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Rotavirus A infection in pre- and post-vaccine period: Risk factors, genotypes distribution by vaccination status and historic period of children in Nampula Province, Northern Mozambique (2015-2019)

• Adilson Fernando Loforte Bauhofer,
• Idalécia Cossa-Moiane,
• Ezequias Sitoe,
• Benilde Munlela,
• Eva Dora João,
• Jerónimo Due south. Langa,
• Jorfélia José Chilaúle,
• Simone Salvador Boene,
• Marta Cassocera,
• Esperança Lourenço Guimarães,
• Timothy A. Kellogg,
• Luzia Gonçalves,
• Nilsa de Deus

Rotavirus A infection in pre- and post-vaccine menses: Risk factors, genotypes distribution by vaccination status and historic period of children in Nampula Province, Northern Mozambique (2015-2019)

• Assucênio Chissaque,
• Adilson Fernando Loforte Bauhofer,
• Idalécia Cossa-Moiane,
• Ezequias Sitoe,
• Benilde Munlela,
• Eva Dora João,
• Jerónimo Southward. Langa,
• Jorfélia José Chilaúle,
• Simone Salvador Boene,
• Marta Cassocera

x

• Published: August half-dozen, 2021
• https://doi.org/10.1371/journal.pone.0255720

Figures

Abstract

Mozambique introduced the monovalent rotavirus vaccine (Rotarix^®, GSK Biologicals, Rixensart, Belgium) in September 2015. Previous analysis, showed that Nampula province continues reporting a high frequency of Rotavirus A (RVA) infection and the emergence of G9P[6], G9P[4] and G3P[4] genotypes. This assay aimed to decide the RVA frequency; risk factors; genotype distribution by vaccination status and age between pre- and post-vaccine periods in children under-five years old with diarrhea in Nampula. A cantankerous-sectional, hospital-based surveillance study was conducted in the Hospital Central de Nampula in Mozambique. Socio-demographic and clinical data were collected to assess factors related to RVA infection in both periods. Stool specimens were screened to detect RVA by ELISA, and positive samples were genotyped. Betwixt 2022 (pre-vaccine flow) and 2016–2019 (post-vaccine period), 614 stool specimens were collected and tested for RVA in which 34.nine% (67/192) were positive in pre-vaccine catamenia and 21.viii% (92/422) in post-vaccine (p = 0.001). In the post-vaccine period, age, twelvemonth, and contact with dissimilar brute species (craven, duck, or multiple animals) were associated with RVA infection. RVA infection was higher in children partially vaccinated (40.7%, xi/27) followed past the fully vaccinated (29.3%, 56/191) and the unvaccinated (15.3%, 21/137) (p = 0.002). G1P[8] and G9P[4] were common in vaccinated children less than 12 months. The nowadays analysis showed that RVA infection reduced slightly in the mail service-vaccine flow, with a high proportion of infection and genotype diverseness in children, nether 12 months of age, vaccinated. Further enquiry on factors associated with RVA infection on vaccinated compared to unvaccinated children and vaccination optimization should be done.

Citation: Chissaque A, Bauhofer AFL, Cossa-Moiane I, Sitoe E, Munlela B, João ED, et al. (2021) Rotavirus A infection in pre- and postal service-vaccine flow: Risk factors, genotypes distribution by vaccination status and historic period of children in Nampula Province, Northern Mozambique (2015-2019). PLoS 1 sixteen(viii): e0255720. https://doi.org/ten.1371/journal.pone.0255720

Editor: Ricardo Q. Gurgel, Federal Academy of Sergipe, BRAZIL

Received: August 26, 2020; Accustomed: July 22, 2021; Published: August 6, 2021

Copyright: © 2022 Chissaque et al. This is an open access article distributed nether the terms of the Creative Eatables Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Information Availability: All relevant data are within the manuscript and its Supporting information files.

Funding: The National Surveillance of Diarrhea was supported by GAVI through the Centers for Disease Command and Prevention (CDC), Atlanta and World Health Arrangement, Regional Office for Africa (WHO / AFRO). N.dD. has a fellowship of the European Foundation Initiative into African Inquiry in Neglected Tropical Diseases (EFINTD, grant number 89539); Due east.D.J. Ph.D. is supported past Calouste Gulbenkian Foundation. B.A.M., A.C. and S.B. received a scholarship from the Deutsche Forschungsgemeinschaft (DFG; grant number JO369/5-one); B.G., A.C., and J.C are fellows of Fundo Nacional de Investigação (FNI); LG was supported past Fundação para Ciência e Tecnologia, Portugal (UID/04413/2020, UIDB/00006/2020, UIDP/00006/2020. The funders had no role in the design of the study; in the collection, analyses, or estimation of information; in the writing of the manuscript, or in the decision to publish the results.

Competing interests: The authors have declared that no competing interests exist.

Introduction

Globally, Rotavirus A (RVA) remains the leading crusade of severe acute gastroenteritis associated with high childhood hospitalization and bloodshed, accounting for an estimated 128,515 deaths among children nether five years erstwhile in 2022 [i, 2]. In Sub-Saharan Africa, RVA associated morbidity and mortality is exceptionally high with approximately 104,733 children dying annually from the disease [3]. In 2009, the World Health Organisation (WHO) recommended the introduction of RVA vaccine in all countries, particularly in those with loftier child mortality [four]. In 2021, four attenuated oral rotavirus vaccines are licensed and available globally: Rotarix^® (GlaxoSmithKline Biologics, Rixensart, Belgium), RotaTeq^® (Merck & Co., United states of america), Rotavac^® (Bharat Biotech, Bharat), and Rotasiil^® (Serum Plant of India Pvt. Ltd. Bharat) [5]. A systematic review of the RVA vaccination touch on on hospitalizations and deaths from 27 countries, found a 67% reduction in children'south hospitalization and outpatient care and a 60% decline in childhood bloodshed due to RVA gastroenteritis in 2022 [6]. Rotavirus morbidity decreased from 38% to 23% in 82 countries between 2008 and 2022 [7].

Studies of molecular characterization of RVA have shown that globally G1P[eight] is the near common genotype combination, followed by G2P[iv], G3P[8], G4P[eight], and G9P[8] [viii–xi]. Following the introduction of the RVA vaccine (Rotarix^® and Rotateq^®), new RVA strains were reported in Southern and Eastern African countries (Republic of angola, Eritrea, Federal democratic republic of ethiopia, Kenya, Kingdom of lesotho, Madagascar, Republic of mauritius, Namibia, Rwanda, Seychelles, Swaziland, Tanzania, Uganda, Zambia and Republic of zimbabwe) betwixt 2010 and 2015; these included: G1P[4], G2P[8], G9P[iv], and G12P[four] [11]. Earlier the RVA vaccine introduction in Mozambique, RVA was identified as the principal etiologic agent of moderate-severe-diarrhea with an owing fraction of 34.8% in children under one year in the southern region of Mozambique [12]. Other studies in children with diarrhea conducted in the southern region (Chókwè, Maputo city, and Manhiça) showed RVA frequencies ranging from 24% to 42.four% [13, fourteen]. Those studies reported mostly the following circulating genotypes: G12P[viii] (57%) and G1P[viii] (ix%) in Chòkwé, G2P[4] (39.4%) in Manhiça and G12P[vi] (28.six%) in Maputo urban center [xiv, 15]. Mozambique introduced the G1P[8] rotavirus vaccine (Rotarix^®) into the expanded plan of immunization in September 2015. Earlier Rotarix^® introduction, the Instituto Nacional de Saúde (INS) implemented the National Surveillance of Diarrhea (ViNaDia) in four provinces of the country equally a platform to monitor diarrhea cases, the master etiologies, and gamble factors associated with RVA infection before and later on Rotarix^® introduction in the land. ViNaDia information indicated a high diversity of RVA genotypes across the country, were uncommon combinations such as G3P[four], G9P[iv], G9P[half dozen], G2P[6], and non-typeable genotypes in Nampula province were seen [16]. ViNaDia as well reported a high proportion of undernourished children with the double brunt of RVA and HIV [17]. An independent assay of RVA in Nampula is relevant considering recurrent reports of poorer wellness indicators in children are described, including a high burden of atmospheric condition such every bit undernourishment, malaria, diarrhea and successive cholera outbreaks [18, 19]. Thus, the present analysis aims to make up one's mind RVA frequency, potential gamble factors and the distribution of RVA genotypes by vaccination status and age among children with diarrhea attention Infirmary Central de Nampula, in the pre- and postal service-vaccine periods.

Materials and methods

Study design, site, population

A cross-sectional, hospital-based surveillance was conducted between the pre-vaccine (March—Dec 2015) and post-vaccine (Jan 2022 –December 2019) periods. The surveillance was conducted at the Hospital Central de Nampula (HCN) in Nampula province, located in the northern region of Mozambique. Nampula province is highly populated, and has enormous challenges related to H2o, Sanitation and Hygiene (Launder), high levels of poverty, and lower vaccination coverage [19, twenty]. Children aged up to 59 months who presented to the HCN pediatric services with diarrhea, divers as the passage of 3 or more loose or liquid stools in the last 24 hours earlier seeking healthcare, were surveyed [21]. Children were non included in this analysis if the caregivers did not consent to their participation equally well every bit children diagnosed with nosocomial diarrhea. Moreover, children considered overweight (+2 < Z-score ≤ +5) or with outlier Z-scores values were excluded from the nutritional status analysis [22].

Data collection

Data was collected by interviewing the child'due south caregiver and by accessing the child's medical records. The chief variables include age (in months), categorized as 0–11, 12–23, 24–59; sex; exclusive breastfeeding; the age of weaning in months, categorized by six months; fauna contact and type of animal; source of drinking water; HIV status; admission blazon; number of diarrhea episodes in the final 24h; vomit; fever; weight; vaccination status, and nutritional condition that was estimated through the weight-for-age Z-score (WAZ), specific to underweight, using WHO software Anthro version 3.2.two. Weight was measured by lying down children younger than ii years, and standing for children with ii years or older. Children were classified also-nourished if the Z-score was between -2 ≤ Z-score ≤ +two and as underweighted if the z-scores was between -6 ≤ Z-score < -two. Vaccination status of the children was confirmed with a valid vaccination menu. Trained healthcare professionals of ViNaDia, completed all information on a structured information collection form.

Sample drove

ViNaDia methodology has been previously described elsewhere [sixteen, 17, 23, 24]. Briefly, a single stool specimen (x ml) was collected from each child in a polyester container and stored at -20°C until shipment, once a week, to the INS laboratory in Maputo for diagnosis.

Laboratory procedures

Collected samples were tested for RVA using the commercial enzyme-immuno-sorbent analysis (ELISA) kit (Prospect, Oxoid Ltd, United Kingdom) according to the manufacturer'due south instructions. All positive samples were submitted to total RNA extraction using the QIAamp Viral RNA protocol (QIAGEN, Hilden, Deutschland) following the manufacturer's instructions.

Extracted RNA (8μl) was contrary transcribed and amplified using a reverse-transcription polymerase chain reaction (RT-PCR) with Avian Myeloblastosis Virus (AMV), reverse transcriptase (Ivitrogen, U.s.a.), Taq Deoxyribonucleic acid polymerase (Ivitrogen, The states) and the primers sBeg9/End9 for the VP7 encoding gene (1062pb) and Con2/Con3 for the partial VP4-encoding gene (VP8*, 876bp) were used [25, 26]. Amplicon products from the first round RT-PCR were added to a second-round multiplex semi-nested PCR containing RVG9 and specific primers for G-type (G1-four, G9-10, and G12) identification were used as described elsewhere [16, 25, 27, 28].

Similarly, Con3 was used in combination with specific primers that identify P-types (P[4], P[6], P[8], P[nine], P[11], and P[fourteen]) as previously described [xvi, 26, 29]. The cycling weather condition consisted of 1 infinitesimal denaturation, followed by 30 cycles of dsRNA denaturation for one infinitesimal at 95°C, annealing for 1 minute at 42°C, 1 minute at 72°C for amplification, and the concluding amplification footstep of 7 minutes at 72°C.

The PCR product was analysed using 2% agarose gel electrophoresis, stained with ethidium bromide, and visualized under ultraviolet illumination.

Sample size

Data used in the present analysis are from a hospital-based surveillance program (ViNaDia), whose primary aim is to monitor diarrhea and RVA cases before and after Rotarix^® vaccine introduction [17]. Since ViNaDia is an ongoing surveillance system, the sample size adding was not estimated for the present analysis. Yet, we calculated the statistical power associated to the obtained sample sizes to compare ii proportions. For children anile up to 59 months, statistical power was 92.i%. For the secondary assay in children younger than 24 months, the sample ability was 88.0% (higher than eighty% minimum required).

Data management and statistical assay

Data collected was double entered in two like databases past ii contained typists in Epi Info^™3.5.i. (Centers for Disease Control and Prevention, Atlanta, 2008), followed past data comparing. IBM SPSS (International Business Machines Corporation Statistical Package for the Social Scientific discipline, Armok, NY: IBM Corp, 2011, version 26.0) software was used to behave the data analysis.

Overall RVA frequencies with the corresponding Wilson'southward 95% Confidence Interval (CI) were estimated, for each RVA vaccine period and year [30]. Besides, RVA proportions by age (in months) groups for each yr were calculated.

Descriptive statistics and chi-square test or Fisher'southward Verbal test were used to identify socio-demographic and epidemiological variables associated with RVA infection in each vaccine period in children historic period upwardly to 59 months and in children younger than 24 months (S1 Table). Due to the absenteeism of RVA cases among children anile between 24–59 months in the post-vaccine menstruation, a more detailed analysis was done to children nether 24 months. Multiple logistic regression models were explored to obtain adjusted odds ratio (aOR), with 95% conviction intervals, for each vaccine menstruum. The bivariate analysis of the socio-demographic and epidemiological characteristics for children under 24 months of age is shown in S1 Table. Variables with initial p < 0.05 were included in the multiple logistic regression model for children under 24 months of age. Goodness-of-fit of the multiple logistic regression models was obtained using Hosmer and Lemeshow test.

For children anile up to 59 months, clinical factors associated with RVA infection in each vaccine catamenia and in general were assessed by cross-tabulation followed past the chi-square exam or Fisher's Exact test if assumptions were non met. Cross-tabulation was performed between vaccination status and RVA infection; vaccination status and genotype distribution; age and genotype distribution. Parameter interpretation was washed using 95% confidence interval, and hypothesis exam were based on a v% level.

Ethical statement

The study protocol was canonical by the National Bioethics Commission for Wellness in Mozambique (IRB00002657, reference 348/CNBS/13). Parents or legal guardians of the children signed or provided their fingerprint to the informed consent form, which described the study objectives and antiseptic that participation in the study was voluntary. Data confidentiality was ensured by storing the physical data collection and consent forms in a lockable chiffonier with limited access.

Results

Overall and yearly RVA frequencies by vaccination period

In total, 700 children were recruited by ViNaDia in Nampula infirmary (221 from the pre-vaccine menstruum and 479 from the postal service-vaccine period), of which 614 (87.seven%) provided a stool sample for laboratory procedures, (192 from the pre-vaccine menstruation and 422 from the post-vaccine period).

Overall, 25.9% (159/614) of the children were positive for RVA- 95% CI: 22.half-dozen–29.5. RVA infection was more frequent in the pre-vaccine (2015) period [34.9% (95% CI: 28.v–41.9); 67/192] than in the postal service-vaccine (2016–2019) flow [21.viii% (95% CI: 18.1–26.0); 92/422] (p = 0.001). RVA frequency by year after vaccine introduction was xiv.6% (29/198) in 2016, 37.five% (45/120) in 2017, 14.eight% (8/54) in 2022 and 20.0% (10/50) in 2022 (Fig i).

RVA frequency by age grouping and year

RVA infection was more frequent among children under 12 months of age than the older ones in each analyzed twelvemonth, 43.4% (36/83) in 2015, 24.0% (23/96) in 2016, 45.five% (30/66) in 2017, 19.ii% (5/26) in 2022 and 27.6% (viii/29) in 2022 (Fig 2). RVA infection in children between 24–59 months was only observed in the pre-vaccine period, 14.3% (half-dozen/42). Each yr, the median age (in months) of positive children was below 12 months, in which the third quartile was lower than 24 months, existence xi (eight–15) for 2015, nine (7–11) for 2016, 10 (viii–12.5) for 2017, 8.v (7.25–12) for 2022 and 9.5 (viii–11.25) for 2019.

Potential risk factors for RVA infection in pre- and post-vaccine flow in Hospital Fundamental de Nampula

In the pre-vaccine period, RVA infection was more than frequent in children younger than 12 months (p < 0.010) (Table ane). Exclusive breastfeeding (44.iv%; 32/72; p < 0.028); drinking water from a piped source (54.7%; 35/64; p < 0.001) and Borehole/well (eighteen.8%; 13/69; p < 0.001) were also associated with RVA infection in the pre-vaccine period. Underweight was negatively associated with RVA infection, as the infection was more frequent in well-nourished children (42.2%; 43/102; p < 0.003) (Table i).

Similarly, to the pre-vaccine period, in the post-vaccine menstruum, the kid'southward age and weight-for-age were also associated to RVA infection, p < 0.001 and p = 0.044 respectively. Several factors that were non associated with RVA infection in the pre-vaccine flow were associated with RVA infection in the post-vaccine period. These included animal contact (27.ane%; 75/277; p < 0.001) and weaning inside the get-go half-dozen months of life (27.3%; 3/xi; p = 0.004) (Table 1).

Type of animal which children had contact in pre- and post-vaccine periods

The animal species that children had contact in pre- and post-vaccine periods bear witness that none of the animals were associated with RVA infection in pre-vaccine period (Table 2). However, it was observed an clan between chicken contact (37.2%; 29/78; p <0.001); duck (37.0%; 17/46; p = 0.008), or multiple animals (30.half dozen%; 34/111; p = 0.009) contact with RVA infection in the postal service-vaccine menstruum (Table 2).

In the multivariable analysis for the pre-vaccine menses, children from household's that drunk piped h2o had two.49 times greater odds of existence infected by RVA compared to the children who did not drink piped water (aOR = 2.49, 95% CI: 2.49 one.04–5.95; p < 0.040) (Table three).

In the post-vaccine menstruum, children between 0–xi months of age were ane.83 times more likely of being infected by RVA than the children betwixt 12–23 months (aOR = 1.83; 95% CI: ane.07–three.13; p = 0.028). Afterwards Rotarix^® introduction, twelvemonth 2017, was the one with the highest chances of infection by RVA compared to 2022 (aOR = 2.40; 95% CI: 1.05–five.50; p = 0.038). Children with animal contact were 1.92 times more likely to be infected by RVA compared to children without beast contact (aOR = ane.92; 95% CI: ane.01–3.66; p = 0.048) (Table three).

Clinical factors related to RVA infection in children from Infirmary Central de Nampula

Overall, the factors related to RVA infection were a greater number of diarrhea episodes in the last 24h before admission (p = 0.041); and the occurrence of airsickness (thirty.vi%; 126/418; p < 0.001) (Table 4). In the pre-vaccine menses occurrence of fever was the only clinical factor related to RVA infection (48.iv%; fifteen/31; p = 0.038) (Table 4).

In the post-vaccine menses, clinical factors related to infection by RVA, were the number of diarrhea episodes in the terminal 24h, infection was more common in children with four or more episodes (p < 0.01); and occurrence of vomit (27.1%, 72/266; p = 0.001) (Table iv).

RVA infection by vaccination status of the children in Infirmary Central de Nampula

A stratified analysis between RVA infection and vaccination status was performed for the postal service-vaccine period, and RVA infection was more mutual in partially vaccinated children (40.seven%, 11/27) followed by the fully vaccinated (29.3%, 56/191) and unvaccinated (15.iii%, 21/137) (p = 0.002).

The most common strains identified were G9P[half dozen] (33.three%; 4/21) in the unvaccinated children, G9P[four] (45.5%; 5/11) in the partially vaccinated, and G1P[viii] (30.4%; 17/56) in the fully vaccinated. Also, most diversity was found in the fully vaccinated children, including the uncommon combinations such as G3P[4] with x.7% (6/56) and G9P[iv] with 17.9% (ten/56). Non-typeable samples were likewise found in fully vaccinated children. The mixed infection (G1G3P[8]) were most common in the partially vaccinated group, with 18.2% (2/11) (Table 5).

RVA genotypes distribution by age grouping in pre- and post-vaccine period in Hospital Key de Nampula

Sixty out of threescore-seven (89.six%) RVA positive samples from the pre-vaccine menses had a sufficient corporeality for RT-PCR. G1P[8] genotype combination was the most common among children younger than 24 months of age (45/55) (Fig three., S2 Table).

All RVA positive samples nerveless in the post-vaccine period were submitted to molecular characterization and were from children beneath 24 months of historic period. The G1P[8] was the almost common with 28.3% (26/92). Yet, in children younger than 12 months of age, a higher frequency of emergent strains that were not detected in the pre-vaccine catamenia were observed, including mixed infections. In the older group (12–23 months) G1P[8] 100% (22/22) was the just genotype reported in the pre-vaccine period (Fig 3). In contrast, in the post-vaccine period, other strains, such as G9P[6] (19.2%, 5/26) and G9P[4] (15.iv%, 4/26), were also reported (Fig four, S3 Table).

Monthly distribution of RVA infection in pre- and post-vaccine menstruation

Since the introduction of the vaccine in the land, the number of diarrhea and RVA cases have declined, mostly since late 2022 at Infirmary Key de Nampula. RVA cases occurred in both seasons, cold/dry out and moisture/rainy. The frequency of RVA during the cold/dry flavour (April to September) was 35.8% (108/302) and in the wet/rainy season (October to March) was 16.3% (51/312) (p < 0.001) (Fig 5).

Discussion

We investigated the epidemiology of RVA, and the distribution of genotypes by vaccination status and age among children with diarrhea attending Infirmary Central de Nampula, in Nampula province northern region of the country. Our assay showed that RVA infection declined following vaccine introduction by 13.1%. In comparing, ii other studies in Maputo city, a southern region of the country, establish a driblet in RVA infection of 31.2% and 14.two% respectively [23, 31]. The differences observed can be explained by the lower vaccine coverage in Nampula province (46%) compared to Maputo city (61%) (data not published from the Expanded Program on Immunization) in 2016, and the lower health indicators in Nampula province [32].

Despite the reduction in RVA morbidity during the post-vaccine period, an increase in RVA infection frequency was seen in 2017. This upshot may exist explained by the lower RVA vaccine coverage [33], and the bear upon of increasing the surveillance after introducing of RVA vaccine in the country.

After the vaccine introduction, there was a reduction of RVA infection in different historic period groups, with a meaning decrease amid children from 24–59 months of age. However, the frequency of RVA infection remains high in children under 12 months of historic period. This finding differs from an analysis from Hospital Geral de Mavalane and Hospital Central de Maputo, which reported a substantial reduction of RVA infections amid children under 12 months of age, with a shift to older age-groups [14, 23].

Differences in the historic period infection shifting may be due to lower vaccination coverage in Nampula [32], reinforced by our data in which 38.6% of the children were not vaccinated even being eligible for vaccination in postal service-vaccine menstruation.

RVA is a zoonotic agent with a chance of interspecies transmission [34, 35]. In Chókwè, a rural area of Mozambique, phylogenetic data of G4P[six] strain detected in children, clustered with porcine and human porcine-similar strains [14]. Animal contact with duck, chicken or multiple animals points to a potential association of RVA interspecies transmission. The occurrence of RVA in chickens was reported in Nigeria [36] and Kenya [37]. Furthermore, a study conducted in Germany identified an avian VP4 cistron, strain P [37] closely related to mammalian RVA [38]. These data highlight the need of expanding the RVA surveillance to domestic animals in Mozambique.

Mozambique has problems related to the availability of water and as a strategy to mitigate the scarcest; intermittently distribution of water between few hours during the mean solar day was adopted, which forces households to storage the h2o in recipients for long use. Our surveillance has express information on the conditions that the piped water were stored, or in what extent would be safe for consumption after storage. Well-nigh of the Mozambican pipelines are one-time and damaged in some sections aligned with the fact that are not properly maintained [39, forty], which tin can contribute for contamination of the piped water mainly in flood situation equally the supply network are emerged [39, 41, 42]. A contempo study conducted in the capital of the country (Maputo), which analyzed different sources of water (habitation bottled, piped and supply well water) observed higher microbiological contagion than recommended for homo consumption in piped water [42]. Although the written report was carried out in Maputo, the company that supplies water at the national level is the same. If then, this finding helps to explain the loftier frequency of RVA in children who eat piped water in Nampula.

The Demographic and Wellness Survey showed that but 43% of the children nether six months are solely breastfed in Mozambique [19]. Surprisingly in this analysis, RVA infection was more common in children exclusively breastfeed. Like results were reported in Kenya in children under 24 months, where a high proportion of positive children were exclusively breastfed than those with other types of food, with 16% and 10.3% respectively in the postal service-vaccine period [43]. Ane of the hypotheses behind this finding is related to the maternal antibodies which may interfere with the RVA vaccine efficacy in lower and middle-income countries, nevertheless, the causal link is not well described [44].

The fact that the proportion of RVA infected children with fever, airsickness, multiple diarrhea episodes, or visit requiring hospitalizations decreased in the mail service-vaccine period, may highlight the role of vaccination in reducing the severity of RVA infection [45, 46].

More than one-third of the children who received simply the start dose of vaccine had a loftier frequency of RVA infection, which raises the question of whether they are shedding the vaccine strain. Vaccine shedding was accessed and the minimum days betwixt the symptoms onset and the vaccination day for dose 1 were 32 days and for dose two were 26 days (data not shown), which excludes the possibility of shedding [47]. This effect indicates a need for further research in Nampula to sympathize which factors are behind the high frequency of infection in vaccinated children.

Dissimilar genotype combinations in the 3 groups of children; the unvaccinated, partially vaccinated, and fully vaccinated were observed. The combination G1P[8] was the almost mutual in fully vaccinated children. The fact that vaccinated children hospitalized due to RVA infection, with the same genotype from the vaccine, may be related to the high prevalence of chronic malnutrition in this province (55%), the highest in the country [19]. It is known that malnutrition can impair the immune arrangement and weaken the vaccine'southward immune response [48, 49]. Nevertheless, this hypothesis cannot be tested in this analysis due to study design, and we cannot rule out other factors as concomitant enteric infections, histo-claret grouping antigen, microbiota composition and mothers antibodies [l, 51].

An increased number of strains reported equally uncommon such equally G3P[four], G9P[4], G9P[half dozen], G2P[vi], G12P[eight] and non-typeable were observed mainly in fully vaccinated children, highlighting the importance of the continuous surveillance.

The G1P[8] strain was the most common genotype combination in all age groups before the introduction of the vaccine. A high genotype multifariousness afterward vaccine introduction was observed in children under 12 months of age. Our findings are non concordant with a study conducted in the southern region of the country in which the diversity of RVA genotypes strains were observed in all age groups during both periods [31]. Also, in Turkey, genotype diversity was common in children from 13 to 24 months of historic period [52].

Regardless of the vaccine period, RVA was more common in the dry/cold flavor (Apr—September) than in the wet/rainy flavor (Oct—March), as expected [23, 31].

The study findings should be interpreted carefully as the post-obit limitations were identified i) variables with non-response in the forms, even with continuous training of the staff, ii) unbalanced sample size between pre and mail-periods and small sample size to some subgroups, iii) fourth dimension period in the pre-vaccine was lower than the ideal minimal two years' flow (March—December 2015). However, our sample size meets the minimum sample power (eighty%) of the chief hypothesis tests. This study was carried out at a quaternary-level hospital, which probably included only children with severe disease, where the epidemiological distribution of the illness may be unlike from hospitals at other levels (tertiary, secondary, rural, post). Despite the limitations, we were able to describe the epidemiology of RVA infection at HCN and the risk factors related to infection in each period (pre- and post-vaccine periods). Some questions demand to be addressed, such as: (i) the reason why vaccinated children are infected with RVA to the bespeak of requiring hospitalization; (ii) the role of animals in the occurrence of new/uncommon RVA genotypes to optimize the vaccination.

In decision, RVA infection was high in Hospital Key de Nampula even afterwards vaccine introduction, mostly in children under 12 months. During the pre-vaccine period, piped water was associated with RVA infection, notwithstanding, boosted studies are needed to investigate this association. In contrast, after vaccine introduction, gamble factors for RVA infection were age (0–11 months) and contact with animal (craven, duck and multiple animals). The infection was more than common in vaccinated children, G9P[4] and G1G3P[8] were the most common genotypes in partially vaccinated, while in fully vaccinated G1P[8], G9P[6], and G9P[4] were the most common. Our results show a need for further inquiry to understand the factors behind RVA infection in vaccinated children such as the vaccine allowed response and factors that contribute to strains diversity through the whole genome sequence and phylogenetic analysis in Nampula.

Supporting information

Acknowledgments

The authors would like to thank the caregivers who consented for their children participation in the ViNaDia. Also thank Elda Anapakala, Júlia Assiat Monteiro Sambo, Diocreciano Matias Bero, Marlene Bernardo Djedje, Selma Marques and Lena Vânia Manhique-Coutinho for their contribution to the surveillance activities. The pediatrics professional from HCN for their dedication and effort with the children enrollment, information collection and shipment of the samples to INS. Marta Cassocera passed away before the submission of the final version of this manuscript. Assucênio Chissaque accepts responsibility for the integrity and validity of the data collected and analyzed.

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