Rotavirus Vaccine

Introduction

Diarrhea is the second leading cause of death only surpass by respiratory tract infections (RTI) and pneumonia, constituting 17% of all under-five mortality worldwide.^1,2 It is estimated that the incidence of diarrhea in India is 1.71 episodes/person/year in rural India and 1.09 episodes/person/year in urban India.³

Rotavirus is a wheel-like icosahedral Reoviridae double-stranded RNA virus. It is subdivided into serogroup A-G and subgroup 1 or 2. Group A rotavirus causes most human diseases. The outer viral capsid is made of protein VP7 (which determine G serotype) and VP4 (which determine P serotype). Each rotavirus is designated by G serotype and P serotype followed by P genotype in bracket e.g. G1P1A.⁸ G1-4 and G9 are predominant 5 strains in the USA and responsible for 90% of rotavirus gastroenteritis (RVGE). Out of these infecting strains, G1 causes 75% of disease. It is very stable and may remain viable if not disinfected. Rotavirus causes diarrhea in maximum among children in the age 6-32 month and 13.3% of rotavirus infection involve children <6 months. Rotavirus diarrhea is markedly seasonal in a temperate climate with peak incidence occurring in the spring and winter season.⁴ Rotavirus spreads through the fico-oral spread, close person to person contact and by fomites.

Disease Burden of Rotavirus

It is estimated that rotavirus causes 160 million episodes of diarrhea world over in children <5 years, out of which 25 million need outdoor visits, 2.5 million require hospitalization and 0.6 million succumb to it. That means death due to rotavirus every minute.^{4, 5} Thirty-one -87% of healthcare-associated diarrhea are rotavirus out of which one third are severe. The incidence is 0.3 to 4.8/1000 hospital days.⁴

In the Indian Rotavirus Strain Surveillance Network from 2005 to 2007, rotavirus was found in approximately 39% of 4243 enrolled patients.⁴ In other studies from Chandigarh, rotavirus constituted 11.5% (25/218) of total diarrheal episodes and 22% (25/115) among the children affected with acute diarrhea.⁶ In India, rotavirus causes more than 1.2 lakh deaths annually, 4.5 lakh hospitalization, 5 million clinic visits, and 25 million diarrheal episodes in under 5 children.^4,5 The study has also documented an earlier onset of rotavirus disease in India. Rotavirus shows marked seasonality in a northern temperate climate but less seasonality in a southern location with a tropical climate. This is due to the high circulation of the virus in the environment with children getting exposed at an early age and contracting severe disease. The most frequent strain in India was mainly G2P⁴ (25.7% of strain), G1P⁸ (8.5%), G9P⁸ (8.5%) in combination with other types.⁴

There is no difference in the epidemiology of diarrhea, incidence is the same in developed and developing nations. It spreads from person to person hence it is difficult to control through the improvement of hygiene and sanitation alone. The difference lies in the outcome of severe diarrhea by rotavirus, chances of death by rotavirus diarrhea is only 1:50000 in the USA as compare to 1:210 in developing countries due to lack of proper medical care.⁵

Types of Rotavirus Vaccine

Two live oral vaccines are licensed in India and internationally.

• Human monovalent live attenuated vaccine derived from human rotavirus strain 89-12 grown in Vero cell culture and contains G1P1⁸ strain. (Rotarix by GSK)
• A human bovine pentavalent live vaccine which is five reassortants between the bovine WC3 strain and human G1, G2, G3, G4, and P1A rotavirus strain grown in Vero cells. (Rotateq by MSD)

Efficacy

Both vaccines are highly immunogenic in developed nations with overall effectiveness of 75 -87% against any rotavirus diarrhea and 90-95% against severe RVGE. Monovalent rotavirus vaccine in developing countries (South Africa and Malawi) has demonstrated the efficacy of 61.2% (44-73.2%) overall in developing countries.¹¹ The pentavalent vaccine has demonstrated efficacy against severe RVGE at 2 years of 48.3% (22.3-66.1%) in Bangladesh and Vietnam.^{5, 12}

A placebo-controlled monovalent rotavirus efficacy study done in India and serum anti-rotavirus IgA antibody was estimated Seroconversion rates were 58.3% (95% CI 48.7-67.4) in vaccinees and 6.3% (95% CI 2.5-12.5) in placebo. Seroconversion rates in the vaccinees were similar to those seen in Latin America study vaccinees which had shown 86% efficacy of the vaccine.⁵

Immunity against rotavirus is complex and involves both B cell (antibody-mediated major) and T cell-mediated (minor). It has been shown that serum anti-IgA correlates maximum with protection but in the absence of IgA, serum IgG is also protective.^13,14. Immunity is mucosal (local) as well as systemic. CD4+ T cell also helps in clearing the virus infections by helping proper induction of B cell response.

Rotavirus Vaccine - Dosing Schedule

Monovalent live vaccine (RV1) is given orally in two doses a minimum 4 weeks apart. It is provided as a lyophilized powder that is reconstituted just before administration. Each reconstituted 1 ml dose of vaccine contains at least 10⁶ median culture infective dose (CCID50) of live attenuated virus G1P1⁸ and no preservative. It can be given after 6 weeks and not after 12 weeks and completed prior to 32 weeks. Recently FDA has extended the deadline of the first dose up to 14 weeks and 6 days. IAP recommends the first dose at 10 weeks and a second dose at 14 weeks due to interference with OPV.

Pentavalent live vaccine (RV5) (Rotateq by MSD) is given orally in 3 doses at age 2, 4, and 6 months. The first dose should be given between age 6-12 weeks and subsequent at 4-8 weeks interval. The first dose can be extended up to 14 weeks and 6 days (recent FDA approval). All doses should be completed before 32 weeks.

In case a dose is missed, it is not necessary to restart the course but it should be completed within the time frame. In a preterm stable newborn if he has completed 6 weeks, is clinically stable and discharged from NICU, a rotavirus vaccine can be given.

Since Rotavirus Infections Are Severe In The First 2 Years Of Life, Why Can't These Vaccines Be Given In Children Beyond 32 Weeks of Life?

The initial rotavirus vaccine was associated with intussusception and was withdrawn from the market because of it. The incidence of intussusception is a maximum of around 9 months of age. Though newer vaccines are not associated with an increased incidence of intussusception but their safety beyond 8 months is not proven due to lack of data hence it is not approved beyond 8 months. Initially rotavirus vaccine was licensed only up to 6 months of age, but with increased usage and safety deadline was extended by the FDA.

Storage and Administration

Rotavirus vaccines are stored at 2-8 degrees C and are protected from light. Monovalent rotavirus vaccine can be stored at room temperature. Do not freeze the diluents or vaccine. Monovalent vaccine (RV1) can be administered within 24 hours of reconstitution, but the pentavalent vaccine (RV5) should be used immediately after reconstitution.

Side Effects and Contraindications

Both rotavirus vaccines are safe and well-tolerated with occasional vomiting, diarrhea. Intussusception incidence is not increased but caution is recommended in children with uncorrected congenital malformation of GI tract which predisposes to intussusception. The vaccine is contraindicated in an infant who has a history of severe allergy (e.g. anaphylaxis) to the rotavirus vaccine previously. Human monovalent vaccine oral applicator contains latex hence this is contraindicated in an infant with severe latex allergy.

The vaccines should not be given in children with a history of previous intussusceptions or immunodeficiency.

What Should Be Done If a Child Spits the Vaccine?

Administration of vaccine is not required if the infant spits, vomits, or regurgitates during or after administration of the vaccine though manufacturers of human monovalent vaccine recommend the dose may be repeated at the same visit. The infant should receive the remaining recommended doses as per the routine schedule.

Can the 2 Rotavirus Vaccines Be Interchanged to Complete the Schedule?

Ideally, the schedule should be completed with the same product. If the previous product is unknown or was a bovine pentavalent vaccine than a total of three doses should be administered.