What is Rotavirus ?

Rotavirus is the most common cause of severe diarrhea among infants and young children worldwide. In developing nations, this virus is responsible for the large majority of diarrhea-related childhood deaths. Infection causes abdominal pain, watery diarrhea, vomiting, and fever. These symptoms can result in rapid dehydration, which can be fatal. Rotavirus spreads via the fecal-oral route and is easily transmitted from person-to-person and through contact with contaminated objects, water, and food. Outbreaks can rapidly take hold in institutional settings, such as daycares, schools, and hospitals.

Global Burden

Rotavirus

Rotavirus is distributed worldwide, and, in the absence of a vaccine, nearly all children in both the developed and developing worlds have been infected by the time they are three years old.1 While nearly every child is at risk of rotavirus infection,complicating factors, such as poverty, malnutrition, and low birth weight, increase the risk for hospitalization irrespective of geographic location. The WHO estimates that each year rotavirus results in over 453,000 deaths and over 2 million hospitalizations of infants and young children around the world.2 Of these deaths, 85 % occur in developing countries in Asia and sub-Saharan Africa where access to treatment is limited or unavailable.3

In the United States alone, rotavirus infection leads to over 200,000 emergency room visits and 55,000 - 70,000 hospitalizations each year, translating into an economic impact of approximately US$1 billion annually.4 Globally, rotavirus is estimated to result in 25 million doctors visits and 2 million hospitalizations each year.5

Causative Agent

example

Rotaviruses are non-enveloped, double-stranded RNA viruses belonging to the family Reoviridae. Rotavirus particles are made up of three concentric layers of capsid proteins, giving them a wheel-like (latin, rota) appearance under the electronmicroscope.

Rotaviruses are classified into seven groups (A-G), which infect different species including humans, other mammals, and birds.6 Group A rotaviruses cause the majority of human infections. Rotaviruses are further characterized into multiple genotypes based on the antigenic specificity of the outer capsid proteins. Primary infection leads to the generation of antibodies that can protect against the initial serotype, and can give partial protection against other serotypes. Although primary infection does not provide full immunity against the many strains of rotavirus, subsequent infections are generally less severe.

Transmission of rotavirus occurs by ingestion of feces from an infected individual. The high numbers of virus particles shed from an acutely infected patient, combined with the low number of viruses required to cause infection, lead to rapid spread of the virus. Rotavirus can be found in the stool of both symptomatic and asymptomatic children. Rotavirus particles are highly stable and can remain infectious for months at room temperature, further facilitating transmission. Rotavirus is so infectious that good hygiene and hand washing are not enough to prevent its spread.In temperate climates, rotavirus infections are seasonal, with the highest incidence from December to June; in the tropics, infections occur year-round with peak infections occurring in some countries during the cool dry months.

Pathogenesis

Rotavirus is taken into the body by ingestion, and infects epithelial cells lining the small intestine. Viral replication in the cytoplasm causes cellular damage and fluid secretion, which result in profuse, watery diarrhea. The appearance of symptoms generally occurs suddenly after an incubation period of 1-2 days. Diarrhea, vomiting, and fever can last between 4-7 days, during which time very large numbers of virus particles are shed in the feces.

Current Control Strategy

There is presently no known effective intervention for rotavirus infection except vaccinarion.. Two rotavirus vaccines were recently approved by the World health Organization (WHO) for inclusion in the Expanded Programme on Immunization (EPI), and vaccination campaigns for children worldwide have begun. These vaccines provide protection against severe disease and are beneficial for reducing infection rates in children in both developed and developing countries.

Existing Products

Drugs

There are no specific antiviral drugs available to treat rotavirus infection. Symptoms are managed by oral or intravenous rehydration therapy.

Vaccines

There are currently two vaccines available for the prevention of rotavirus: 

  1. RotaTeq, developed by Merck: Contains five strains of rotaviruses, each of which is a reassortant of the bovine rotavirus isolate (G genotype) and a human isolate (P genotype) attenuated through multiple passages in culture.
  2. Rotarix, developed by GlaxoSmithKline: Contains a single strain of rotavirus, which is derived from a human isolate and was attenuated by multiple passages in cell culture.

Both vaccines are administered orally and are based on live attenuated viruses. Although vaccination does not completely protect against the many rotavirus strains, it is effective at preventing severe infection. These vaccines have been highly beneficial in the United States, reducing rotavirus infections by 50% in the 2007-2008 season as immunization became widespread.1 In the developing world (El Salvador, Nicaragua, Mexico, etc.) these vaccines have also shown high efficacy and reduced the number of infections and diarrhea incidence significantly.9-16

Country Vaccine Impact1,6
Australia Rotateq and Rotarix 89-94% vaccine efficacy; 68-93% reduction in hospital admissions for rotavirus in children <1 year old
Belgium Rotarix 65-83% reduction in rotavirus hospitalizations
El Salvador Rotarix 35-48% decrease in all diarrhea events; 69-81% decrease in rotavirus hospitalizations in children <5 years old
Mexico Rotarix 11-40% reduction in all cause diarrhea hospitalization in children <5 years old
Panama Rotarix 22-37% reduction in all cause diarrhea hospitalizations in children <5 years old
United States Rotateq ~50% decrease in rotavirus infections; no rotavirus epidemic detected in 2010 (first time in 19 years no epidemic occurred)

Diagnostics

Commercial Enzyme based Immunosorbent Assays (EIA) are available for rotavirus diagnosis as well as nucleic acid amplification-based diagnostic techniques.. It should be noted that the nucleic acid based methods require access to sophisticated laboratory facilities.

As diarrhea due to rotavirus, like other diarrheal disease, is primarily treated by supportive rehydration therapy rather than medications, specific diagnosis of rotavirus is not considered essential.

References

  1. WHO, Initiative for Vaccine Research: Diarrheal Diseases.
  2. Tate JE et al. 2008 estimate of worldwide rotavirus-associated mortality in children younger than 5 years before the introduction of universal rotavirus vaccination programmes: a systematic review and meta-analysis. Lancet Infectious Diseases, 2011, doi:10.1016/S1473-3099(11)70253-5.)
  3. WHO. 2008 rotavirus deaths, under 5 years of age, as of 31 January 2012. Available here.
  4. Parashar UD et al. (2006) “Prevention of Rotavirus Gastroenteritis Among Infants and Children.” MMWR 55: 1-13.
  5. Parashar UD et al. (2003) “Global illness and deaths caused by rotavirus disease in children.” Emerg Infect Dis 9: 565-72.
  6. Desselberger U et al. (2009) “Rotaviruses and rotavirus vaccines.” Br Med Bull 90: 37-51.
  7. CDC: About Rotavirus.
  8. Patel MM et al (2010) “Real-world Impact of Rotavirus Vaccination.” The Pediatric Infectious Disease Journal 30: S1-S5
  9. Linhares AC, et al. Lancet 2008; 371: 1181–9, 2. Ruiz-Palacios GM, et al. N Engl J Med 2006; 354: 11–22
  10. Vesikari T, et al. Lancet 2007; 370: 1757–63
  11. Tregnaghi M et al. ICID. 2008
  12. Phua KB, et al. APCP. 2009,
  13. Phua KB, et al. Vaccine 2009; 27: 5936–41
  14. Phua KB, et al. ESPID. 2009,
  15. Madhi S et al. N Engl J Med 2010; 362: 289–98,;
  16. Armah GE et al. Efficacy of pentavalent rotavirus vaccine against severe rotavirus gastroenteritis in infants in developing countries in sub-Saharan Africa: a randomised, double-blind, placebo-controlled trial. The Lancet. 2010;376(9741):606–614.

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Drugs

Rotavirus, like other diarrheal diseases, is effectively managed by oral or intravenous rehydration therapy. Therefore, development of specific antiviral agents for rotavirus is not considered a priority.

Vaccines

Analysis

As there are already two vaccines commercially available for rotavirus, the primary focus for vaccine development includes:

  1. Expanding clinical research on existing vaccines to more fully characterize their safety and efficacy in developing world populations
  2. Increasing access to existing vaccines, including lowering the vaccine cost

New vaccine development is relatively limited for rotavirus, but includes two clinical phase vaccines. These vaccines are focusing on improving efficacy and allowing for at birth dosing. The value and best strategies for new vaccine development should be guided by limitations identified in the current vaccines as they are studied in more detail in developing world populations.

 StrengthsWeaknessesOpportunitiesRisks
Live attenuated
Most advanced program:  Rotarix and Rotateq, On Market; ORV 166E, Phase III; RV3 and BRV-TV, Phase I Proven vaccine approach for rotavirus Requires cold chain for delivery Efficacy and safety in developing world populations still unknown  Reduced number of doses At birth dosing Optimization for efficacy and safety in developing world Two vaccines are already on market so may be difficult to improve upon those

Diagnostics

 As disease specific treatment is not available for rotavirus, the development of new diagnostics is not a high priority for this disease.

References

Get Involved

To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs.

The following series of tables describe the availability of tools for research, discovery, and development of novel drugs, vaccines, and diagnostics for rotavirus. The tools listed in the following tables are not intended to be an all-inclusive list but rather capture the most common tools used for drug, vaccine, and diagnostic development.

Drugs Development Tools

Basic Research: Target IdentificationTarget ValidationScreening: Hit/Lead Identification OptimizationPre-clinical ValidationClinical Validation

Genome:  Sequenced 

Key databases: Virus Sequence Database 

In vitro culture: Yes, need to activate virus by trypsin proteolysis; reverse genetics system is available but limited by low efficiency and requirement for wild-type helper rotavirus

Gene knock-outs:Yes, but subject to limitations of reverse genetics system 

Conditional gene knock-outs: Yes, temperature sensitive mutants

Transposon mutagenesis: Possible, but subject to limitations of reverse genetics system 

RNAi: Yes, using host cell machinery

Other antisense technology: Host cell only 

Viability assays:Yes, virus causes cytopathic effect to infected cells

Transcription microarrays: Yes, of infected cells 

Proteomics: Yes  

Crystal structures:Yescryoelectron microscopy structures of whole viral particles also available

Whole-cell screening assays: Yes, using virus infected cells or cells expressing viral proteins 

Enzymatic screening assays: Yes

Animal models:  Yes, mice infected with rotavirus are useful for immunity studies, but only mimic human pathogenesis during first two weeks of life

Gnotobiotic newborn pigs mimic human symptoms of rotavirus infection

Rabbits and calves are also used

Monitoring treatment efficacy: Yes

Availability of endpoints: Yes, clearance of virus

Availability of surrogate endpoints: No 

Access to clinical trial patients/sites: Yes

Vaccines Development Tools

Basic Research: Antigen IdentificationImmune Response CharacterizationClinical Validation

See drug development tools above

Predictive animal models: Yes, gnotobiotic newborn pig mimics human disease most closely, but time window for vaccination and challenge is short; adult mouse model is useful for studying immunity, but does not mimic human pathogenesis 

Detection of endogenous antigen specific response in clinical samples:Yes 

Natural immunity well characterized:Yes, virus-specific IgA is important  

Surrogate markers of protection: Yes, serum IgA and neutralizing antibodies 

Challenge studies possible: Used in adults in the 1980s and 1990s but most likely not possible in children, the target population for a vaccine 

Diagnostics Development Tools

Basic Research: Biomarker IdentificationBiomarker ValidationClinical Validation

See drug development tools above

Biomarkers known: Yes, viral RNA and proteins 

Access to clinical samples: Yes 

Possible sample types: Stool, serum

Access to clinical trial patients/sites: Yes 

Treatment available if diagnosed: Oral rehydration therapy available but no specific antivirals

References

Get Involved

To learn how you can get involved in neglected disease drug, vaccine or diagnostic research and development, or to provide updates, changes, or corrections to the Global Health Primer website, please view our FAQs.