Rotavirus Vaccine - an overview | ScienceDirect Topics

Rotavirus Vaccine
Rotavirus vaccines are attenuated strains given in multiple doses designed to replace a child's initial exposures to wild-type rotavirus with strains that will not cause disease but will generate an adequate immune response to confer protection.
Rotarix and RotaTeq differ in composition, with Rotarix containing a single human G1P[8] strain and RotaTeq containing five reassortant rotaviruses developed from human and bovine parent rotavirus strains. Four of the bovine-human reassortant rotaviruses express human virus VP7 from serotypes G1, G2, G3, or G4, whereas the fifth reassortant virus contains VP4 (P[8]) from a human rotavirus strain. Given its monovalent composition, a priori concerns existed about how well Rotarix would protect against rotavirus disease caused by strains partially (different G or P type) or fully (different G and P type) heterotypic to the vaccine strain. In particular, concerns focused on protection against fully heterotypic G2P[4] strains that also have a different overall genomic RNA constellation defined by RNA–RNA hybridization assays and hence belong to a different genogroup than the G1P[8] Rotarix strain.
In the pivotal prelicensure trial in Latin America, Rotarix prevented 87–91% of severe rotavirus diarrhea caused by partially-heterotypic G3P[8], G4P[8], and G9P[8] strains as well as fully-homotypic G1P[8] strains.18 While fully heterotypic G2P[4] strains were uncommon, protection appeared to be lower (45%) against these strains. However, in a later trial conducted in Europe35 as well as a meta-analysis study integrating all previous trials,36 RV1 provided statistically significant protection against severe rotavirus diarrhea caused by G2P[4]. In the African clinical trial of Rotarix conducted in Malawi and South Africa,30 great diversity of circulating rotavirus strains was observed, with the G1P[8] vaccine-type strains accounting for 57% of strains detected in South Africa and only 13% of strains in Malawi. Nevertheless, the vaccine demonstrated good efficacy against a range of G types—efficacy against G1, G12, and G8 types of 64, 52, and 64%, respectively—as well as a range of circulating P types—efficacy against P[8], P[4], and P[6] of 59, 71, and 55%, respectively.37
During the first 2 years after the introduction of Rotarix in Brazil, a nationwide predominance of G2P[4] strains was reported.38–40 A similar observation was made following vaccine introduction in Australia, where a higher prevalence of G2P[4] strains was seen in states that exclusively used Rotarix compared to states using RotaTeq, where G3P[8] was the predominant strain.41,42 These reports prompted an international discussion over the potential linkage of the appearance of these strains with the introduction of rotavirus vaccines.43,44 However, with additional years of monitoring, further strain changes were observed and G2P4 strains no longer remained the predominant strain in either Brazil or in Australian states using Rotarix.45–47 The observed strain changes may thus represent natural secular variation in rotavirus strain that has been well documented in the years prior to introduction of rotavirus vaccines,48 rather than vaccine selection pressure. Additional evidence of good cross-protection from Rotarix comes from observational studies in several countries of Latin America that have demonstrated high vaccine effectiveness against rotavirus disease caused by nonvaccine type strains.
In summary, no clear pattern of sustained vaccine-associated rotavirus strain shift have been documented and both vaccines appear to provide a high level of protection against severe rotavirus disease from a variety of heterotypic strains. However, data from middle- and low-income countries on these issues are sparse, and ongoing postintroduction surveillance is crucial for interpreting data on emergence novel or unusual strains, assessing vaccine impact, and strain specific vaccine effectiveness.
Recommendations for Rotavirus Vaccine Use in the Expanded Programme on Immunization
WHO recommends that rotavirus vaccines be included in all national immunization programs and be considered a priority in countries with high rotavirus fatality rates.427,428 Two vaccines are currently widely available. Rotarix is recommended to be given in a 2-dose schedule at the time of DTP1 and DTP2; RotaTeq is recommended to be given in a 3-dose schedule at the time of DTP1, DPT2, and DPT3. For both vaccines, a minimum interval of 4 weeks is recommended between doses.
WHO recommendations state that although early immunization is still favored, with the first dose of rotavirus vaccine administered as soon as possible after 6 weeks of age, immunization programs can allow children to receive rotavirus vaccine together with DTP regardless of the time of vaccination (to age 24 months). These updated recommendations were made following review of data on the potential impact of the manufacturers’ conventional age restrictions on the first and last doses of the series427; in countries where rotavirus mortality is the highest, delays in immunization are common and hence strict limits on maximum ages for administration of rotavirus vaccine can substantially reduce the number of children who can receive rotavirus vaccine. A modeling study had assessed the potential benefits of mortality reduction from rotavirus versus the risk of fatal intussusception in low- and low/middle-income countries when the first dose of the vaccine is strictly administered by 15 weeks of age and the last dose is administered by 32 weeks of age, compared with a unrestricted age strategy with rotavirus vaccine administered at the time of DTP administration (up to age 3 years).429 This analysis demonstrated that removing the age restrictions in these countries (which would allow an additional 21% to 25% of children to receive rotavirus vaccine) would avert an additional 47,200 rotavirus deaths and cause an additional 294 intussusception deaths, for an incremental benefit-to-risk ratio of 154 deaths averted for every death caused by vaccine. Postintroduction intussusception assessments are underway in Africa.
Future development and introduction of rotavirus vaccines will require substantial input from the international donor community, including the Vaccine Alliance, Gavi, and the Bill & Melinda Gates Foundation. Many local vaccine makers in China, India, Indonesia, and other settings have begun their own programs for rotavirus vaccine development and introduction, and these efforts could provide an additional supply of vaccine at an affordable cost to ensure that they reach the poorest children in the world who need them the most. In addition to other candidate oral rotavirus vaccines, approaches such as inactivated rotavirus vaccines are being pursued, especially since this could help overcome some of the challenges to diminished performance of oral rotavirus vaccines in developing countries and also potentially avoid a risk of intussusception.383 Such new vaccines are unlikely to be proposed for international use for many years.
Routine administration
Recommendations for the use of rotavirus vaccines have been issued by several committees.308,309 The ACIP recommends routine oral immunization of US infants with either three doses of RotaTeq administered at 2, 4, and 6 months of age, or two doses of Rotarix administered at 2 and 4 months of age.232 The minimum age for the first dose is 6 weeks, and the maximum age is 14 weeks and 6 days. Subsequent doses should be given with an interval of at least 4 weeks, and all doses of vaccine should be administered by age 8 months and 0 days. The first dose of vaccine was not recommended for infants more than 14 weeks and 6 days old, to avoid the age range at which idiopathic intussusception occurs. It was also recommended that no dose of vaccine be administered to infants more than 8 months and 0 days of age because of insufficient data on safety. It is unlikely that these age restrictions will be loosened any time soon.
Rotavirus vaccines can be administered together with diphtheria, tetanus, and pertussis (DTaP), Haemophilus influenzae type B (Hib), inactivated polio (IPV), hepatitis B, and pneumococcal conjugate vaccines. Rotavirus vaccine can be administered to infants with mild illness. Infants with moderate to severe illness should be vaccinated as soon as they recover from the acute phase of the illness.231
The effect of simultaneous administration of both RotaTeq and Rotarix with OPV on the immune response to each of the vaccines has been evaluated.310–312 Neither rotavirus vaccine interferes with the immune response to any of the three antigens in OPV. OPV appears to interfere with the immune response of the first dose of rotavirus vaccine, but this interference is largely overcome after administration of the complete vaccination series.
Placebo-controlled studies
A live oral human rotavirus vaccine 89-12 was assessed in 213 US infants in a randomized, placebo-controlled, double-blind, multicenter trial [9]. The infants received two doses of vaccine or placebo and were followed up through one rotavirus season. There was an immune response to vaccine in 94.4% of vaccinees, and vaccine efficacy was 89%. Adverse reactions were mild. Low-grade fever after the first dose was the only adverse reaction that was significantly more common with the vaccine than with placebo.
187 Rotavirus vaccine and intussusception: how are they intertwined?
Rotashield, an oral rotavirus vaccine, licensed in the United States in 1998, was suspended from use in 1999 when increased rates of intussusception were noted. A new rotavirus vaccine, RotaTeq, was introduced in 2006 and, to date, has not been shown to increase the rate of intussusception.
Rotavirus
Rotavirus vaccine should be given to premature infants, if the recommended schedule can be accomplished in a timely manner. In the phase III trials of RotaTeq, vaccine or a placebo was administered to 2070 preterm infants (25 to 36 weeks of gestational age; median: 34 weeks) [97]. The ACIP considers the benefits of rotavirus vaccine vaccination of premature infants to outweigh the theoretical risks of horizontal transmission by shedding. Given this recommendation, premature infants should be immunized with rotavirus vaccine upon discharge from the neonatal intensive care unit if between 6 and 12 weeks of chronologic age.
E RotaTeq and Rotarix, the Second Generation of Licensed Rotavirus Vaccines
RotaShield clinical trials likely failed to identify a link between the vaccine and intussusception because the frequency of this adverse outcome was so low. Accordingly, new RV vaccine candidates were tested in very large subject pools. In the early 2000s, two vaccine candidates, RotaTeq and Rotarix, underwent large-scale testing involving more than 60,000 infants each. and were licensed in the United States in 2006 and 2008, respectively.
RotaTeq, manufactured by Merck, is a pentavalent vaccine composed of reassortant viruses between the bovine WC-3 vaccine strain and human RV strains [26]. Four reassortants express the VP4 protein from WC-3 and different VP7 proteins from human RV strains (serotype G1, G2, G3, or G4), while the fifth virus expresses a human RV VP4 protein and the VP7 protein from WC-3 (serotype G6). A large clinical trial was carried out from 2001 to 2004 in which more than 70,000 participants from 11 countries were immunized with RotaTeq and evaluated for safety and efficacy. This trial demonstrated that RotaTeq was well tolerated with no increase in intussusception compared to the placebo group. The trial also demonstrated that RotaTeq vaccination led to a 95% decrease in severe disease when administered in three doses separated by 4–10 weeks beginning when the infant was 6–12 weeks old [27]. RotaTeq was licensed for use in the United States and Canada in 2006. Unfortunately, vaccine efficacy is substantially lower in developing countries than in developed nations. For example, while RotaTeq provided over 90% protection from severe disease in Finnish children [28], it provided only 39% and 48% protection in sub-Saharan Africa and Asia, respectively [29,30].
Rotarix, manufactured by GlaxoSmithKline, is composed of a single live attenuated serotype G1 human RV. The vaccine strain was originally isolated from a naturally infected infant in Cincinnati, and was subsequently passaged in African green monkey kidney cells, cloned, and minimally passaged in Vero cells [31,32]. In a phase 3 clinical trial conducted in 11 Latin American countries and Finland, 63,225 infants were administered Rotarix in two doses 4 weeks apart between 6 and 24 weeks of age. The vaccine was well tolerated, was not associated with intussusception, and resulted in a vaccine efficacy of 85% against severe disease [33]. Of note, considering that Rotarix is a monovalent vaccine, the large clinical trial and subsequent trials have demonstrated that Rotarix can provide cross-protection against other RV serotypes [34–36]. In 2004, Mexico and the Dominican Republic were the first countries to license Rotarix. It was subsequently licensed in the United States in 2008, and is currently licensed for use in more than 120 countries [37]. Although Rotarix is highly effective at reducing severe disease, its efficacy and its ability to provide protection for more than a year is diminished in developing countries compared to developed countries [38–41].
Since 2009, the World Health Organization has recommended that all countries include a RV vaccine in their national immunization programs. As of December 2016, 82 countries do so [42]. Current recommendations are that the first dose of RotaTeq or Rotarix be administered between 6 and 15 weeks of age and that all doses be given by 32 weeks of age. Specifically, RotaTeq is given in three doses at 2, 4, and 6 months of age, while Rotarix is given in two doses at 2 and 4 months of age. Importantly, both RotaTeq and Rotarix have recently been implicated in associations with intussusception, though at even lower rates (1–6 cases per 100,000 vaccine recipients) than with RotaShield. In response to these reports, the US Food and Drug Administration initiated a study of the vaccines in their Post-Licensure Rapid Immunization Safety Monitoring (PRISM) program, which found a significant increase in the risk of intussusception after the first dose of RotaTeq, but no increased risk with Rotarix [43]. The Vaccine Safety Datalink project, a collaboration between the CDC and large managed care organizations, also examined this question but attained conflicting data compared to the PRISM study, since there appeared to be increased risk associated with Rotarix, but not with RotaTeq [44]. Regardless, it is widely agreed among policymakers and health providers that the protection provided by RV vaccines against potentially severe gastroenteritis far outweighs the extremely low risk of intussusception.
5.5.3 Immunodeficiency
RV vaccine causes symptomatic disease (prolonged diarrhea and viral shedding) in children with severe combined immunodeficiency (SCID) (Werther et al., 2009; Bakare et al., 2010; Patel et al., 2010), and therefore vaccination is contraindicated and exposure to RV vaccine shedders should be avoided in such children. Other immunodeficiencies may be regarded similarly. Selective IgA deficiency may result in prolonged shedding of RV vaccine, but does not constitute a safety problem and, in any case, is usually not diagnosed by the time of RV vaccination (Vesikari et al., 2015).
Gastrointestinal
RotaShield was a tetravalent rhesus-based rotavirus vaccine, which was linked to a rare bowel obstruction called intussusception in some children and was therefore withdrawn from the US immunization schedule in 1999 (SED-14, 1091; SEDA-23, 354; SEDA-25, 390; SEDA-26, 360). The two frontrunners in the race to replace it are GlaxoSmithKline and Merck & Co. Both are currently testing their oral vaccine candidates (GSK human strains, Merck a mixture of cow and human strains) for safety and efficacy. GSK is conducting clinical trials in 60 000 children in Latin America. Both companies say their vaccines do not appear to cause intussusception (54r). Meanwhile, the US National Institutes of Health (NIH) has licensed the rights of RotaShield to Minneapolis-based BIOVIRx, which hopes to eliminate the risk of intussusception and re-introduce the vaccine into the US market (55r).
4.6 Impact of Vaccination on Genotype Distributions
Two rotavirus vaccines have been available since 2006, including the monovalent Rotarix® vaccine (GlaxoSmithKline Biologicals, Rixensart, and Belgium) and the pentavalent RotaTeq® vaccine (Merck and Co., Whitestation, NJ, and USA). These vaccines differ in their approach to eliciting immunity (Ward, 2009). The Rotarix vaccine consists of an attenuated Wa-like G1P[8] strain, whereas RotaTeq contains a mixture of 5 bovine-human monoreassortant RVA strains, where each strain contains either a human VP7 (G1, G2, G3, and G4) or VP4 (P1A[8]) gene, introduced by in vitro reassortment in the genetic background of the bovine WC3 rotavirus (G6P7[5]) strain. (See Chapter 2.11.)
Although there is a broad scientific consensus that both vaccines are effective in reducing the burden of severe RVGE, there is still controversy regarding the long-term effects of vaccination on the circulating RV genotype distribution (Matthijnssens et al., 2012a). Vaccine effectiveness has been found to be equally high against both homotypic and heterotypic strains (Leshem et al., 2014). Nevertheless, transient changes in the genotype distribution have been observed following large-scale vaccination with Rotarix and/or RotaTeq.
The introduction of RotaTeq was followed by an increase in the prevalence of the G3P[8] genotype in some places, including the United States and some Australian states (Hull et al., 2011; Kirkwood et al., 2011), raising concern that this could be linked to lower rates of seroconversion to the G3 component of the pentavalent vaccine (Matthijnssens et al., 2012a). However, similar observations have not persisted. Other genotypes, including G9P[8], G12P[8], and G2P[4], have predominated for a year or two in certain locations, but overall G1P[8] has remained the predominant genotype in countries using RotaTeq.
For Rotarix, a consistent and more prolonged increase in the relative prevalence of the fully heterotypic G2P[4] genotype has been observed following large-scale vaccination (Dóró et al., 2014), particularly in Brazil, Belgium, and some Australian states. However, the magnitude and duration of the increase varied between locations. In Australia, the increase G2P[4] was seen for two seasons following vaccine introduction (2007–09) and again in 2012, but G1P[8] and G3P[8] were the most common genotypes in 2009–11 and 2013, respectively, in states using Rotarix. A clear increase in G2P[4] after vaccine introduction has also been noted in Belgium, and has been sustained for at least seven seasons, 2006–13 (Zeller et al., 2010; Pitzer et al., 2015). In Brazil, G2P[4] has been the predominant genotype for at least six years since vaccine introduction (2006–11), with prevalence ≥50% in all years except 2009 (Gómez et al., 2014). Furthermore, G1P[8] has been relatively rare, having been detected in ≤20% of samples in all seasons since vaccine introduction in Brazil (Carvalho-Costa et al., 2011), while another fully heterotypic genotype (G8P[4]) emerged in Northeast Brazil in 2012 (Gurgel et al., 2014). The high prevalence of G2P[4] RVA strains in Brazil after introduction of the universal RV vaccination with Rotarix was not unique but also recorded in other South American countries where no RV vaccination program had been established (Matthijnssens et al., 2009).
Finally, a number of vaccine-derived reassortant strains have also been isolated from individuals both with and without a history of vaccination. In particular, vaccine-derived reassortant G1P[8] strains have been described in patients from the United States, Australia, and Finland following vaccination with RotaTeq. Reassortment between wild-type G1P[8] and the Rotarix vaccine strain has also occurred (Dóró et al., 2014). This has important implications for surveillance, as more advanced laboratory methods may be needed to differentiate between wild-type and vaccine-derived strains.