Evaluating the first introduction of rotavirus vaccine in Thailand: Moving from evidence to policy

Vaccine 35 (2017) 796–801

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Evaluating the first introduction of rotavirus vaccine in Thailand: Moving from evidence to policy Piyanit Tharmaphornpilas a,⇑, Suchada Jiamsiri a, Somchit Boonchaiya a, Onwipa Rochanathimoke b, Wiravan Thinyounyong c, Sumana Tuntiwitayapun d, Ratigorn Guntapong e, Arthorn Riewpaiboon b, Aim-on Rasdjarmrearnsook a, Roger I. Glass f a

Department of Disease Control, Ministry of Public Health, Nonthaburi, Thailand Faculty of Pharmacy, Mahidol University, Bangkok, Thailand Phetchabun Provincial Health Office, Phetchabun, Thailand d Sukhothai Provincial Health Office, Sukhothai, Thailand e Department of Medical Science, Ministry of Public Health, Nonthaburi, Thailand f Fogarty International Center, National Institutes of Health, Bethesda, MD, USA b c

a r t i c l e

i n f o

Article history: Received 26 August 2016 Received in revised form 14 December 2016 Accepted 15 December 2016 Available online 2 January 2017 Keywords: Rotavirus vaccine Vaccine effectiveness Vaccine impact

a b s t r a c t Background: We assessed the effectiveness and possible impact of introducing rotavirus vaccine into the routine immunization program. Methods: Two provinces were selected for an observational study, one where vaccine was introduced and another where vaccine was not available. In these areas, two sub-studies were linked. The prospective cohort study enrolled children 2 month old and followed them to the age of 18 months to detect all diarrhea episodes. The hospital surveillance study enrolled all children up to age 5 hospitalized with diarrhea whose fecal samples were tested for rotavirus. Rates of rotavirus hospitalizations in older children who had not been vaccinated in both settings provided data to determine whether immunization had an indirect herd effect. The key endpoints for the study were both vaccine effectiveness (VE) based upon hospitalized rotavirus diarrhea and herd protection. Findings: From the cohort study, the overall VE for hospitalized rotavirus diarrhea was 88% (95%CI 76–94). Data from hospital surveillance indicated that for 2 consecutive years, the seasonal peak of rotavirus admissions was no longer present in the vaccinated area. Herd protection was observed among older children born before the rotavirus vaccine program was introduced, who experienced a 40–69% reduction in admission for rotavirus. Conclusions: Rotavirus vaccine was highly effective in preventing diarrheal hospitalizations and in conferring herd protection among older children who had not been vaccinated. Ó 2016 Elsevier Ltd. All rights reserved.

1. Introduction In 2009, the World Health Organization recommended that rotavirus vaccine should be included in all national childhood immunization programs as part of a comprehensive strategy to control diarrheal diseases [1]. By May 2016, 81 countries had introduced the vaccine but notably, none of these countries was in Asia [2]. This was surprising because in 1999, the first regional hospital surveillance network for rotavirus diarrhea was established in Asia and documented the high burden of the disease throughout the ⇑ Corresponding author at: Department of Disease Control, Ministry of Public Health, Muang, Nonthaburi 11000, Thailand. E-mail address: [email protected] (P. Tharmaphornpilas). http://dx.doi.org/10.1016/j.vaccine.2016.12.043 0264-410X/Ó 2016 Elsevier Ltd. All rights reserved.

region [3]. Many studies elsewhere in the world have demonstrated the impressive impact of the introduction of rotavirus vaccine to reduce both hospitalizations and death from this common childhood disease [4–6]. Reasons for this delayed introduction in Asia include concern for the lower efficacy of live oral vaccine in low income countries [7,8], questions about the true burden of this usually mild cause of diarrhea, and the substantial cost of the vaccine for national immunization programs already challenged to introduce other new vaccines for Streptococcus pneumoniae and human papillomavirus [9]. Consequently, seven years after the WHO recommendation, Asia with 40% or more of the world’s population is not yet benefitting from the introduction of rotavirus vaccine.

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To address this issue in Thailand, the National Vaccine Committee considered introduction of this vaccine in 2010. Seeking more local evidence to assess this strategy, it recommended conducting a pilot study to ascertain effectiveness of a rotavirus vaccination program [10]. In response to their recommendation, we conducted this study in a province where local health leaders had just decided to introduce the monovalent RIX4144 strain human vaccine (RotarixÒ) into the routine program of childhood immunization. Evaluation of the impact of this intervention would provide evidence to inform policy makers in Thailand and throughout Asia on the potential merit of vaccine introduction. 2. Methods 2.1. Study location We compared data from two provinces, Sukhothai which began a routine immunization program with rotavirus vaccine in October 2011 with three districts of Phetchabun province where immunization had not begun. Sukhothai province in the central plains agricultural area has a population of mostly indigenous Thais who have good access to health service facilities and an annual cohort of about 5000 births per year. Three districts of Phetchabun province (Muang, Lomsak, Nongpai) were selected as the nonvaccinated area because the geography, population, and health service system were similar to those of Sukhothai. For the period 2008–2010, before the vaccine was introduced in Sukhothai, the rate of hospitalization for diarrhea in children under 2 years was comparable between Sukhothai and the three districts of Phetchabun (3935 vs 4254 per 100,000 populations, respectively) (Health Service Database, retrieved on 19 April 2011). 2.2. Vaccination schedules Both areas provide free immunization service in public clinics for children less than 5 years according to the National Immunization Program which included BCG, HB, DTP, OPV, JE, and MMR [11]. During the study period, vaccination with DTPw-HB and OPV was provided to children 2 and 4 months of age in both sites, but in Sukhothai, monovalent Rotavirus vaccine (RotarixÒ) was added at both visits. 2.3. Observational cohort study From September 2012 to June 2013, all 204 immunization clinics in the study areas invited parents of the infants arriving for their 2-month old visit to join the study and give their informed consents (Fig. 1). The initial visit was followed by four face-toface interviews when children came back for their 4, 6, 9, and 18-month visits and an additional telephone contact when children were 13 months of age. At each visit, parents were queried about the occurrence of episodes of diarrhea, treatment and its cost since the last visit (the economic study is reported separately). A diarrheal episode was defined as the occurrence of 1 watery or 3 or more loose stool in a 24 h period. A new diarrheal episode had to be separated by at least 14 days from a patient’s full recovery from a previous diarrhea illness. In Sukhothai, children had to have received at least one dose of rotavirus vaccine with the first dose administered between 6 and 15 weeks of age to be included in the study. In Phetchabun, the non-vaccinated area, the children who received rotavirus vaccine were excluded. We estimated the sample size for the study using a study power of 80%, an alpha error of 0.05, vaccine efficacy of 71% [12], and a rate of hospitalized rotavirus diarrhea among the non-vaccinated group of 1.2%, with 30% lost to follow up and/or

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lost from case detection at hospitals. Using cohorts of equal size [13], we would require approximately 2696 children in each group to document a significant reduction in rotavirus hospitalization. 2.4. Hospital surveillance study Hospital surveillance for diarrhea among children 2–59 months of age was conducted in all 12 public hospitals in the study areas from the day the first cohort volunteer was recruited in September 2012 until the end of follow up in October 2014 (Fig. 1). This data allowed us to detect rotavirus diarrhea admissions among infants enrolled in the cohort study and provided information on the epidemiology of severe rotavirus leading to hospital admissions among all children less than 5 years. We could then look for herd protection as evidenced by a decrease in hospitalization from rotavirus among older children in both areas who had not been vaccinated against rotavirus because they were born before the vaccination program began in Sukhothai. All children hospitalized with diarrhea between 2 and 59 months of age were invited to participate in the surveillance study. If parents consented, we queried them for information on the diarrheal episode and treatment. One fecal sample was collected on admission and sent for rotavirus detection. The ward staff who conducted the hospital surveillance were neither aware of the rotavirus vaccination status of the patients nor whether patients were participants in the cohort study. 2.5. Rotavirus laboratory tests Each month, fecal specimens (5 ml) collected in the hospitals were kept frozen and sent to the Department of Medical Science at the Ministry of Public Health. Rotavirus was tested by polyacrylamide gel electrophoresis (PAGE) [14] and positive samples were characterized further to identify G- and P-types by reverse transcription-PCR (RT-PCR) [15,16] 2.6. Data analysis The incidence of diarrhea was calculated in the cohort study as the number of episodes per 100 person-year (P-Y) of follow up. The time period began from the initial interview and stopped on the day of the last follow up visit. We excluded the 14 days after the 2- month vaccinations as well as the 14-day period after each diarrheal episode. Multiple Poisson regression was used to control for confounding factors and the ‘‘Adjusted Odds Ratio” (adjOR) with 95% confidence interval was used to compare the diarrheal risk between vaccinated versus non-vaccinated children. Vaccine effectiveness (VE) was ((1 adjOR)  100). Statistical analysis was performed using SPSS 20. 3. Results 3.1. Observational cohort study Since vaccination was conducted in only one province, Sukhothai, and the results were to be compared with a similar province where vaccination was not offered, Phetchabun, we first assessed the comparability of children at these two locations (Appendix 1). The 2893 infants enrolled in Sukhothai and 1937 in Phetchabun, were comparable in terms of their distribution of gender, gestational age, birth weight, family income. Groups did not differ significantly in their age of enrollment (73 ± 10 day old in both groups) or the end of follow up (533 ± 118 vs 541 ± 103 day old), and 90–92% participated until the end of the follow up time. The non-vaccinated group from Phetchabun came

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1. Observaonal cohort study

2. Hospital surveillance study

2-month old infants coming for immunizaon visit

2-59 month old children hospitalized due to diarrhea regardless of their vaccinaon status

2,893 infants from Sukhothai (vaccinated only ) 1,937 infants from Phetchabun (non-vaccinated only )

Follow up at age 4,6,9, 13,18 month to detect all diarrhea episodes (self-care, outpaent visit, hospitalizaon)

End of follow up aer the 18month old interview

1,544 children from Sukhothai 1,784 children from Phetchabun Rota virus tesng & interview for parents’ expenses

Rota +ve episodes and the follow up me used for calculang incidence of hospitalized rotavirus diarrhea and VE

Rota +ve

Young children from the cohort study

Rota -ve

Older children who were not in the cohort study

Age-specific proporon of rotavirus hospitalizaon from two areas was compared to esmate herd protecon Fig. 1. Study design: observational cohort study and hospital surveillance study in the vaccinated area (Sukhothai) and non-vaccinated area (Phetchabun), September 2012October 2014.

from families with more than one children less than 5 years of age (24% vs 30%) and was more likely to be breastfed (89% vs 94%). The coverage of 2nd dose of DTP-HB vaccine given at age 4 months were 97% and 98% in Sukhothai and Phetchabun. The coverage of 2nd dose of Rotavirus vaccine in Sukhothai was 97%. A total of 25 infants were excluded after enrollment (12 in Sukhothai and 13 in Phetchabun). Five in Sukhothai were excluded because of receiving rotavirus vaccine before age 6 weeks or after age 15 weeks. Seven in Phetchabun were excluded because of receiving rotavirus vaccine from private providers. In the 25 months of follow up (September 2012 to October 2014), a total of 903 episodes of diarrhea were reported among children from the vaccinated area and 852 from those in the non-vaccinated area, of which 203 and 232 ended with hospitalization, respectively (Fig. 2). Only 2 children, one from each province, were admitted in private hospitals and not captured by our surveillance. We plotted monthly data on diarrhea and rotavirus admissions to look for differences in the magnitude and seasonality between the two cohorts. The monthly pattern of rotavirus diarrhea admissions was strikingly different between the two areas: the January-February peak normally associated with rotavirus that was visible in Phetchabun but not present in Sukhothai in 2014 (44 vs 4 cases). Sporadic cases of rotavirus occurred thought out the years in both areas. The distribution of rotavirus genotypes in the two areas was similar, dominated by G1P[8] (56 to 70%) followed by G8P[8] (20 to 23%) and G2P[4] (10 to 20%). All of the rotavirus positive cases were among infants older than 6 months. Admissions for diarrhea of all causes outside the rotavirus peak period were similar between the two areas. The smaller numbers of cases at the beginning and the end of graph were due to lower numbers of children under observation. From hospital surveillance of the two cohorts, we first calculated the incidence of hospitalization for diarrhea of all causes and for rotavirus measured as episodes per 100 P-Y and then calculated vaccine effectiveness (Table 1). Overall, the rate of hospitalizations for diarrhea of all causes was 41% (95% CI

29–51) lower in the vaccinated site, Sukhothai, than in Phetchabun (5.6 vs 9.4 episodes/100 P-Y). Fecal specimens were tested from 90% of children in the vaccinated area and 77% of those in the non-vaccinated area. Without correcting for this difference, the incidence of hospitalized rotavirus diarrhea was reduced by 88% (95%CI 76–94) in Sukhothai (0.3 vs 2.2 episodes/100 P-Y). Only 6% of the fecal specimens tested for rotavirus in Sukhothai were positive versus 31% of those from Phetchabun (10/182 vs 55/179; P < 0.01). In addition, the rate of outpatient and self-care diarrhea episodes of all causes was also reduced by 24% (95%CI 15–32) in the vaccinated area. Vaccine effectiveness against different rotavirus genotypes were similar: 86% (95%CI 68–94) against G1P[8], 94% (95%CI 53–99) against G2P[4], and 90% (95%CI 53–98) against G8P[8].

3.2. Hospital surveillance study A total of 3995 children less than 5 years of age were hospitalized for diarrhea, of whom 3328 (83%) participated in the hospital surveillance study, 1544 were from Sukhothai and 1784 from Phetchabun. Fecal specimens were collected from 89% of these participants. We compared the number of admission for rotavirus diarrhea among children less than 5 years in the vaccinated area of Sukhothai and the non-vaccinated area of Phetchabun (Fig. 3). In total, 673 were positive for rotavirus, 14% (216 cases) of children from Sukhothai and 26% (457 cases) from Phetchabun (p < 0.01). This reduction in Sukhothai was prominent during seasonal rotavirus peak from January to March 2014, similar to that observed in the cohort study. In 2013, there was also a small rotavirus peak during March to April which was not seen in the smaller cohort study. Major rotavirus genotypes were comparable between Sukhothai and Phetchabun – G1P[8] (64% vs 52%) followed by G2P[4] (19% vs. 24%), and G8P[8] (13% vs. 23%) respectively. A few cases of other strains were also identified as G2P[8], G3P[8], G3P[9], G6P[14], G8P[4], and G9P[8].

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Fig. 2. Cohort study: Monthly hospital admission for diarrhea of all causes and rotavirus in the vaccinated (Sukhothai) and non-vaccinated (Phetchabun) cohorts.

Table 1 Cohort study: Rotavirus vaccine effectiveness for all causes diarrhea and rotavirus diarrhea, September 2012-October 2014. Location of diarrhea treatment Hospital admissiona All causes Number Incidenceb Rotavirus +ve % of positive specimen Number Incidenceb Outpatient and self-care Number Incidenceb

VE (95%CI)

Sukhothai (vaccinated) (N = 3622 P-Y)

Phetchabun (non-vaccinated) (N = 2472 P-Y)

203 5.6

232 9.4

6

31

10 0.3

55 2.2

88% (76–94)

700 19

620 25

24% (15–32)

41% (29–51)

a

Stool collection from 182 (90%) vaccinated and 179 (77%) non-vaccinated patients. b Episode/100 P-Y.

With hospitalizations for rotavirus diarrhea markedly decreased in the Sukhothai versus Phetchabun, we then examined the age specific data (Table 2). The reduction was greatest (85–90%) in children less than 2 years of age with high vaccine coverage in Sukhothai. Moreover, older children in Sukhothai who had not been vaccinated also experienced a 40–69% reduction in hospitalizations for rotavirus, suggesting strong herd or community protection. The vaccination program changed the age of children hospitalized for rotavirus diarrhea. The median age of children hospitalized for rotavirus diarrhea was 10 months older in Sukhothai where vaccine had been introduced than in Phetchabun (32 vs 22 months, p < 0.01), due to a deficit of rotavirus admissions among children under 2 years in the vaccinated group in Sukhothai (Fig. 4). In the non-vaccinated area, Phetchabun, 16% of cases were aged less than one year, 54% aged less than 2 years, and 76% aged less than 3 years versus 7%, 27%, and 61% in Sukhothai, respectively. 4. Discussion Our results demonstrate that rotavirus vaccine administered simultaneously with DTP-HB and OPV in the routine program of childhood immunization is highly effective in preventing rotavirus

hospitalization (88%, 95%CI 76–94%), comparable to the effectiveness seen in countries with the lowest under 5 mortality in the region of the Americas, Europe, and the Western Pacific [1]. Like other studies [12,17], our effectiveness result is similar against all strains of rotavirus, both those homotypic (G1P[8]) and fully heterotypic (G2P[4]) with the vaccine, and ranged from 86 to 94%. Indirect protection was clearly seen, consistent with similar findings from Australia [18], Europe [19,20], the United States [21], and Latin America [21]. In this study, with very high rotavirus vaccine coverage in the birth cohorts, the older children who were too old to have received the rotavirus vaccine nonetheless experienced a 40–69% reduction in rotavirus hospitalizations. One practical limitation of this study was its observational design, dictated by the reality existing in Thailand. Our Ethical Review Committee for Research on Human Subjects [22] would not allow a randomized control trial for a vaccine that was already available in the private market. At the same time, vaccine coverage of rotavirus in Sukhothai was very high (97%) making it difficult to conduct a case-control study. We therefore resorted to conduct a large scale observational cohort study comparing children in two areas, 200 km s apart. These two areas were reasonably comparable, having similar rates of hospitalization for diarrhea in children before the vaccine was introduced in Sukhothai in October 2011. The rotavirus cases in both areas during the study occurred at the same period of the year and with similar rotavirus genotypes. Case selection bias was unlikely, considering the high rate of participation in hospital surveillance at all sites. Laboratory staffs did not access to patients’ rotavirus vaccine status. Although ward staff were able to ask parents for the vaccination status of patients, they were in reality not doing so and vaccination cards were not part of children’s admission forms. The rate of stool testing was lower in Phetchabun (77%) than Sukhothai (90%) throughout the study period. We had noticed and discussed this with the ward nurses who explained that they were occupied with general patients and did not have time to follow up with study subjects. If we adjusted for patients in both areas who had not been tested for rotavirus, the vaccine effectiveness would increase from 88% to 90%. It was possible that a few children in Phetchabun may have been vaccinated against rotavirus in private clinics without our knowledge, a small bias that would have only slightly lowered the vaccine effectiveness result. A separate cost-effectiveness study has been conducted using data generated from this study. Its preliminary result indicated

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Fig. 3. Hospital surveillance study: Rotavirus diarrhea admissions among children less than 5 years in the vaccinated area (Sukhothai) and non-vaccinated area (Phetchabun).

Table 2 Hospital surveillance study: Age-specific decline in the proportion of rotavirus hospitalization comparing Sukhothai and Phetchabun in 2014: evidence of herd protection.a Age at onset (month)

Rotavirus vaccine coverage in Sukhothai (%)

Sukhothai Diarrhea with rotavirus testingb (N)

Rotavirus positive% (n)

Phetchabun Diarrhea with rotavirus testingb (N)

Rotavirus positive% (n)

6–11 12–23 24–35 36–47 48–59

97 97 68 <1 <1

175 157 77 50 28

2.3 (5) 6.4 (10) 20.8 (16) 20.0 (10) 35.7 (10)

179 268 138 77 40

22.9 42.2 52.2 63.6 60.0

(41) (113) (72) (49) (24)

% Decline in rotavirus hospitalizations§

90 85 60 69 40

a

Data ending October 2014. 97% and 85% of patients in Sukhothai and Phetchabun provided a fecal specimen for rotavirus testing. (percentage of rotavirus positive in Phetchabun - percentage of rotavirus positive in Sukhothai)/percentage of rotavirus positive in Phetchabun, all values are significant difference (P < 0.01). b

§

100

Cumulave frequency (%)

90

Phetchabun

80 70 60

Sukhothai

50 40 30

10 months apart

20 10

age (months)

0 <6

12

18

24

30

36

42

48

54

60

Fig. 4. Hospital surveillance study: Children less than 5 years hospitalized for rotavirus diarrhea in the vaccinated area (Sukhothai) and non-vaccinated area (Phetchabun), September 2012-October 2014.

that the vaccine is cost-effectiveness at the current public sector price in Thailand of 399 baht (US$12) per dose of Rotarix. However, the annual budget needed to purchase vaccine for the entire birth cohort of Thailand was estimated at 585 million baht (US$18 million), equal to 45% of the total vaccine cost for the National Immunization Program in 2014 (US$43 million). In December 2015, based on our study result, the National Vaccine Committee has decided to recommend rotavirus vaccine for Thai children, pending the availability of budget and further

negotiation concerning price with the manufacturers [23]. For countries in Asia, our evidence confirmed that introduction of rotavirus vaccine would result in a real economic and health benefit to children and families. With the new monovalent rotavirus 116E strain (G9P[11]) vaccine (ROTAVACÒ) [24] from an Indian manufacturer entering global market and other rotavirus vaccines in advanced development in China, Indonesia, India, and Vietnam, we expect the vaccine price to be reduced in the near future.

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Declaration of interests All authors declare no conflict of interests. Ethical approval

[7]

[8] [9]

This study was approved by the Ethical Review Committee for Research in Human Subjects, Ministry of Public Health, Thailand (Ref.no. 10/2555).

[10] [11]

Acknowledgement [12]

We thank the public health staff of Sukhothai and Phetchabun provinces for their help in collecting field data and following up subjects, the Department of Disease Control for their administrative support. We are grateful to the Ad Hoc Group of Experts on Rotavirus from the Immunization Practice Subcommittee for their valuable suggestions. This study was fully funded by the Department of Disease Control.

[15]

Appendix A. Supplementary material

[16]

Supplementary data associated with this article can be found, in the online version, at http://dx.doi.org/10.1016/j.vaccine.2016.12. 043.

[13] [14]

[17]

[18]

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