Use of rotavirus vaccines in preterm babies on the neonatal unit

KEYWORDS:

• Immunisation
• neonatal
• premature
• protection
• rotavirus
• shedding
• transmission

1. Introduction

Rotavirus (RV) infection is the leading cause of severe gastroenteritis globally in infants and young children. Preterm infants are the most vulnerable for severe infection. Despite the availability of highly effective RV vaccines, which are immunogenic and safe in preterm infants, this group has reduced vaccination rates. Guidelines for RV vaccine use in preterm babies’ resident on neonatal units at the time of vaccination vary greatly based on the same evidence. This is due to theoretical concerns about vaccine virus shedding and transmission to other babies on the unit. In this editorial, we consider the benefits and perceived risks of vaccinating preterm hospitalized infants with RV vaccines.

2. The impact of RV vaccine introduction

In children under 5 years of age, before the widespread global introduction of RV vaccines, it was estimated that RV gastroenteritis was responsible for 453,000 deaths, equivalent to 37% of diarrhea-related deaths and 5% of deaths worldwide [1]. A more recent study showed that in 2013, after RV vaccines had been introduced in many countries, RV gastroenteritis caused approximately 215,000 deaths [2]. RV vaccines are highly effective, with efficacy between 57% and 87% against severe RV-associated diarrhea, and higher efficacy in industrialized countries [3]. Since vaccine introduction, hospitalization rates due to RV gastroenteritis in children under 5 years have decreased by 65–84% in Europe, in Australia by 71%, and in the USA by 60–75% [4–6]. However, RV vaccines remain underutilized globally – as of April 2016, only 85 countries (44%) included routine vaccination in their national program (http://www.who.int/immunization/monitoring_surveillance/data/en/, accessed 5 May 2016).

3. RV vaccines – the importance of timely immunization

There are currently two licensed RV vaccines available globally; both are oral, live attenuated vaccines but have different compositions and dosing regimens. RV1 is a monovalent vaccine based on a human RV strain, given as two doses at least 4 weeks apart with the first dose from 6–8 weeks of age. RV5 is a pentavalent human–bovine reassortant vaccine containing five strains with three doses administered from 6–8 weeks of age with a minimum of 4-week intervals between doses. Unlike other childhood vaccines, which can be given late, RV vaccines are unique in having a maximum age beyond which they are not licensed or recommended for safety reasons. The maximum licensed ages are 14 weeks 6 days (RV1) and 12 weeks (RV5) for the first dose, and for course completion is 24 weeks (RV1) and 32 weeks (RV5). These strict criteria have their foundations in the development of the first RV vaccine developed in 1998 – RotaShield^®, a rhesus–human reassortant vaccine. RotaShield was subsequently withdrawn following the finding from post-licensure surveillance that it could cause intussusception leading to death of infants. This risk was shown to be proportional to the time from birth to first dose with delayed dosing resulting in an increased risk of life-threatening intussusception [7]. Although pre-licensure studies showed no significant increase in intussusception for both current vaccines compared with placebo, data now suggest there is an increased risk, albeit substantially lower than with RotaShield [8,9]. The risk of intussusception following current RV vaccines administered within the correct time window is 1.5–6 per 100,000 compared with a 10-fold higher risk of 1 per 10,000 with RotaShield. Additional RV vaccines have been licensed (http://sites.path.org/rotavirusvaccine/rotavirus-faq, accessed 7 July 2016), but only for use within limited jurisdictions due to absence of sufficient pre-licensure data so far to confirm the intussusception risk – for example, Rotavac has only been licensed for use in India. In the context of markedly reduced mortality, morbidity, and hospitalizations in vaccinated infants, the benefits of vaccination significantly outweigh the risks based on current data. Furthermore, given the public health benefits of the vaccine to improve vaccine uptake in 2013, the World Health Organization proposed that the age limitations be removed for countries with high mortality from RV infection, despite the increased risk of intussusception. Ongoing surveillance following ‘late’ vaccination of preterm infants will be required, so that the risk of intussusception can be properly weighed against the benefit of vaccination.

4. RV vaccination in preterm infants

The strict timeline for RV vaccination is especially pertinent in preterm infants since their protracted hospital stays often mean they are inpatients when the first dose is due. This has raised concerns around immunization of hospitalized preterm infants due to theoretical risk of fecal shedding of vaccine virus and transmission to other babies within the neonatal unit.

Preterm infants are at particular risk of severe RV infection with increased hospitalization rates, increased intestinal dilatation, abdominal distension, and mucoid stools [10–12]. Very low birth weight infants have a 2.6-fold increase in hospitalization compared to their term counterparts [11]. Protection of this group through vaccination should therefore be a high priority. They have reduced maternal antibody since placental transmission of immunoglobulin G (IgG) begins from 28 weeks gestation and highest antibody transfer rates occur after 36 weeks. Longer hospital stays, multiple comorbidities, and low birth weight increase the risk of hospital acquired infection.

Evidence of immunogenicity and efficacy of RV vaccines extends to preterm infants, in pre-licensure and post-licensure studies [13]. The efficacy of the vaccine for preterms was estimated at 70%, although this was not statistically significant due to a small sample size. To estimate efficacy, one study in France used modeling to quantify the relative reduction in the number of hospitalizations in premature infants compared to the expected number following immunization introduction. They found a 2.6–11-fold decrease in hospitalization secondary to RV gastroenteritis [14]. In a pre-licensure phase III study, which included 2074 premature infants, there was a 100% reduction in hospitalization compared with placebo [12]. The safety profile for medically stable preterm infants following RV vaccination has been shown to be similar to term infants in multiple studies, including a large international randomized controlled trial [13,14]. These studies have also demonstrated no significant differences in adverse events in babies receiving other routine immunizations with or without RV vaccine [14]. More specifically, one recent study found no changes in feeding or the risk of gastrointestinal complications in 102 hospitalized babies after administration of RV5 [15]. Despite evidence of safety and immunogenicity, preterm babies remain an undervaccinated group.

5. Shedding and transmission of RV vaccine

Since nosocomial transmission of wild-type RV occurs in infected individuals, the vaccine viruses have potential to be shed in the stool and transmitted to close contacts. Shedding of the vaccine virus occurs in up to 80% of babies, is greater after the first dose, and tends to peak at 7 days, although it is unclear how this is related to transmission and the clinical relevance [16]. Shedding has been documented up to 15 days postimmunization [16]. In a twin study, 29% of unvaccinated contacts had evidence of seroconversion following vaccination of their twin, but none reported gastroenteritis symptoms [17]. This study, however, is not necessarily transferrable to infants in the neonatal units given that in this study the twins were in a nonclinical environment with no infection control precautions and may not be as susceptible to infection. Symptomatic transmission to an unvaccinated contact has seldom been documented, with a single case report to date [18].

6. Variation in immunization guidelines for preterm infants

There is varying guidance internationally regarding use of RV vaccines in preterm babies who are hospitalized at the time when immunization should occur. Due to the concerns about shedding and transmission, the Advisory Committee on Immunization Practices (ACIP) in the USA advise vaccine administration at time of discharge, to minimize potential unwanted effects to other babies on the unit, stating that ‘the risk from shedding outweighs the benefit of vaccinating the infant who will remain in the neonatal intensive care unit (NICU) or nursery.’ This has resulted in lower vaccination rates in preterm infants compared with their term counterparts [19]. A study conducted over 2 years in Texas found that this recommendation resulted in only 27% of very low birth weight preterm infants receiving the RV vaccine, with a quarter too old at discharge to receive it. This was more marked for the extremely low birth weight infants, with the majority (75%) found to be too old for vaccination at discharge. Contrary to the ACIP recommendation, one unit in Philadelphia continued to vaccinate preterm infants in NICU without waiting for discharge; resulting in a third of infants who otherwise would have missed their dose receiving it with no additional safety or transmission concern [20].

In contrast to the US guidance, the UK Department of Health recommends vaccination occur in neonatal units when due, on the basis that there is ‘low risk for transmission of the vaccine virus if standard infection control precautions are maintained.’ However, data from a telephone survey indicated that only 20% of neonatal units in the UK were administering the vaccine at all and in one unit only 38% of those preterm infants eligible received the vaccine in the absence of any contraindications. This led to the development of a RV vaccine administration guidance chart to improve uptake for preterm infants [21,22]. Similar to the UK, the Australian Immunization Handbook suggests that if infection control precautions are maintained, no special dosing requirements are necessary for preterm infants. The National Advisory Committee on Immunization in Canada does not have a definitive recommendation, but suggests discussion with local infection control experts and neonatologists. Longer-term post-surveillance studies in NICU are required to evaluate whether standard precautions are sufficient to avert symptomatic transmission.

7. Conclusion

The international recommendations for preterm RV vaccination eligibility differ as a result of varying expert committee opinion reviewing the same literature. The more recent recommendations by the UK and Australia reflect the absence of evidence to indicate safety concern or considerable transmission risk in age eligible, hospitalized preterm infants. Complete, age-appropriate vaccination of this highly vulnerable group should be regarded as a priority for neonatologists and others providing medical care for them. By vaccinating hospitalized infants, with appropriate infection control precautions to reduce the risk of transmission, an increased proportion of these infants, many of whom are currently unimmunized against RV, will be protected from the severe gastroenteritis.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

Additional information

Funding

This paper was not funded.