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Dilemmas With Rotavirus Vaccine: The Neonate and Immunocompromised

Chiu, Melissa BSc*; Bao, Carol BSc*; Sadarangani, Manish DPhil

Author Information
The Pediatric Infectious Disease Journal: June 2019 - Volume 38 - Issue 6S - p S43-S46
doi: 10.1097/INF.0000000000002322
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Abstract

Rotavirus (RV) is the most common cause of severe gastroenteritis in young children. RV1, a live-attenuated monovalent vaccine based on a single human strain and RV5, a live, oral, pentavalent bovine human reassortant vaccine, are highly effective at preventing disease.1 Since the introduction of RV vaccine as part of routine infant immunization schedules, hospitalization rates due to RV gastroenteritis among children under 5 years have decreased by 60%–75%, 71% and 65%–84% in the United States, Australia and Europe, respectively.2–4 However, unlike other vaccines, there is an upper age limit for the RV vaccine (first dose before age 15 weeks, all doses by 24–32 weeks) as delayed vaccination increases the risk of intussusception.5 RV vaccine safety and effectiveness have been well documented in the general population, but there remains debate regarding use in preterm and immunocompromised infants, which will be reviewed here.

PRETERM INFANTS

Vaccination of Preterm Infants

Preterm infants who remain hospitalized beyond the age of 2 months often do not receive RV vaccine because of concerns regarding severe illness from the attenuated vaccine virus strain, transmission of vaccine virus to other infants in neonatal intensive care unit (NICU) and decreased vaccine efficacy. However, preterm infants are at a greater risk of severe RV infection, with previous studies showing greater hospitalization rates, and increased gastrointestinal symptoms including intestinal dilation, abdominal distension and mucoid stools.6 In addition, preterm babies will receive little or no benefit from transplacental transfer of maternal IgG, which begins at 28 weeks gestation and occurs at maximal rate beyond 36 weeks gestation. It is therefore important to ensure the best possible protection of these highly vulnerable infants, including the use of RV vaccines as evidence supports their safety and effectiveness.

Safety

In a randomized control trial with 1009 preterm infants, there were no significant differences in severe adverse effects of the RV1 vaccine on preterm infants (gestational age (GA) 27–30 weeks: 3.7%, GA 31–36 weeks: 5.4%) compared with placebo (GA 27–30 weeks: 11.3%, GA 31–36 weeks: 5.6%), including events that resulted in death, were life-threatening, required hospitalization or led to disability/incapacity.7 Comparison between the 2 GA groups was not statistically appropriate in this study, and thus it is inconclusive whether GA is proportionally related to the number of severe adverse effects. The number of adverse events in preterm infants post-RV5 vaccine is similar to term infants.8 RV5 was also well tolerated in infants in the NICU, where postvaccination symptoms were no different from preexisting symptoms (Table 1).9

TABLE 1.
TABLE 1.:
Symptoms of Infants in the Neonatal Intensive Care Unit Before and After Rotavirus Vaccination

Immunogenicity/Effectiveness

The RV1 vaccine has been shown to have similar immunogenicity in preterm infants compared with healthy term infants. In a study comparing the anti-RV IgA seroconversion rate in preterm versus term infants following RV1, 85.7% of vaccine recipients had seroconverted at 30–83 days after the second dose of vaccine compared with 16.0% in the placebo group.7 This was comparable to the seroconversion rate of RV1 in healthy term infants (86.5%).10 Specifically, the antirotavirus IgA antibody concentrations were 236.5 and 359.1 U/mL and the seroconversion rates were 75.9% and 88.1% in 27–30 and 31–36 week infants, respectively, both of which are comparable to that in healthy term infants and thus signify similar immunogenicity.7,10 Vaccination of preterm infants has been largely effective in lowering the rates of hospitalization due to RV gastroenteritis in infants. A large-scale, blinded, placebo-controlled study (REST) that investigated the effect of the RV5 vaccine on 2070 infants between the gestational ages of 25–36 showed a 100% (95% CI: 82.2–100) reduction in hospitalization and emergency department visits compared with placebo and a 73% (95% CI: −2.2–95.2) reduction in RV gastroenteritis overall.11 Another study that used the IVANHOE active hospital-based surveillance system, reported a 2.6-fold (95% CI: 1.3–5.2) and an 11-fold (95% CI: 3.5–34.8) decrease in hospitalizations of premature infants due to RV gastroenteritis in the 2 epidemic seasons after vaccination with RV5.8

Transmission and Shedding of Vaccine Virus

Transmission of RV occurs primarily through the fecal-oral route. Nosocomial transmission of wild-type RV in European and North American hospitals is 0.7 per 100 hospitalizations in children less than 5 years of age.12 Similarly, after vaccination, the attenuated vaccine virus replicates in the gastrointestinal tract and is later shed in the stools. Thus, there is a possibility for the vaccine virus in the stool to be transmitted to close contacts (who may or may not be vaccinated). This has raised questions around the safety of vaccination in hospitalized infants.

Various studies have investigated the rate of shedding of the RV vaccines in infants, and all have confirmed that shedding occurs in both healthy infants vaccinated in the community and hospitalized infants in NICU, including preterm infants.13–15 Shedding rates vary according to the population studies and laboratory assays employed for detection, but regardless of method, are higher after the first dose of vaccine (Table 2).13,15,16 Shedding occurred on days 4–6 post first dose of RV5 in the REST study; similarly, Hsieh et al16 reported peak shedding time for both RV1 and RV5 to be between day 4 and 7 after the first dose.11 A preterm study by Smith et al13 found that shedding occurred between days 0 and 15 after the first dose of RV5. A review of the shedding and transmission of RV in infants found that 50% of the infants shed the virus after the first dose of vaccine, but, of the 8 studies that investigated transmission of virus from vaccinated infant to a placebo infant, transmission was only detected in 5/945 cases.17 Thus, although the virus may be shed, it is rare for transmission to take place. In another randomized control study in the Dominican Republic, 15 cases of transmission, where the RV vaccine was detected in the stools of the unvaccinated twin, occurred in a paired-twin study with an N of 80.14 The live virus was only found in 3 of these cases, and in none of the cases were the infants symptomatic.14 Hiramatsu et al15 also showed through the absence of viral genome in the stool samples of unvaccinated infants that no viral dissemination took place in NICU following vaccination of infants with RV1 and RV5. Similar conclusions were suggested in another study with preterm infants, where no symptomatic transmission of RV to household contacts were found.13 This suggests that even though transmission may occur, it is unlikely to cause adverse events in those who have not been vaccinated.

TABLE 2.
TABLE 2.:
Shedding Rates of Rotavirus Vaccines Vary According to Population Studied and Laboratory Assays Employed for Detection

Vaccination in the NICU

Currently, there are different guidelines for RV immunization throughout the world. The United Kingdom and Australia promote the immunization of babies during their NICU stay according to standard schedules. Immunization is considered on an individual institution basis in Canada. Conversely, in the United States, it is recommended that RV vaccines are not given until discharge or after discharge—although a number of hospitals continue to administer RV vaccines to hospitalized infants. In studies in the United States, 63% of the infants in NICU were not immunized, with 36%–43% of those infants not immunized because they were too old at discharge.18,19 Many infants in the United States are missing their opportunity to get vaccinated during their NICU course and are not protected from the risks of RV gastroenteritis. RV vaccines are well tolerated in NICU infants, with no significant increase in nosocomial infection post NICU-based vaccination and no changes in the risk for gastrointestinal complications or feeding difficulties.15,20

IMMUNOCOMPROMISED INFANTS

Immunocompromised Term Infants

The safety of the RV vaccine in immunocompromised patients (both adults and children) has not been well studied—with a systematic review in 2017 failing to identify any study on RV vaccination safety in patients with immunosuppression from immune-mediated inflammatory disease, solid organ transplant or bone marrow transplant.21 However, in the more specific instance of infants with severe combined immunodeficiency, multiple case reports have noted adverse events in infants with who were vaccinated against RV.22,23 These adverse events included severe diarrhea, vomiting, fever or failure to thrive.22,23 Severe combined immunodeficiency is therefore considered a contraindication to RV vaccination.

In HIV-infected or HIV-exposed uninfected infants, RV administration did not increase the rate of adverse events. In a Kenyan study evaluating the safety of RV in 1308 infants randomized to receive RV or placebo, 37 infants were infected with HIV. Of those infants, 5/21 (23.8%) were vaccinated with RV and had serious adverse events within 14 days of administration as compared with 2/16 (12.5%) of infants receiving placebo (P = 0.67).24 Additionally, of the 177 HIV exposed but uninfected (HEU) infants, 88 received RV and 89 received placebo and there was no significant difference in severe and nonsevere adverse events between the 2 groups.24 A similar study on the safety of RV administered to HIV infected and HEU infants in 4 African countries also found no difference in rate of adverse events between vaccinated and placebo recipients for either groups.25 This study also noted that RV stimulated an appropriate immunogenic response of 3-fold increase from baseline of anti-RV IgA in 81% of both the HIV-infected and HEU infants; with this response being 2.5-fold to 3-fold higher than infants receiving placebo.25 However, the transplacental transfer of maternal antibodies may have impacted the immunogenicity of RV as measured by serum anti-RV neutralizing antibodies, with a higher proportion of HIV-infected infants responding to RV as compared with HEU infants.25 This is attributed to the higher level of circulating maternal antibodies in these HEU infants which may have blunted their synthesis of serum anti-RV neutralizing antibodies post-RV administration.25

Household Contacts

The subject of whether to immunize infants living in close contact with pregnant women or other immunocompromised children and adults has not been well researched. There is a theoretical risk of transmission as RV antigen can be detected in fecal matter for at least 14 days after immunization.17 However, there are no data available on the risk of transmission to household contacts. Recommendations in Canada, the United States and United Kingdom agree that vaccinating an infant protects immunocompromised household contacts from the wild-type RV, and this benefit is deemed to outweigh the small risk of transmission of the vaccine virus.26–28 To minimize the risk, these immunization bodies recommend careful hand hygiene after diaper changing, before food preparation, and before direct contact with immunocompromised individuals.26–28

Infants of Immune Suppressed Mothers

The issue of safety in administering the RV vaccine to infants born to immune suppressed mothers is pertinent as biologic therapies are being increasingly used during pregnancy to treat various autoimmune conditions. Medications such as infliximab and rituximab are monoclonal antibodies which cross the placenta in similar fashion to other antigen-specific IgGs molecules.29 These compounds can be detected in infants up to 12 months of age and may play an immunosuppressive role in the infant.29 Indeed, a case of fatal disseminated bacille calmette-guerin infection has been reported in an infant following in utero exposure to infliximab.30 With regards to the RV vaccine, the US PIANO registry collated data on adverse events that occurred following in utero exposure to biologics. Of the 43 infants vaccinated against RV, 6 (15%) had fevers and 1 (3%) had diarrhea.31 Smaller studies on the outcomes of infants born to mothers exposed to biologics during their pregnancies further supports the safety of the RV vaccine in these infants. In a Spanish study, 7 infants were exposed to anti-TNF-α (adalimumab/infliximab) in mothers with inflammatory bowel disease and all had detectable levels of the drugs in their blood until 6 months of age.32 During that time, 4 infants received the RV vaccine and no adverse events were noted.32 Similarly, a Belgium study determined the outcomes of 18 infants with in utero exposure to vedolizumab—an anti-a4ß7 integrin used in the treatment of inflammatory bowel disease.33 Of the 8 infants that received the RV vaccination, no adverse events occurred in the first year of life.33 The impact of other immunosuppressants during pregnancy (prednisone, azathioprine and tacrolimus or cyclosporine) on the neonate has been examined in a Brazilian study.34 Of the 24 exposed infants, all received the RV vaccination and had no adverse events.34

However, given the limited scope of investigation into RV vaccine safety in infants with in utero exposure to immunosuppressive agents, it may be prudent to avoid administering the RV vaccine unless there is documented clearance of the biologic agent in the infant or there is a current outbreak or potential for travel exposure. The current United Kingdom and United States recommendations are to not administer RV to infants with in utero exposure to biologics until at least 6–12 months of age, respectively.35,36

CONCLUSION

The RV vaccine well tolerated in preterm infants and select immunocompromised infants (such as HIV-infected or HIV-exposed babies). Consequently, these infants should be vaccinated according to the standard immunization schedule to reduce the incidences of gastroenteritis.

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Keywords:

vaccine; rotavirus; neonate; immunocompromised; preterm

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