Diarrhea remains a major cause of child morbidity and death mostly in low-income countries including Yemen. Rotavirus is the primary cause of severe dehydrating diarrhea in children under 5 years of age. The health and economic burdens are substantial, affecting already overcrowded emergency rooms and hospital inpatient facilities in addition to increasing the financial stresses on poor parents [11, 12].
Following the introduction of RV vaccine, impressive declines in RV and all-cause diarrhea hospitalizations were observed in many countries [13]. This study of the epidemiology of all-cause and rotavirus-specific diarrhea hospitalization is the first to report that rotavirus vaccine introduction in Yemen may have resulted in important epidemiological changes in infant and childhood diarrhea. The study showed an impressive 50 % reduction in all-cause severe dehydrating diarrhea and a statistically significant reduction of rotavirus diarrhea by 48 % in the post-vaccine period (Table 3). After Rotarix vaccine introduction, the prevalence of RVAGE was also significantly reduced in children <12 months of age, who are the most vulnerable (Table 2). Our study also showed that among all children with severe all-cause GE that needed hospitalization, severe RVAGE hospitalization was significantly reduced by 67 % from 43.5 % (796/1828) to 20.1 % (136/675), an OR of 0.33 (95 % CI: 0.27–0.403; p < 0.0001) after Rotarix vaccine introduced in Yemen. There was also a significant reduction of 49 % of RVAGE patients visiting the emergency room from 44 % (672/1528) to 28.8 % (67/233), an OR of 0.51 (0.38–0.69; p < 0.0001). Despite successful treatment outcome remained unchanged in the pre- and postvaccine periods, we observed a statistically significant reduction with an adjusted OR of 0.615 (95 % CI: 0.400–0.946) of children referred for further intensive care in the post-vaccine period (Table 3). These results suggest reductions in both RV mortality and in the cost of hospitalization may have occurred. Previous reviews of RV vaccine and diarrhea mortality included efficacy studies that showed regional variation, with 91 % prevention of severe RV diarrhea in developed countries, but efficacy as low as 42.2 % in high-mortality countries. The evidence provided by these efficacy studies suggests that RV vaccine has decreased RV-specific and all-cause diarrhea mortality in all regions of the world [14, 15]. In GAVI-eligible countries, including Yemen—one of world’s poorest countries—RV vaccine could prevent an estimated 2.46 million childhood deaths between 2011 and 2030, with an annual decrease of 180,000 at peak vaccine uptake [16].
Rotavirus is most frequently associated with severe dehydrating diarrhea, substantial hospitalization, increased emergency room visits, and increased costs for both hospitals and parents [12]. In this study, in addition to greater than 60 and 49 % reductions of severe RVAGE hospitalization and emergency room visits, respectively, we also observed significant reductions in severe dehydration among severe all-cause and severe RAVGE inpatients. Both showed significant reductions of 58 % from 33.1 % (648/1960) to 17.2 % (117/681), an OR of 0.42 (95 % CI 0.34–0.52), and 55 % from 34.7 % (276/795) to 19.3 % (26/135), an OR of 0.45 (95 % CI: 0.29–0.71), respectively. The introduction of RV vaccine in Yemen opened a new era of vaccine-based intervention for diarrhea control with extensive health and economic benefits. The monitoring of changes in the burden of RV and all-cause diarrhea provides important information to assist health policy-makers in Yemen and neighboring poor countries in the horn of Africa.
Following the introduction of RV vaccine, we observed an important and significant increase in the proportion of children with non-RV AGE at the sentinel hospitals as RVAGE prevalence significantly decreased. We observed an overall increase in the proportion of hospital visits for non-RV AGE to 80.1 % (940/1173) from 59.4 % (2239/3767) in the prevaccine period. Emergency room visits for non-RV AGE increased to 81.3 % (292/359) from 60.8 % (1041/1713), and hospitalization for severe nonRV AGE increased to 79.9 % (539/675) from 56.5 % (1032/1828). A recent study from Nicaragua reported that norovirus (NV) was more commonly detected as a cause of diarrhea while rotavirus became less common following rotavirus vaccine introduction [17]. The study reported that more than 57 % of diarrhea in children under 24 months of age was caused by NV. Another study reported that NV has become the leading viral cause of gastroenteritis in both hospital and community settings in Nicaragua following the implementation of RV vaccination [18]. In Yemen before rotavirus vaccine introduction, NV was detected in 10 % of children from 1 to 60 months of age with AGE [8]. To establish effective management guidelines, epidemiological changes in the causes of childhood diarrhea following introduction of rotavirus vaccine need ongoing surveillance. Our findings of increasing non-RV severe GE could indicate that NV may be increasing and needs close monitoring. Additional preventive interventions that reduce the burden of diarrhea-related morbidity and mortality need consideration. These include promotion of breastfeeding, provision of safe water, and improving sanitation and hygiene in low-income countries, including Yemen, and particularly in communities with poor socioeconomic status.
Worldwide, the most common G genotypes reported are G1, G2, G3, and G9; P[4] and P[8] are the common P genotypes [19, 20]. Before rotavirus vaccine introduction, five G–P combinations: G1P[8], G2P[4], G3P[8], G4P[8], G9P[8] accounted for almost 90 % of rotavirus disease in children worldwide [20]. The only study in Yemen before rotavirus vaccine introduction reported that 55 % of the G–P strains were G1P[8], 21 % were G9P[8], and 12 % were G2P[4], but the study was limited by its restriction to one city (Sana’a) in the highlands. In our study, which was conducted in two cities (Taiz, located at an altitude of 1400 m, and Aden, a coastal city) included surveillance data from a 5-year prevaccine period. We observed that the most prevalent strains were G1P[8], isolated from 15/33 patients (45.5 %), and G2P[4], isolated from 26/34 patients (76.5 %). The G9P[8] strain had not been detected before Rotarix introduction, which may indicate temporal and geographical variations [21].
Many low-income countries in addition to Yemen have added rotavirus vaccine to their national immunization programs. Monitoring vaccine effectiveness against the circulating rotavirus strains and any accompanying changes in strain diversity need continuous active rotavirus surveillance. It is crucial to identify rotavirus strain diversity. Our study revealed a statistically significant 38.3 % (95 % CI: −50.6; −26.1) reduction of G2 (heterotypic) circulating strains in the post-vaccine period even though they are not included in the monovalent G1P[8] vaccine. The G1 strain (partly homotypic) decreased to 33.3 % (16/48) from 41.3 % (33/80), a nonsignificant reduction of 7.9 % (Table 4). Additionally, G9 strains significantly increased in the post-vaccine period, with the emergence of G9P[8] and G9P[4], which were not detected in RV from the pre-vaccine period (Table 4). These findings may indicate that variations in circulating rotavirus strains can occur independently and not as a result of rotavirus vaccine selective pressure. Existing evidence confirms that Rotarix provides good protection against both fully and partly homotypic, and fully heterotypic circulating strains including G2P[4], G9P[4], and G9P[8] [22–24]. A recent systematic review and meta-analysis of published research reports on the distribution of rotavirus strains and strain-specific rotavirus vaccine effectiveness in high- and middle-income Latin America countries showed that rotavirus vaccines (RV1 and RV5) provided adequate protection against RV disease, and that the protection was effective against various homotypic, partly heterotypic, and fully heterotypic rotavirus strains. The review also confirmed that vaccine-induced selective pressure had not occurred. The authors acknowledged the lack of data from low-income countries [25]. A previous study conducted in a low-income setting in Chiapas, the poorest state in Mexico, showed that Rotarix provided adequate protection against severe RVAGE caused by a fully heterotypic strain (G9P[4]), and reported a vaccine effectiveness of 94 % [24]. These findings are reassuring for low-income countries that have recently introduced rotavirus vaccines.
In our study, we observed increase in the prevalence of mixed G and [P] circulating strains after Rotarix vaccine introduction. The G-mix prevalence increased to 20.8 % and [P] mix to 22.9 % (Table 4). Similar observations were reported in a study from Bangladesh [26] that reported a substantial proportion of mixed rotavirus circulating strains of more than 14 %, and exceeding 37 % in 2009–2010 that could have resulted in the generation of unusual combined G[P] circulating strains in 2011–2012. Similar observations have been reported in other countries in the Indian subcontinent [27].
The study has several limitations. It was conducted based on surveillance data collected from two sentinel hospitals, which are not devoid of problems such as missing data. Other limitations are the observational design, and a short post-vaccine period. Lack of information on the vaccination status of children included in the surveillance was a major limitation. The treatment outcomes of 6.8 % of children in the pre-vaccine and 15.8 % in the post-vaccine periods were not known (Table 2), and that may have affected the result of the vaccine impact on the treatment outcomes, particularly diarrhea-related mortality. In addition, follow-up of children with severe AGE who were hospitalized ended on the day of discharge. However, the proportion of children hospitalized with severe all-cause or RVAGE who needed referral for intensive care was significantly reduced (by 38 %) in 2013–2014 (Tables 2 and 3). Finally, the surveillance data were from two governorates, Taiz and Aden, and may not be directly applicable to settings in other governorates of Yemen. However the results provide an important indication of the potential benefits of rotavirus vaccine in other regions of Yemen and the neighboring low-income countries in the horn of Africa because these countries and Yemen have high levels of poverty and high infant and childhood mortality rates.
