In 2006, a second generation of rotavirus vaccines entered markets in America and Europe after the first licensed rotavirus vaccine had been withdrawn in 1999 due to a rare association with intussusception. In 2009, with additional proof of vaccine efficacy in Asia and Africa, the World Health Organization (WHO) recommended that rotavirus vaccines for infants should be included in every country’s national immunization program. As of 1 May 2016, 81 countries worldwide have introduced infant rotavirus vaccination. Two life-attenuated oral rotavirus vaccines, Rotarix (monovalent human-derived vaccine, GlaxoSmithKline Biologicals, Rixensart, Belgium) and RotaTeq (pentavalent bovine-derived vaccine, Merck & Co. Inc., Kenilworth, NJ), are licensed globally and 3 other vaccines are available on local markets. Current vaccines are considered safe and well tolerated. Almost a decade of experience with these vaccines in high-income settings and with increasing data available from low- and middle-income settings (LMIC), we have reached a compelling conclusion: these vaccines have contributed to a significant decrease in diarrheal morbidity and mortality among infants worldwide. However, there are some concerns regarding use of the currently licensed rotavirus vaccines that may require that the repertoire of rotavirus vaccines be extended in the near future.
CURRENT ROTAVIRUS VACCINES: BENEFITS
Up to 8 years, postimplementation data are now available from some of the countries that first adopted universal rotavirus vaccination. In the United States, Australia, Belgium, Austria and Finland, sustained reductions of 50%–90% in rotavirus-related hospitalizations and a 30%–60% decrease in all-cause gastroenteritis hospitalizations was reported compared with prevaccine years.1,2 An additional benefit of universal infant rotavirus vaccination is achieved through herd protection of older unvaccinated children. Recent data also demonstrated a sustained reduction of just over 50% in rotavirus hospitalizations among infants ≤42 days of age, who are ineligible for vaccination.3 Herd protection results from reduced circulation of rotavirus in the community. Susceptible (unvaccinated) persons are less likely to come into contact with the virus, resulting in a lower incidence of infection. These effects have been observed predominantly in the United States and Europe where coverage rates are relatively high.
Current vaccines have demonstrated reduced efficacy in LMIC compared with high-income countries, which may be due to interference by high levels of rotavirus antibodies acquired transplacentally, micronutrient deficiency, malnutrition, interfering gut microflora, enteric co-infections, concomitant disease such as HIV infection and differences in rotavirus epidemiology, including the high genetic diversity of circulating rotavirus strains. However, due to the high incidence of severe rotavirus disease in these countries, vaccine introduction has nevertheless resulted in considerable public health impact as evidenced by significant reductions in all-cause diarrhea hospitalizations, rotavirus hospitalizations and diarrheal deaths in many LMIC countries.4
CURRENT ROTAVIRUS VACCINES: CONCERNS AND LIMITATIONS
Although the successes of the second generation of rotavirus vaccines are evident, some subpopulation-specific barriers remain that currently restrict the full potential of global rotavirus prevention. These include safety concerns regarding the risk of intussusception, age restrictions on vaccine use, the life-attenuated nature of the vaccines and the substantial cost of rotavirus vaccine introduction.
Global data suggest that currently licensed rotavirus vaccines are associated with a small risk of intussusception, primarily shortly after the first dose of vaccine, in some settings (estimated 0.7−7 excess cases per 100,000 vaccinated infants); although of a magnitude substantially less than that associated with Rotashield (1 excess case per 10,000 vaccinated infants).5 However, the benefits due to reductions in rotavirus hospitalizations and mortality far outweigh the relatively few excess cases of vaccine-associated intussusception, and thus national immunization remains a valuable public health intervention. There are limited data on rates of intussusception in lower income settings and, although studies assessing the intussusception risk following routine introduction of oral rotavirus vaccine are currently underway in many LMIC, none have yet been completed. Further research is also needed to better understand the possible etiologies and mechanisms of intussusception.
Concerns regarding intussusception led to age restrictions on administration of the first (initiate by 15 weeks of age) and last doses (complete by 32 weeks of age) of rotavirus vaccine being recommended by the WHO, with some professional organizations and guidelines recommending even stricter limitations of use. As vaccines cannot be administered before 6 weeks of age according to the manufacturers’ labels, this leaves a relatively narrow window of opportunity to initiate vaccination in an infant. These restrictions excluded a substantial number of children from receiving vaccination especially in LMIC where delays in vaccination are common. Using modeling, it was estimated that in LMIC the additional rotavirus deaths prevented by vaccination without age restrictions far exceeded the excess vaccine-associated intussusception deaths. The WHO continues to recommend that the first dose be given as soon as possible after 6 weeks of age, to ensure protection before natural infection, but infants should be allowed to receive rotavirus vaccine together with Diphteria, Tetanus, Pertussis regardless of the time of vaccination. This would allow immunization programs to reach children who were previously excluded from the benefits of the vaccines. However, vaccination of children beyond 24 months of age is not recommended.
Infants With Perinatal Morbidity
Most high-income country guidelines still adhere to the conventional, narrower age-restrictions, which can make timely vaccination challenging here too, in particular for infants with low-birth weight or other conditions that require prolonged hospitalization in early life. Administration of rotavirus vaccination during hospitalization can be considered for these infants, but the frequent occurrence of vaccine strain shedding in stools, in particular after the first dose in preterm infants, is a concern.6 In-hospital vaccine strain shedding and transmission could pose a potential hazard to vulnerable ward-mates, although this has never been confirmed. Neonatologists in many instances remain reluctant to use a potentially transmissible vaccine on their wards and The American Association of Pediatrics guideline even advices against it. Consequently, although rotavirus prevention is of highest priority for these vulnerable infants, vaccine coverage rates remain low. Prematurity (<37 weeks) does not seem to impair immune response to rotavirus vaccines and premature infants should follow the vaccination schedules recommended for their chronologic age.
HIV Infection and Exposure
Although, diarrheal disease is more common among HIV-infected children than HIV-uninfected children, rotavirus does not seem to cause more frequent or more severe disease in HIV-infected children. Limited data are available from clinical trials on the safety of rotavirus vaccines in HIV-infected infants, who were clinically asymptomatic or mildly symptomatic when vaccinated. The vaccine was found to be safe, well tolerated and immunogenic in this subpopulation, with no effect on their immunologic condition.7 For HIV-infected infants with low CD4 percentage or number, rotavirus vaccine should be administered at the discretion of the physicians, after considering the potential risks and benefits. However, available data indicate suboptimal coverage rates for routine vaccination among these children due in part to concerns regarding the safety of live-attenuated vaccines. HIV-exposed-uninfected children have been identified as having an increased risk of morbidity and mortality from diarrheal disease, but there are limited data on rotavirus-specific diarrhea in these children. Vaccine effectiveness was, however, found to be similar among HIV-exposed-uninfected and HIV-unexposed-uninfected children. An added benefit of immunizing HIV-exposed/infected infants could be the protection of immunocompromised household contacts (ie, HIV-infected mothers) from naturally occurring rotavirus (RV). It is generally believed that this protective effect outweighs the theoretical risk of transmitting vaccine virus between the infant and the immunocompromised household contact.8
Parenterally-administered, nonreplicating rotavirus vaccines could provide a valuable addition to the current repertoire of available rotavirus vaccines and may evade some of the barriers discussed here. In addition to improved efficacy in LMIC, these vaccines can be produced at a very low cost, can potentially be combined with other childhood vaccines, thereby facilitating delivery, and may avoid concerns regarding replicating vaccines and the associated risk of intussusception and possible vaccine strain transmission.9 Preclinical studies have demonstrated that various nonreplicating rotavirus vaccines can induce serum rotavirus-specific binding and neutralizing antibodies which are protective in experimental models. Vaccine candidates include protein subunit vaccines, inactivated virus and virus-like particle vaccines, and there is a rich rotavirus vaccine pipeline with several vaccine candidates under development. One such vaccine candidate is currently in phase I/II trials in infants in South Africa, after a first-in-human clinical trial of this P2-VP8 subunit vaccine found it to be well tolerated and demonstrated promising immunogenicity when administered intramuscularly to adults.
Rotavirus infection occurs at an early age in LMIC, and infants may be exposed to natural rotavirus and acquire disease before their first vaccination, even with a dose given as early as 6 weeks of age. Similarly, nosocomial rotavirus infections that occur predominantly in children with chronic medical conditions, frequently affect children <3 months of age, not yet fully protected by vaccination.10 One alternative approach is to use a birth dose of rotavirus vaccine, which would enable completion of 3 doses of vaccine before 3 months of age, that is, 0, 6 and 10 weeks, and in addition minimize any potential risk of intussusception associated with the first dose as intussusception risk is low in the neonatal period. The neonatal vaccine candidate RV3-BB was found to be immunogenic and well tolerated in phase I and II trials, with further clinical trials ongoing, and this birth-dose strategy also potentially provides a way to improve the safety and effectiveness of rotavirus vaccines in LMIC.11 Continued research and development of new live-attenuated rotavirus vaccines is also warranted to ensure a sustainable and uninterrupted vaccine supply as the demand for rotavirus vaccines increase. Alternative dosing schedules of the currently-licensed vaccines should also be explored in view of the potential inhibition by maternal rotavirus antibodies with an early vaccine dose.
Life-attenuated rotavirus vaccines have had a tremendous impact on rotavirus disease and mortality worldwide, but their potential remains limited in certain subpopulations. Parenterally-administered, nonreplicating rotavirus vaccines and neonatal vaccines could provide valuable safe and relatively cheap additions to the current repertoire of available rotavirus vaccines thereby promoting vaccine coverage, in particular in LMIC countries. The use of rotavirus vaccines should be part of a comprehensive strategy to control diarrheal disease in children.
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