Rotavirus vaccines: the benefits outweigh the risks

Published in Health News and Evidence

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Clinical content may change after this date. This information is not intended as a substitute for medical advice from a qualified health professional. Health professionals should rely on their own expertise and enquiries when providing medical advice or treatment.

 

Practice points | Rotavirus — a global problem | First US rotavirus vaccine withdrawn on safety issues | Intussusception — a rare cause of intestinal obstruction | Rotavirus vaccination in Australia considered safe and effective | Rotavirus vaccines cause a small increase in risk of intussusception | Are there ways to minimise the risk of intussusception? | Information for parents and carers | References

Summary

An investigation into the use of rotavirus vaccines (RotaTeq and Rotarix) in Australia has identified with both vaccines a small elevated risk of intussusception, an intestinal complication that can cause obstruction, especially after the first dose.

However, a risk–benefit analysis concluded that the benefit of protection from rotavirus infection far outweighs the risk of intussusception.

Counsel parents and carers on the risk of intussusception after each dose of rotavirus vaccine. Advise them that the benefits outweigh the risk of intussusception but to be alert for symptoms and seek medical assistance in suspected cases.

Practice points

  • The two oral rotavirus vaccines used in Australia, RotaTeq and Rotarix, are highly effective in protecting infants against severe rotavirus gastroenteritis.1,2
  • Advise parents at both the first and second doses of vaccine that there is a small elevated risk of intussusception but this is far outweighed by the benefits.3
  • Administer rotavirus vaccine according to the NIP schedule, at 2 and 4 months of age (Rotarix) or 2, 4 and 6 months of age (RotaTeq).4
  • Rotavirus vaccines can be safely co-administered with other vaccines in the NIP schedule.5–7
  • If necessary, the first dose of either vaccine can be given as early as 6 weeks of age.7
  • The interval between doses should not be less than 4 weeks.7
  • Ensure that the full vaccination course is completed by 24 weeks (Rotarix) or 32 weeks (RotaTeq).7 Safety of either vaccine has not been assessed in older children.5,6
  • Encourage parents to ensure infants receive the full course of rotavirus vaccine for maximum protection.5,6,8
  • Do not administer rotavirus vaccine to infants with:
    • severe combined immunodeficiency disease7,9
    • a previous allergic reaction to rotavirus vaccine7,9
    • a history of intussusception or a congenital abnormality that may predispose to intussusception.7,9
  • Delay vaccination in cases of moderate to severe gastroenteritis or acute febrile illness until the infant is well.7,9 In immunocompromised children or those with a history of gastrointestinal illness, consider whether benefit outweighs risk.9
  • Vaccinate healthy preterm babies according to usual chronological age. Monitor hospitalised babies for apnoea or bradycardia for up to 48 hours after vaccination, as they are at increased risk of apnoea.9
  • Be vigilant for symptoms of intussusception after each dose of rotavirus vaccine, particularly in the 7 days after the first dose.3 Advise parents to seek medical advice for infants showing:
    • severe colic-like symptoms
    • high fever
    • vomiting
    • bloody stools
    • an action of drawing the legs up to the stomach.10

Rotavirus — a global problem

Rotavirus is the most common cause of severe gastroenteritis globally in children under 5 years of age, with most children experiencing rotavirus infection in infancy.7,8

Rotavirus infection can vary from a mild presentation with loose stools to severe diarrhoea and vomiting, dehydration and death.8

Before the addition of rotavirus vaccines to the NIP in July 2007, rotavirus caused 10,000 hospitalisations, 22,000 ED presentations and 11,500 GP consultations per year in Australia among children under 5.11,1

First US rotavirus vaccine withdrawn on safety issues

Rotavirus vaccines developed to date consist of live attenuated viruses that are delivered orally.

In 1999 the first rotavirus vaccine licensed in the US, RotaShield (RRV-TV, Wyeth-Ledele), was withdrawn from the market after it was associated with a > 30-fold increased risk of intussusception (vaccine-attributable risk estimated from around one in 4670 to one in 10,000) in infants in the first 3–7 days after their first dose.13-15

Intussusception — a rare cause of intestinal obstruction

Intussusception is a rare condition that each year in Australia affects about 200 infants aged under 1 year.10

It occurs when a section of the bowel invaginates into an adjacent region, which can result in intestinal obstruction and cause severe abdominal pain, bloody stools, vomiting and a palpable lump in the abdomen.8 The condition can lead to intestinal perforation and can be fatal.8,10

Intussusception rates vary by region and ethnicity; in Australia the incidence of intussusception is low, at 81 per 100,000 infants under 1 year.16 Baseline incidence increases sharply and is highest in the first 6–8 months of life, coinciding with the time frame in which the rotavirus vaccine is delivered.16

Rotavirus vaccination in Australia considered safe and effective

Two rotavirus vaccines are currently available in Australia — RotaTeq (a pentavalent human–bovine reassortment; Merck Sharp & Dohme) and Rotarix (a monovalent human vaccine; GlaxoSmithKline).

In Australia both RotaTeq or Rotarix are funded under the NIP, but the choice of vaccine may differ between States.7

Doses are recommended to be administered at 2 months and 4 months, and for RotaTeq a third dose at 6 months.4

Both vaccines have shown high efficacy in preventing rotavirus infection compared with placebo1,2 but there are no head-to-head data comparing the relative safety and efficacy of the two vaccines.

Widespread implementation of rotavirus vaccination in Australia has resulted in a large decline in hospitalisations due to rotavirus gastroenteritis as well as overall gastroenteritis. 17

Coverage in Australia is high (around 85% in 2010)18 and has proved effective: rates of rotavirus hospitalisations fell by between 71%19 and 75%12 in children under 5 in the few years following introduction of the rotavirus vaccines to the schedule.

Reduced rotavirus hospitalisation rates in older children and adults suggest that vaccination has also been successful in establishing herd immunity in the community.12,17

In large-scale pre-registration trials, neither vaccine was found to be associated with an increased incidence of intussusception and both were assessed as safe.1,2

However, after the experience with RotaShield, the WHO recommended postmarketing surveillance for both vaccines to assess intussusception risk.

Rotavirus vaccines cause a small increase in risk of intussusception

A TGA-commissioned investigation into the risk of intussusception and disease prevention associated with rotavirus vaccines in Australia has been recently completed.3 The study retrospectively examined cases of intussusception in Australian infants aged 1–12 months between 2007 and 2010.

A self-controlled case-series analysis examined the incidence of intussusception during pre-specified time periods of 1–7 days and 8–21 days after administration of the first and second doses of Rotarix or RotaTeq.

Rates of intussusception falling within these date ranges were compared with baseline incidence during the non-exposure period, defined as time before the vaccination or more than 21 days after the first or second dose.3

There was a clear increase in intussusception incidence in the period 1–7 days after the first dose for both vaccines, with a smaller increase at 8–21 days after the first dose and at 7 days after the second dose (Table 1).

There was no increase in intussusception incidence after dose 3 of RotaTeq.

A case–control analysis using age-matched controls, reported in the same study, confirmed these results.3

Table 1. Relative incidence* of intussusception after the first and second doses of Rotarix and RotaTeq3

  Dose 1 Dose 2
Vaccine-attributable risk per 100,000 infants
 Day 1–7 Day 8–21 Day 1–7

Rotarix
(95% CI)

6.8 (2.4–19.0)
p < 0.001

3.5 (1.3–8.9)
p = 0.01

2.8 (1.1–7.3)
p = 0.03

4.3 (0.8–23.3)

RotaTeq
(95% CI)

9.9 (3.7–26.4)
p < 0.001

6.3 (2.8–14.4)
p < 0.001

2.8 (1.2–6.8)
p = 0.02

7.0 (1.5–33.1)

* Relative incidence: the frequency of intussusception in each 1–7-day and 8–21-day exposure period relative to its occurrence in the unexposed period


Risk–benefit analysis

The vaccine-attributable risk for RotaTeq and Rotarix was considered to be the same (based on the overlapping confidence intervals; Table 1).

Rotavirus vaccine attributable risk is estimated at 5.6 additional cases of intussusception per 100,000 vaccinated infants, or an excess of 14.3 cases annually in Australia.

In comparison, in the absence of rotavirus vaccination there would be an expected 6500 cases of hospitalisation due to rotavirus in children under 5.3

On a risk–benefit analysis, these data support the continued use of RotaTeq and Rotarix in infants younger than 14 weeks at the first dose.3

The global experience with rotavirus vaccines

These results are in line with an earlier, smaller, Australian postmarketing surveillance study of both vaccines, which also found evidence of an increased intussusception risk in the 7 days following the first dose, although that study observed an elevated risk only in babies < 3 months of age.20

Also consistent with the new data, two similar case-series studies of Rotarix vaccine in Mexico reported relative incidences of intussusception in the first 7 days after dose 1 of 6.49 (95% CI 4.17 to 10.09, p < 0.001)21 and 5.3 (95% CI 3.0 to 9.3).22

In the US, postmarketing surveillance of RotaTeq reported no elevation in intussusception incidence,15 while another study indicated that overall rates of intussusception have continued along a downward trend since reintroduction of rotavirus vaccines.23

Interestingly, data on Rotarix vaccination in Brazil showed no significant increase in risk of intussusception after the first dose; there was, however, a small elevation in risk after the second dose.22 The authors speculated that Brazil's system of co-administering the first dose of Rotarix with the oral polio vaccine may have reduced the Rotarix's immunogenicity; thus, the second dose may act as the first immunising dose.

This is not a concern in Australia, where only the inactivated polio vaccine is now used.7

Are there ways to minimise the risk of intussusception?

When administering rotavirus vaccines, take precautions to minimise intussusception risk.

  • Administer rotavirus vaccine in accordance with the NIP schedule4,7 (Table 2).
  • If a catch-up schedule is required, infants should start the course of rotavirus vaccination within the recommended age limits for the first dose, and doses should not be given beyond the upper age limits for the final dose of the vaccine course.7 The interval between the two doses should not be less than 4 weeks.
  • Do not administer rotavirus vaccine to infants with:
    • severe combined immunodeficiency disease4,8
    • a previous allergic reaction to rotavirus vaccine4,8
    • a history of intussusception[8] or a congenital abnormality that may predispose to intussusception.4,8
  • Delay vaccination in cases of moderate to severe gastroenteritis or acute febrile illness until the infant is well.4,8 In immunocompromised children or those with a history of gastrointestinal illness, consider whether benefit outweighs risk.8
  • Be vigilant for symptoms of intussusception in the first 21 days after each dose, particularly the first 7 days.3
  • Advise parents to be alert to infants showing severe colic-like symptoms, high fever, vomiting, bloody stools and an action of drawing the legs up to the stomach.7

Table 2. Rotavirus vaccine dosing schedules5-7

 

Recommended
age limits

  Australian Health jurisdiction
 Age of routine administration First dose Second dose Third dose Minimal interval between doses

Rotarix

NSW, NT, Tas, ACT

2 and 4 months

6–14 weeks

10–24 weeks

n/a

4 weeks

RotaTeq

Vic, SA, Qld, WA

2, 4 and 6 months

6–12 weeks

10–32 weeks

14–32 weeks

4 weeks

Information for parents and carers

  • Rotavirus is a common cause of severe gastroenteritis in children. It can cause severe diarrhoea and dehydration as well as vomiting, fever and shock, and can require hospitalisation.8
  • Vaccination is the best way to protect your child against rotavirus infection.
  • The rotavirus vaccine carries a small risk of intussusception — folding of a section of the small intestines into a nearby region, sometimes causing a blockage.
  • This complication is very rare, and most babies treated for intussusception recover with no further problems.10
  • The benefits of the rotavirus vaccine in preventing hospitalisation rates far outweigh the small risk of intussusception.3

 Online resources

References
  1. 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. [PubMed]
  2. Vesikari T, Matson DO, Dennehy P, et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine. N Engl J Med 2006;354:23–33. [PubMed]
  3. Carlin JB, Macartney K, Lee KJ, et al. Intussusception risk and disease prevention associated with rotavirus vaccines in Australia's national immunisation program. Clin Infect Dis 2013. [PubMed]
  4. Australian Government Department of Health and Ageing. National Immunisation Program Schedule. 2013. http://www.health.gov.au/internet/immunise/publishing.nsf/Content/nips-ctn (accessed 23 September 2013).
  5. Merck Sharp & Dohme. RotaTeq Product Information. 2013.
  6. GlaxoSmithKline. Rotarix Product Information. 2013.
  7. Australian Government Department of Health and Ageing. The Australian Immunisation Handbook. 2013. http://www.health.gov.au/internet/immunise/publishing.nsf/Content/Handbook10-home (accessed 16 September 2013).
  8. World Health Organization. Rotavirus vaccines. WHO position paper – January 2013. Weekly epidemiological record 2013;88:49–64. http://www.who.int/wer/2013/wer8805.pdf
  9. Australian Medicines Handbook. 2013. https://www.amh.net.au/ (accessed 26 September 2013).
  10. Australian Government Department of Health and Ageing. Rotavirus Immunisation. Information for parents and guardians. 2013. http://www.health.gov.au/internet/immunise/publishing.nsf/Content/ITO136-cnt
  11. Galati JC, Harsley S, Richmond P, et al. The burden of rotavirus-related illness among young children on the Australian health care system. Aust N Z J Public Health 2006;30:416–21. [PubMed]
  12. Macartney KK, Porwal M, Dalton D, et al. Decline in rotavirus hospitalisations following introduction of Australia's national rotavirus immunisation programme. J Paediatr Child Health 2011;47:266–70. [PubMed]
  13. Murphy TV, Gargiullo PM, Massoudi MS, et al. Intussusception among infants given an oral rotavirus vaccine. N Engl J Med 2001;344:564–72. [PubMed]
  14. Peter G, Myers MG. Intussusception, rotavirus, and oral vaccines: summary of a workshop. Pediatrics 2002;110:e67. [PubMed]
  15. Shui IM, Baggs J, Patel M, et al. Risk of intussusception following administration of a pentavalent rotavirus vaccine in US infants. JAMA 2012;307:598–604. [PubMed]
  16. Justice F, Carlin J, Bines J. Changing epidemiology of intussusception in Australia. J Paediatr Child Health 2005;41:475–8. [PubMed]
  17. Pendleton A, Galic M, Clarke C, et al. Impact of rotavirus vaccination in Australian children below 5 years of age: A database study. Hum Vaccin Immunother 2013;9. [PubMed]
  18. Hull B, Dey A, Menzies R, et al. Annual immunisation coverage report, 2010. Commun Dis Intell Q Rep 2013;37:E21–39. [PubMed]
  19. Dey A, Wang H, Menzies R, et al. Changes in hospitalisations for acute gastroenteritis in Australia after the national rotavirus vaccination program. Med J Aust 2012;197:453–7. [PubMed]
  20. Buttery JP, Danchin MH, Lee KJ, et al. Intussusception following rotavirus vaccine administration: post-marketing surveillance in the National Immunization Program in Australia. Vaccine 2011;29:3061–6. [PubMed]
  21. Velazquez FR, Colindres RE, Grajales C, et al. Postmarketing surveillance of intussusception following mass introduction of the attenuated human rotavirus vaccine in Mexico. Pediatr Infect Dis J 2012;31:736–44. [PubMed]
  22. Patel MM, Lopez-Collada VR, Bulhoes MM, et al. Intussusception risk and health benefits of rotavirus vaccination in Mexico and Brazil. N Engl J Med 2011;364:2283–92. [PubMed]
  23. Zickafoose JS, Benneyworth BD, Riebschleger MP, et al. Hospitalizations for intussusception before and after the reintroduction of rotavirus vaccine in the United States. Arch Pediatr Adolesc Med 2012;166:350–5. [PubMed]