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Early impact of rotavirus vaccination in children less than five years of age in Mozambique
Vaccine xxx (2017) xxx–xxx
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Early impact of rotavirus vaccination in children less than five years of age in Mozambique Nilsa de Deus a,⇑, Jorfélia José Chilaúle a, Marta Cassocera a, Miguel Bambo a, Jerónimo Sozinho Langa a, Ezequias Sitoe b, Assucênio Chissaque c, Elda Anapakala a, Júlia Sambo a, Esperança Lourenço Guimarães a, Diocreciano Matias Bero a, Eva Dora João a,d, Idalécia Cossa-Moiane a, Jason M. Mwenda e, Goitom G. Weldegebriel f, Umesh D. Parashar g, Jacqueline E. Tate g a
Instituto Nacional de Saúde, Ministério da Saúde, Maputo, Mozambique Hospital Central de Nampula, Ministério da Saúde, Nampula, Mozambique c Faculdade de Ciências, Universidade Eduardo Mondlane, Mozambique d Institute of Hygiene and Tropical Medicine, New University of Lisbon, Lisbon, Portugal e World Health Organization (WHO), Regional Office for Africa, Brazzaville, People’s Republic of Congo f Intercountry Support Team (IST), World Health Organization (WHO), Harare, Zimbabwe g Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia b
a r t i c l e
i n f o
Article history: Available online xxxx Keywords: Children Acute diarrhea disease Rotavirus vaccine Impact vaccine
a b s t r a c t Background: Mozambique 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. Methods: We 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. Results: During 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. Conclusion: We 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. Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction Rotavirus is the major cause of acute gastroenteritis (AGE) in children worldwide with an estimated 215,000 deaths in 2013 in infants and young children less than 5 years of age [1]. Sub-Saharan Africa has the largest number of rotavirus deaths and a slower rate of decrease resulting in an increased proportion of deaths from 47.3% in 2000 to 56.3% in 2013 occurring in the region [1]. ⇑ Corresponding author. E-mail address: [email protected] (N. de Deus).
Access to clean water, improved sanitation and hygiene measures are not sufficient to reduce the prevalence of rotavirus; the best preventive measure is vaccination [2]. Two live attenuated oral vaccines against rotavirus (a pentavalent bovine-human reassortant vaccine (RV5; RotaTeq, Merck & Co) and a monovalent human vaccine (RV1; Rotarix GSK Biologicals, Rixensart, Belgium) are licensed and prequalified by the World Health Organization [3]. The introduction of rotavirus vaccine in the national immunization programs has been responsible for a decline in the burden of severe acute gastroenteritis (AGE) in countries such as Australia and United States [4,5]. In Africa, where the burden of disease is
https://doi.org/10.1016/j.vaccine.2017.10.060 0264-410X/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: de Deus N et al. Early impact of rotavirus vaccination in children less than five years of age in Mozambique. Vaccine (2017), https://doi.org/10.1016/j.vaccine.2017.10.060
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N. de Deus et al. / Vaccine xxx (2017) xxx–xxx
greater, the efficacy of the vaccine is lower compared to developed countries [6]. However, the public health benefits of vaccination is high in terms of reduction in the number of severe rotavirus gastroenteritis episodes presented in developed countries because of the greater baseline rate of severe rotavirus gastroenteritis [7]. In Mozambique, the results from the Global Enteric Multicenter Study (GEMS) showed that rotavirus is the most prevalent agent of acute diarrhea in children under the age of 5 years with acute diarrhea [8,9]. The Mozambican government, through the Ministry of Health, with the assistance of Gavi, the Vaccine Alliance, introduced the oral monovalent rotavirus vaccine (Rotarix; GlaxoSmithKline Biologicals) in the National Immunization Program in September 2015. The monovalent rotavirus vaccine is administrated at 2 and 3 months of age. To evaluate the early impact of rotavirus vaccine in Mozambique, we used the National Surveillance of Acute Diarrhea (ViNaDiA) implemented since 2014 as well as hospital discharge data to compared all-cause AGE and rotavirus-associated hospitalizations during the pre-vaccine period to one year after the introduction of the vaccine. 2. Methodology 2.1. Study design Data from the present analysis originates from the National Surveillance of Acute Diarrhea (ViNaDiA) implemented in six sentinel sites: Hospital Geral de Mavalane (HGM), Hospital Geral José Macamo (HJM) and Hospital Central de Maputo (HCM) in Maputo City; Hospital Central da Beira (HCB) in Sofala; Hospital Provincial de Quelimane (HPQ) in Zambézia and Hospital Central de Nampula (HCN) in Nampula. The surveillance system began in May of 2014 in HGM (with a pilot phase from January to April 2014), and gradually included other sentinel sites: HCN and HJM in March 2015, HCB and HPQ in June 2015, and HCM in October 2015. The study population included children aged between 0 and 59 months who presented to sentinel sites or were admitted as inpatients with acute diarrhea disease between the start of surveillance and June 2017. Acute diarrhea disease was defined as the passage of three or more loose or liquid stools in the last 24 h and less than 7 days duration. Fecal specimens were collected from children’s diapers, transferred to polystyrene tubes, kept refrigerated in cooler boxes, and then sent to the laboratory of Instituto Nacional de Saúde (INS) in Maputo City. Fecal specimens from sentinel sites outside of Maputo were kept at 20 °C until shipment. 2.2. Data analysis For the analysis of rotavirus vaccine impact, we conducted the analysis into two parts, the data from all sentinel sites (HGM, HJM, HCM, HCN, HPQ and HCB); and the data from HGM only, because this is the only sentinel site with complete rotavirus testing data for three full years (January 2014 – June 2017). HGM was the first sentinel site where the surveillance system was implemented and thus used as model sentinel site to show the impact rotavirus vaccine. 2.2.1. Acute gastroenteritis-related hospitalizations To assess the impact of rotavirus vaccine on all-cause acute diarrhea hospitalizations during the three years period (January 2014 – June 2017), we reviewed data from the paediatric discharge logbooks from all sentinel sites. We abstracted data on month of age discharge and age of child for all AGE hospitalizations among children <5 years of age.
2.2.2. Laboratory diagnosis Rotavirus antigen was detected in the specimens by enzyme immunoassay (EIA) carried out at the INS laboratory using the WHO-approved commercial kit (IDEIATM, Prospect Diagnostics, United Kingdom) in accordance with manufacturer recommendations. 2.3. Data management and statistical procedures The data were double entered into Epi InfoTM 3.5.1 (CDC, 2008) and exported to SPSS for analyses (Statistical Package for the Social Sciences, Armok, NY: IBM Corp, 2011, version 20.0). Continuous variables were summarized as medians. Cross tabulation was made to obtain the proportion of rotavirus infection during the three years. As a measure of association, prevalence ratios were used and calculated from log-binomial approximation through Poisson regression with robust standard errors. 2.4. Ethical approval The protocol was approved by the National Bioethical Committee for Health from Mozambique (IRB00002657, reference No: 348/ CNBS/13). Parents or guardians of eligible children provided informed consent after receiving information about the purpose of the study. 3. Results 3.1. Overall prevalence <5 years of age From January 2014 to June 2017, 1296 children were included in diarrheal surveillance. All 1296 samples were tested and 26.3% (341/1296) were positive for rotavirus. During the first complete year (2014) of the surveillance, rotavirus positivity rate was 40.2% (39/97) and 38.3% (225/588) in the second year (2015), before rotavirus introduction. After introduction of vaccine, rotavirus positivity rate was 12.2% (53/433) in 2016 and 13.5% (24/178) in 2017. The median age of children hospitalized for rotavirus was 9 and 11 months in 2014 and 2015 and 10 months in 2016 and 2017 (Table 1). 3.2. Rotavirus frequency by age group Rotavirus infection occurred in all age groups of children during the surveillance period (0–11 months, 12–23 months and 24–59 months), with a decrease in the infection rate in all age groups from 2014 to 2016 (Table 1). A greater reduction in the proportion of rotavirus infection was observed in the 0–11 months group than in older age groups (Table 1). At HGM, approximately half of all-cause AGE hospitalizations in the 0–11 months age group were due to rotavirus in 2014 and 2015, but no rotavirus infection was observed in this age group in 2016 and 2017 (Table 2). In HGM the median age of children positive for rotavirus, increased to 17 months in 2016. In 2017 only one child who was 24 months of age was positive for rotavirus (Table 2). 3.3. Seasonal distribution Rotavirus hospitalizations peaked annually prior to vaccination introduction, between June and September (44.4–75.0%) in 2014 and between June and September (43.5–72.8%) in 2015, coinciding with winter period in Mozambique. After vaccine introduction, rotavirus occurred during all year period, however, the peak moved to August to December (20.3–28.6%) in 2016 and was substantially blunted (Fig. 1).
Please cite this article in press as: de Deus N et al. Early impact of rotavirus vaccination in children less than five years of age in Mozambique. Vaccine (2017), https://doi.org/10.1016/j.vaccine.2017.10.060
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N. de Deus et al. / Vaccine xxx (2017) xxx–xxx Table 1 Number of samples tested and positive for rotavirus and median age of positive children per year (2014, 2015, 2016, 2017) in six ViNaDiA sentinel sites. Year
Tested samples (N)
Number of positive (N)
Positive rotavirus (%)
Median age of positive children in months (SD)
2014 0–11 months 12–23 months 24–59 months 0–59 months
64 29 4 97
30 8 1 39
46.9 27.6 25.0 40.2
– – – 9.0 (7.34)
2015 0–11 months 12–23 months 24–59 months 0–59 months
300 224 64 588
140 75 10 225
46.7 33.5 15.6 38.3
– – – 11.0 (6.73)
2016 0–11 months 12–23 months 24–59 months 0–59 months
217 145 71 433
29 19 5 53
13.4 13.1 7.0 12.2
– – – 10.0 (10.63)
2017 0–11 months 12–23 months 24–59 months 0–59 months
83 69 26 178
13 10 1 24
15.7 14.5 3.8 13.5
– – – 10.0 (5.67)
The surveillance began in May of 2014 in HGM, and gradually included other sentinel sites: in March of 2015 we added HCN and HJM, in June of 2015 HCB and HPQ and in October of 2015 HCM.
Table 2 Number of samples tested, positive and median age of positive children per year (2014, 2015, 2016, 2017) in Hospital Geral de Mavalane (HGM).
a
Year
Tested samples (N)
Number of positive (N)
Positive rotavirus (%)
Median age of positive children in months (SD)
2014 0–11 months 12–23 months 24–59 months 0–59 months
64 29 4 97
30 8 1 39
46.9 27.6 25.0 40.2
– – – 9.0 (7.34)
2015 0–11 months 12–23 months 24–59 months 0–59 months
97 75 13 185
50 26 2 78
51.5 34.7 15.4 42.2
– – – 11.0 (5.34)
2016 0–11 months 12–23 months 24–59 months 0–59 months
16 27 6 49
0 7 1 8
0.0 25.9 16.7 16.3
– – – 17.0 (11.35)
2017 0–11 months 12–23 months 24–59 months 0–59 months
13 22 7 42
0 0 1 1
0.0 0.0 14.3 2.4
– – – 24a
Was not possible to estimate the SD with one child.
The pattern of rotavirus infection at HGM was similar to general pattern with a delay in the rotavirus season in 2016 (Fig. 2). This analysis was not possible to do in 2017 yet. 3.4. Trends in diarrheal hospitalizations We sought information on diarrheal hospitalization in different sentinel sites, but we found the following challenges: loss of logbook with diarrhea cases, lack of standardization in diarrhea cases (for example, some sites did not indicate the age of the child and if was hospitalized or not). These aspects have made it difficult to analyze the data, thus we have included only information from the HGM. The analysis from HGM, showed that during the four years period 1021 all-cause AGE hospitalizations occurred in children under five years. Prior to vaccination introduction, in 2014 and 2015 children age 0–11 months were responsible for 51.6%
(173/335) and 50.3% (200/398), respectively, followed by 12–23 and 24–59 months age. In comparison to after vaccination introduction, in 2016, the proportion of all-cause AGE hospitalizations was 37.0% (61/165), 38.2% (63/165), and 24.8% (41/165) in the age group of 0–11 months, 12–23 months and 24–59 months, respectively (Fig. 3). 4. Discussion This analysis suggests evidence of early impact of RV1 vaccination in Mozambique, with marked reductions in the proportion of rotavirus infection rates in hospitalized children with AGE, a shift in rotavirus disease to older age groups, and a delay in the start of the 2016 rotavirus season. After vaccine introduction, rotavirus positivity decreased about 69%. This reduction was observed in all age groups but was greatest in young children resulting in an
Please cite this article in press as: de Deus N et al. Early impact of rotavirus vaccination in children less than five years of age in Mozambique. Vaccine (2017), https://doi.org/10.1016/j.vaccine.2017.10.060
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N. de Deus et al. / Vaccine xxx (2017) xxx–xxx
Vaccine Introduction HJM & HCN
140
&
80
HCM
70
50 80 40 60 30 40
Rotavirus (%)
60
100
20
2014
2015
2016
Mai
Mar
Jan
Nov
Set
Jul
Mai
Mar
Jan
Nov
Jul
Set
Mai
Mar
Jan
Nov
Set
0 Jul
0 Mai
10 Mar
20
Jan
Tested samples
120
HGM
HCB HPQ
2017
Months Negative (N)
Positive (N)
Rotavirus (%)
Fig. 1. Monthly cases of negative and positive samples for rotavirus and percentage of positive cases during the four years period in six ViNaDiA sentinel sites.
70
80.0
60
70.0 60.0
50
50.0
40
40.0 30
30.0
20
20.0
10
Positive Rotavirus (%)
Tested samples (N)
Vaccine Introduction
10.0 0.0
0 Jan Mar May Jul Sep Nov Jan Mar May Jul Sep Nov Jan Mar May Jul Sep Nov Jan Mar May 2014 Negative
2015
2016
Number of Positive Rotavirus (N)
2017
Positive Rotavirus (%)
Fig. 2. Monthly cases of negative and positive samples for rotavirus and percentage of positive cases during the four years period in Hospital Geral de Mavalane.
increased median age at rotavirus infection from 9 to 10 months. The reduction of rotavirus hospitalizations in the unvaccinated age groups, can be due indirect effects from the vaccination (herd immunity), by reducing the disease transmission in the community [6]. This can be sustained by the high rates of rotavirus vaccine coverage in Mozambique, 76% in 2016 [10] and 89% in 2017 (National Immunization Program, 2017. Data not published). The reduction in severe rotavirus disease in children younger than 12 months after vaccine introduction, was also observed in Malawi and Ghana [11,12] as well as other African countries [13,14] thus supporting the hypothesis that the observed decline in the rotavirus infection rates can be attributed largely to the introduction of rotavirus vaccine in the routine immunization program. This observation is also supported by discharge data from our initial sentinel site (HGM), where we observed a reduction in the number of AGE hospitalizations mainly in children under 12 months, which mirrors the reduction of rotavirus infections in this age group. In this site, a decrease in the proportion of hospitalizations in children from 0 to 11 months resulting in an increasing proportion of hospitalizations of children 12–23 and 24–59 months age.
Despite the reduction observed in the rotavirus infection rates, we still have children hospitalized with diarrhea and negative to rotavirus. This suggests differences between regions and necessity for a specific analyse/study for each sentinel site to access some factors like malnutrition, infection with other enteropathogens, HIV and vaccination coverage, since these factors may differ from one province to another and may contribute negatively for the impact of rotavirus vaccine in the country. The pattern of rotavirus infection two years before vaccine introduction was characterized by peaks in the winter period from July to September. However, in the corresponding period of the post vaccination year, this peak did not happen and moved to August and September. This result was also observed in South Africa [15] and other African countries being attributed to the introduction of rotavirus vaccination in the routine immunization [13,14]. There are some limitations in the analyses reported in this paper including the lack of retrospective data of AGE hospitalization for all sentinel sites except for HGM and only 18 months of post vaccine introduction and limited pre-vaccine data. However,
Please cite this article in press as: de Deus N et al. Early impact of rotavirus vaccination in children less than five years of age in Mozambique. Vaccine (2017), https://doi.org/10.1016/j.vaccine.2017.10.060
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Fig. 3. Number of all-cause diarrhea hospitalizations during 4 years period in Hospital Geral de Mavalane.
given the dramatic reduction of rotavirus infection rate observed, our data suggests a substantial impact of vaccine on rotavirus disease and hospitalizations in Mozambique. Continued surveillance and monitoring of vaccine impact is needed to ensure that these reductions are sustained over time. Disclaimer The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the US Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO). Acknowledgements This study was supported by European Foundation Initiative into African Research in Neglected Tropical Diseases (EFINTD) from where Nilsa de Deus is fellow, and World Health Organization (WHO). We would like to thank the parents or guardians who consented for their children to be enrolled in the surveillance. For their efforts with recruitment, data collection and shipment of specimens to Maputo, we would like to thank Mércia Nhaca, Judite Salência, Félix Gundane, Aunésia Marurele, Angelina Pereira, Mulaja Kabeya Étienne, Celso Gabriel, Titos Maulate, Julieta Ernesto, Siasa Mendes, Hércio Simbine, Susete de Carvalho, Marcos Joaquim, Elvira Sarguene, Fernando Vilanculos, Felicidade Martins, Dulce Graça, Edma Samuel, Vivaldo Pedro, Lúcia Matabel, Maria Safrina, Natércia Abreu, Vanessa da Silva, Nazareth Mabutana, Carlos Guilamba and Celina Nhamuave. Conflict of interest statement The authors have declared no conflict of interest. References [1] Tate JE, Burton AH, Boschi-Pinto C, Parashar UD, World Health Organization– Coordinated Global Rotavirus Surveillance Network. Global, regional, and national estimates of rotavirus mortality in children <5 years of age, 2000– 2013. Clin Infect Dis Off Publ Infect Dis Soc Am 2016;62(Suppl 2):S96–S105. https://doi.org/10.1093/cid/civ1013. [2] Dennehy PH. Rotavirus vaccines: an overview. Clin Microbiol Rev 2008;21:198–208. https://doi.org/10.1128/CMR.00029-07.
[3] Mwenda JM, Tate JE, Steele AD, Parashar UD. Preparing for the scale-up of rotavirus vaccine introduction in Africa: establishing surveillance platforms to monitor disease burden and vaccine impact. Pediatr Infect Dis J 2014;33(Suppl 1):S1–5. https://doi.org/10.1097/INF.0000000000000132. [4] Clark HF, Lawley D, Mallette LA, DiNubile MJ, Hodinka RL. Decline in cases of rotavirus gastroenteritis presenting to the Children’s Hospital of Philadelphia after introduction of a pentavalent rotavirus vaccine. Clin Vaccine Immunol 2009;16:382–6. https://doi.org/10.1128/CVI.00382-08. [5] Lambert SB, Faux CE, Hall L, Birrell FA, Peterson KV, Selvey CE, et al. Early evidence for direct and indirect effects of the infant rotavirus vaccine program in Queensland. Med J Aust 2009;191. [6] Parashar UD, Johnson H, Steele AD, Tate JE. Health impact of rotavirus vaccination in developing countries: progress and way forward. Clin Infect Dis 2016;62:S91–5. https://doi.org/10.1093/cid/civ1015. [7] Armah GE, Sow SO, Breiman RF, Dallas MJ, Tapia MD, Feikin DR, et al. Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in sub-Saharan Africa: a randomised, doubleblind, placebo-controlled trial. Lancet 2010;376:606–14. https://doi.org/ 10.1016/S0140-6736(10)60889-6. [8] Nhampossa T, Mandomando I, Acacio S, Quintó L, Vubil D, Ruiz J, et al. Diarrheal disease in rural mozambique: burden, risk factors and etiology of diarrheal disease among children aged 0–59 months seeking care at health facilities. PLoS ONE 2015;10:e0119824. https://doi.org/10.1371/journal. pone.0119824. [9] Kotloff KL, Nataro JP, Blackwelder WC, Nasrin D, Farag TH, Panchalingam S, et al. Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study. Lancet 2013;382:209–22. https://doi.org/ 10.1016/S0140-6736(13)60844-2. [10] WHO UNICEF coverage estimates WHO World Health Organization: Immunization, Vaccines And Biologicals. Vaccine preventable diseases Vaccines monitoring system 2017 Global Summary Reference Time Series: DTP3 n.d. http://apps.who.int/immunization_monitoring/globalsummary/timeseries/ tswucoveragedtp3.html [accessed September 4, 2017]. [11] Enweronu-Laryea CC, Boamah I, Sifah E, Diamenu SK, Armah G. Decline in severe diarrhea hospitalizations after the introduction of rotavirus vaccination in Ghana: a prevalence study. BMC Infect Dis 2014;14:431. https://doi.org/ 10.1186/1471-2334-14-431. [12] Bar-Zeev N, Kapanda L, Tate JE, Jere KC, Iturriza-Gomara M, Nakagomi O, et al. Effectiveness of a monovalent rotavirus vaccine in infants in Malawi after programmatic roll-out: an observational and case-control study. Lancet Infect Dis 2015;15:422–8. https://doi.org/10.1016/S1473-3099(14)71060-6. [13] Landoh D, Atakouma Y, Tate JE, Mwenda JM, Godonou M, Tsolenyanu E, et al. Early evidence of impact of monovalent rotavirus vaccine in Togo. Clin Infect Dis 2016;62(Suppl):2. https://doi.org/10.1093/cid/civ1182. [14] Mpabalwani EM, Simwaka CJ, Mwenda JM, Mubanga CP, Monze M, Matapo B, et al. Impact of rotavirus vaccination on diarrheal hospitalizations in children aged <5 years in Lusaka, Zambia. Clin Infect Dis Off Publ Infect Dis Soc Am 2016;62(Suppl 2):S183–7. https://doi.org/10.1093/cid/civ1027. [15] Groome MJ, Zell ER, Solomon F, Nzenze S, Parashar UD, Izu A, et al. Temporal association of rotavirus vaccine introduction and reduction in all-cause childhood diarrheal hospitalizations in South Africa. Clin Infect Dis Off Publ Infect Dis Soc Am 2016;62(Suppl 2):S188–95. https://doi.org/ 10.1093/cid/civ1204.
Please cite this article in press as: de Deus N et al. Early impact of rotavirus vaccination in children less than five years of age in Mozambique. Vaccine (2017), https://doi.org/10.1016/j.vaccine.2017.10.060
Contents lists available at ScienceDirect
Vaccine journal homepage: www.elsevier.com/locate/vaccine
Early impact of rotavirus vaccination in children less than five years of age in Mozambique Nilsa de Deus a,⇑, Jorfélia José Chilaúle a, Marta Cassocera a, Miguel Bambo a, Jerónimo Sozinho Langa a, Ezequias Sitoe b, Assucênio Chissaque c, Elda Anapakala a, Júlia Sambo a, Esperança Lourenço Guimarães a, Diocreciano Matias Bero a, Eva Dora João a,d, Idalécia Cossa-Moiane a, Jason M. Mwenda e, Goitom G. Weldegebriel f, Umesh D. Parashar g, Jacqueline E. Tate g a
Instituto Nacional de Saúde, Ministério da Saúde, Maputo, Mozambique Hospital Central de Nampula, Ministério da Saúde, Nampula, Mozambique c Faculdade de Ciências, Universidade Eduardo Mondlane, Mozambique d Institute of Hygiene and Tropical Medicine, New University of Lisbon, Lisbon, Portugal e World Health Organization (WHO), Regional Office for Africa, Brazzaville, People’s Republic of Congo f Intercountry Support Team (IST), World Health Organization (WHO), Harare, Zimbabwe g Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, Georgia b
a r t i c l e
i n f o
Article history: Available online xxxx Keywords: Children Acute diarrhea disease Rotavirus vaccine Impact vaccine
a b s t r a c t Background: Mozambique 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. Methods: We 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. Results: During 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. Conclusion: We 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. Ó 2017 Elsevier Ltd. All rights reserved.
1. Introduction Rotavirus is the major cause of acute gastroenteritis (AGE) in children worldwide with an estimated 215,000 deaths in 2013 in infants and young children less than 5 years of age [1]. Sub-Saharan Africa has the largest number of rotavirus deaths and a slower rate of decrease resulting in an increased proportion of deaths from 47.3% in 2000 to 56.3% in 2013 occurring in the region [1]. ⇑ Corresponding author. E-mail address: [email protected] (N. de Deus).
Access to clean water, improved sanitation and hygiene measures are not sufficient to reduce the prevalence of rotavirus; the best preventive measure is vaccination [2]. Two live attenuated oral vaccines against rotavirus (a pentavalent bovine-human reassortant vaccine (RV5; RotaTeq, Merck & Co) and a monovalent human vaccine (RV1; Rotarix GSK Biologicals, Rixensart, Belgium) are licensed and prequalified by the World Health Organization [3]. The introduction of rotavirus vaccine in the national immunization programs has been responsible for a decline in the burden of severe acute gastroenteritis (AGE) in countries such as Australia and United States [4,5]. In Africa, where the burden of disease is
https://doi.org/10.1016/j.vaccine.2017.10.060 0264-410X/Ó 2017 Elsevier Ltd. All rights reserved.
Please cite this article in press as: de Deus N et al. Early impact of rotavirus vaccination in children less than five years of age in Mozambique. Vaccine (2017), https://doi.org/10.1016/j.vaccine.2017.10.060
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N. de Deus et al. / Vaccine xxx (2017) xxx–xxx
greater, the efficacy of the vaccine is lower compared to developed countries [6]. However, the public health benefits of vaccination is high in terms of reduction in the number of severe rotavirus gastroenteritis episodes presented in developed countries because of the greater baseline rate of severe rotavirus gastroenteritis [7]. In Mozambique, the results from the Global Enteric Multicenter Study (GEMS) showed that rotavirus is the most prevalent agent of acute diarrhea in children under the age of 5 years with acute diarrhea [8,9]. The Mozambican government, through the Ministry of Health, with the assistance of Gavi, the Vaccine Alliance, introduced the oral monovalent rotavirus vaccine (Rotarix; GlaxoSmithKline Biologicals) in the National Immunization Program in September 2015. The monovalent rotavirus vaccine is administrated at 2 and 3 months of age. To evaluate the early impact of rotavirus vaccine in Mozambique, we used the National Surveillance of Acute Diarrhea (ViNaDiA) implemented since 2014 as well as hospital discharge data to compared all-cause AGE and rotavirus-associated hospitalizations during the pre-vaccine period to one year after the introduction of the vaccine. 2. Methodology 2.1. Study design Data from the present analysis originates from the National Surveillance of Acute Diarrhea (ViNaDiA) implemented in six sentinel sites: Hospital Geral de Mavalane (HGM), Hospital Geral José Macamo (HJM) and Hospital Central de Maputo (HCM) in Maputo City; Hospital Central da Beira (HCB) in Sofala; Hospital Provincial de Quelimane (HPQ) in Zambézia and Hospital Central de Nampula (HCN) in Nampula. The surveillance system began in May of 2014 in HGM (with a pilot phase from January to April 2014), and gradually included other sentinel sites: HCN and HJM in March 2015, HCB and HPQ in June 2015, and HCM in October 2015. The study population included children aged between 0 and 59 months who presented to sentinel sites or were admitted as inpatients with acute diarrhea disease between the start of surveillance and June 2017. Acute diarrhea disease was defined as the passage of three or more loose or liquid stools in the last 24 h and less than 7 days duration. Fecal specimens were collected from children’s diapers, transferred to polystyrene tubes, kept refrigerated in cooler boxes, and then sent to the laboratory of Instituto Nacional de Saúde (INS) in Maputo City. Fecal specimens from sentinel sites outside of Maputo were kept at 20 °C until shipment. 2.2. Data analysis For the analysis of rotavirus vaccine impact, we conducted the analysis into two parts, the data from all sentinel sites (HGM, HJM, HCM, HCN, HPQ and HCB); and the data from HGM only, because this is the only sentinel site with complete rotavirus testing data for three full years (January 2014 – June 2017). HGM was the first sentinel site where the surveillance system was implemented and thus used as model sentinel site to show the impact rotavirus vaccine. 2.2.1. Acute gastroenteritis-related hospitalizations To assess the impact of rotavirus vaccine on all-cause acute diarrhea hospitalizations during the three years period (January 2014 – June 2017), we reviewed data from the paediatric discharge logbooks from all sentinel sites. We abstracted data on month of age discharge and age of child for all AGE hospitalizations among children <5 years of age.
2.2.2. Laboratory diagnosis Rotavirus antigen was detected in the specimens by enzyme immunoassay (EIA) carried out at the INS laboratory using the WHO-approved commercial kit (IDEIATM, Prospect Diagnostics, United Kingdom) in accordance with manufacturer recommendations. 2.3. Data management and statistical procedures The data were double entered into Epi InfoTM 3.5.1 (CDC, 2008) and exported to SPSS for analyses (Statistical Package for the Social Sciences, Armok, NY: IBM Corp, 2011, version 20.0). Continuous variables were summarized as medians. Cross tabulation was made to obtain the proportion of rotavirus infection during the three years. As a measure of association, prevalence ratios were used and calculated from log-binomial approximation through Poisson regression with robust standard errors. 2.4. Ethical approval The protocol was approved by the National Bioethical Committee for Health from Mozambique (IRB00002657, reference No: 348/ CNBS/13). Parents or guardians of eligible children provided informed consent after receiving information about the purpose of the study. 3. Results 3.1. Overall prevalence <5 years of age From January 2014 to June 2017, 1296 children were included in diarrheal surveillance. All 1296 samples were tested and 26.3% (341/1296) were positive for rotavirus. During the first complete year (2014) of the surveillance, rotavirus positivity rate was 40.2% (39/97) and 38.3% (225/588) in the second year (2015), before rotavirus introduction. After introduction of vaccine, rotavirus positivity rate was 12.2% (53/433) in 2016 and 13.5% (24/178) in 2017. The median age of children hospitalized for rotavirus was 9 and 11 months in 2014 and 2015 and 10 months in 2016 and 2017 (Table 1). 3.2. Rotavirus frequency by age group Rotavirus infection occurred in all age groups of children during the surveillance period (0–11 months, 12–23 months and 24–59 months), with a decrease in the infection rate in all age groups from 2014 to 2016 (Table 1). A greater reduction in the proportion of rotavirus infection was observed in the 0–11 months group than in older age groups (Table 1). At HGM, approximately half of all-cause AGE hospitalizations in the 0–11 months age group were due to rotavirus in 2014 and 2015, but no rotavirus infection was observed in this age group in 2016 and 2017 (Table 2). In HGM the median age of children positive for rotavirus, increased to 17 months in 2016. In 2017 only one child who was 24 months of age was positive for rotavirus (Table 2). 3.3. Seasonal distribution Rotavirus hospitalizations peaked annually prior to vaccination introduction, between June and September (44.4–75.0%) in 2014 and between June and September (43.5–72.8%) in 2015, coinciding with winter period in Mozambique. After vaccine introduction, rotavirus occurred during all year period, however, the peak moved to August to December (20.3–28.6%) in 2016 and was substantially blunted (Fig. 1).
Please cite this article in press as: de Deus N et al. Early impact of rotavirus vaccination in children less than five years of age in Mozambique. Vaccine (2017), https://doi.org/10.1016/j.vaccine.2017.10.060
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N. de Deus et al. / Vaccine xxx (2017) xxx–xxx Table 1 Number of samples tested and positive for rotavirus and median age of positive children per year (2014, 2015, 2016, 2017) in six ViNaDiA sentinel sites. Year
Tested samples (N)
Number of positive (N)
Positive rotavirus (%)
Median age of positive children in months (SD)
2014 0–11 months 12–23 months 24–59 months 0–59 months
64 29 4 97
30 8 1 39
46.9 27.6 25.0 40.2
– – – 9.0 (7.34)
2015 0–11 months 12–23 months 24–59 months 0–59 months
300 224 64 588
140 75 10 225
46.7 33.5 15.6 38.3
– – – 11.0 (6.73)
2016 0–11 months 12–23 months 24–59 months 0–59 months
217 145 71 433
29 19 5 53
13.4 13.1 7.0 12.2
– – – 10.0 (10.63)
2017 0–11 months 12–23 months 24–59 months 0–59 months
83 69 26 178
13 10 1 24
15.7 14.5 3.8 13.5
– – – 10.0 (5.67)
The surveillance began in May of 2014 in HGM, and gradually included other sentinel sites: in March of 2015 we added HCN and HJM, in June of 2015 HCB and HPQ and in October of 2015 HCM.
Table 2 Number of samples tested, positive and median age of positive children per year (2014, 2015, 2016, 2017) in Hospital Geral de Mavalane (HGM).
a
Year
Tested samples (N)
Number of positive (N)
Positive rotavirus (%)
Median age of positive children in months (SD)
2014 0–11 months 12–23 months 24–59 months 0–59 months
64 29 4 97
30 8 1 39
46.9 27.6 25.0 40.2
– – – 9.0 (7.34)
2015 0–11 months 12–23 months 24–59 months 0–59 months
97 75 13 185
50 26 2 78
51.5 34.7 15.4 42.2
– – – 11.0 (5.34)
2016 0–11 months 12–23 months 24–59 months 0–59 months
16 27 6 49
0 7 1 8
0.0 25.9 16.7 16.3
– – – 17.0 (11.35)
2017 0–11 months 12–23 months 24–59 months 0–59 months
13 22 7 42
0 0 1 1
0.0 0.0 14.3 2.4
– – – 24a
Was not possible to estimate the SD with one child.
The pattern of rotavirus infection at HGM was similar to general pattern with a delay in the rotavirus season in 2016 (Fig. 2). This analysis was not possible to do in 2017 yet. 3.4. Trends in diarrheal hospitalizations We sought information on diarrheal hospitalization in different sentinel sites, but we found the following challenges: loss of logbook with diarrhea cases, lack of standardization in diarrhea cases (for example, some sites did not indicate the age of the child and if was hospitalized or not). These aspects have made it difficult to analyze the data, thus we have included only information from the HGM. The analysis from HGM, showed that during the four years period 1021 all-cause AGE hospitalizations occurred in children under five years. Prior to vaccination introduction, in 2014 and 2015 children age 0–11 months were responsible for 51.6%
(173/335) and 50.3% (200/398), respectively, followed by 12–23 and 24–59 months age. In comparison to after vaccination introduction, in 2016, the proportion of all-cause AGE hospitalizations was 37.0% (61/165), 38.2% (63/165), and 24.8% (41/165) in the age group of 0–11 months, 12–23 months and 24–59 months, respectively (Fig. 3). 4. Discussion This analysis suggests evidence of early impact of RV1 vaccination in Mozambique, with marked reductions in the proportion of rotavirus infection rates in hospitalized children with AGE, a shift in rotavirus disease to older age groups, and a delay in the start of the 2016 rotavirus season. After vaccine introduction, rotavirus positivity decreased about 69%. This reduction was observed in all age groups but was greatest in young children resulting in an
Please cite this article in press as: de Deus N et al. Early impact of rotavirus vaccination in children less than five years of age in Mozambique. Vaccine (2017), https://doi.org/10.1016/j.vaccine.2017.10.060
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N. de Deus et al. / Vaccine xxx (2017) xxx–xxx
Vaccine Introduction HJM & HCN
140
&
80
HCM
70
50 80 40 60 30 40
Rotavirus (%)
60
100
20
2014
2015
2016
Mai
Mar
Jan
Nov
Set
Jul
Mai
Mar
Jan
Nov
Jul
Set
Mai
Mar
Jan
Nov
Set
0 Jul
0 Mai
10 Mar
20
Jan
Tested samples
120
HGM
HCB HPQ
2017
Months Negative (N)
Positive (N)
Rotavirus (%)
Fig. 1. Monthly cases of negative and positive samples for rotavirus and percentage of positive cases during the four years period in six ViNaDiA sentinel sites.
70
80.0
60
70.0 60.0
50
50.0
40
40.0 30
30.0
20
20.0
10
Positive Rotavirus (%)
Tested samples (N)
Vaccine Introduction
10.0 0.0
0 Jan Mar May Jul Sep Nov Jan Mar May Jul Sep Nov Jan Mar May Jul Sep Nov Jan Mar May 2014 Negative
2015
2016
Number of Positive Rotavirus (N)
2017
Positive Rotavirus (%)
Fig. 2. Monthly cases of negative and positive samples for rotavirus and percentage of positive cases during the four years period in Hospital Geral de Mavalane.
increased median age at rotavirus infection from 9 to 10 months. The reduction of rotavirus hospitalizations in the unvaccinated age groups, can be due indirect effects from the vaccination (herd immunity), by reducing the disease transmission in the community [6]. This can be sustained by the high rates of rotavirus vaccine coverage in Mozambique, 76% in 2016 [10] and 89% in 2017 (National Immunization Program, 2017. Data not published). The reduction in severe rotavirus disease in children younger than 12 months after vaccine introduction, was also observed in Malawi and Ghana [11,12] as well as other African countries [13,14] thus supporting the hypothesis that the observed decline in the rotavirus infection rates can be attributed largely to the introduction of rotavirus vaccine in the routine immunization program. This observation is also supported by discharge data from our initial sentinel site (HGM), where we observed a reduction in the number of AGE hospitalizations mainly in children under 12 months, which mirrors the reduction of rotavirus infections in this age group. In this site, a decrease in the proportion of hospitalizations in children from 0 to 11 months resulting in an increasing proportion of hospitalizations of children 12–23 and 24–59 months age.
Despite the reduction observed in the rotavirus infection rates, we still have children hospitalized with diarrhea and negative to rotavirus. This suggests differences between regions and necessity for a specific analyse/study for each sentinel site to access some factors like malnutrition, infection with other enteropathogens, HIV and vaccination coverage, since these factors may differ from one province to another and may contribute negatively for the impact of rotavirus vaccine in the country. The pattern of rotavirus infection two years before vaccine introduction was characterized by peaks in the winter period from July to September. However, in the corresponding period of the post vaccination year, this peak did not happen and moved to August and September. This result was also observed in South Africa [15] and other African countries being attributed to the introduction of rotavirus vaccination in the routine immunization [13,14]. There are some limitations in the analyses reported in this paper including the lack of retrospective data of AGE hospitalization for all sentinel sites except for HGM and only 18 months of post vaccine introduction and limited pre-vaccine data. However,
Please cite this article in press as: de Deus N et al. Early impact of rotavirus vaccination in children less than five years of age in Mozambique. Vaccine (2017), https://doi.org/10.1016/j.vaccine.2017.10.060
N. de Deus et al. / Vaccine xxx (2017) xxx–xxx
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Fig. 3. Number of all-cause diarrhea hospitalizations during 4 years period in Hospital Geral de Mavalane.
given the dramatic reduction of rotavirus infection rate observed, our data suggests a substantial impact of vaccine on rotavirus disease and hospitalizations in Mozambique. Continued surveillance and monitoring of vaccine impact is needed to ensure that these reductions are sustained over time. Disclaimer The findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the US Centers for Disease Control and Prevention (CDC) and World Health Organization (WHO). Acknowledgements This study was supported by European Foundation Initiative into African Research in Neglected Tropical Diseases (EFINTD) from where Nilsa de Deus is fellow, and World Health Organization (WHO). We would like to thank the parents or guardians who consented for their children to be enrolled in the surveillance. For their efforts with recruitment, data collection and shipment of specimens to Maputo, we would like to thank Mércia Nhaca, Judite Salência, Félix Gundane, Aunésia Marurele, Angelina Pereira, Mulaja Kabeya Étienne, Celso Gabriel, Titos Maulate, Julieta Ernesto, Siasa Mendes, Hércio Simbine, Susete de Carvalho, Marcos Joaquim, Elvira Sarguene, Fernando Vilanculos, Felicidade Martins, Dulce Graça, Edma Samuel, Vivaldo Pedro, Lúcia Matabel, Maria Safrina, Natércia Abreu, Vanessa da Silva, Nazareth Mabutana, Carlos Guilamba and Celina Nhamuave. Conflict of interest statement The authors have declared no conflict of interest. References [1] Tate JE, Burton AH, Boschi-Pinto C, Parashar UD, World Health Organization– Coordinated Global Rotavirus Surveillance Network. Global, regional, and national estimates of rotavirus mortality in children <5 years of age, 2000– 2013. Clin Infect Dis Off Publ Infect Dis Soc Am 2016;62(Suppl 2):S96–S105. https://doi.org/10.1093/cid/civ1013. [2] Dennehy PH. Rotavirus vaccines: an overview. Clin Microbiol Rev 2008;21:198–208. https://doi.org/10.1128/CMR.00029-07.
[3] Mwenda JM, Tate JE, Steele AD, Parashar UD. Preparing for the scale-up of rotavirus vaccine introduction in Africa: establishing surveillance platforms to monitor disease burden and vaccine impact. Pediatr Infect Dis J 2014;33(Suppl 1):S1–5. https://doi.org/10.1097/INF.0000000000000132. [4] Clark HF, Lawley D, Mallette LA, DiNubile MJ, Hodinka RL. Decline in cases of rotavirus gastroenteritis presenting to the Children’s Hospital of Philadelphia after introduction of a pentavalent rotavirus vaccine. Clin Vaccine Immunol 2009;16:382–6. https://doi.org/10.1128/CVI.00382-08. [5] Lambert SB, Faux CE, Hall L, Birrell FA, Peterson KV, Selvey CE, et al. Early evidence for direct and indirect effects of the infant rotavirus vaccine program in Queensland. Med J Aust 2009;191. [6] Parashar UD, Johnson H, Steele AD, Tate JE. Health impact of rotavirus vaccination in developing countries: progress and way forward. Clin Infect Dis 2016;62:S91–5. https://doi.org/10.1093/cid/civ1015. [7] Armah GE, Sow SO, Breiman RF, Dallas MJ, Tapia MD, Feikin DR, et al. Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in sub-Saharan Africa: a randomised, doubleblind, placebo-controlled trial. Lancet 2010;376:606–14. https://doi.org/ 10.1016/S0140-6736(10)60889-6. [8] Nhampossa T, Mandomando I, Acacio S, Quintó L, Vubil D, Ruiz J, et al. Diarrheal disease in rural mozambique: burden, risk factors and etiology of diarrheal disease among children aged 0–59 months seeking care at health facilities. PLoS ONE 2015;10:e0119824. https://doi.org/10.1371/journal. pone.0119824. [9] Kotloff KL, Nataro JP, Blackwelder WC, Nasrin D, Farag TH, Panchalingam S, et al. Burden and aetiology of diarrhoeal disease in infants and young children in developing countries (the Global Enteric Multicenter Study, GEMS): a prospective, case-control study. Lancet 2013;382:209–22. https://doi.org/ 10.1016/S0140-6736(13)60844-2. [10] WHO UNICEF coverage estimates WHO World Health Organization: Immunization, Vaccines And Biologicals. Vaccine preventable diseases Vaccines monitoring system 2017 Global Summary Reference Time Series: DTP3 n.d. http://apps.who.int/immunization_monitoring/globalsummary/timeseries/ tswucoveragedtp3.html [accessed September 4, 2017]. [11] Enweronu-Laryea CC, Boamah I, Sifah E, Diamenu SK, Armah G. Decline in severe diarrhea hospitalizations after the introduction of rotavirus vaccination in Ghana: a prevalence study. BMC Infect Dis 2014;14:431. https://doi.org/ 10.1186/1471-2334-14-431. [12] Bar-Zeev N, Kapanda L, Tate JE, Jere KC, Iturriza-Gomara M, Nakagomi O, et al. Effectiveness of a monovalent rotavirus vaccine in infants in Malawi after programmatic roll-out: an observational and case-control study. Lancet Infect Dis 2015;15:422–8. https://doi.org/10.1016/S1473-3099(14)71060-6. [13] Landoh D, Atakouma Y, Tate JE, Mwenda JM, Godonou M, Tsolenyanu E, et al. Early evidence of impact of monovalent rotavirus vaccine in Togo. Clin Infect Dis 2016;62(Suppl):2. https://doi.org/10.1093/cid/civ1182. [14] Mpabalwani EM, Simwaka CJ, Mwenda JM, Mubanga CP, Monze M, Matapo B, et al. Impact of rotavirus vaccination on diarrheal hospitalizations in children aged <5 years in Lusaka, Zambia. Clin Infect Dis Off Publ Infect Dis Soc Am 2016;62(Suppl 2):S183–7. https://doi.org/10.1093/cid/civ1027. [15] Groome MJ, Zell ER, Solomon F, Nzenze S, Parashar UD, Izu A, et al. Temporal association of rotavirus vaccine introduction and reduction in all-cause childhood diarrheal hospitalizations in South Africa. Clin Infect Dis Off Publ Infect Dis Soc Am 2016;62(Suppl 2):S188–95. https://doi.org/ 10.1093/cid/civ1204.
Please cite this article in press as: de Deus N et al. Early impact of rotavirus vaccination in children less than five years of age in Mozambique. Vaccine (2017), https://doi.org/10.1016/j.vaccine.2017.10.060