Cost-effectiveness of rotavirus vaccination in Mozambique

IntroductionRotavirus is one of the most common cause of severe gastroenteritis in children, with the largest mortality burden in low- and middle-income countries. To prevent rotavirus gastroenteritis, Mozambique introduced ROTARIX® vaccine in 2015, however, its cost-effectiveness has never been established in the country. In 2018, additional vaccines became available globally. This study estimates the cost-effectiveness of the recently introduced ROTARIX in Mozambique and compares the cost-effectiveness of ROTARIX®, ROTAVAC®, and ROTASIIL® to inform future use.MethodsWe used a decision-support model to calculate the potential cost-effectiveness of vaccination with ROTARIX compared to no vaccination over a five-year period (2016–2020) and to compare the cost-effectiveness of ROTARIX, ROTAVAC, and ROTASIIL to no vaccination and to each other over a ten-year period (2021–2030). The primary outcome was the incremental cost per disability-adjusted life-year (DALY) averted from a government perspective. We assessed uncertainty through sensitivity analyses.ResultsFrom 2016 to 2020, we estimate the vaccine program with ROTARIX cost US$12.3 million, prevented 4,628 deaths, and averted US$3.1 million in healthcare costs. The cost per DALY averted was US$70. From 2021 to 2030, we estimate all three vaccines could prevent 9,000 deaths and avert US$7.8 million in healthcare costs. With Global Alliance for Vaccines and Immunization (Gavi) support, ROTARIX would have the lowest vaccine program cost (US$31 million) and 98 % probability of being cost-effective at a willingness-to-pay threshold of 0.5x GDP per capita. Without Gavi support, ROTASIIL would have the lowest vaccine program cost (US$75.8 million) and 30 % probability of being cost-effective at the same threshold.ConclusionROTARIX vaccination had a substantial public health impact in Mozambique between 2016 and 2020. ROTARIX is currently estimated to be the most cost-effective product, but the choice of vaccine should be re-evaluated as more evidence emerges on the price, incremental delivery cost, wastage, and impact associated with each of the different rotavirus vaccines.     

Prevalence and complete genome characterization of turkey picobirnaviruses

The “light turkey syndrome” (LTS), in which birds weigh less than their standard breed character at the marketing time, is believed to be a consequence of viral enteritis at an early age (3–5 weeks) from which the birds never fully recover. In a previously published study, we collected fecal pools from 2, 3, 5 and 8 week old turkey poults (80 pools from LTS farms and 40 from non-LTS farms) and examined them for the presence of astro-, rota-, reo-, and coronaviruses. To determine the presence of additional enteric viruses, we analyzed a fecal pool by Illumina sequencing and found picobirnavirus (PBV). Segments 1 and 2 of this virus shared 45.8% aa and 60.9–64.5% aa identity with genogroup I of human PBV, respectively. Primers based on RNA-dependent RNA polymerase and capsid genes were designed for detection and molecular characterization of PBVs in the 120 fecal pools described above. From LTS farms, 39 of 80 (48.8%) pools were PBV positive while 23 of 40 (57.5%) were positive from non-LTS farms. The phylogenetic analysis of 15 randomly selected strains divided them into four subgroups within genogroup I (subgroups 1A–D). Nine strains were in subgroup IA showing 69.9–76.4% nt identity with human PBV GI strainVS111 from the Netherlands. Strains in subgroup IB (n = 2) had 91.4–91.7% nt identity with chicken PBV GI strain AVE 42v1 from Brazil. Two strains in subgroup IC had 72.3–74.2% nt identity with chicken PBV strain AVE 71v3 from Brazil. In subgroup ID, two strains showed 72.4–81.8% nt identity with chicken PBV GI strain AVE 57v2 from Brazil. Subgroup IC and ID were the most divergent. Five of the 15 strains were typed using capsid gene primers. They showed 32.6–33.4% nt and 39.5–41.3% aa identity with VS10 human PBV strain. These results indicate co-circulation of divergent strains of PBVs among Minnesota turkeys.     

Whole genome detection of rotavirus mixed infections in human,porcine and bovine samples co-infected with various rotavirus strains collected from sub-Saharan Africa

Group A rotaviruses (RVA) are among the main global causes of severe diarrhea in children under the age of 5 years. Strain diversity, mixed infections and untypeable RVA strains are frequently reported in Africa. We analysed rotavirus-positive human stool samples (n = 13) obtained from hospitalised children under the age of 5 years who presented with acute gastroenteritis at sentinel hospital sites in six African countries, as well as bovine and porcine stool samples (n = 1 each), to gain insights into rotavirus diversity and evolution. Polyacrylamide gel electrophoresis (PAGE) analysis and genotyping with G-(VP7) and P-specific (VP4) typing primers suggested that 13 of the 15 samples contained more than 11 segments and/or mixed G/P genotypes. Full-length amplicons for each segment were generated using RVA-specific primers and sequenced using the Ion Torrent and/or Illumina MiSeq next-generation sequencing platforms. Sequencing detected at least one segment in each sample for which duplicate sequences, often having distinct genotypes, existed. This supported and extended the PAGE and RT-PCR genotyping findings that suggested these samples were collected from individuals that had mixed rotavirus infections. The study reports the first porcine (MRC-DPRU1567) and bovine (MRC-DPRU3010) mixed infections. We also report a unique genome segment 9 (VP7), whose G9 genotype belongs to lineage VI and clusters with porcine reference strains. Previously, African G9 strains have all been in lineage III. Furthermore, additional RVA segments isolated from humans have a clear evolutionary relationship with porcine, bovine and ovine rotavirus sequences, indicating relatively recent interspecies transmission and reassortment. Thus, multiple RVA strains from sub-Saharan Africa are infecting mammalian hosts with unpredictable variations in their gene segment combinations. Whole-genome sequence analyses of mixed RVA strains underscore the considerable diversity of rotavirus sequences and genome segment combinations that result from a complex evolutionary history involving multiple host species.     

Whole genome analyses of DS-1-like Rotavirus A strains detected in children with acute diarrhoea in southern Mozambique suggest several reassortment events

We report the first whole genome constellations of Mozambican rotavirus A strains detected between 2012 and 2013 in the Mavalane General Hospital in Maputo city and Manhiça District Hospital in the Manhiça district. Consensus sequences for ten DS-1-like strains (G2P[4] and G8P[4]) were identified with an Illumina Miseq platform using cDNA prepared from dsRNA extracted from stool samples, without genome amplification or prior adaptation to cell culture. Comparison of previously reported genotyping results and the consensus sequences described in this study, indicated that the genotype primers specific for G12 and P[4] might require revision. Phylogenetic analyses indicated diversity among the G2P[4] Mozambican strains and suggested reassortment between G2P[4] and G8P[4] Mozambican strains, as well as the intragenogroup reassortment of all the genome segments encoding VP1, 2, 3 and 6 for strain RVA/Human-wt/MOZ/0045/2012G8P[4]. These results highlight the necessity to determine whole genome constellations to confirm surveillance data in Africa and to monitor the growing diversity in DS-1-like strains.     

Impact of rotavirus vaccination on diarrheal hospitalizations in children younger than 5 years of age in a rural southern Mozambique

BackgroundRotavirus vaccine (Rotarix®) was introduced in Mozambique through its Expanded Program of Immunization in September 2015. We assessed the impact of rotavirus vaccination on childhood gastroenteritis-associated hospitalizations post-vaccine introduction in a high HIV prevalence rural setting of southern Mozambique.MethodsWe reviewed and compared the trend of hospitalizations (prevalence) and incidence rates of acute gastroenteritis (AGE), and rotavirus associated-diarrhea (laboratory confirmed rotavirus) in pre- (January 2008–August 2015) and post-rotavirus vaccine introduction periods (September 2015–December 2020), among children <5 years of age admitted to Manhiça District Hospital.ResultsFrom January 2008 to December 2020, rotavirus vaccination was found to contribute to the decline of the prevalence of AGE from 19% (95% CI: 18.14–20.44) prior to the vaccine introduction to 10% (95% CI: 8.89–11.48) in the post-introduction period, preventing 40% (95 % IE: 38–42) and 84% (95 % IE: 80–87) of the expected AGE and laboratory confirmed rotavirus cases, respectively, among infants. Similarly, the overall incidence of rotavirus was 11.8-fold lower in the post-vaccine introduction period (0.4/1000 child-years-at-risk [CYAR]; 95% CI: 0.3–0.6) compared with the pre-vaccination period (4.7/1000 CYAR; 95% CI: 4.2–5.1) with the highest reduction being observed among infants (16.8-fold lower from the 15.1/1000 CYAR in the pre-vaccine to 0.9/1000 CYAR in the post-vaccine eras).ConclusionsWe documented a significant reduction in all-cause diarrhea hospitalizations and rotavirus positivity after vaccine introduction demonstrating the beneficial impact of rotavirus vaccination in a highly vulnerable population.     

Prevalence of enteropathogenic viruses and molecular characterization of group A rotavirus among children with diarrhea in Dar es Salaam Tanzania

Background  

Different groups of viruses have been shown to be responsible for acute diarrhea among children during their first few years of life. Epidemiological knowledge of viral agents is critical for the development of effective preventive measures, including vaccines.     

Early impact of rotavirus vaccination in children less than five years of age in Mozambique

BackgroundMozambique introduced rotavirus vaccine (Rotarix, GSK Biologicals) in the National Immunization Program in September 2015 with the objective of reducing the burden of total diarrheal disease and specifically severe rotavirus disease. This study aimed to evaluate the early impact of rotavirus vaccine in reducing all-cause diarrhea and rotavirus-specific hospitalizations.MethodsWe analysed stool specimens collected from children under five years old, between January 2014 and June 2017 within the National Surveillance for Acute Diarrhea. We compared annual changes in rotavirus positivity, median age of children hospitalized for rotavirus and the number of all-cause for diarrheal hospitalizations. Rotavirus detection was performed using enzyme immunoassay.ResultsDuring this period, 1296 samples were collected and analyzed. Rotavirus positivity before vaccine introduction was 40.2% (39/97) in 2014 and 38.3% (225/588) in 2015, then after vaccine introduction reduced to 12.2% and 13.5% in 2016 and 2017, respectively. The median age of children hospitalized for rotavirus was 9 and 11 months in 2014 and 2015 and 10 months in 2016 and 2017. Rotavirus hospitalizations exhibited a seasonal peak prior to vaccine introduction, between June and September in 2014 and 2015, coinciding with winter period in Mozambique. After vaccine introduction, the peak was delayed until August to December in 2016 and was substantially diminished. There was a reduction in all-cause acute diarrhea hospitalizations in children aged 0–11 months after vaccine introduction.ConclusionWe observed a reduction in rotavirus positivity and in the number of all-cause diarrhea hospitalizations after vaccine introduction. The data suggest rotavirus vaccine is having a positive impact on the control of rotavirus diarrheal disease in Mozambique.     

456例儿童腹泻轮状病毒感染调查分析

目的 了解恩施地区儿童腹泻与轮状病毒关系,为地区儿童腹泻防治工作提供依据.方法 采用胶体金法对医院2010年1月-2012年1月收治的456例腹泻患儿的粪便标本进行A型轮状病毒快速检测.结果 所有患儿A型轮状病毒感染率为41.7％,以＜1岁组和1～3岁组为最高,感染率分别为44.4％、66.6％;所有感染A型轮状病毒患儿中＜1岁组约占42.1％,1～3岁患儿组约占52.6％,合计超过所有阳性患儿的94.7％;感染发病与季节变换相关,秋冬季高发.结论 地区儿童腹泻轮状病毒感染情况与国内外流行病学分布一致,为当地儿童腹泻防治工作提供了可靠依据.     

Analysis of complete genome sequences of G9P[19] rotavirus strains from human and piglet with diarrhea provides evidence for whole-genome interspecies transmission of nonreassorted porcine rotavirus

Whole genomes of G9P[19] human (RVA/Human-wt/THA/CMH-S070-13/2013/G9P[19]) and porcine (RVA/Pig-wt/THA/CMP-015-12/2012/G9P[19]) rotaviruses concurrently detected in the same geographical area in northern Thailand were sequenced and analyzed for their genetic relationships using bioinformatic tools. The complete genome sequence of human rotavirus RVA/Human-wt/THA/CMH-S070-13/2013/G9P[19] was most closely related to those of porcine rotavirus RVA/Pig-wt/THA/CMP-015-12/2012/G9P[19] and to those of porcine-like human and porcine rotaviruses reference strains than to those of human rotavirus reference strains. The genotype constellation of G9P[19] detected in human and piglet were identical and displayed as the G9-P[19]-I5-R1-C1-M1-A8-N1-T1-E1-H1 genotypes with the nucleotide sequence identities of VP7, VP4, VP6, VP1, VP2, VP3, NSP1, NSP2, NSP3, NSP4, and NSP5 at 99.0%, 99.5%, 93.2%, 97.7%, 97.7%, 85.6%, 89.5%, 93.2%, 92.9%, 94.0%, and 98.1%, respectively. The findings indicate that human rotavirus strain RVA/Human-wt/THA/CMH-S070-13/2013/G9P[19] containing the genome segments of porcine genetic backbone is most likely a human rotavirus of porcine origin. Our data provide an evidence of interspecies transmission and whole-genome transmission of nonreassorted G9P[19] porcine RVA to human occurring in nature in northern Thailand.     

Prevalence and severity of xerophthalmia in southern Malawi

The first population-based study of xerophthalmia in Africa was conducted in the Lower Shire River Valley of Malawi in the autumn of 1983. A total of 5,436 children under six years of age were examined by three survey teams over an eight-week period. The prevalence of active xerophthalmia was 3.9%. Rates for night blindness and active corneal disease were more than five times the World Health Organization criterion for a problem of public health importance. Xerophthalmic corneal scarring occurred at a rate of 5.9/1,000, more than 10 times the World Health Organization criterion. All cases of bilateral blindness in this age group were considered to be due to vitamin A deficiency. Given recent evidence from Asia linking even subclinical vitamin A deficiency to increased risk of mortality and morbidity, this disease is not only a leading cause of blindness in this area, but may have an important impact on child survival as well.     

Prevalence and genetic characterization of Toxoplasma gondii in badgers (Melogale moschata) in southern China by PCR-RFLP

Toxoplasma gondii is an obligate intracellular apicomplexan parasite which is able to infect almost all warm-blooded animals. There is no information about the prevalence and genetic characterization of T. gondii in badgers (Melogale moschata) in China. Here, a total of 367 badgers were captured from different cities in Jiangxi province, Southern China. Genomic DNA was extracted from brain tissues of each badgers, and 57 (15.45%) of them were positive for T. gondii by semi-nested PCR of the B1 gene. The positive DNA samples were typed at 11 genetic markers, including 10 nuclear loci (SAG1, 5′-SAG2 and 3′-SAG2, alternative SAG2, SAG3, BTUB, GRA6, c22-8, c29-2, L358, PK1) and an apicoplast locus (Apico), with multilocus polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technology. Among them, 4 were completely typed at all loci, and 2 was genotyped for 9 loci, showing that they belong to ToxoDB#9. This is the first report of prevalence and genetic characterization of T. gondii isolates from badgers in China, which contributes to broader understanding of population structure of T. gondii in China. It is important for the prevention and control of T. gondii infection in wild animals.     

Porcine rotavirus strain Gottfried-based human rotavirus candidate vaccines: construction and characterization

Rotavirus gastroenteritis remains the leading cause of severe diarrheal disease in infants and young children worldwide, and thus, a safe and effective rotavirus vaccine is urgently needed in both developing and developed countries. Various candidate rotavirus vaccines that were developed by us and others have been or are being evaluated in different populations in various parts of the world. We have recently confirmed that a porcine rotavirus Gottfried strain bears a P (VP4) serotype (P2B[6]) closely related to human rotavirus P serotype 2A[6] which is of epidemiologic importance in some regions of the world. Based on the modified Jennerian approach to immunization, we have constructed 11 Gottfried-based single VP7 or VP4 gene substitution reassortant vaccine candidates which could provide: (i) an attenuation phenotype of a porcine rotavirus in humans; and (ii) antigenic coverage for G serotypes 1-6 and 8-10 and P serotype 1A[8], 1B[4] and 2A[6]. In addition, following immunization of guinea pigs with Gottfried VP4, we found low but consistent levels of neutralizing antibodies to VP4 with P1A[8] or P1B[4] specificity, both of which are of global epidemiologic importance. Thus, porcine-based VP7 reassortant rotavirus vaccines may provide an advantage over rhesus- or bovine-based VP7 reassortant vaccines since the VP4s of the latter vaccines do not evoke antibodies capable of neutralizing the viruses bearing P1A[8], P1B[4] or P2A[6] VP4.     

Prevalence of diabetes mellitus in southern Wisconsin

The prevalence of known cases of diabetes was ascertained from patient records in an 11-county area in Wisconsin in July 1979 to June 1980. The prevalence in the noninstitutionalized population was found to be 1%. Prevalence rates rose from 0.5 cases per 1000 population in the first decade of life to 44.7 cases per 1000 population in the eighth decade. The highest rates were found in the nursing home population. Males had higher age-adjusted rates than females. No difference in prevalence was found between persons living in metropolitan or nonmetropolitan counties. Determination of prevalence by these methods is a rapid and inexpensive means of ascertainment of known cases of diabetes.     

First genetic characterization of rotavirus C in Russia

Rotaviruses C (RVC) cause sporadic cases and outbreaks of diarrhea in humans and animals worldwide. The aim of this study was to monitor RVC during a surveillance study of sporadic cases of viral gastroenteritis in the Novosibirsk and Omsk regions of Russia from 2006 to 2011. A total of 2144 stool samples from children and adults hospitalized with acute gastroenteritis were tested for RVC by RT-PCR. Sixteen RVC-positive stool samples were detected at a rate of 0.6% (13/2037) in children and 2.8% (3/107) in adults. The low detection rate suggested that RVC infection was an uncommon cause of hospitalization in Russia. The complete VP7, VP4, VP6, and NSP4 gene sequences were determined. It was found that RVCs with at least two different genome backgrounds circulated in Siberia. VP4, VP6, and NSP4 gene sequences of most Russian RVC strains clustered with South Asian strains, while the VP7 gene showed a closer relationship to European strains. Meanwhile, only VP4 and NSP4 sequences of the strain Omsk08-386 clustered with South Asian strains, while its VP6 and VP7 sequences clustered with European strains. This is the first genetic characterization of Russian RVC strains and the first report on the prevalence of RVC in the Asian part of Russia.     

Analysis of rotavirus species diversity and evolution including the newly determined full-length genome sequences of rotavirus F and G

Rotaviruses are a leading cause of viral acute gastroenteritis in humans and animals. Eight different rotavirus species (A–H) have been defined based on antigenicity and nucleotide sequence identities of the VP6 gene. Here, the first complete genome sequences of rotavirus F (strain 03V0568) and G (strain 03V0567) with lengths of 18,341 and 18,186 bp, respectively, are described. Both viruses have open reading frames for rotavirus proteins VP1 to VP7 and NSP1 to NSP5 located at the 11 genome segments. Nucleotide sequence identities to other rotaviruses ranged between 29.8% (NSP1 gene) and 61.7% (VP1 gene) for rotavirus F and between 29.3% (NSP1-2 gene) and 65.9% (NSP2 gene) for rotavirus G, thus confirming their classification as separate virus species. Encoded proteins revealed remarkable sequence differences among the rotavirus species. In contrast, the non-coding 5′-terminal sequences of the genome segments are highly conserved among all rotavirus species. Different 3′-terminal consensus sequences are found between rotavirus A/D/F, rotavirus C and rotavirus B/G/H. Phylogenetic analyses indicated a separation of rotaviruses in two major clades consisting of rotavirus A/C/D/F and rotavirus B/G/H. Within these clades, rotavirus F mainly clustered with rotavirus D and rotavirus G with rotavirus B. In addition, differentiation among mammalian and avian rotavirus A strains, host-specific evolution of rotavirus B and C as well as an ancient reassortment event between avian rotavirus A and D are indicated by the phylogenetic data. These results underline the high diversity of rotaviruses as a result of a complex evolutionary history.     

Prevalence and phylogenetic analysis of rotavirus genotypes in Thailand between 2007 and 2009

Rotaviruses are the most common cause of severe diarrhea among infants and young children worldwide, especially in developing countries. In Thailand, rotavirus has presented a major public health problem causing severe diarrhea in infants and young children. It was responsible for about one-third of diarrheal diseases in hospitalized patients. In this study, we have analyzed the distribution and performed molecular characterization of rotaviruses circulating in infants and young children with diarrhea admitted to the city and rural hospitals in Thailand between July 2007 and May 2009. Group A human rotavirus was detected in 158 (28.4%) of 557 fecal specimens by RT-PCR. The peak incidence of infection was found in the winter months between December and March. The G1P[8] strain was identified as the most prevalent (49.4%) followed by G9P[8] (22.2%), G2P[4] (20.2%) and G3P[8] (0.6%). The uncommon strains G12P[8], G12P[6] and G3P[9] were also detected. Phylogenetic analysis of selected G and P genotypes isolated in this study was performed to compare with the reference strains from different countries. Emergence of G12 in the northern part of Thailand was observed and phylogenetic analysis demonstrated close relation between Thai isolates and strains from India. The present study reveals the recurring changing genotypes of rotavirus circulating in Thailand. The genetic association between isolates from Thailand and other countries ought to be considered with regard to local and global dissemination of rotavirus as it is crucial for prevention especially, with respect to vaccine implementation.     

Full genome based sequence and structural characterization of an unusual group A rotavirus G12P[11] isolated from neonates in Pune,western India

Studies conducted at neonatal intensive care units in Pune, western India, suggested early exposure to rotaviruses and predominance of unusual human–bovine-like G12P[11] strains. The whole genome sequencing and phylogenetic analyses of a naturally attenuated, culture adapted neonatal strain, (NIV-1740121) revealed multiple-gene reassortment events, containing ROTAVAC® vaccine strain, 116E-like VP4, VP6, NSP3, NSP5 genes, VP7 gene of G12 origin and VP3 gene of porcine ancestry in a human Wa-like backbone. Analysis of 3D structure modeling of the VP7 and VP4 proteins with respect to 116E suggested amino acid variations in the major neutralizing epitopes of VP7, contributed to a modified charge density. Visualization of receptor-glycan interaction structures of NIV-1740121 and 116E VP8* showed type I glycan binds with a similar conformation at the same active site as represented in the available crystal structure of G10P[11] VP8*. The study adds to the knowledge of age restricted tropism of P[11] strains in neonates.