Rotavirus is a ubiquitous infection that is the leading cause of severe diarrhea worldwide. Severe infections are most commonly observed in the first 2 years of life. Rotavirus-induced diarrhea is associated with substantial morbidity and mortality rates and socioeconomic costs with adverse outcomes particularly prevalent in developing countries. The natural history of rotavirus infection can provide guidance for the development and optimization of an effective vaccine. Epidemiologic studies have demonstrated that children who acquire natural rotavirus infections develop immunity to subsequent infections, with the protective effect increasing with each natural infection. Natural infections also decrease the severity of any subsequent rotavirus infections. Notably, asymptomatic infections provide protection similar to that induced by symptomatic infections. Data also suggest that the antibody response to natural infection is heterotypic, and therefore may provide protection against multiple serotypes. These data suggest that the development of a vaccine that produces asymptomatic infection at an optimal time point may provide effective immunity. An effective vaccine should mimic protection provided by natural infection and provide protection against the most common rotavirus serotypes (ie, G1, G2, G3, G4, G9) and be able to decrease disease severity, reduce hospitalizations, and decrease disease-related costs.
From the Medical Research Unit on Infectious Diseases, Pediatrics Hospital, National Medical Center SXXI, Mexican Institute of Social Security, Mexico City, D.F., Mexico.
Disclosure: Dr. Velázquez has received grant support from GlaxoSmithKline and has provided expert testimony for them.
Address for correspondence: F. Raúl Velázquez, MD, MSc, Medical Research Unit on Infectious Diseases, Pediatrics Hospital, National Medical Center SXXI, Mexican Institute of Social Security, Av. Cuauhtemoc No. 330, Colonia Doctores, C.P. 06725, Mexico City, D.F., Mexico. E-mail: firstname.lastname@example.org.
Rotavirus is the leading cause of severe diarrhea worldwide, defined as diarrhea requiring hospitalization.1 Rotavirus infection is ubiquitous, occurring worldwide and affecting nearly all children (∼95%) by the age of 5 years.1–3 Although the incidence of rotavirus disease is similar between industrialized and developing countries, adverse outcomes are more likely in children from developing countries.1–3 There are approximately 611,000 rotavirus-related deaths worldwide annually, with most (80%) occurring in low-income countries in south Asia and sub-Saharan Africa.1 Although the estimated number of deaths from diarrhea has fallen dramatically over the past 2 decades as a result of improved treatment with oral rehydration therapy and sanitation and water interventions, the number of deaths from rotavirus has not decreased as much.2 In addition, the proportion of diarrhea hospitalizations attributable to rotavirus has increased in recent years, from 21% in 1986–1999 to 39% in 2000–2004, in both developed and developing countries (Fig. 1). 1 This increased relative importance of rotavirus as a cause of diarrhea hospitalizations is likely related to a slower rate of decrease in hospitalizations for rotavirus compared with other causes of severe diarrhea.1
A significant factor for rotavirus disease severity is the age of the child. Younger children have a significantly higher risk of a primary infection leading to severe disease, with most cases of severe, dehydrating diarrhea occurring among children aged 3 to 35 months.3 In the United States, 17% of rotavirus-induced hospitalizations occur during the first 6 months, increasing to 40% by age 1 year, and 75% by age 2 years.3 In developed countries, the peak incidence of rotavirus is 6 to 24 months. Peak incidence in developing countries is somewhat earlier, with peak incidence in the first year of life.4 For example, approximately 80% of hospitalizations in India and Myanmar occur among children during the first yeas of life, compared with 30% for children in developed countries such as Korea, Hong Kong, and Taiwan.5 The severity of disease can also be influenced by rotavirus serotype. In a study from Latin American, the G9 serotype was shown to be associated with a significantly increased risk of hospitalization (67% vs. 7%; P < 0.001), dehydration ≥6% of body weight (47% vs. 0%; P < 0.001), and a higher Vesikari severity score (16 vs. 11; P = 0.003) compared with the G1 serotype.6 The difference may be related to the relatively new introduction of the G9 serotype.6
PROTECTION CONFERRED FROM NATURAL INFECTION
An understanding of the immunology and protective effect provided by natural rotavirus infections against subsequent infections is important for the development of an effective vaccine. Epidemiologic studies have suggested that natural immunity is acquired after early exposure to the virus, although the protective effect is variable. Several studies have demonstrated that natural infection confers protection against subsequent infection, with the benefit increasing with each new infection. For example, Velázquez et al7 conducted a prospective analysis of 200 Mexican infants from birth to 2 years of age. Stool samples were collected weekly and whenever diarrhea occurred, and serum samples were collected at birth and every 4 months. Overall, a total of 316 rotavirus infections occurred, with 52% being primary infections. Thirty-four percent of children experienced a primary infection by the age of 6 months, increasing to 67% and 96%, respectively, at 1 and 2 years of age. Children with 1, 2, or 3 previous infections had progressively lower risks of subsequent rotavirus infection (adjusted relative risk, 0.62, 0.40, and 0.34, respectively). Similarly, the incidence of rotavirus-induced diarrhea decreased significantly with increasing numbers of previous infections (adjusted relative risk, 0.23, 0.17, 0.08, respectively). Subsequent infections were also significantly less severe than first infections (P = 0.024). The degree of protection was greatest against more severe illness with complete protection against moderate-to-severe diarrhea resulting after 2 infections (Fig. 2). 7 The first infection provided 87% protection against moderate-to-severe disease, whereas the second infection provided 100% protection against moderate-to-severe disease. Natural rotavirus infection was less efficacious in protecting against mild diarrhea (73% and 75% after 1 and 2 infections, respectively) and least efficacious in protecting against asymptomatic infection (38% after 1, 62% after 2, and 74% after 3 infections).7
The protective effect of primary rotavirus infection on new rotavirus infection was evaluated in a prospective 2-year study in newborn infants from Guinea-Bissau in West Africa.8 Two hundred randomly selected newborns were followed (weekly visits) from birth to 2 years of age. The overall incidence of rotavirus infections (including reinfections) was 0.6 infections per child-year, with an incidence of 74% by 2 years of age. Forty-four percent of primary infections were symptomatic compared with only 20% for second and third infections. The adjusted odds ratio for subsequent infections was 0.48 [95% confidence interval (CI), 0.27–0.84] indicating that natural rotavirus infection conferred a 52% protection against subsequent rotavirus infection. In addition, the odds ratio for a symptomatic postprimary infection was 0.30 (95% CI, 0.13–0.71), corresponding to 70% protection against subsequent rotavirus diarrhea.8
Protection after natural rotavirus infection has also been observed in the placebo arms of rotavirus vaccine trials.9,10 One trial involved 163 infants (81 vaccines, 82 placebo recipients) aged 2 to 12 months enrolled from private practices from Cincinnati, who were prospectively followed for 2 years.9 Significantly fewer infants infected before enrollment developed a symptomatic reinfection (0 of 21) or any reinfection (4 of 21) compared with previously uninfected infants (P = 0.0003). Among placebo recipients who were previously infected, 0 of 15 developed symptomatic reinfection and only 4 of 15 developed symptomatic reinfection over the 2 years of observation compared with placebo recipients who were not previously infected (26 and 46 of 67, respectively; P < 0.004 for both). Of the 60 infants who developed a primary rotavirus infection in the first year (40 symptomatic, 20 asymptomatic), only 4 were reinfected in the second year compared with 29 of 82 subjects not previously infected (P = 0.00003). Asymptomatic primary infection seemed to be as protective as symptomatic primary infection. Only 1 of 20 patients with asymptomatic infection during year 1 was reinfected in year 2 compared with 29 of 82 previously uninfected subjects (P = 0.005).9
Data from placebo recipients in a large 2-year rotavirus vaccine trial also provide evidence of the protective efficacy of natural rotavirus infection.10 Healthy infants aged 4 to 20 weeks enrolled at 23 sites in the United States were included. The study evaluated whether rotavirus infection in year 1 protected against infection in year 2 among placebo recipients. Of the 280 placebo recipients who completed the 2-year study, 45 experienced a documented episode of rotavirus illness during year 1. Of these, 1 developed rotavirus disease in year 2 compared with 29 of the other 235 placebo recipients (P = 0.03). Among all 171 subjects for whom serologic data were available, 31 had symptomatic infection in the first year and 37 had asymptomatic infection. Of these, only 1 had rotavirus illness in year 2 compared with 22 of 103 not infected in the first year (P < 0.001). This corresponded to an overall efficacy after natural rotavirus infection of 93% (95% CI, 50%–99%).10
There are conflicting data regarding the protective effect of rotavirus infection in the neonatal period. Bhan et al11 followed a cohort of newborns with and without rotavirus infection in the first few days of life to assess whether neonatal infection is protective. Those infected in the neonatal period had 22% fewer episodes of diarrhea and 46% fewer episodes of rotavirus diarrhea during the follow-up period. In addition, those in the infected group tended to have less severe symptoms (fever, vomiting, and dehydration) and a shorter duration of illness, although the difference was not statistically significant. Furthermore, a prospective longitudinal study conducted by Bishop et al12 found that infection during the first 14 days of life was not associated with protection against subsequent infection (ie, within 3 years), although it was associated with a decrease in the frequency and severity of symptoms. In contrast, a prospective study conducted in South India13 compared the incidence of rotavirus infection and diarrhea during the first 2 years of life between children infected with the G10P strain during the neonatal period and uninfected children. There was no significant difference in the rates of rotavirus-positive diarrhea, moderate or severe rotavirus-positive diarrhea, or asymptomatic rotavirus shedding between the 2 groups.13
CORRELATES OF PROTECTION FROM NATURAL INFECTION
The mechanisms and effectors of protection against rotavirus after either natural infection or vaccination remain unclear (for a relevant discussion, see article by Ward in this issue14). Several studies have illustrated that the first infection with rotavirus elicits a predominantly homotypic, serum-neutralizing antibody response to the virus, and subsequent infections elicit a broader, heterotypic response.15–19 It is not clear whether serum antibodies are directly involved in protection or merely reflect recent infection. Serum antibodies (eg, IgA, IgG) are either protective themselves or are correlates of protection against rotavirus disease.20
In a study assessing serum antibody responses among children involved in rotavirus outbreaks in day care centers, serum antirotavirus IgA and IgG antibody titers were increased in both patients with symptomatic and asymptomatic infection.19 In addition, subsequent exposure to G1 rotavirus infection was associated with the development of heterotypic antibody response. Fifty-four percent of children infected with G1 had a heterotypic response, defined as a ≥33% increase in epitope-blocking value for G2 and G4 and ≥28% for G3 serotypes. These children were older and had higher preexisting G1 antibody levels than children who only had a homotypic response. Among children who had pre-exposure G1 epitope blocking >44%, 8 of 9 developed a heterotypic response compared with only 3 of 12 with pre-exposure G1 epitope-blocking levels <15% (P = 0.004). It was suggested that the higher level of preexisting blocking antibody was associated with a heterotypic response because the new infection probably boosted memory cells already primed by one or more previous infections.19
In the previously described cohort of 200 Mexican children,7 serum specimens were analyzed for antirotavirus IgA and IgG antibodies.17 The purpose of these analyses was to evaluate the association of naturally acquired serum antirotavirus IgA and IgG antibodies with protection against rotavirus infection and illness, and the extent to which each was associated with protection against any rotavirus infection and moderate-to-severe rotavirus diarrhea. Although significant protection was observed with a range of antibody titers, the titers corresponding to those achieved after a second infection appeared to be most strongly associated with protection. Children with an IgA titer >1:800 and, to a lesser extent, an IgG titer >1:6400 had a lower risk of any rotavirus infection and diarrhea. Protective titers were reached after 2 consecutive rotavirus infections, regardless of whether these infections were symptomatic or asymptomatic. Protection was greatest against moderate-to-severe disease and least against mild infections. Type-specific antibodies produced heterotypic protection after 2 infections.17
GOALS OF ROTAVIRUS VACCINATION
Vaccination of infants is the primary public health measure for prevention of severe rotavirus disease. Rates of rotavirus illness among children in industrialized and less developed countries are similar, indicating that clean water supplies and good hygiene have little effect on virus transmission; therefore, further improvements in water or hygiene are unlikely to have a substantial impact on disease prevention.3 Given the complexity of rotavirus infection, epidemiologic studies provide valuable information for the development of an effective vaccine. Data suggest that children who experience natural infections develop immunity to subsequent infection.7–10,17 Because asymptomatic infection seems to be as protective as symptomatic primary infection,7 a vaccine that could cause asymptomatic infection might provide effective immunity. Epidemiologic studies also suggest that the timing of infection is important. Forty percent of rotavirus-induced hospitalizations occur in the first year of life,1 but very early infections (neonatal period) may not provide optimal immunity.12,13 These finding suggest that early (but not too early) vaccination is important to optimize the clinical benefit.
In summary, the clinical immunity produced by natural rotavirus infection suggests that vaccine-induced protection against rotavirus infection is feasible. The overall approach to vaccine development is to mimic the protection conferred by natural infection.7 The goals associated with the development of an effective rotavirus vaccine are summarized in Table 1. 7,21 The diversity of viral strains and the emergence of new serotypes underscore the need for vaccines to protect against multiple serotypes.21 An effective vaccine should be effective against the most clinically significant serotypes, ie, G1, G2, G3, G4, and the newly emerging G9.13 Vaccines should also be able to reduce the severity and duration of disease (particularly in those with moderate-to- severe illness) and improve clinical outcomes, thereby reducing the need for hospitalization and socioeconomic burden.
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17. Velázquez FR, Matson DO, Guerrero ML, et al. Serum antibody as a marker of protection against natural rotavirus infection and disease. J Infect Dis
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21. Salinas B, Pérez Schael I, Linhares AC, et al. Evaluation of safety, immunogenicity, and efficacy of an attenuated rotavirus vaccine, RIX4414: a randomized, placebo-controlled trial in Latin American infants. Pediatr Infect Dis J