Direct and indirect costs of acute diarrhea in children under five years of age in Indonesia: Health facilities and community survey.

BACKGROUND: Diarrhea remains a major cause of child morbidity and mortality in low- and middle-income countries. Reliable data on the economic burden of diarrhea is required to support the selection of appropriate health intervention programs. This study aimed to estimate the costs of acute diarrhea in children under five years of age in Indonesia, a large middle-income country with a substantial diarrheal burden. METHODS: Direct medical cost data were extracted retrospectively for 1050 children under five years of age with acute diarrhea receiving inpatient care across 45 health facilities in seven Indonesian provinces during 2017-2020. Direct medical costs for children treated in outpatient settings were estimated by collecting unit costs associated with standard diarrhea case management in children. A structured interview of 240 caregivers of inpatients was also conducted retrospectively to estimate direct non-medical costs as well as indirect costs from caregiver income loss. RESULTS: The weighted average direct medical cost for treatment of acute diarrhea as an inpatient and outpatient across health facility types was US$99.8 (SD±$56.8)(35% room costs, 29% professional fees, 26% medication costs, 10% diagnostic costs) and US$7.6 (SD±$4.3) (34% diagnostic costs, 28% medication costs, 27% professional fees, 10% registration fees), respectively. The average direct non-medical household cost for an acute diarrheal admission was US$4.90 and the indirect cost was US$9.90. CONCLUSION: There is a significant economic burden associated with acute diarrhea in children in Indonesia. This study, based on a wide variety of health care settings and geographical regions, provides data to inform the economic evaluation of rotavirus vaccines and other diarrheal prevention programs. FUNDING: This work was supported by a research grant from the Murdoch Children's Research Institute (MCRI) and PATH; and the Indonesian Technical Advisory Group on Immunization (ITAGI).

Developing a manufacturing process to deliver a cost effective and stable liquid human rotavirus vaccine.

Despite solid evidence of the success of rotavirus vaccines in saving children from fatal gastroenteritis, more than 82 million infants worldwide still lack access to a rotavirus vaccine. The main barriers to global rotavirus vaccine coverage include cost, manufacturing capacity and suboptimal efficacy in low- and lower-middle income countries. One vaccine candidate with the potential to address the latter is based on the novel, naturally attenuated RV3 strain of rotavirus, RV3-BB vaccine administered in a birth dose strategy had a vaccine efficacy against severe rotavirus gastroenteritis of 94% at 12 months of age in infants in Indonesia. To further develop this vaccine candidate, a well-documented and low-cost manufacturing process is required. A target fully loaded cost of goods (COGs) of ≤$3.50 per course of three doses was set based on predicted market requirements. COGs modelling was leveraged to develop a process using Vero cells in cell factories reaching high titers, reducing or replacing expensive reagents and shortening process time to maximise output. Stable candidate liquid formulations were developed allowing two-year storage at 2-8 °C. In addition, the formulation potentially renders needless the pretreatment of vaccinees with antacid to ensure adequate gastric acid neutralization for routine oral vaccination. As a result, the formulation allows small volume dosing and reduction of supply chain costs. A dose ranging study is currently underway in Malawi that will inform the final clinical dose required. At a clinical dose of ≤6.3 log10 FFU, the COGs target of ≤$3.50 per three dose course was met. At a clinical dose of 6.5 log10 FFU, the final manufacturing process resulted in a COGs that is substantially lower than the current average market price, 2.44 USD per dose. The manufacturing and formulation processes were transferred to BioFarma in Indonesia to enable future RV3-BB vaccine production.

Rotavirus specific maternal antibodies and immune response to RV3-BB neonatal rotavirus vaccine in New Zealand.

BACKGROUND: Maternal antibodies, acquired passively via placenta and/or breast milk, may contribute to the reduced efficacy of oral rotavirus vaccines observed in children in developing countries. This study aimed to investigate the effect of rotavirus specific maternal antibodies on the serum IgA response or stool excretion of vaccine virus after any dose of an oral rotavirus vaccine, RV3-BB, in parallel to a Phase IIa clinical trial conducted at Dunedin Hospital, New Zealand. At the time of the study rotavirus vaccines had not been introduced in New Zealand and the burden of rotavirus disease was evident. METHODS: Rotavirus specific IgG and serum neutralizing antibody (SNA) levels in cord blood and IgA levels in colostrum and breast milk samples collected ∼4 weeks, ∼20 weeks and ∼28 weeks after birth were measured. Infants were randomized to receive the first dose of vaccine at 0-5 d (neonatal schedule) or 8 weeks (infant schedule). Breast feeding was with-held for 30 minutes before and after vaccine administration. The relationship between rotavirus specific IgG and SNA levels in cord blood and IgA in colostrum and breast milk at the time of first active dose of RV3-BB vaccine and level of IgA response and stool excretion after 3 doses of vaccine was assessed using linear and logistic regression. RESULTS: Forty infants received 3 doses of RV3-BB rotavirus vaccine and were included in the analysis of the neonatal and infant groups. Rotavirus specific IgA in colostrum (neonatal schedule group) and breast milk at 4 weeks (infant schedule group) was identified in 14/21 (67%) and 14/17 (82%) of infants respectively. There was little evidence of an association between IgA in colostrum or breast milk IgA at 4 weeks, or between cord IgG or SNA level, and IgA response or stool excretion after 3 doses of RV3-BB, or after one dose (neonatal schedule) (all p>0.05). CONCLUSIONS: The level of IgA in colostrum or breast milk and level of placental IgG and SNA did not impact on the serum IgA response or stool excretion following 3 doses of RV3-BB Rotavirus Vaccine administered using either a neonatal or infant schedule in New Zealand infants.

Optimizing immunization in pediatric special risk groups.

This article analyzes the current recommended practices and evidence in the immunization of pediatric 'special risk groups'. Special risk group patients are at higher risk of vaccine-preventable diseases and hence require additional strategies to maximize protection against these diseases. The special risk groups include those with an underlying chronic disease, some of whom are on immunosuppressive therapy to treat that condition. The article uses four special risk groups (acute lymphoblastic leukemia; preterm birth; juvenile idiopathic arthritis; and inflammatory bowel disease), to highlight the management considerations and potential vaccination strategies. The risks, benefits and timing of vaccination in the setting of immunosuppression require detailed discussion with treating clinicians, in particular the use of live-attenuated vaccines. The immunogenicity of vaccines in these special risk groups helps provide the evidence base for their immunization guidelines. Protection can include 'cocooning' (i.e., ensuring appropriate immunizations within the immediate family; e.g., varicella, influenza and pertussis vaccination). Improving timeliness and minimizing missed opportunities to vaccinate individuals with these special risk conditions will also optimize protection from vaccine-preventable diseases.

The burden of hospitalised rotavirus infections in Fiji.

Rotavirus is the most common cause of acute severe dehydrating diarrhoea in young children worldwide. We describe the burden of rotavirus disease and the rotavirus types causing it in the largest city in Fiji. During 2006 and 2007, 592 children under 5 years of age were admitted to hospital in Suva, Fiji with acute diarrhoea. Of the 454 children for whom a stool specimen was tested, 39% were positive for rotavirus and the predominant strain found was the serotype G3[P8]. There is a significant burden of disease due to rotavirus in Fiji and the introduction of rotavirus vaccines into the national immunization schedule may drastically reduce inpatient diarrhoeal disease.

Assessment of postlicensure safety of rotavirus vaccines, with emphasis on intussusception.

The global implementation of rotavirus vaccines will result in a major step toward limiting the disease burden of rotavirus infection. However, as history has shown with the experience of Rotashield (Wyeth Lederle Vaccines), the introduction of a new vaccine should occur in parallel with a postmarketing surveillance strategy to detect any unexpected or rare adverse events. Two new rotavirus vaccines (Rotarix [GSK Biologicals] and RotaTeq [Merck]) have been found to be safe and effective in large clinical trials involving >60,000 infants in the Americas and Europe. However, given that intussusception is an extremely rare event, some risk could be detected as the vaccine is administered to a larger number of infants. In response to a recommendation of the World Health Organization Global Advisory Committee for Vaccine Safety, a standardized approach to the postmarketing surveillance of rotavirus vaccine safety has been developed. We review the principal safety issues requiring further evaluation in postlicensure use of rotavirus vaccines. For intussusception, we also discuss challenges and approaches to monitoring.