[Human Vaccines 5:6, 414-419; June 2009]; ©2009 Landes Bioscience
Research Paper
Immunogenicity, reactogenicity and safety of human rotavirus vaccine (RIX4414) in Indian infants Anil Narang,1 Anuradha Bose,2 Anand Nilkanth Pandit,3 Phalguni Dutta,4 Gagandeep Kang,2 Sujit Kumar Bhattacharya,4 Sanjoy Kumar Datta,5,* P.V. Suryakiran,5 Andrée Delem,5 Htay Htay Han5 and Hans Ludwig Bock5 1Post-Graduate 4National
Institute of Medical Education and Research; Chandigarh, India; 2Christian Medical College; Vellore, India; 3King Edward Memorial Hospital; Pune, India; Institute of Cholera and Enteric Diseases; Kolkata, India; 5GlaxoSmithKline Biologicals; Rixensart, Belgium
Abbreviations: ORS, oral rehydration solution; CCID50, cell culture infectious dose; RV, rotavirus; DTPw, diphtheria, tetanus, whole-cell pertussis; ELISA, enzyme-linked immunosorbent assay; SC, seroconversion; GMC, geometric mean concentration; RT-PCR, reverse transcriptase polymerase chain reaction; SAE, serious adverse event; ATP, according to protocol; CI, confidence interval; SD, standard deviation; Min, minimum; Max, maximum; GSK, GlaxoSmithKline Key words: rotavirus, gastrointestinal disease, vaccine, immunogenicity, reactogenicity, safety
Aim: This study was undertaken to assess the immunogenicity, reactogenicity and safety of two doses of an oral live-attenuated human rotavirus vaccine, strain RIX4414 (RotarixTM) in an Indian setting. Results: The seroconversion rate observed one month post-dose 2 in the RIX4414 group 58.3% [95% CI: 48.7; 67.4] was significantly higher when compared to the placebo group 6.3%; [95% CI: 2.5; 12.5]. The reactogenicity and safety profile was similar for both groups. Patients and methods: Healthy infants (N = 363), approximately eight weeks of age were enrolled to receive two doses of RIX4414 vaccine (n = 182) or placebo (n = 181) separated by one month. To assess the immune response, blood samples were taken before vaccination and one month post-dose 2 of RIX4414/placebo. Solicited symptoms were collected for eight-days post each dose and safety data was collected throughout the study. Conclusions: Two doses of RIX4414 (RotarixTM) were immunogenic, had a good safety profile and were well-tolerated when administered to healthy Indian infants. Clinical trials registration: ClinicalTrials.gov; NCT00289172; eTrack 103792.
Introduction Despite the success of oral rehydration solution (ORS) in reducing diarrheal mortality, the annual mortality of rotavirus disease has been estimated at more than 527,000 infant deaths.1,2 The majority of these deaths occur in the developing world, especially in the South Asian region. India alone accounts for approximately 100,000 or more estimated infant deaths per annum due to rotavirus disease.2,3 *Correspondence to: Sanjoy Kumar Datta; GlaxoSmithKline Biologicals; Rue de l’Institut 89; Rixensart 1330 Belgium; Tel.: +322.656.6554; Fax: +322.656.8033; Email:
[email protected] Submitted: 12/08/08; Revised: 02/07/09; Accepted: 02/15/09 Previously published online as a Human Vaccines E-publication: http://www.landesbioscience.com/journals/vaccines/article/8176 414
Treatment of severe rotavirus disease requires access to oral rehydration therapy and zinc supplementation, as the disease is characterized by emesis, in addition to the dehydration caused by abundant watery diarrhea.2 Rotavirus disease is generally not perceived as waterborne (as is the case with Hepatitis A or Salmonella typhi) but usually transmitted from person to person via the fecal-oral route. Therefore, improvements in sanitation and hygiene alone may not lower the burden of the disease. It has been established in earlier studies that young children generally have multiple episodes of natural rotavirus infections.2,4 The first infection is known to be more severe than the subsequent infections which are either mild or asymptomatic in nature. It is therefore most important to prevent the first rotavirus infection in infants, as the recurrent milder infections may actually help in boosting immunity. Rotavirus vaccination of children early in life mimics the first natural rotavirus infection, thus preventing severe morbidity and a prolonged protection can be expected through recurrent boosting provided by subsequent asymptomatic infections after vaccination.5,6 Hence, a vaccine that effectively prevents the first severe rotavirus infection in children is key to the reduction in the overall rotavirus disease burden.2 In order to effectively combat rotavirus disease worldwide, two rotavirus vaccines have been licensed globally since 2005, a bovinehuman reassortant vaccine by Merck & Co., Inc.,—RotateqTM and a live attenuated human strain vaccine by GlaxoSmithKline (GSK) Biologicals—RotarixTM. This study was conducted to assess the immunogenicity, reactogenicity and safety of RotarixTM (RIX4414) in an Indian setting.
Results The study was conducted between February 10, 2006 and September 8, 2006 with a total of 363 infants in RIX4414 group (N = 182) and in placebo group (N = 181) enrolled and vaccinated (Fig. 1). Of the enrolled infants, 27.1% (49 infants from the RIX4414 group and 45 infants from the placebo group) were initially seropositive and about one-third participated in the Pulse Polio program (56 infants from the RIX4414 group and
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Human rotavirus vaccine in Indian infants
Figure 1. Enrolled infants—safety and immunogenicity subsets.
52 infants from the placebo group). The demographic profile of the two study groups was similar (Table 1). All infants were of Indian ethnicity. Immunogenicity of RIX4414. In the ATP cohort for immunogenicity, the seroconversion rate one month post-dose 2 in the RIX4414 group was 58.3% [95% CI: 48.7; 67.4] and 6.3% [95% CI: 2.5; 12.5] in the placebo group (Table 2). Anti-RV IgA GMCs calculated on all subjects at one month post-dose 2 were 49.2 U/ml [95% CI: 36.2; 66.8] in the RIX4414 group and was below the cut-off in the placebo group. The immunogenicity results from the total vaccinated cohort were consistent with those from the ATP cohort (Table 2). A post-hoc analysis of infants initially seropositive for rotavirus IgA showed that in the RIX4414 group, the concentrations of rotavirus IgA (GMCs) increased more than two-fold in 60.5% of infants and more than four-fold in 39.5% of infants, while 7.5% of placebo www.landesbioscience.com
recipients showed a two-fold increase and 5.0% showed a four-fold increase (Table 3). An ongoing Pulse Polio Program at two centers enabled a posthoc analysis of immune response of anti-rotavirus IgA at one month post-dose 2, although the protocol defined two-week interval between RIX4414/placebo administration and OPV was not respected. SC rates calculated one month post-dose 2, on infants affected by the Pulse Polio Program, was 77.8% in the RIX4414 group and 24.5% in the placebo group. In all analyses, a significant difference between vaccine and placebo groups was observed for anti-IgA SC rates and for the GMC post-dose 2 (Table 2). Reactogenicity and safety of RIX4414. No significant difference in the incidence of solicited symptoms following administration of RIX4414/placebo was observed, between RIX4414 and placebo group (Fig. 2). Few symptoms of grade 3 intensity were reported.
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Table 1 Demographic results (ATP cohort for immunogenicity) Characteristics RIX4414 (N = 115) Placebo (N = 112) value or n % value or n % Age at Dose 1 of Mean 8.7 8.7 RIX4414/placebo SD 0.65 0.67 (weeks) Min 8 8
Max
10
10
Age at Dose 2 of RIX4414/placebo (weeks)
Mean
13.4
13.4
SD
0.81
0.8
Min
12
12
Max
16
16
Gender
Male
56
48.7
64
57.1
Female
59
51.3
48
42.9
Race Height at Visit 1 (cm)
Indian
115
100
112
100
Mean
55.1
-
56
-
SD
3.29
-
2.91
-
Mean
4.6
-
4.7
-
SD
0.67
-
0.69
-
Weight at Visit 1 (kg)
Value, value of the considered parameter; n (%), number (percentage) of infants in given category; SD, standard deviation; Min, minimum age; Max, maximum age.
During the 31-day follow-up period after each dose, a similar proportion of infants in each group reported unsolicited symptoms: 19.8% [95% CI: 14.3; 26.3] in the RIX4414 group and 17.7% [95% CI: 12.4; 24.0] in the placebo group. Upper respiratory tract infection was the most commonly reported unsolicited diagnosis: 5.5% in RIX4414 group and 6.6% in placebo group. One grade three unsolicited symptom was reported in the RIX4414 group (respiratory tract infection) and three were reported in the placebo group (pharyngitis, respiratory tract infection and bronchiolitis). Safety results of the total vaccinated cohort were similar in the RIX4414 vaccine group and placebo group. There were five serious adverse events (SAEs) reported: three among the RIX4414 recipients and two among the placebo recipients. Of these, two cases of lower respiratory tract infections and one case of pneumonia were seen in the RIX4414 group while one case of bronchiolitis and one case of parotitis were seen in the placebo group. None of these SAEs were considered to be related to vaccination by the investigators. Both groups reported similar percentages of subjects reporting GE episodes from dose 1 to one month post-dose 2: 12.6% of subjects in the RIX4414 group and 13.3% of subjects in the placebo group. Stool samples were not available from 30.4% and 15.4% of the GE episodes in the RIX4414 group and the placebo group, respectively. Rotavirus was not isolated from any of the stool samples collected during the study.
Discussion Rotavirus infection is a global public health problem in both developed and developing countries. While high mortality due to rotavirus disease is observed in developing countries, RV-associated morbidity continues to be a major issue in developed countries. Although improvement in hygiene and sanitation helps in reducing the overall burden of diarrheal diseases, it does not appear to have 416
any impact in reducing RV-associated mortality and morbidity worldwide. Similarity in the incidence of rotavirus in developed and developing countries clearly indicate that the disease is spread mostly through person-to-person contact rather than poor hygienic or sanitary conditions.7 When we consider the RV disease burden in a developing country setting like India, morbidity and mortality due to RV disease might depend on the socio-economic conditions. While morbidity of RV disease is significant in the upper socio-economic classes, mortality is usually seen in lower economic settings where the population often has limited access to healthcare.8 Given the high burden of rotavirus disease in India, there is a pressing need for an effective vaccine. This study demonstrated that in an Indian setting, two doses of RIX4414 vaccine were immunogenic: seroconversion rate of 58.3% at one month after receiving the second dose. Vaccination with RIX4414 vaccine had a mild reactogenicity profile in Indian with similar profile observed in other trials9,10 and there were no safety concerns during the study. The seroconversion rate observed in this study was in line with the results obtained from other studies done in the developing world.9,11,12 However, higher seroconversion rates have been observed in more developed Asian settings, including infants of Indian ethnicity.13 While the effect of socio-economic status on the immunogenicity of the vaccine is not fully determined yet, data from a wide range of countries suggest that lower socio-economic status may be associated with lower seroconversion rate, but not necessarily a lower efficacy.14,15 In developing countries (e.g., Latin America) where the observed seroconversion rate ranged between 61% and 65%, the protective efficacy against severe rotavirus disease of 85% exceeded the observed vaccine seroconversion rate.9,15 Hence, although the correlates of protection to rotavirus infection are not fully defined yet, clinical studies with RIX4414 vaccine have demonstrated efficacy against severe RVGE is higher than the seroconversion rates observed. The routine vaccines were planned to be given 14 days prior to each dose of RIX4414/placebo according to the study protocol. However, during the study, many of the infants received doses of OPV as part of the ongoing oral Pulse Polio Program conducted by the Government of India. These OPV doses were administered within the protocol defined forbidden 14-day window and the dates of OPV vaccination were not well-documented in some cases. A post-hoc analysis was performed to assess the impact of routine vaccines which revealed that the administration of OPV within the forbidden interval did not negatively impact the immune response to RIX4414 vaccine. Although, the infants who received OPV on Pulse Polio Day appeared to have higher anti-RV IgA GMC (105.0 U/ml) when compared to infants belonging to the ATP cohort (49.2 U/ml), there appeared to be no significant difference between the groups as evident from overlapping 95% CI. Furthermore, there has been evidence from earlier studies in South Africa and Bangladesh which indicates a lack of interference between RIX4414 and OPV in terms of immunogenicity of both vaccines even when the two vaccines were co-administered.11,12 In our study, we found that at the age of enrolment (eight weeks), about a quarter of the infants were already seropositive for anti-rotavirus IgA. Similarly high initial seropositivity rates (in the absence of prior vaccination) have been observed in South Asia
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Table 2 Immunogenicity of RIX4414/placebo in the various analyses Group Timing N Seroconversion GMC (≥20 U/ml)/Seropositivity n (%) 95% CI U/ml 95% CI LL UL LL UL Total Vaccinated Cohort
RIX4414
Placebo
According to Protocol
RIX4414
Placebo
Infants in ‘Pulse Polio Day’
RIX4414
Placebo
PRE
176
49 (27.8)
21.4
35.1
