20. Rotavirus

Rotavirus gastroenteritis is a significant cause of infant diarrhoea worldwide, both in high- and low-income countries. Virtually all children are infected by age 5 years.[1] Each year rotavirus causes the death of approximately 200,000 to 450,000 children aged under 5 years worldwide[10, 11] and results in 2.4 million paediatric hospital admissions.[12] Virtually all of the deaths occur in low-income countries. Prior to the introduction of licensed rotavirus vaccines in high-income countries, more than 220,000 children were hospitalised with rotavirus gastroenteritis every year.[13, 14]

Rates of rotavirus illness in children before the introduction of vaccine were similar in high- and low-income countries, indicating that good hygiene and clean water supplies are unlikely to have a significant impact on disease prevention. As a result, immunisation is the primary public health measure for the reduction of rotavirus disease burden.[1]

In countries with a temperate climate, rotavirus epidemics occur every winter and spring. Factors associated with an increased risk of severe rotavirus gastroenteritis include age under 2 years, low birthweight, premature gestation, lack of breastfeeding, socioeconomic disadvantage, malnutrition and impaired immunity.[1, 15, 16, 17, 18] Rotavirus gastroenteritis is not, however, more severe in HIV-infected children, although viral shedding may be longer.[3]

Rotavirus is an important cause of hospital-acquired infection[19] and can also cause disease in adults, especially those caring for children[20] and those living in aged-care facilities. During outbreaks in early childhood settings, rotavirus has been isolated from telephone receivers, drinking fountains, water-play tables and toilet handles.[21] Outbreaks in elderly populations may be linked to waning immunity, institutional crowding or both.

Children and adults can be infected with rotavirus several times in their lives. After a single natural infection during infancy, approximately one‑third are protected against subsequent rotavirus infection, more than three-quarters are protected against subsequent rotavirus gastroenteritis and 85–90 percent are protected against severe rotavirus gastroenteritis.[22] The proportion with protection against both infection and symptomatic rotavirus gastroenteritis increases with successive episodes.[22]

These observations serve as the biological basis for rotavirus vaccines, whereby live attenuated strains can induce cumulative protective immunity similar to that following natural infection by wild-type rotaviruses. Although the immune mechanism and correlates of protection against rotavirus infection are incompletely understood, it is likely that both mucosal and serum antibodies are associated with protection against rotavirus infection and disease.[23]

Since the introduction of the vaccine in other high-income countries, there have been reductions in all-cause and rotavirus gastroenteritis in age groups not eligible for the vaccine, suggesting herd immunity effects as a result of rotavirus vaccines[3, 24, 25] (see ‘Herd immunity in the post-licensure period’ in section 20.4.2).

Rotavirus vaccine was introduced in July 2014, as a three-dose schedule to infants at ages 6 weeks, 3 months and 5 months, using the RV5 vaccine (RotaTeq) (see Appendix 1).

At present rotavirus is not a notifiable disease, so there is no national surveillance data available. National hospital discharge rates, community and hospital laboratory data plus a sentinel hospital-based surveillance system have been used to monitor rotavirus disease since vaccine introduction. The sentinel hospital-based rotavirus surveillance was introduced in December 2014 at Kidz First Children’s Hospital in Counties Manukau district and extended to Wellington, Hutt and Christchurch Hospitals in April 2016.

For detailed information about rotavirus surveillance and rotavirus infections in New Zealand, see the ESR website.

Pre-vaccine epidemiology

Prior to the introduction of vaccine, by the age of 5 years, it is estimated 1 in 5 children had sought medical advice for rotavirus gastroenteritis and 1 in 43 children had been hospitalised.[13]

From 2010 to 2014, the average annual national hospitalisation rate for rotavirus in children aged under 5 years was 215.4 per 100,000.[26] The highest hospitalisation rates for children aged under 5 years were in those from the Middle Eastern/Latin American/African ethnic group, followed by Pacific and Māori ethnic groups. Hospitalisation rates in children aged under 5 years who reside in the most deprived NZDep2013 quintiles (quintiles 4 and 5) were significantly higher than those who reside in the least deprived quintile. There is a seasonal peak for rotavirus hospitalisations, usually occurring around September each year.

Post-vaccine epidemiology

The introduction of rotavirus vaccination in Australia resulted in a 70 percent decrease in rotavirus hospitalisations in the two and a half years post-vaccine introduction.[27]

A similar decline has been noted in New Zealand in the first year post-vaccine introduction, where rotavirus hospitalisation rates for children aged under 5 years declined by 85 percent in 2015 compared with the previous five-year average (2010–2014)[26] (Figure 20.1). The vaccine has been effective in decreasing the most severe rotavirus disease. Hospitalisation rates decreased for all ethnic groups and levels of socioeconomic deprivation. Community laboratory data also supports the large decrease in rotavirus infections in the community.

Although only children aged under 1 year were eligible for rotavirus vaccination, hospital discharge rates decreased in all children aged under 5 years in 2015[26] (Figure 20.2). Older children are more likely to have been exposed to rotavirus already, and are less likely to benefit from vaccination.

Hospital discharges for rotavirus ranged from 510 to 822 cases per year in the four years prior to vaccine introduction (2010–2013).[26] There were 99 hospital discharges for rotavirus in children aged under 5 years in New Zealand in 2015, compared with 770 in 2014. This reduction in rotavirus hospitalisations of children aged under 5 years was maintained to 2019, with 80 cases hospitalised in the year to June 2019.

There was a 93.6 percent decrease in rotavirus outbreaks (three outbreaks reported in 2015 compared with 47 in 2014) after the introduction of vaccine in New Zealand.[26] This demonstrates that universal rotavirus vaccination is an effective public health intervention.

Figure 20.1: Rotavirus hospital discharges and as a percentage of all gastroenteritis discharges for children aged under 5 years, all New Zealand, June 2009–June 2019

Figure 20.2: Rotavirus hospital discharge rates for children aged under 5 years by age and year, all New Zealand, 2010–2015

The types of virus assessed for use as rotavirus vaccines have included live attenuated virus, both human and animal strains of the virus, and human–animal reassortant viruses. Two rotavirus vaccines have been used in New Zealand. Both are orally administered live attenuated vaccines and have been extensively evaluated.[28, 29] The live attenuated vaccine viruses replicate in the intestinal mucosa and are shed in the stools of vaccine recipients.[28, 30, 31]

Funded vaccine

Prevention of disease

A 2012 Cochrane review[32] of the efficacy of rotavirus vaccines for the prevention of rotavirus diarrhoea assessed 41 trials which met the inclusion criteria, involving 186,263 enrolled participants. Of these, 29 trials assessed the monovalent vaccine (RV1; Rotarix) and 12 trials assessed the pentavalent vaccine (RV5; RotaTeq).

For the first two years of life in countries with low mortality rates, both vaccines prevented over 80 percent of cases of severe rotavirus diarrhoea (Table 20.1). Both vaccines impact severe all-cause diarrhoea (moderate to low quality of evidence). See also Figure 20.1 and Figure 20.2 above, which show a reduction in rotavirus hospitalisations in New Zealand children aged under 5 years after rotavirus vaccine was introduced in 2014.

Transport according to the National Standards for Vaccine Storage and Transportation for Immunisation Providers 2017 (2nd edition).

Store in the dark at +2°C to +8°C. Do not freeze.

The dose of RV1 (Rotarix) is 1.5 mL, administered orally (for administration instructions see section A7.2.4 of this Handbook or the vaccine data sheet, available on the Medsafe website). Do not inject RV1.

Two doses are given, at ages 6 weeks and 3 months. See section 20.5 below for more information.

Co-administration with other vaccines

Rotavirus vaccines can be administered at the same time as other scheduled vaccines. Note that no time interval is required between administration of rotavirus and BCG vaccines; the two live vaccines likely to be administered to infants aged under 6 months.

If the dose is regurgitated or vomited

If the dose of rotavirus vaccine is regurgitated or vomited during or after administration, a repeat dose should not be given.[52] The second dose should be administered as per the schedule. Receptor binding of vaccine is instantaneous, making repeat dosing unnecessary.

If the first dose is immediately spat out then a single repeat dose could be given.

Two RV1 doses are given orally, at ages 6 weeks and 3 months.

The first dose of RV1 should be given before age 15 weeks (ie, 14 weeks and 6 days), and the second dose administered at least four weeks later (see Table 20.2). An infant who has not had the first dose before age 15 weeks will not be able to commence the rotavirus course. Where the first dose is inadvertently given at age 15 weeks or older, the second dose should be given, but both doses should be given before age 25 weeks (ie, the latest is 24 weeks and 6 days).[1] Rotavirus vaccine is not intended for use in older children, adolescents or adults.

The age limits for initiating and completing the vaccine series are recommended because there is insufficient safety data on the use of these vaccines outside this age range. If a partially vaccinated infant reaches age 25 weeks before the second dose is given, the first dose already given will offer them partial protection against disease.

The severity of rotavirus infection decreases with age, so a cost–benefit analysis for vaccinating older children is a low priority and has not been done.

Vaccination as per the Schedule (ie, at the usual chronological age, with the usual vaccine dosage and interval) is recommended for preterm infants and infants with low birthweight, including those still in hospital (see below). Rotavirus vaccine can be given to preterm infants born who are receiving corticosteroids. (See also 4.2.1 for more immunisation recommendations for preterm infants.)

Rotavirus vaccine should be given on time to any infant admitted to a general hospital ward (where other patients are not high risk). If standard infection control precautions are maintained, there is no risk of transmission of vaccine strain rotavirus when rotavirus vaccine is administered to hospitalised infants, including hospitalised preterm infants and those in neonatal units.[53, 54] (See also section 4.2 for more information about infants with special immunisation recommendations.)

There is no concern caused by vaccine exposure during pregnancy. There is no restriction for breastfeeding before or after vaccination of the infant (see ‘Shedding’ in section 20.6.2).

Rotavirus vaccine should not be given to infants with:

• a history of a severe (anaphylactic) allergic reaction after a previous dose or to a vaccine component
• a history of intussusception or an uncorrected congenital malformation of the gastrointestinal tract that would predispose the infant to intussusceptions (see section 20.7.1).
• severe combined immunodeficiency (SCID).[55]

Rotavirus vaccine can be administered to infants with a mild illness, including gastroenteritis and upper respiratory tract infections. Infants with moderate to severe gastroenteritis should not be vaccinated until symptoms resolve.

There is very little safety data on infants with predisposing conditions such as metabolic disorders and chronic gastrointestinal diseases (Hirschsprung’s, malabsorption syndromes or short gut syndromes). Since there is a greater risk of serious wild-type rotavirus disease, the benefits outweigh the risk, and vaccination is encouraged.[52]

Infants who have received antibody-containing blood products and are the appropriate age should be vaccinated. Rotavirus vaccine and antibody-containing blood products can be administered simultaneously.[52] There is a theoretical risk of interference in the immune response to the vaccine; therefore the interval between vaccination and receipt of blood products should ideally be as long as possible within the age limits of the vaccine schedule.

Administration of RV1 in immunosuppressed infants, including infants on immunosuppressive therapy, should be based on careful consideration of potential benefits and risks.

Infants born to mothers on immunosuppressive therapies

There is limited data on rotavirus vaccination safety when given to infants born to mothers receiving immunosuppressive therapy during pregnancy.[19, 36, 56] Although in most cases it is likely to be safe, caution is required. The level of circulating wild-type rotavirus is currently very low in New Zealand; therefore, the risk of gastroenteritis following rotavirus vaccination in this cohort of infants may be greater than the risk of acquiring the disease. The decision to administer rotavirus vaccine to infants born to mothers who received immunosuppressive agents (biologic agents) during pregnancy should be determined case by case.

If an infant turns 15 weeks of age before the first rotavirus vaccine dose can be administered, they will not be able to receive any rotavirus vaccine doses.

See section 4.2.5 'Infants of mothers who received immunomodulatory biologic agents during pregnancy' and Table 4.2 for a list of the highly immunomodulatory biologic agents with long half-lives that require a prolonged delay before vaccination (for up to one year in those being treated). These include monoclonal antibody (mab) agents that readily cross the placenta.

Each case should be assessed on a risk–benefit basis and with specialist advice.

Shedding

Since rotavirus vaccine virus replicates in the gastrointestinal tract, it can be shed in stools – especially after the first dose.[57] Shedding is also more likely in immunocompromised patients (eg, children with HIV). The vaccine virus could then be transmitted to unvaccinated populations; a feature that is generally beneficial as it promotes herd immunity.

Infants living in households with immunocompromised individuals should be vaccinated. So far there are no safety concerns, but there is also no data to confirm the safety of these vaccines for immunocompromised patients. Infants living in households with pregnant women should also be vaccinated. Hand washing and the careful disposal of soiled nappies are likely to minimise any risk of vaccine transmission to household members.[52, 53]

Intussusception is a cause of an acute abdomen when one part of the intestine telescopes into another part of the intestine; the mechanism by which these events occur remains uncertain. In 1999 an oral human–rhesus rotavirus quadrivalent vaccine (RotaShield) was licensed in the US and on the infant schedule but was withdrawn later that year after reports of an association with intussusception (a risk of approximately one case in 5,000–10,000 vaccine recipients).

No increased risk of intussusception was detected in the large phase III pre-licensure clinical trials of RV1 (Rotarix) and RV5 (RotaTeq), despite this being a specifically monitored adverse event. However, post-marketing surveillance of both rotavirus vaccines indicates the possibility of an increased risk of intussusception shortly after the first dose of rotavirus vaccination. Evidence from Australia[58] indicates that after the first dose, RV1 had a relative incidence (relative risk) of 6.8 (95% CI: 2.4–19.0, p<0.001) and 3.5 (95% CI: 1.3–8.9, p=0.01) for the periods of 1–7 days and 8–21 days after vaccination, respectively. For RV5, the relative incidence was 9.9 (95% CI: 3.7–26.4, p<0.001) and 6.3 (95% CI: 2.8–14.4, p<0.001) for the same time periods.

There was also some elevated risk of intussusception 1 to 7 days after the second dose of both vaccines. The relative incidence for RV1 was 2.8 (95% CI: 1.1–7.3, p=0.03) and for RV5 was 2.8 (95% CI: 1.2–6.8, p=0.02). There was no evidence of increased risk of intussusception following a third dose of RV5.[58] The increased risk of intussusception following rotavirus vaccination is estimated at approximately 6 additional cases of intussusception among every 100,000 infants vaccinated (approximately 1 in 15,500 vaccine recipientss), or 14 additional cases per year in Australia.[58]

Studies in the post-licensure period continue to show small increases in risk for both RV1 and RV5 and primarily within seven days of the first dose of vaccine.[59, 60] Recent safety data has continued to emphasise the clear and dramatic benefit of vaccination over the very low risk of vaccine-associated intussusception.[41] For example, a self-controlled case-series study estimated that the RV1 programme in England caused 21 intussusception admissions annually and prevented 25,000 gastrointestinal infection admissions with a clear risk–benefit ratio.[61]

While there appears to be an increased relative risk of intussusception, the condition remains rare, and this risk is outweighed by the benefits of rotavirus vaccination in preventing rotavirus infections; there was an estimated 70 percent reduction in hospitalisations in young children after the vaccine’s introduction to the Australian schedule.[62] It is uncertain whether rotavirus vaccine administration affects the overall incidence of intussusception: US data suggests no increased overall rate in infants despite a small cluster effect.[63] Both the WHO[64] and the Australian Technical Advisory Group on Immunisation[62] continue to recommend the use of rotavirus vaccine for infants.

Although the risk of intussusception after rotavirus immunisation is very small, it is recommended that parents seek medical advice and health care professionals are attentive if the baby develops intermittent crying or screaming episodes, pulling their knees towards their chest and vomiting, or pink- or red-coloured jelly-like stools.

A recent study has described the epidemiology of intussusception in New Zealand children aged 0–36 months (794 cases) for a 16-year period before the introduction of routine rotavirus vaccination.[65] This study will provide a valuable baseline to determine if the introduction of the vaccine has significant effects on intussusception rates in the New Zealand population.

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