five years of age who were hospitalized with diarrhea between 2008-2018. Case fatality risks were calculated, and multivariable logistic regression was performed to identify risk factors for mortality. RESULTS: This analysis is comprised of 234,781 cases, including 1,219 deaths, across 57 countries. The overall case fatality risk was found to be 0.5%. Risk factors for death in the multivariable analysis included younger age (for <6 months compared with older ages, OR = 3.54; 95% CI = 2.81-4.50), female sex (OR = 1.18; 95% CI= 1.06-1.81), presenting with persistent diarrhea (OR = 1.91; 95% CI= 1.01-3.25), no vomiting (OR = 1.13, 95% CI= 0.98-1.30), severe dehydration (OR = 3.79; 95% CI = 3.01-4.83), and being negative for rotavirus on an ELISA test (OR = 2.29; 95% CI= 1.92-2.74). Cases from the African Region had the highest odds of death compared with other WHO Regions (OR = 130.62 comparing the African Region to the European region; 95% CI= 55.72-422.73), while cases from the European region had the lowest odds of death. CONCLUSIONS: Our findings support known risk factors for childhood diarrheal mortality and highlight the need for interventions to address dehydration and rotavirus-negative diarrheal infections

Genomic characterization of the rotavirus G3P[8] strain in vaccinated children, reveals possible reassortment events between human and animal strains in Manhiça District, Mozambique

Mozambique introduced the rotavirus vaccine (Rotarix®; GlaxoSmithKline Biologicals, Rixensart, Belgium) in 2015, and since then, the Centro de Investigação em Saúde de Manhiça has been monitoring its impact on rotavirus-associated diarrhea and the trend of circulating strains, where G3P[8] was reported as the predominant strain after the vaccine introduction. Genotype G3 is among the most commonly detected Rotavirus strains in humans and animals, and herein, we report on the whole genome constellation of G3P[8] detected in two children (aged 18 months old) hospitalized with moderate-to-severe diarrhea at the Manhiça District Hospital. The two strains had a typical Wa-like genome constellation (I1-R1-C1-M1-A1-N1-T1-E1-H1) and shared 100% nucleotide (nt) and amino acid (aa) identities in 10 gene segments, except for VP6. Phylogenetic analysis demonstrated that genome segments encoding VP7, VP6, VP1, NSP3, and NSP4 of the two strains clustered most closely with porcine, bovine, and equine strains with identities ranging from 86.9–99.9% nt and 97.2–100% aa. Moreover, they consistently formed distinct clusters with some G1P[8], G3P[8], G9P[8], G12P[6], and G12P[8] strains circulating from 2012 to 2019 in Africa (Mozambique, Kenya, Rwanda, and Malawi) and Asia (Japan, China, and India) in genome segments encoding six proteins (VP2, VP3, NSP1-NSP2, NSP5/6). The identification of segments exhibiting the closest relationships with animal strains shows significant diversity of rotavirus and suggests the possible occurrence of reassortment events between human and animal strains. This demonstrates the importance of applying next-generation sequencing to monitor and understand the evolutionary changes of strains and evaluate the impact of vaccines on strain diversity

Evaluation of Intussusception after Monovalent Rotavirus Vaccination in Africa.

Postlicensure evaluations have identified an association between rotavirus vaccination and intussusception in several high- and middle-income countries. We assessed the association between monovalent human rotavirus vaccine and intussusception in lower-income sub-Saharan African countries.Using active surveillance, we enrolled patients from seven countries (Ethiopia, Ghana, Kenya, Malawi, Tanzania, Zambia, and Zimbabwe) who had intussusception that met international (Brighton Collaboration level 1) criteria. Rotavirus vaccination status was confirmed by review of the vaccine card or clinic records. The risk of intussusception within 1 to 7 days and 8 to 21 days after vaccination among infants 28 to 245 days of age was assessed by means of the self-controlled case-series method.Data on 717 infants who had intussusception and confirmed vaccination status were analyzed. One case occurred in the 1 to 7 days after dose 1, and 6 cases occurred in the 8 to 21 days after dose 1. Five cases and 16 cases occurred in the 1 to 7 days and 8 to 21 days, respectively, after dose 2. The risk of intussusception in the 1 to 7 days after dose 1 was not higher than the background risk of intussusception (relative incidence [i.e., the incidence during the risk window vs. all other times], 0.25; 95% confidence interval [CI], <0.001 to 1.16); findings were similar for the 1 to 7 days after dose 2 (relative incidence, 0.76; 95% CI, 0.16 to 1.87). In addition, the risk of intussusception in the 8 to 21 days or 1 to 21 days after either dose was not found to be higher than the background risk.The risk of intussusception after administration of monovalent human rotavirus vaccine was not higher than the background risk of intussusception in seven lower-income sub-Saharan African countries. (Funded by the GAVI Alliance through the CDC Foundation.)

The Global Landscape of Pediatric Bacterial Meningitis Data Reported to the World Health Organization-Coordinated Invasive Bacterial Vaccine-Preventable Disease Surveillance Network, 2014-2019.

BACKGROUND: The World Health Organization (WHO) coordinates the Global Invasive Bacterial Vaccine-Preventable Diseases (IB-VPD) Surveillance Network to support vaccine introduction decisions and use. The network was established to strengthen surveillance and laboratory confirmation of meningitis caused by Streptococcus pneumoniae, Haemophilus influenzae, and Neisseria meningitidis. METHODS: Sentinel hospitals report cases of children 137 000 suspected meningitis cases were reported by 58 participating countries, with 44.6% (n = 61 386) reported from countries in the WHO African Region. More than half (56.6%, n = 77 873) were among children <1 year of age, and 4.0% (n = 4010) died among those with reported disease outcome. Among suspected meningitis cases, 8.6% (n = 11 798) were classified as probable bacterial meningitis. One of 3 bacterial pathogens was identified in 30.3% (n = 3576) of these cases, namely S. pneumoniae (n = 2177 [60.9%]), H. influenzae (n = 633 [17.7%]), and N. meningitidis (n = 766 [21.4%]). Among confirmed bacterial meningitis cases with outcome reported, 11.0% died; case fatality ratio varied by pathogen (S. pneumoniae, 12.2%; H. influenzae, 6.1%; N. meningitidis, 11.0%). Among the 277 children who died with confirmed bacterial meningitis, 189 (68.2%) had confirmed S. pneumoniae. The proportion of pneumococcal cases with pneumococcal conjugate vaccine (PCV) serotypes decreased as the number of countries implementing PCV increased, from 77.8% (n = 273) to 47.5% (n = 248). Of 397 H. influenzae specimens serotyped, 49.1% (n = 195) were type b. Predominant N. meningitidis serogroups varied by region. CONCLUSIONS: This multitier, global surveillance network has supported countries in detecting and serotyping the 3 principal invasive bacterial pathogens that cause pediatric meningitis. Streptococcus pneumoniae was the most common bacterial pathogen detected globally despite the growing number of countries that have nationally introduced PCV. The large proportions of deaths due to S. pneumoniae reflect the high proportion of meningitis cases caused by this pathogen. This global network demonstrated a strong correlation between PCV introduction status and reduction in the proportion of pneumococcal meningitis infections caused by vaccine serotypes. Maintaining case-based, active surveillance with laboratory confirmation for prioritized vaccine-preventable diseases remains a critical component of the global agenda in public health.The World Health Organization (WHO)-coordinated Invasive Bacterial Vaccine-Preventable Disease (IB-VPD) Surveillance Network reported data from 2014 to 2019, contributing to the estimates of the disease burden and serotypes of pediatric meningitis caused by Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis

Aetiology and incidence of diarrhoea requiring hospitalisation in children under 5 years of age in 28 low-income and middle-income countries: findings from the Global Pediatric Diarrhea Surveillance network.

Introduction: Diarrhoea remains a leading cause of child morbidity and mortality. Systematically collected and analysed data on the aetiology of hospitalised diarrhoea in low-income and middle-income countries are needed to prioritise interventions. Methods: We established the Global Pediatric Diarrhea Surveillance network, in which children under 5 years hospitalised with diarrhoea were enrolled at 33 sentinel surveillance hospitals in 28 low-income and middle-income countries. Randomly selected stool specimens were tested by quantitative PCR for 16 causes of diarrhoea. We estimated pathogen-specific attributable burdens of diarrhoeal hospitalisations and deaths. We incorporated country-level incidence to estimate the number of pathogen-specific deaths on a global scale. Results: During 2017–2018, 29 502 diarrhoea hospitalisations were enrolled, of which 5465 were randomly selected and tested. Rotavirus was the leading cause of diarrhoea requiring hospitalisation (attributable fraction (AF) 33.3%; 95% CI 27.7 to 40.3), followed by Shigella (9.7%; 95% CI 7.7 to 11.6), norovirus (6.5%; 95% CI 5.4 to 7.6) and adenovirus 40/41 (5.5%; 95% CI 4.4 to 6.7). Rotavirus was the leading cause of hospitalised diarrhoea in all regions except the Americas, where the leading aetiologies were Shigella (19.2%; 95% CI 11.4 to 28.1) and norovirus (22.2%; 95% CI 17.5 to 27.9) in Central and South America, respectively. The proportion of hospitalisations attributable to rotavirus was approximately 50% lower in sites that had introduced rotavirus vaccine (AF 20.8%; 95% CI 18.0 to 24.1) compared with sites that had not (42.1%; 95% CI 33.2 to 53.4). Globally, we estimated 208 009 annual rotavirus-attributable deaths (95% CI 169 561 to 259 216), 62 853 Shigella-attributable deaths (95% CI 48 656 to 78 805), 36 922 adenovirus 40/41-attributable deaths (95% CI 28 469 to 46 672) and 35 914 norovirus-attributable deaths (95% CI 27 258 to 46 516). Conclusions: Despite the substantial impact of rotavirus vaccine introduction, rotavirus remained the leading cause of paediatric diarrhoea hospitalisations. Improving the efficacy and coverage of rotavirus vaccination and prioritising interventions against Shigella, norovirus and adenovirus could further reduce diarrhoea morbidity and mortality

Genomic characterization of the rotavirus G3P[8] strain in vaccinated children, reveals possible reassortment events between human and animal strains in Manhiça District, Mozambique

870–15 SC; the United States Agency for International Development (USAID), grant number AID-656-F-16-00002 and Fundo Nacional de Investigação (FNI), Moçambique, grant number 245-INV, funded the surveillance of rotavirus and other enteropathogens in children less than 5 years of age in Manhiça, in the context of the implementation of the diarrhoeal disease surveillance platform. The Child Health and Mortality Prevention program (Surveillance), CHAMPS funded by the Bill & Melinda Gates Foundation under Grant OPP1126780, the Instituto de Higiene e Medicina Tropical (IHMT), Universidade Nova de Lisboa, Portugal, the Next Generation Sequencing Unit, and the Division of Virology, Faculty of Health Sciences, University of the Free State, South Africa, supported the whole genome analysis costs. The Calouste Gulbenkian Foundation finances Filomena Manjate’s Ph.D. studies under grant number 234066. CISM receives core funding from the Mozambican government and the “Agencia Española de Cooperacion Internacional para el Desarollo (AECID).” Publisher Copyright: Copyright © 2023 Manjate, João, Mwangi, Chirinda, Mogotsi, Messa, Garrine, Vubil, Nobela, Nhampossa, Acácio, Tate, Parashar, Weldegebriel, Mwenda, Alonso, Cunha, Nyaga and Mandomando.Mozambique introduced the rotavirus vaccine (Rotarix®; GlaxoSmithKline Biologicals, Rixensart, Belgium) in 2015, and since then, the Centro de Investigação em Saúde de Manhiça has been monitoring its impact on rotavirus-associated diarrhea and the trend of circulating strains, where G3P[8] was reported as the predominant strain after the vaccine introduction. Genotype G3 is among the most commonly detected Rotavirus strains in humans and animals, and herein, we report on the whole genome constellation of G3P[8] detected in two children (aged 18 months old) hospitalized with moderate-to-severe diarrhea at the Manhiça District Hospital. The two strains had a typical Wa-like genome constellation (I1-R1-C1-M1-A1-N1-T1-E1-H1) and shared 100% nucleotide (nt) and amino acid (aa) identities in 10 gene segments, except for VP6. Phylogenetic analysis demonstrated that genome segments encoding VP7, VP6, VP1, NSP3, and NSP4 of the two strains clustered most closely with porcine, bovine, and equine strains with identities ranging from 86.9–99.9% nt and 97.2–100% aa. Moreover, they consistently formed distinct clusters with some G1P[8], G3P[8], G9P[8], G12P[6], and G12P[8] strains circulating from 2012 to 2019 in Africa (Mozambique, Kenya, Rwanda, and Malawi) and Asia (Japan, China, and India) in genome segments encoding six proteins (VP2, VP3, NSP1-NSP2, NSP5/6). The identification of segments exhibiting the closest relationships with animal strains shows significant diversity of rotavirus and suggests the possible occurrence of reassortment events between human and animal strains. This demonstrates the importance of applying next-generation sequencing to monitor and understand the evolutionary changes of strains and evaluate the impact of vaccines on strain diversity.publishersversionpublishe

Evaluation of Laboratories Supporting Invasive Bacterial Vaccine-Preventable Disease (IB-VPD) Surveillance in the World Health Organization African Region, through the Performance of Coordinated External Quality Assessment

(1) Background: Laboratories supporting the invasive bacteria preventable disease (IB-VPD) network are expected to demonstrate the capacity to identify the main etiological agents of pediatric bacterial meningitis (PBM) (Neisseria meningitidis, Streptococcus pneumoniae and Haemophilus influenzae) on Gram stains and in phenotypic identification. Individual reports of sentinel site (SSL), national (NL) and regional reference (RRL) laboratories participating in the World Health Organization (WHO)-coordinated external quality assessment, distributed by the United Kingdom National External Quality Assessment (EQA) Services (UK NEQAS) for Microbiology between 2014 and 2019 were analyzed. (2) Methods: The panels consisted of (1) unstained bacterial smears for Gram staining, (2) viable isolates for identification and serotyping/serogrouping (ST/SG) and (3) simulated cerebral spinal fluid (CSF) samples for species detection and ST/SG using polymerase chain reaction (PCR). SSLs and NLs tested for Gram staining and species identification (partial panel). RRLs, plus any SSLs and NLs (optionally) also analyzed the simulated CSF samples (full panel). The passing score was ≥75% for NLs and SSLs, and ≥90% for RRLs and NLs/SSLs testing the full panel. (3) Results: Overall, 63% (5/8) of the SSLs and NLs were able to correctly identify the targeted pathogens, in 2019; but there were challenges to identify Haemophilus influenzae either on Gram stains (35% of the labs failed 2014), or in culture. Individual performance showed inconsistent capacity, with only 39% (13/33) of the SSLs/NLs passing the EQA exercise throughout all surveys in which they participated. RRLs performed well over the study period, but one of the two failed to reach the minimal passing score in 2016 and 2018; while the SSLs/NLs that optionally tested the full panel scored between 75% and 90% (intermediate pass category). (4) Conclusions: We identified a need for implementing a robust quality management system for timely identification of the gaps and then implementing corrective and preventive actions, in addition to continuous refresher training in the SSLs and NLs supporting the IB-VPD surveillance in the World Health Organization, Regional Office for Africa (WHO AFRO)

Surveillance of impact of PCV-10 vaccine on pneumococcal meningitis in Mozambique, 2013 – 2015

<div><p>Background</p><p>Vaccination using the 10-valent conjugate vaccine (PCV-10) was introduced into the Extended Program on Immunization in Mozambique in March 2013, however its impact on pediatric pneumococcal meningitis is unknown. In this study, we assessed for the first time the impact of PCV10 on the burden of pneumococcal meningitis in children less than 5 years of age at the three largest hospitals in Mozambique.</p><p>Method</p><p>Between March 2013 and December 2015, a total of 744 cerebrospinal fluid (CSF) samples were collected from eligible children, of which 160 (21.5%) were positive for <i>S</i>. <i>pneumoniae</i>. Of these, only 86 samples met the criteria for serotyping and were subsequently serotyped using sequential multiplex PCR (SM-PCR), but 17 samples were non-typable.</p><p>Results</p><p>The proportion of cases of pneumococcal meningitis decreased from 33.6% (124 of 369) in 2013 to 1.9% (3 of 160) in 2015 (<i>p</i> < 0.001). The relative frequency of PCV10 serotype cases also decreased from 84.2% (48 of 57) in 2013 to 0% (0 of 3) in 2015 (<i>p</i> = 0.006). Between 2013 and 2015, serotype coverage of PCV-10 and PCV13 vaccine formulations was 66.7% and 81.2%, respectively.</p><p>Conclusion</p><p>Altogether, our findings shows that introduction of PCV-10 immunization resulted in rapid decline of pneumococcal meningitis children less than 5 years old in Mozambique. This decline was accompanied by substantial changes in the pattern of circulating pneumococcal serotypes.</p></div