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Rhesus rotavirus-based quadrivalent vaccine is efficacious despite age, socioeconomic conditions and seasonality in Venezuela
Vaccine 19 (2001) 976 – 981 www.elsevier.com/locate/vaccine
Rhesus rotavirus-based quadrivalent vaccine is efficacious despite age, socioeconomic conditions and seasonality in Venezuela Marı´a Eglee´ Pe´rez a, Roger Glass b, Giselle Alvarez a, Luis Rau´l Pericchi a, Rosabel Gonza´lez c, Albert Z. Kapikian d, Irene Pe´rez-Schael c,* a
Centro de Estadı´stica y Software Matema´tico, CESMa, Departamento de Computo Cientı´fico y Estadı´stica, Uni6ersidad Simo´n Bolı´6ar, Caracas, Venezuela b Viral Gastroenteritis Section, National Center for Infectious Diseases, Center for Disease Control and Pre6ention, Atlanta, GA, USA c Seccio´n de In6estigacio´n de Enfermedades Ente´ricas, Instituto de Biomedicina – Fu6esin, Uni6ersidad Central de Venezuela, Ministerio de Sanidad y Asistencia Social, A.P. 4043, Carmelitas, Caracas 1010A, Venezuela d Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA Received 9 June 1999; accepted 1 June 2000
Abstract This report describes the results of additional analyses of the trial carried out with the rhesus rotavirus-based quadrivalent vaccine in Venezuela. In the present study, we re-examined the data from this previous rotavirus vaccine trial to assess the statistical interaction between vaccine efficacy and (i) the duration of efficacy into the second year of life, (ii) socioeconomic conditions, and (iii) rotavirus seasonality. We found that among Venezuelan children, the rotavirus vaccine confers protection against severe diarrhea during the first 2 years of life independently of socioeconomic conditions and seasonality. © 2000 Elsevier Science Ltd. All rights reserved. Keywords: Rotavirus; Vaccine; Efficacy; Seasonality; Socioeconomic status
1. Introduction Group A rotavirus diarrhea is a universal disease of infants and young children worldwide. It is estimated that rotaviruses are responsible for the death of 600 000–800 000 children and for 17 million episodes of moderate to severe illness in developing countries each year [1,2]. The first rotavirus vaccine for the prevention of severe disease was recently licensed in the US by the US Food and Drug Administration (FDA). Field trials in the US [3,4], Finland [5] and Venezuela [6] have shown that three doses of rhesus rotavirusbased quadrivalent vaccine can prevent severe rotavirus diarrhea in infants and young children. The first trial to demonstrate significant efficacy of this rotavirus vaccine in a developing country was conducted in Venezuela [6]. However, in the previously described report, we did * Corresponding author. Tel. + 58-2-831007/8630568; fax: +58-28611258. E-mail address: [email protected] (I. Pe´rez-Schael).
not analyze the influence, if any, of various parameters on vaccine efficacy such as socioeconomic status, age and seasonality. We have examined these questions by using data from the efficacy trial conducted in Venezuela [6].
2. Methods
2.1. Population and study design The trial was conducted in Caricuao, a middle-tolower class urban area southwest of Caracas, as previously described [6]. In a double-blinded, placebo-controlled, randomized trial, infants received three doses of rotavirus vaccine or placebo at 2, 3 and 4 months of age. As part of this study, socioeconomic status was assessed with the modified Graffar method, which considers the professional activity of the father, educational level of the mother, income level of the family, and sanitary conditions in the home, using a
0264-410X/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S 0 2 6 4 - 4 1 0 X ( 0 0 ) 0 0 2 1 1 - 5
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5-point scale (1, high class; 2, high-middle class; 3, middle to low class; 4, low class and 5, marginal class) [7]. At the time of vaccination, status of feeding was defined as breast-feeding only, breast and bottle-feeding, and no breast-feeding [6]. In a catchment study, passive surveillance of patients with diarrhea was conducted at the Hospital Materno Infantil de Caricuao and follow up of infants was from 15 days after they received their third dose of vaccine or placebo and for the most part lasted 19 or 20 months until they reached 24 months of age and thus completed surveillance. A diarrheal episode was defined as the presence of three or more liquid or semi-liquid stools or a single stool with blood during a 24 h period. Stool samples collected from each diarrheal episode were tested for rotavirus by a confirmatory pre-post enzymelinked immunosorbent assay as previously described [8]. A period of 48 h without symptoms was required for subsequent diarrhea to be considered a new episode [9]. Dehydration was defined according to the published criteria of the World Health Organization [10]. A 20point severity score system, previously described [11], was used to grade the severity of diarrheal episodes (score of 1–8 was considered mild, 9 – 14 moderate, and 15 or more severe). Only the first rotavirus-positive diarrheal episodes detected during surveillance were included in the analysis. Efficacy was calculated using the formula: 1−(rate of rotavirus diarrheal episodes in the vaccinated population/rate of rotavirus-positive episodes in the unvaccinated group)× 100 [12].
2.2. Statistical analysis Various statistical methods were used, including x 2, Fisher’s exact test (two-tailed), and log-linear and logistic models [13]. Survival analysis methods, Kaplan– Meier estimates, and the Cox proportional-hazards
977
regression model, including time-dependent covariates were used to compare the relative risk of rotavirus diarrhea between vaccine and placebo groups [14]. For the purpose of this incidence analysis we included only infants who received all three doses and were followed for 19 or 20 months until they reached the age of 24 months and thus completed surveillance, i.e. 1027 in the vaccine group and 1010 in the placebo group. Survival time was defined as the period from the 15th day after a child received the third dose to the onset of the first rotavirus-positive episode. The age-dependent probability of rotavirus illness was calculated as 1 minus the Kaplan-Meier estimate of the probability of survival. Variables used in this analysis included socioeconomic level (i.e. Graffar score), time of first vaccination (determined by 3-month periods), and age (defined as: 0–11 months and 12 months or more). Data were analyzed using S-Plus statistical software (version 3.4).
3. Results
3.1. Study population Two-thousand two-hundred and seven infants who received three doses of vaccine (N= 1112) or placebo (N= 1095) were included in the analysis as described in the initial report. These groups were similar in sex, socioeconomic status, median age at time of vaccination, and type of feeding [6]. During surveillance, 219 (14%) of 1537 diarrheal episodes (737 from vaccinated infants and 800 from the placebo group) were rotavirus positive: 75 (10%) in the vaccinees and 144 (18%) in the placebo group. Of these rotaviruses, 205 were isolated from the first episode of rotavirus diarrhea in recipients of vaccine (70) compared with placebo (135). As noted previously, only the 1027 vaccine recipients and 1010 placebo recipients who were followed for 19 or 20 months until they reached 24 months of age and thus completed surveillance were included for the incidence analysis.
3.2. Vaccine efficacy by disease se6erity and age
Fig. 1. Frequency of the first rotavirus diarrheal episode and cumulative efficacy against rotavirus illness at each severity score.
The overall efficacy of rotavirus vaccine was 48% (95% CI, 33,61; PB 0.001 by Fisher’s exact test, two tailed) and increased directly with the severity of rotavirus diarrhea. Cumulative vaccine efficacy ranged from 45 to 88% when comparing vaccine and placebo recipients (of adequate numerical size) who had an illness severity score of ] 4 and ]15, respectively (Fig. 1). Among the recipients of either the placebo or vaccine, most (79%) of the 28 severe episodes occurred during the first year of life. Among vaccinees, all three severe episodes occurred in infants less than 9 months of age, whereas 18 (72%) of the 25 severe episodes in
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Fig. 2. Vaccine efficacy by age at the onset of the first rotavirus-positive diarrheal episode of any severity. Table 1 Vaccine efficacy against the first rotavirus-positive episode by severity and time of onset Percent efficacy by time of onset (No. of rotavirus-positive episodes in recipients of vaccine/placebo)a Severity of episode
January–March
April–June
July–September
October–December
Any severity Mild Moderate Severe
52 25 47 100
54 56 34 100
45 36 47 67
45 2 54 80
a
(27/55) (13/17) (14/26) (0/12)
(8/17) (4/9) (4/6) (0/2)
(20/36) (11/17) (7/13) (2/6)
(15/27) (7/7) (7/15) (1/5)
No. of infants: vaccine, 1112; placebo, 1095.
the placebo recipients occurred in this age group. However, among recipients of either vaccine or placebo, 61 and 57% of moderate and mild illness occurred in infants younger than 1 year, respectively. The vaccine maintained its efficacy (around 50%) against all episodes throughout the first 2 years of life, and it seems to increase after 18 months of age (Fig. 2). In general, rotavirus vaccine induced greater protection against severe rotavirus diarrhea than against mild disease independent of age.
This observation encouraged us to use the log-linear model to evaluate rotavirus seasonality, severity of illness, and study group (i.e. vaccine vs. placebo). While the frequency of rotavirus positive episodes again differed significantly by season (i.e. fewer episodes from April to June; PB 0.001), the model failed to identify a significant interaction between seasonality and disease severity (P= 0.47) or seasonality and study groups (P= 0.98). However, the model did identify a significant interaction between severity of illness and vaccine efficacy (P= 0.006), which is consistent with our previous results.
3.3. Vaccine efficacy by season and disease se6erity Rotavirus diarrhea occurred during the entire year, the low period of detection was from April to June (12%), the high period from January to March (40%), and intermediate periods were in July – September (27%) and October– December (20%) (Table 1). Vaccine efficacy did not differ significantly by season (Table 1).
3.4. Vaccine efficacy by socioeconomic status and time of 6accination Analysis of the socioeconomic conditions of our population showed that none of the study subjects were in the highest class and very few were in high-middle class
M. Eglee´ Pe´rez et al. / Vaccine 19 (2001) 976–981
groups. We therefore categorized the data into two groups: high-middle and middle to low class (Graffar score 2+3), and low and marginal class (Graffar score 4 +5) and found that the socioeconomic conditions of the study population did not affect vaccine efficacy (Table 2). While efficacy was greater among the poorer children (52 vs. 40%), this difference was not significant (P=0.97 by x 2). As shown by the logistic model, children from low versus higher socioeconomic levels had a 1.39 times greater risk of suffering a rotavirus episode (P =0.038), but this difference did not significantly affect vaccine efficacy. Vaccine efficacy was not affected by the time of vaccination with the first or third dose or the socioeconomic status using the logistic model (data not shown).
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3.5. Incidence analysis Ninety-two percent of infants who received either vaccine (N= 1027) or placebo (N=1010) and either completed the surveillance period or were excluded when they had their first rotavirus episode were used to perform the analysis of the cumulative probability of rotavirus diarrhea, using survival analysis methodology (Fig. 3). The probability of having rotavirus diarrhea was greater for unvaccinated than for vaccinated infants, regardless of duration of surveillance or the severity of the episode. By 4 months after vaccination, vaccinated children had no further episodes of severe rotavirus diarrhea. Moreover, the efficacy of the vaccine against rotavirus diarrhea of any severity was provided throughout the 19–20 months of the surveil-
Table 2 Vaccine efficacy against the first rotavirus-positive episode by socio-economic level Socio-economic status
2–3 4–5 a b
No. of rotavirus-positive episodes (No. of infants with indicate socio-economic status)a Vaccine (N =1103)
Placebo (N= 1082)
Percent efficacy (95% CI)
Pb
22 (382) 48 (721)
39 (407) 94 (675)
40 (0.64) 52 (33.66)
0.0445 B0.0001
No infant had socio-economic level of 1. Data were not available for 9 and 13 infants belonging to vaccine or placebo groups, respectively. Vaccine and placebo groups compared by x 2 test within each group.
Fig. 3. Cumulative probability of the first rotavirus-positive diarrheal episode during surveillance period in infants receiving rotavirus vaccine or placebo in Venezuela.
980
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lance period until children reached 2 years of age. The Cox proportional hazards model was used to compare rates of the first rotavirus episode among vaccine and placebo groups for episodes of any severity and severe episodes. Other variables considered in this analysis were time of vaccination with the first dose, socioeconomic conditions, and age at the onset of the episode (0 – 11 months old and ]12 months of age). Of this set of variables, only vaccine status and socioeconomic conditions seems to affect the risk of having a rotavirus-positive episode and thus were included in the model. However, the interaction between vaccine efficacy and socioeconomic level was not significant (P= 0.65 for episodes of any severity and P = 0.32 for severe episodes) showing again that efficacy was not affected by socioeconomic condition. In addition, efficacy was maintained throughout the study until the children reached 2 years of age. The efficacy of rotavirus vaccine estimated by the model was 52% (95% CI, 36,64; PB 0.001) against rotavirus-positive episodes of any severity and 89% (95% CI, 63,97; P B0.001) against severe episodes. In conclusion, the analysis by these models confirmed the former results: three doses of rhesus rotavirus-based quadrivalent vaccine are efficacious independent of socioeconomic status, time of vaccination and duration of follow up until to 2 years of age.
4. Discussion The rotavirus-based quadrivalent vaccine has proven its efficacy against severe rotavirus disease in developed [3 – 5] and developing countries [6]. This study demonstrates that this vaccine would make an important impact in the developing countries as efficacy was not influenced by socioeconomic status, age or seasonality. Various studies have shown that vaccine efficacy is lower in developing than in developed countries [3,5,15,16]. This difference has been attributed to adverse environmental conditions such as high diarrhea rates and low socioeconomic status in the developing countries [6,15,16]. Although the current study does not compare the poverty levels of other countries where the rotavirus vaccine was not as effective as in Venezuela [15], the current study provides some cause for optimism because in the analysis of data from the only trial of the first licensed rotavirus vaccine in a developing country the vaccine protected children of middle or low socioeconomic status equally well against rotavirus disease. We found that efficacy increases directly with the severity of rotavirus illness and is maintained throughout the first 2 years of life, as observed in Finland [5] and the USA [17]. Cumulative vaccine efficacy ranged from a low of 45% against illness with a severity score of ] 4 to a high of 88% for a score of ] 15 in a
population of vaccine and placebo recipients of sufficient size to render the observed differences statistically significant. In addition, the vaccine shifted the severity of disease toward milder illness. This finding is consistent with the results observed in studies of natural infection [18,19], in which disease severity decreases with age as a consequence of the boosting effect of numerous infections experienced by a child. These results are also consistent with a study in immunized infants who received three doses of the rhesus-based quadrivalent vaccine [20]. After full vaccination and follow up to 16–18 months of age, most of the infants (86%) maintained elevated IgA antibody levels, probably because reinfections boosted the immune response. At least 46% of infants were reinfected as indicated by an IgA seroresponse [20]. On the other hand, poor efficacy was reported in Native American populations after 12 months of age [4]. In this population, early rotavirus infection [21], as well as poor living conditions and overcrowding, may have been decreased vaccine efficacy because of the rapid spread of vaccine virus (or herd immunity) [6,15], or because of a high level of transmission of wild rotaviruses [22]. In this study, efficacy was not affected either by seasonality or by time of vaccination. These results corroborate the observations in Finland [5], where apparent differences in vaccine efficacy between children first vaccinated in April–June (45%), the low season, versus October–December (70–85%), the high season, were not, in fact, statistically different. In Venezuela, where seasonal differences occur but are not striking, neither severity of rotavirus disease nor vaccine efficacy were affected by seasonality. Despite the higher risk of rotavirus disease among children of low socioeconomic status compared with those of higher socioeconomic status, the vaccine efficacy did not differ significantly between the groups. In conclusion, the rhesus rotavirus-based quadrivalent vaccine confers protection against severe disease during the first 2 years of life independently of socioeconomic conditions and seasonality in poor Venezuelan children. The recommendation for use of rotavirus vaccine in the US has been recently withdrawn. However, the observations of this study may be applied to any other oral rotavirus vaccine currently tested in field trials.
Acknowledgements This study was partially supported by grants from the Agency for International Development Vaccine Program through an Agency for International Development–Public Health Service Participating Agency Service Agreement (PASA BTS-5947-PHI-4265) with the National Institute of Allergy and Infectious Diseases (87-I-113), The World Health Organization (C6/181/
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341), and Wyeth-Ayerst Research (0587B-309-VE). We thank Dr Robert M. Chanock for reviewing the manuscript.
References [1] Institute of Medicine. The prospects for immunizing against rotavirus. In: New Vaccine Development: Establishing Priorities, vol. II. Diseases of Importance in Developing Countries. National Academic Press, Washington DC, 1986, pp. 308–318. [2] Bern C, Glass RI. Impact of diarrheal disease worldwide. In: Kapikian AZ, editor. Viral Infections of the Gastrointestinal Tract, 2nd ed. New York: Marcel Dekker, 1994:1–26. [3] Rennels MB, Glass RG, Dennehy PH, Bernstein DI, Pichichero ME, Zito ET, et al. Safety and efficacy of high dose rhesus-human reassortant rotavirus vaccine vaccines report of the National Multicenter Trial. Pediatrics 1996;97:7–13. [4] Santosham M, Moulton LH, Reid R, Croll J, Weatherbolt R, Ward R, et al. Efficacy and safety of high-dose rhesus-human reassortant rotavirus vaccine in Native American populations. J Pediatric 1997;131:632–8. [5] Joensuu J, Koskenniemi E, Pang X, Vesikari T. Randomized placebo-controlled trial of rhesus-human reassortant rotavirus vaccine for prevention of severe rotavirus gastroenteritis. Lancet 1997;350:1205– 9. [6] Pe´rez-Schael I, Guntin˜as MJ, Pe´rez M, Pagone V, Rojas AM, Gonza´lez R, et al. Efficacy of the rhesus rotavirus-based quadrivalent vaccine in infants and young children in Venezuela. N Engl J Med 1997;337:1181–7. [7] Me´ndez Castellano H, De Me´ndez MC. Estratificacio´n social y biologı´a humana: Me´todo Graffar modificado. Arch Venez Puerc Pediatr 1986;49:93–104. [8] Kapikian AZ, Yolken RH, Greenberg HB, Wyath RG, Kalica AR, Chanock RM, et al. Gastroenteritis viruses. In: Lennette EH, Schmidt NJ, editors. Diagnostic Procedures for: Viral, Rickettsial and Chlamydial Infections, 5th ed. Washington, DC: American Public Health Association, 1979:927–95. [9] Morris SS, Lanata CF, Kirkwood BR. Diarrhoea — defining the episode. Int J Epidemiol 1994;23:617–23.
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[10] WHO. A Manual for the Treatment of Diarrhoea: for use by Physicians and Other Senior Health Worker. Geneva: WHO, 1990. [11] Ruuska T, Vesikari T. Rotavirus disease in Finnish children: use of numerical scores for clinical severity of diarrhoeal episodes. Scand J Infect Dis 1990;22:259 – 67. [12] Orenstein WA, Bernier RH, Dondero TJ, Hinman AR, Marks JS, Bart KJ, et al. Field evaluation of vaccine efficacy. Bull WHO 1985;63:1055 – 68. [13] Agresti A. Categorical Data Analysis. New York: John Wiley and Sons, 1990. [14] Cox D, Oakes D. Analysis of Survival Data. London: Chapman and Hall, 1984:91 – 140. [15] Linhares AC, Gabbay YB, Mascarenhas JDP, de Freitas RB, Oliveira CS, Bellesi N, et al. Immunogenicity, safety and efficacy of tetravalent rhesus-human, reassortant rotavirus vaccine in Belem, Brazil. Bull WHO 1996;74:491 – 500. [16] Lanata CF, Midthun K, Black RE, Butron B, Huapaya A, Penny ME, et al. Safety, immunogenicity, and protective efficacy of one and three doses of the tetravalent rhesus rotavirus vaccine in infants in Lima, Peru. J Infect Dis 1996;174:S268– 75. [17] Bernstein DI, Glass RG, Rodgers G, Davidson BL, Sack DA. Evaluation of rhesus rotavirus monovalent and tetravalent reassortant vaccines in US children. J Am Med Assoc 1995;273:1191– 6. [18] Vela´squez FR, Matson D, Calva JJ, Guerrero LM, Morrow AL, Carter-Campbell S, et al. Rotavirus infection in infants as protection against subsequent infections. N Engl J Med 1996;335:1022– 8. [19] Rojas AZ, Boher Y, Guntin˜as MJ, Pe´rez-Schael I. Homotypic immune response to primary infection with rotavirus serotype G1. J Med Virol 1995;47:404 – 9. [20] Va´zquez J, Boher Y, Pe´rez M, Guntin˜as MJ, Rojas AM. Immune response to three doses of quadrivalent rotavirus vaccine: 1-year follow-up. Vaccine 1998;15:1179 – 83. [21] Santhosham M, Letson GW, Wolff M, Reid R, Gahagan S, Adams R, et al. A field study of the safety and efficacy of two candidate rotavirus vaccines in a Native American population. J Infect Dis 1991;163:483 – 7. [22] Pericchi LR, Pe´rez-Schael I, Viana G, Cunto W, Kapikian A, Flores J. Statistical analysis of a rhesus rotavirus vaccine trial to assess protective effect against diarrhea in Venezuelan children of 2 – 4 months of age. Interciencia 1989;14:199 – 202.
Rhesus rotavirus-based quadrivalent vaccine is efficacious despite age, socioeconomic conditions and seasonality in Venezuela Marı´a Eglee´ Pe´rez a, Roger Glass b, Giselle Alvarez a, Luis Rau´l Pericchi a, Rosabel Gonza´lez c, Albert Z. Kapikian d, Irene Pe´rez-Schael c,* a
Centro de Estadı´stica y Software Matema´tico, CESMa, Departamento de Computo Cientı´fico y Estadı´stica, Uni6ersidad Simo´n Bolı´6ar, Caracas, Venezuela b Viral Gastroenteritis Section, National Center for Infectious Diseases, Center for Disease Control and Pre6ention, Atlanta, GA, USA c Seccio´n de In6estigacio´n de Enfermedades Ente´ricas, Instituto de Biomedicina – Fu6esin, Uni6ersidad Central de Venezuela, Ministerio de Sanidad y Asistencia Social, A.P. 4043, Carmelitas, Caracas 1010A, Venezuela d Laboratory of Infectious Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD, USA Received 9 June 1999; accepted 1 June 2000
Abstract This report describes the results of additional analyses of the trial carried out with the rhesus rotavirus-based quadrivalent vaccine in Venezuela. In the present study, we re-examined the data from this previous rotavirus vaccine trial to assess the statistical interaction between vaccine efficacy and (i) the duration of efficacy into the second year of life, (ii) socioeconomic conditions, and (iii) rotavirus seasonality. We found that among Venezuelan children, the rotavirus vaccine confers protection against severe diarrhea during the first 2 years of life independently of socioeconomic conditions and seasonality. © 2000 Elsevier Science Ltd. All rights reserved. Keywords: Rotavirus; Vaccine; Efficacy; Seasonality; Socioeconomic status
1. Introduction Group A rotavirus diarrhea is a universal disease of infants and young children worldwide. It is estimated that rotaviruses are responsible for the death of 600 000–800 000 children and for 17 million episodes of moderate to severe illness in developing countries each year [1,2]. The first rotavirus vaccine for the prevention of severe disease was recently licensed in the US by the US Food and Drug Administration (FDA). Field trials in the US [3,4], Finland [5] and Venezuela [6] have shown that three doses of rhesus rotavirusbased quadrivalent vaccine can prevent severe rotavirus diarrhea in infants and young children. The first trial to demonstrate significant efficacy of this rotavirus vaccine in a developing country was conducted in Venezuela [6]. However, in the previously described report, we did * Corresponding author. Tel. + 58-2-831007/8630568; fax: +58-28611258. E-mail address: [email protected] (I. Pe´rez-Schael).
not analyze the influence, if any, of various parameters on vaccine efficacy such as socioeconomic status, age and seasonality. We have examined these questions by using data from the efficacy trial conducted in Venezuela [6].
2. Methods
2.1. Population and study design The trial was conducted in Caricuao, a middle-tolower class urban area southwest of Caracas, as previously described [6]. In a double-blinded, placebo-controlled, randomized trial, infants received three doses of rotavirus vaccine or placebo at 2, 3 and 4 months of age. As part of this study, socioeconomic status was assessed with the modified Graffar method, which considers the professional activity of the father, educational level of the mother, income level of the family, and sanitary conditions in the home, using a
0264-410X/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved. PII: S 0 2 6 4 - 4 1 0 X ( 0 0 ) 0 0 2 1 1 - 5
M. Eglee´ Pe´rez et al. / Vaccine 19 (2001) 976–981
5-point scale (1, high class; 2, high-middle class; 3, middle to low class; 4, low class and 5, marginal class) [7]. At the time of vaccination, status of feeding was defined as breast-feeding only, breast and bottle-feeding, and no breast-feeding [6]. In a catchment study, passive surveillance of patients with diarrhea was conducted at the Hospital Materno Infantil de Caricuao and follow up of infants was from 15 days after they received their third dose of vaccine or placebo and for the most part lasted 19 or 20 months until they reached 24 months of age and thus completed surveillance. A diarrheal episode was defined as the presence of three or more liquid or semi-liquid stools or a single stool with blood during a 24 h period. Stool samples collected from each diarrheal episode were tested for rotavirus by a confirmatory pre-post enzymelinked immunosorbent assay as previously described [8]. A period of 48 h without symptoms was required for subsequent diarrhea to be considered a new episode [9]. Dehydration was defined according to the published criteria of the World Health Organization [10]. A 20point severity score system, previously described [11], was used to grade the severity of diarrheal episodes (score of 1–8 was considered mild, 9 – 14 moderate, and 15 or more severe). Only the first rotavirus-positive diarrheal episodes detected during surveillance were included in the analysis. Efficacy was calculated using the formula: 1−(rate of rotavirus diarrheal episodes in the vaccinated population/rate of rotavirus-positive episodes in the unvaccinated group)× 100 [12].
2.2. Statistical analysis Various statistical methods were used, including x 2, Fisher’s exact test (two-tailed), and log-linear and logistic models [13]. Survival analysis methods, Kaplan– Meier estimates, and the Cox proportional-hazards
977
regression model, including time-dependent covariates were used to compare the relative risk of rotavirus diarrhea between vaccine and placebo groups [14]. For the purpose of this incidence analysis we included only infants who received all three doses and were followed for 19 or 20 months until they reached the age of 24 months and thus completed surveillance, i.e. 1027 in the vaccine group and 1010 in the placebo group. Survival time was defined as the period from the 15th day after a child received the third dose to the onset of the first rotavirus-positive episode. The age-dependent probability of rotavirus illness was calculated as 1 minus the Kaplan-Meier estimate of the probability of survival. Variables used in this analysis included socioeconomic level (i.e. Graffar score), time of first vaccination (determined by 3-month periods), and age (defined as: 0–11 months and 12 months or more). Data were analyzed using S-Plus statistical software (version 3.4).
3. Results
3.1. Study population Two-thousand two-hundred and seven infants who received three doses of vaccine (N= 1112) or placebo (N= 1095) were included in the analysis as described in the initial report. These groups were similar in sex, socioeconomic status, median age at time of vaccination, and type of feeding [6]. During surveillance, 219 (14%) of 1537 diarrheal episodes (737 from vaccinated infants and 800 from the placebo group) were rotavirus positive: 75 (10%) in the vaccinees and 144 (18%) in the placebo group. Of these rotaviruses, 205 were isolated from the first episode of rotavirus diarrhea in recipients of vaccine (70) compared with placebo (135). As noted previously, only the 1027 vaccine recipients and 1010 placebo recipients who were followed for 19 or 20 months until they reached 24 months of age and thus completed surveillance were included for the incidence analysis.
3.2. Vaccine efficacy by disease se6erity and age
Fig. 1. Frequency of the first rotavirus diarrheal episode and cumulative efficacy against rotavirus illness at each severity score.
The overall efficacy of rotavirus vaccine was 48% (95% CI, 33,61; PB 0.001 by Fisher’s exact test, two tailed) and increased directly with the severity of rotavirus diarrhea. Cumulative vaccine efficacy ranged from 45 to 88% when comparing vaccine and placebo recipients (of adequate numerical size) who had an illness severity score of ] 4 and ]15, respectively (Fig. 1). Among the recipients of either the placebo or vaccine, most (79%) of the 28 severe episodes occurred during the first year of life. Among vaccinees, all three severe episodes occurred in infants less than 9 months of age, whereas 18 (72%) of the 25 severe episodes in
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978
Fig. 2. Vaccine efficacy by age at the onset of the first rotavirus-positive diarrheal episode of any severity. Table 1 Vaccine efficacy against the first rotavirus-positive episode by severity and time of onset Percent efficacy by time of onset (No. of rotavirus-positive episodes in recipients of vaccine/placebo)a Severity of episode
January–March
April–June
July–September
October–December
Any severity Mild Moderate Severe
52 25 47 100
54 56 34 100
45 36 47 67
45 2 54 80
a
(27/55) (13/17) (14/26) (0/12)
(8/17) (4/9) (4/6) (0/2)
(20/36) (11/17) (7/13) (2/6)
(15/27) (7/7) (7/15) (1/5)
No. of infants: vaccine, 1112; placebo, 1095.
the placebo recipients occurred in this age group. However, among recipients of either vaccine or placebo, 61 and 57% of moderate and mild illness occurred in infants younger than 1 year, respectively. The vaccine maintained its efficacy (around 50%) against all episodes throughout the first 2 years of life, and it seems to increase after 18 months of age (Fig. 2). In general, rotavirus vaccine induced greater protection against severe rotavirus diarrhea than against mild disease independent of age.
This observation encouraged us to use the log-linear model to evaluate rotavirus seasonality, severity of illness, and study group (i.e. vaccine vs. placebo). While the frequency of rotavirus positive episodes again differed significantly by season (i.e. fewer episodes from April to June; PB 0.001), the model failed to identify a significant interaction between seasonality and disease severity (P= 0.47) or seasonality and study groups (P= 0.98). However, the model did identify a significant interaction between severity of illness and vaccine efficacy (P= 0.006), which is consistent with our previous results.
3.3. Vaccine efficacy by season and disease se6erity Rotavirus diarrhea occurred during the entire year, the low period of detection was from April to June (12%), the high period from January to March (40%), and intermediate periods were in July – September (27%) and October– December (20%) (Table 1). Vaccine efficacy did not differ significantly by season (Table 1).
3.4. Vaccine efficacy by socioeconomic status and time of 6accination Analysis of the socioeconomic conditions of our population showed that none of the study subjects were in the highest class and very few were in high-middle class
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groups. We therefore categorized the data into two groups: high-middle and middle to low class (Graffar score 2+3), and low and marginal class (Graffar score 4 +5) and found that the socioeconomic conditions of the study population did not affect vaccine efficacy (Table 2). While efficacy was greater among the poorer children (52 vs. 40%), this difference was not significant (P=0.97 by x 2). As shown by the logistic model, children from low versus higher socioeconomic levels had a 1.39 times greater risk of suffering a rotavirus episode (P =0.038), but this difference did not significantly affect vaccine efficacy. Vaccine efficacy was not affected by the time of vaccination with the first or third dose or the socioeconomic status using the logistic model (data not shown).
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3.5. Incidence analysis Ninety-two percent of infants who received either vaccine (N= 1027) or placebo (N=1010) and either completed the surveillance period or were excluded when they had their first rotavirus episode were used to perform the analysis of the cumulative probability of rotavirus diarrhea, using survival analysis methodology (Fig. 3). The probability of having rotavirus diarrhea was greater for unvaccinated than for vaccinated infants, regardless of duration of surveillance or the severity of the episode. By 4 months after vaccination, vaccinated children had no further episodes of severe rotavirus diarrhea. Moreover, the efficacy of the vaccine against rotavirus diarrhea of any severity was provided throughout the 19–20 months of the surveil-
Table 2 Vaccine efficacy against the first rotavirus-positive episode by socio-economic level Socio-economic status
2–3 4–5 a b
No. of rotavirus-positive episodes (No. of infants with indicate socio-economic status)a Vaccine (N =1103)
Placebo (N= 1082)
Percent efficacy (95% CI)
Pb
22 (382) 48 (721)
39 (407) 94 (675)
40 (0.64) 52 (33.66)
0.0445 B0.0001
No infant had socio-economic level of 1. Data were not available for 9 and 13 infants belonging to vaccine or placebo groups, respectively. Vaccine and placebo groups compared by x 2 test within each group.
Fig. 3. Cumulative probability of the first rotavirus-positive diarrheal episode during surveillance period in infants receiving rotavirus vaccine or placebo in Venezuela.
980
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lance period until children reached 2 years of age. The Cox proportional hazards model was used to compare rates of the first rotavirus episode among vaccine and placebo groups for episodes of any severity and severe episodes. Other variables considered in this analysis were time of vaccination with the first dose, socioeconomic conditions, and age at the onset of the episode (0 – 11 months old and ]12 months of age). Of this set of variables, only vaccine status and socioeconomic conditions seems to affect the risk of having a rotavirus-positive episode and thus were included in the model. However, the interaction between vaccine efficacy and socioeconomic level was not significant (P= 0.65 for episodes of any severity and P = 0.32 for severe episodes) showing again that efficacy was not affected by socioeconomic condition. In addition, efficacy was maintained throughout the study until the children reached 2 years of age. The efficacy of rotavirus vaccine estimated by the model was 52% (95% CI, 36,64; PB 0.001) against rotavirus-positive episodes of any severity and 89% (95% CI, 63,97; P B0.001) against severe episodes. In conclusion, the analysis by these models confirmed the former results: three doses of rhesus rotavirus-based quadrivalent vaccine are efficacious independent of socioeconomic status, time of vaccination and duration of follow up until to 2 years of age.
4. Discussion The rotavirus-based quadrivalent vaccine has proven its efficacy against severe rotavirus disease in developed [3 – 5] and developing countries [6]. This study demonstrates that this vaccine would make an important impact in the developing countries as efficacy was not influenced by socioeconomic status, age or seasonality. Various studies have shown that vaccine efficacy is lower in developing than in developed countries [3,5,15,16]. This difference has been attributed to adverse environmental conditions such as high diarrhea rates and low socioeconomic status in the developing countries [6,15,16]. Although the current study does not compare the poverty levels of other countries where the rotavirus vaccine was not as effective as in Venezuela [15], the current study provides some cause for optimism because in the analysis of data from the only trial of the first licensed rotavirus vaccine in a developing country the vaccine protected children of middle or low socioeconomic status equally well against rotavirus disease. We found that efficacy increases directly with the severity of rotavirus illness and is maintained throughout the first 2 years of life, as observed in Finland [5] and the USA [17]. Cumulative vaccine efficacy ranged from a low of 45% against illness with a severity score of ] 4 to a high of 88% for a score of ] 15 in a
population of vaccine and placebo recipients of sufficient size to render the observed differences statistically significant. In addition, the vaccine shifted the severity of disease toward milder illness. This finding is consistent with the results observed in studies of natural infection [18,19], in which disease severity decreases with age as a consequence of the boosting effect of numerous infections experienced by a child. These results are also consistent with a study in immunized infants who received three doses of the rhesus-based quadrivalent vaccine [20]. After full vaccination and follow up to 16–18 months of age, most of the infants (86%) maintained elevated IgA antibody levels, probably because reinfections boosted the immune response. At least 46% of infants were reinfected as indicated by an IgA seroresponse [20]. On the other hand, poor efficacy was reported in Native American populations after 12 months of age [4]. In this population, early rotavirus infection [21], as well as poor living conditions and overcrowding, may have been decreased vaccine efficacy because of the rapid spread of vaccine virus (or herd immunity) [6,15], or because of a high level of transmission of wild rotaviruses [22]. In this study, efficacy was not affected either by seasonality or by time of vaccination. These results corroborate the observations in Finland [5], where apparent differences in vaccine efficacy between children first vaccinated in April–June (45%), the low season, versus October–December (70–85%), the high season, were not, in fact, statistically different. In Venezuela, where seasonal differences occur but are not striking, neither severity of rotavirus disease nor vaccine efficacy were affected by seasonality. Despite the higher risk of rotavirus disease among children of low socioeconomic status compared with those of higher socioeconomic status, the vaccine efficacy did not differ significantly between the groups. In conclusion, the rhesus rotavirus-based quadrivalent vaccine confers protection against severe disease during the first 2 years of life independently of socioeconomic conditions and seasonality in poor Venezuelan children. The recommendation for use of rotavirus vaccine in the US has been recently withdrawn. However, the observations of this study may be applied to any other oral rotavirus vaccine currently tested in field trials.
Acknowledgements This study was partially supported by grants from the Agency for International Development Vaccine Program through an Agency for International Development–Public Health Service Participating Agency Service Agreement (PASA BTS-5947-PHI-4265) with the National Institute of Allergy and Infectious Diseases (87-I-113), The World Health Organization (C6/181/
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341), and Wyeth-Ayerst Research (0587B-309-VE). We thank Dr Robert M. Chanock for reviewing the manuscript.
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