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Rotavirus: disease and vaccine update, 2007.

Rotavirus infection is a ubiquitous illness, infecting the vast majority of children worldwide in the first 5 years of life. Rotavirus is one of the major causes of severe diarrhea in infants and young children throughout the developing and developed world. An estimated 500,000 deaths per year occur, with the burden of morbidity and mortality highest in the poorest nations. (1) Two new oral, live, attenuated vaccines have recently shown efficacy and safety in clinical trials, and one of these, RotaTeq[R], was approved by the US Food and Drug Administration on February 3, 2006. RotaTeq is recommended for general use by the Centers for Disease Control and Prevention, American Academy of Family Practice, and American Academy of Pediatrics.

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Diarrheal illness is the second leading cause of death among children from birth to 5 years of age, resulting in 1.6 million deaths per year worldwide. Rotavirus (RV) infection is the largest single cause, accounting for one third, with death typically due to severe dehydration. As such, mortality and severe morbidity are much lower in countries that have comprehensive medical systems. Oral rehydration therapy can also significantly improve survival; however, the 3 to 5 vomiting episodes per day seen in severe RV infection forestall these efforts, as does the fact that oral rehydration therapy is not available in all settings.

In addition to mortality, RV also causes high morbidity in infants and young children and is responsible for millions of hospitalizations, tens of millions of outpatient visits, and hundreds of millions of infections every year (TABLE 1). (2)

RV infections occur in all countries, and almost every child will suffer at least 1 infection in the first few years of life. (3) The amount of virus needed to cause infection is very small, and the concentration of virus excreted in the stool of children is very high, both of which contribute to the highly contagious nature of the disease. RV is also relatively hardy and can survive on cool, nonporous surfaces for days. This combination of factors, in addition to the many genetic subtypes and the frequency of asymptomatic infection, helps explain the ubiquitous nature of the virus as well as the sustained high attack rates and population prevalence--even in developed countries with sophisticated water and sewer systems.

Pathophysiology

RV primarily infects the cells near the tips of the small intestinal villi, leading to malabsorption and excessive fluid loss. Incubation time is 18 to 36 hours from initial exposure, typically followed by 2 to 3 days of fever and vomiting. Non-bloody diarrhea, which can be profuse, ensues with as many as 10 to 20 episodes per day. Viral shedding begins shortly before the onset of symptoms and lasts for 2 weeks or longer in children. Adults typically shed the virus for shorter periods of time and in lower concentrations.

Epidemiology

World

RV is a double-stranded RNA virus first isolated in 1973 by Bishop and colleagues (4) (coincidentally, just 1 year after the discovery of Norwalk virus). Following closely upon these discoveries was the recognition that RV was the predominant cause of nonbacterial gastroenteritis in infants and young children. A host of research since that time has helped delineate morbidity, mortality, subtypes, patterns of spread, and vaccine opportunities.

The Asian Rotavirus Surveillance Network (ARSN), founded in 2001, is a network of providers, laboratories, institutions, and governmental agencies working to track RV disease and speed development and use of effective RV vaccines in Asia. Recent studies from the ARSN show that RV infections are responsible for 43% of childhood hospitalizations for gastroenteritis in Asia. (5) This number is almost double the historic estimates and adds further impetus to the movement for global vaccination.

United States

Each year in the United States, RV is estimated to cause more than 500,000 clinic and emergency department visits, 55,000 hospitalizations, and from 40 to several hundred deaths in infants and young children. (6) RV infections occur predominantly in the cold months, with few cases during the summer. More than 70 laboratories in the United States send weekly reports of RV infection to the National Respiratory and Enteric Virus Surveillance System (NREVSS) at the CDC. A recent analysis of the 48 contiguous states shows characteristic seasonal patterns of infection, beginning in the southwestern part of the country in December/January and ending in northern/northeastern regions in April and May (FIGURE). (7)

[FIGURE OMITTED]

Genetics

The many types and subtypes of RV form the genus Rotavirus in the Reoviridae family. The genome consists of 11 ds-RNA segments, enclosed within a 3-layer nucleocapsid protein structure. The most clinically important proteins are VP4 and VP7, which comprise the outer layer, and VP6, which comprises the middle layer. Variations in VP6 determine the group specificity, with VP7 being the "G" type and VP4 the "P" type (TABLE 2).

The 4 major genotype combinations, which represent more than 90% of isolates in developed countries, are G1P[8], G2P[4], G3P[8], and G4P[8]. In developing nations, strains exhibit much greater variability. However, in both developed and developing nations, G9 is rapidly increasing in population prevalence, most commonly (but not always) in combination with P[8]. (8) G9 now accounts for more than 50% of strains in some Asian countries. (5) Serotypes have been observed to change through a variety of mechanisms, including point mutation, reassortment, gene rearrangements, and introduction of animal RVs into human populations (as noted with RV Group B in China).

Nosocomial Infections

Proper infection control is essential to prevent and control RV outbreaks, particularly in neonatal intensive care wards and other settings that house groups of infants. RV is the major cause of nosocomial diarrhea in pediatric hospital settings, affecting predominantly very young children (birth to 5 months of age). (9) A significant percentage of these infections (20%-40%) are asymptomatic, once again highlighting both the importance of early vaccination and the need for comprehensive hygiene and infection control in high-risk settings. RVs survive well on nonporous surfaces at room temperature and can also survive for an hour or more on contaminated hands and fingers. (10) Phenolic disinfectants are not effective; chlorine-based disinfectants or 70% ethanol solutions are required to eliminate RV. A recent study showed that intensive attention to hand hygiene was successful in reducing nosocomial RV infections by more than half in a children's hospital. (11)

Immunity

Despite the complexity of RV genetics, 1 to 2 wild-type infections typically provide individuals with excellent immunity against future clinically significant episodes, although mild or asymptomatic infections are still quite possible. (12) This fact, as well as clinical data from a number of vaccine studies, suggests that vaccines that protect directly against only a few RV subtypes can provide broad protection against severe illness from any RV subtype, although spread through subclinical disease is still possible.

However, it is not infrequent for parents and caregivers to have either mild symptoms or to be asymptomatic carriers either immediately before or after illness in their children. One study estimated that one third of parents were ill during the same week their child was hospitalized for RV-related diarrhea. (13)

Rotavirus Vaccine

RV infection was recognized shortly after discovery as a vaccine-preventable disease, and the focus has consistently been on the use of live, oral vaccines attenuated either naturally or in the laboratory. Although an injectable vaccine is under consideration by some manufacturers, the oral vaccine has generally been preferred because of its effectiveness and ease of use. In addition, live vaccine can lead to "herd immunity" by exposing nonimmunized children, since it is excreted in the stool of children who have been recently immunized.

Although initial tests with bovine strains were promising, they ultimately produced inconsistent results, particularly in developing countries. Rhesus-strain vaccines have also shown effectiveness; however, the quadrivalent rhesus-human reassortant rotavirus vaccine (RRV-TV), RotaShield[R], was withdrawn from the market in 1999 after reports of an increased risk of intussusception in the United States. (14) The withdrawal of RotaShield by the FDA led to an intense international debate over whether the apparently small increase in the risk of intussusception should prevail over what would likely have been a much larger reduction in morbidity and mortality in the developing world. Ultimately, RotaShield was not reintroduced to the market and it is no longer produced. (15)

More recently, manufacturers have concentrated on developing non-rhesus-based vaccines. Current efforts use both improved human-bovine reassortant vaccines and human strains that are either artificially or naturally attenuated. Two vaccines, RotaTeq[R] and Rotarix[R], have recently completed large-scale trials that specifically assessed the risk of intussusception. When used as directed by the manufacturers, both vaccines were shown to be highly effective--with no known association with an elevated risk of intussusception--when compared to placebo recipients. (16,17) RotaTeq was approved in January 2006 for use in the United States, while Rotarix has been approved in recent years in several other countries.

The risk of intussusception when the vaccine is given out of sequence or later than the recommended ages has not been evaluated in these studies; however, post-licensure studies from the manufacturer and CDC may address this issue. The choice of vaccine to be used in developed versus developing countries is limited by the licensing agencies. However, both vaccines appear to be highly efficacious, so choice may depend on cost and other factors such as number of doses and extent of fecal shedding of live-virus vaccine (TABLE 3).

RotaTeq Administration (18)

Routine immunization is 3 doses administered orally at 2, 4, and 6 months of age. The first dose should be administered between 6 and 12 weeks of age, and vaccination should not be initiated for infants older than 12 weeks of age. Subsequent doses should be administered at 4- to 10-week intervals and all 3 doses should be completed by 32 weeks of age. See http://www.cispimmunize.org/pro/pdf/RotaVaccine Implementation2006.pdf for additional information and helpful tips.

RotaTeq is provided in a squeezable plastic dosing tube with a twist-off cap designed to allow for the vaccine to be administered directly to infants by mouth. Each tube contains a single 2-mL dose of the vaccine as a liquid buffered-stabilized solution that is pale yellow in color but might have a pink tint. This formulation protects the vaccine virus from gastric acid and stabilizes the vaccine, allowing for storage at refrigerator temperatures (2[degrees]C-8[degrees]C [36[degrees]F-46[degrees]F]) for 24 months. RotaTeq should be administered as soon as possible after being removed from refrigeration. Additional information on stability under conditions other than those recommended is available by calling 1-800-637-2590. The vaccine is currently available at a listed price (as of this printing) of $63.25 per dose; the CPT code is 90680.

RotaTeq may be given with other currently approved childhood vaccines. However, because validation of the pertussis assays is under review, insufficient immunogenicity data are available to confirm the lack of interference of immune responses when RV vaccine is concomitantly administered with childhood vaccines to prevent pertussis.

Precautions

Premature infants (<37 weeks' gestation). Practitioners should consider the potential risks and benefits of vaccinating premature infants against RV. ACIP supports vaccination of prematurely born infants if they are at least aged 6 weeks, are being or have been discharged from the hospital nursery, and are clinically stable. Until further data are available, ACIP considers that the benefits of RV vaccination of premature infants outweigh the theoretical risks.

Exposure of immunocompromised persons to vaccinated infants. Infants living in households with persons who have or are suspected of having an immunodeficiency disorder or impaired immune status can be vaccinated. To minimize potential virus transmission, all members of the household should employ measures such as good hand washing after contact with the feces of the infant (eg, after changing a diaper) for at least 2 weeks postvaccination.

Exposure of pregnant women to vaccinated infants. Infants living in households with pregnant women can be vaccinated. The majority of women of childbearing age would have pre-existing immunity to RV and so the risk for infection and disease from potential exposure to the attenuated vaccine virus strain is low. In addition, no evidence exists that RV infection or disease during pregnancy poses any risk to the fetus.

Regurgitation of vaccine. The practitioner should not readminister a dose of RV vaccine to an infant who regurgitates, spits out, or vomits during or after administration of vaccine. The infant can receive the remaining recommended doses of RV vaccine at appropriate intervals.

Adverse Reactions

Intussusception. The risk for intussusception was evaluated in 71,725 persons enrolled in phase 3 efficacy trials. (16) No evidence of clustering of cases of intussusception was observed within a 7- or 14-day window postvaccination for any dose, the period of greatest risk for intussusception associated with the RRV-TV vaccine. For the 1-year follow-up period after administration of the first dose, 13 cases of intussusception were observed in the RotaTeq group versus 15 cases in the placebo group (adjusted relative risk, 0.9; 95% confidence interval, 0.4-1.9).

Other adverse events. Among RotaTeq and placebo recipients, the incidence of serious adverse events (2.4% vs 2.6%, respectively), including deaths (<0.1% [n=25] vs <0.1% [n=27], respectively), was similar. No deaths were attributed to vaccination by blinded investigators. In the 7-day postvaccination period, vaccinees had a small but statistically significantly greater rate of diarrhea, with an excess of 1% after dose 1 (10% vs 9%, respectively), 3% after dose 2 (9% vs 6%, respectively), and 3% after any dose (18% vs 15%, respectively). Similarly, vaccinees had a small but statistically significantly greater rate of vomiting, with an excess of 2% after dose 1 (7% vs 5%, respectively) and 2% after any dose (12% and 10%, respectively). The incidence of fever and irritability during the 7-day period after any vaccine dose was similar among RotaTeq and placebo recipients.

Preterm infants. RotaTeq or placebo was administered to 2070 preterm infants (25-36 weeks' gestational age; median: 34 weeks) in the phase 3 trials. All preterm infants were monitored for severe adverse events, and a subset of 308 was monitored in detail for all adverse events. No cases of intussusception were reported among preterm infants. Among preterm infants administered RotaTeq and placebo, the incidence of serious adverse events (5.5% vs 5.8%, respectively) was similar.

Contraindications

Infants older than 12 weeks should not initiate the vaccine series because of insufficient safety data. Infants older than 32 weeks should not receive any doses. RV vaccine should not be administered to infants who have severe hypersensitivity to any component of the vaccine or who have experienced a serious allergic reaction to a previous dose of the rotavirus vaccine.

Precautions. Safety and efficacy data are lacking for the administration of RV vaccine to immunocompromised infants, including those with blood dyscrasias or neoplasms affecting the bone marrow or lymphatic system; those receiving immunosuppressive therapy; and infants with primary and acquired immunodeficiency states. In addition, infants born to mothers with HIV should not receive the vaccine unless it has been established that the infant is not infected with HIV, and infants should not receive RV vaccine within 42 days of receipt of blood transfusion or blood products, including immunoglobulins.

Infants with moderate-to-severe illness (including gastroenteritis) should be vaccinated as soon as they have recovered from the acute phase of their illness. Practitioners should consider the potential risks for and benefits of administering RV vaccine to infants with pre-existing chronic gastrointestinal disease and/or a prior episode of intussusception.

Vaccination Implementation

One outstanding question--perhaps the most important one--is whether medical providers and parents will embrace RV vaccination. Although the total number of possible cases of intussusception in the years 1998 through 1999 due to RotaShield vaccination was low, the memory of those cases lingers in the minds of parents and physicians. A 2003 survey of pediatricians in Wisconsin indicated that 94% would use a new RV vaccine if it proved safer than RotaShield and if it were recommended for routine use in infants by the ACIP and the AAP. However, 95% expressed concern about adverse reactions, 63% about high vaccine cost, and 57% about the amount of time that would be required to educate parents. These concerns will likely remain as significant barriers that must be comprehensively addressed by public health and medical groups if RV vaccination is to gain acceptance by physicians and their patients' parents.

Internationally, the Rotavirus Vaccine Program (RVP) was established in 2003 to reduce the time it takes to make a safe and effective vaccine available to children in developing countries. The RVP is located at PATH (Program for Appropriate Technology in Health)--an international, nonprofit organization--in partnership with the CDC, the WHO, and the Global Alliance for Vaccines and Immunization, with partial funding from The Vaccine Fund. Recognizing that an effective RV vaccination campaign will require substantial and sustained efforts worldwide, the RVP has recently completed a comprehensive guide, available in the public domain, titled The Development of Live, Attenuated Rotavirus Vaccines: A Manufacturer's Resource Guide (available at http://www.rotavirusvaccine.org/ documents/RotaManufResourceGuide.pdf) as a tool to assist countries and companies in this effort.

References

(1.) Parashar UD, Gibson CJ, Bresse JS, Glass RI. Rotavirus and severe childhood diarrhea. Emerg Infect Dis. 2006;12:304-306.

(2.) Parashar UD, Hummelman EG, Bresee JS, Miller MA, Glass RI. Global illness and deaths caused by rotavirus disease in children. Emerg Infect Dis. 2003;9:565-572.

(3.) Rotavirus Vaccine Program. Rotavirus facts. January 2006. Available at: http://www.rotavirusvaccine.org/rotavirus-facts.htm. Accessed October 20, 2006.

(4.) Bishop RF, Davidson GP, Holmes IH, Ruck BJ. Virus particles in epithelial cells of duodenal mucosa from children with acute non-bacterial gastroenteritis. Lancet. 1973;2:1281-1283.

(5.) Bresee JS, Hummelman E, Nelson EAS, Glass, RI. Rotavirus in Asia. The Value of Surveillance for Monitoring Decisions about the Introduction of New Vaccines. J Infect Dis. 2005;192(suppl 1) S1-5. Available at: http://www.journals.uchicago.edu/ JID/journal/issues/v192nS1/33792/33792.web.pdf. Accessed October 20, 2006.

(6.) Bresee JS, Parashar UD, Widdowson MA, Gentsch JR, Steele AD, Glass RI. Update on rotavirus vaccines. Pediatr Infect Dis J. 2005;24:947-952.

(7.) Turcios RM, Curns AT, Holman PC, et al; for the National Respiratory and Enteric Virus Surveillance System Collaborating Laboratories. Temporal and geographic trends of rotavirus activity in the United States, 1997-2004. Pediatr Infect Dis J. 2006;25:451-454.

(8.) Desselberger U, Wolleswinkel-van den Bosch J, Mrukowicz J, Rodrigo C, Giaquinto C, Vesikari T. Rotavirus types in Europe and their significance for vaccination. Pediatr Infect Dis J. 2006;25(suppl):S30-S41.

(9.) Gleizes O, Desselberger U, Tatochenko V, et al. Nosocomial rotavirus infection in European countries: a review of the epidemiology, severity and economic burden of hospital-acquired rotavirus disease. Pediatr Infect Dis J. 2006;25(suppl):S12-S21.

(10.) Ansari SA, Sartar SA, Springthorpe VS, Wells GA, Tostowaryk W. Rotavirus survival on human hands and transfer of infectious virus to animate and nonporous inanimate surfaces. J Clin Microbiol. 1988;26:1513-1518.

(11.) Zerr DM, Allpress AL, Heath J, Bornemann R, Bennett E. Decreasing hospital-associated rotavirus infection: a multidisciplinary hand hygiene campaign in a children's hospital. Pediatr Infect Dis J. 2005;24:397-403.

(12.) Velazquez FR, Matson DO, Calva JJ, et al. Rotavirus infections in infants as protection against subsequent infections. N Engl J Med. 1996;335:1022-1028.

(13.) Matson DO; for the National Foundation for Infectious Diseases. Clinical updates in pediatric infectious diseases. Current status of rotavirus immunization. September 1997;2(4). Available at: http://www.nfid.org/%5Fold/publications/clinicalupdates/ pediatric/rotavirus.html. Accessed October 20, 2006.

(14.) Centers for Disease Control and Prevention (CDC). Intussusception among recipients of rotavirus vaccine--United States, 1998-1999. MMWR Morb Mortal Wkly Rep. 1999:48:577-581. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/mm4827al.htm. Accessed October 20, 2006.

(15.) Weijer C. The future of research into rotavirus vaccine. BMJ. 2000;321:525-526.

(16.) Vesikari T, Matson DO, Dennehy P, et al. Safety and efficacy of a pentavalent humanbovine (WC3) reassortant rotavirus vaccine. N Engl J Med. 2006;354:23-33.

(17.) Ruiz-Palacios GM, Perez-Schael I, Velazquez FR, et al. Safety and efficacy of an attenuated vaccine against severe rotavirus gastroenteritis. N Engl J Med. 2006;354:11-22.

(18.) Parashar UD, Alexander JP, Glass RI; Advisory Committee on Immunization Practices (ACIP), Centers for Disease Control and Prevention (CDC). Prevention of rotavirus gastroenteritis among infants and children. Recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep. 2006;55(RR-12):1-13.

SAMUEL STEBBINS, MD, MPH
TABLE 1
Annual incidence of rotavirus infection
in children from birth to age 5

             Developing   Developed
             Countries    Countries      Total
Setting      (millions)   (millions)   (millions)

Home          51.5-157       2-18       53.5-175
Outpatient     19-27       0.7-3.5     19.7-30.5
Inpatient     1.55-2.6    0.14-0.36    1.69-2.96
Total         72-186.6    2.84-21.86   74.9-208.5

TABLE 2
Key rotavirus proteins, known types,
and predominant human strains

         Viral Protein   Known Types

Group    VP6             A-G
G Type   VP7             15 types
P Type   VP4             23 types

         Predominant Human Strains

Group    A               B and C occasionally
G Type   1, 2, 3, 4, 9   G9 increasing rapidly
P Type   8               4 and 6 as well

TABLE 3
Recently approved rotavirus vaccines

                      RotaTeq[R]             Rotarix[R]

Approved by           United States          * Mexico
                                             * Philippines
                                             * Thailand
                                             * 15 Latin American
                                               countries
                                             * European Commission

Vaccine basis         Bovine WC3 (human      Human (attenuated)
                      reassortant)

Valences              G1, G2, G3, G4, P8     G1, P8

Reduction in          59%                    42%
hospitalization for
diarrhea (from any
cause)

Reduction in          96%                    85%
hospitalization for
diarrhea (caused by
rotavirus)

Number of doses,      3, oral                2, oral
route

Timing of doses       First: At age          First: At age
                      6-12 weeks             6-13 weeks
                      Second: 4-10 weeks     Second: 4-8 weeks
                      after first dose       after first dose
                      Third: 4-10 weeks
                      after second dose

Fecal shedding        Low (13%)              High (>50%)
after first dose

Notes                 Parents/caregivers     Tested primarily
                      of vaccine             among infants of
                      recipients reported    poor and middle-
                      a large reduction in   income families in
                      lost workdays          Latin America

Resources

ACIP recommendations:   http://www.cdc.gov/mmwr/preview/mmwrhtml/
                        rr5512a1.htm?s_cid=rr5512a1_e
Recent articles on RV:  http://www.immunize.org/rotavirus/rota_
                        journal.htm
CDC FAQs:               http://www.cdc.gov/nip/diseases/rota-faqs.htm
FDA approval or
 RotaTeq:               http:/www.fda.gov/bbs/topics/news/2006/
                        NEW01307.html
Rotavirus Vaccine
 Project:               http://www.rotavirusvaccine.org
Global Alliance:        http://www.gavialliance.org
Red Book[R] Online:     http://aapredbook.aappublications.org/news/
                        vaccstatus.shtml
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Author:Stebbins, Samuel
Publication:Journal of Family Practice
Geographic Code:1USA
Date:Feb 1, 2007
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