Current and new rotavirus vaccines

Purpose of review As of 2019, four rotavirus vaccines have been prequalified by the WHO for use worldwide. This review highlights current knowledge regarding rotavirus vaccines available, and provides a brief summary of the rotavirus vaccine pipeline. Recent findings Data generated from use of currently available products supports their effectiveness and impact in diverse settings. Rotavirus vaccines have a favorable risk–benefit profile, but previous associations of rotavirus vaccination with intussusception necessitate continued monitoring for this rare but serious adverse event. Implementation of rotavirus vaccines was jeopardized in late 2018 and 2019 by a shortage of vaccine supply. Fortunately, with the prequalification of two additional vaccines in 2018, countries have increased choice in products with different characteristics, pricing, and implementation strategies. Other vaccines currently in development may open up further immunization strategies, such as neonatal vaccination schedules or parenteral administration. Summary Rotavirus vaccines have demonstrated impact in reducing diarrheal morbidity and mortality worldwide. As countries begin to introduce the newly prequalified vaccines, additional data will become available on the safety and effectiveness of those products. Products in the pipeline have distinct profiles and could be an essential part of the expansion of rotavirus vaccine use worldwide.


INTRODUCTION
Rotavirus is one of the leading causes of severe pediatric diarrhea globally, and is associated with $125 000-200 000 deaths each year in children under 5 years [1 && ,2,3]; approximately half of all rotavirus-associated deaths occur in just four countries (India, Nigeria, Pakistan, and the Democratic Republic of the Congo) [3]. The WHO recommends rotavirus vaccination as part of an integrated package of prevention-oriented and treatment-oriented interventions to reduce diarrheal morbidity and mortality [4]. In 2006, two rotavirus vaccines -Rotarix (GlaxoSmithKline Biologicals SA, Rixensart, Belgium) and RotaTeq (Merck & Co., Inc., West Point, PA, USA) -were licensed and almost immediately introduced into the national immunization programs of several countries. In 2009, after the liveattenuated, oral vaccines had been shown to be efficacious in developing countries in Africa and Asia, WHO recommended rotavirus vaccines for priority inclusion in national immunization programs worldwide [4]. Currently, rotavirus vaccines are in wide use globally, and have made a demonstrable impact on the burden of disease [5].
Nonetheless, opportunities for growth in global coverage remain. The prequalification of two products previously available only on a national level may help to alleviate global rotavirus vaccine supply constraints [6 & ,7]. This review provides a brief summary of the current status of rotavirus vaccine introductions globally, available knowledge on the impact and safety of rotavirus vaccines, and future directions in rotavirus vaccine development.
FIGURE 1. Map of rotavirus vaccine introduction worldwide. The status of rotavirus vaccine introduction is indicated by color, with dark green for universal (national) introduction, and light green for introduction on a phased or regional basis. Countries that have not introduced rotavirus vaccine into their national immunization schedules are shown in gray; rotavirus vaccine may be available via the private market in some countries.

KEY POINTS
Rotavirus is one of the leading causes of severe pediatric diarrhea, and vaccination against rotavirus is an important component of prevention strategies.
As of the end of 2018, 98 countries had introduced rotavirus vaccine on a phased, regional, or national basis, and four rotavirus vaccines had been prequalified by the WHO.
Rotavirus vaccines have been shown to have significant impact on diarrheal morbidity and mortality in diverse geographies, though effectiveness tends to be higher in higher resource settings.
Although rotavirus vaccines are generally well tolerated, rotavirus vaccine has been associated with a temporally limited increase in the risk of intussusception; this risk may vary by setting, infant age, or product, and ongoing evaluation across products and geographies is critical.
Several rotavirus vaccines are under development, with some pursuing new strategies, such as neonatal dosing or parenteral administration. unique presentation and profile, resulting in distinct considerations for introduction (Table 1).

Impact and effectiveness
In 2019, we will mark 10 years since WHO first recommended rotavirus vaccination for children worldwide [4]. Since that time, data on the impact and effectiveness of rotavirus vaccines have continued to be generated in diverse settings. These data are especially important for countries transitioning from Gavi support to self-financing, as they provide evidence-based rationale for continued support of rotavirus vaccination.
The Americas, on the basis of existing efficacy data for the region and consequent WHO recommendation, began to introduce rotavirus vaccines soon after licensure in 2006 [11 & ]. A 2018 metaanalysis of studies from Latin America estimated a vaccine effectiveness of 71% (95% confidence interval (CI) 61-79%) against rotavirus hospitalization in children less than 12 months of age in the region [11 & ]. This same review calculated a median reduction of 43% [interquartile range (IQR) 37-50%] in acute gastroenteritis death rates in children less than 1 year in low-mortality countries, and 45% (IQR: 30-55%) in high-mortality countries. The authors further estimated that in 2015, rotavirus vaccination averted a median of $123 000 rotavirus-associated hospitalizations and $660 rotavirus-associated deaths in the 15 Latin American countries that have introduced rotavirus vaccine, and $2260 rotavirus-associated hospitalizations and 180 rotavirus-associated deaths in the two rotavirus vaccine-using Caribbean countries. A review and meta-analysis of rotavirus vaccine impact and effectiveness in the United States found a median vaccine effectiveness of 84% (IQR: 83-91%) against rotavirus-associated hospitalizations or emergency department visits [12 & ]. Vaccine effectiveness estimated via meta-analysis (using mixed effects models) were similar for RV5 (84%) and RV1 (83%).
Although rotavirus vaccines are available on the private market in many countries in the WHO European region, only 18 of 53 have introduced rotavirus into their national vaccine program [8]. Vaccine effectiveness estimates for the region vary, with the highest effectiveness seen in higher resource countries [e.g. 86% (95% CI: 83-89%) against rotavirus hospitalization in German children less than 5 years [13], and 94% (95% CI: 80-98%) against rotavirus hospitalization in Finnish children eligible for vaccination [14]), and lower effectiveness seen in lower resource countries [e.g. 62% (95% CI: 36-77%) against rotavirus hospitalization in Armenian children less than 2 years [15], and 79% [95% CI: 62-88%] against rotavirus hospitalization in children less than 2 years in the Republic of Moldova [16]].
In the WHO African region, 35 of 47 countries have introduced rotavirus vaccine into their national immunization schedules as of 2018, and several more are planning for imminent introduction [8]. Of seven African countries in the WHO Eastern Mediterranean region (EMRO), four have introduced the vaccine [17]. In 2005, the African Rotavirus Surveillance Network was established to document the rotavirus disease burden in Africa; by 2013, there were 22 countries participating in the network [18 & ]. Data from this network were recently analyzed to compare rotavirus burden in countries that had introduced the  [15] Liquid Vial a Nonfrozen presentation expected in 2020 but not yet prequalified. b Liquid presentation expected in 2020 but not yet prequalified.
vaccine before 2013, versus those countries who had yet to introduce rotavirus vaccine by 2015 [18 & ]. Rotavirus positivity declined significantly over time in countries that were early introducers of the vaccine (35% in 2010 to 19% in 2015 for countries introducing before 2013); the decline was less marked for countries introducing after 2013 (44% in 2010 to 25% in 2015). Countries that had not introduced the vaccine by the end of the study period showed no significant change in rotavirus positivity (32% in 2010 and 30% in 2015) [18 & ]. Other recently published data from the region showed estimates of vaccine effectiveness ranging from 49 to 86%, with the greatest effectiveness observed against severe disease and in younger infants [19][20][21][22].
In Asia, only eight countries have introduced rotavirus vaccine on a national basis; two additional countries (India and Pakistan) have begun a phased introduction [23 & ]. A recent review and analysis of data from this region found a median vaccine effectiveness of 94% in low child mortality countries, 64% in medium child mortality countries, and 49% in high child mortality countries [23 & ]. This analysis further estimated that universal introduction of rotavirus vaccine in all 43 countries in the studied region could avert 710 000 rotavirus hospitalizations and 35 000 rotavirus deaths annually, assuming an achieved coverage equal to that of the third dose of diphtheria-tetanus-pertussis (DTaP) vaccines [23 & ]. Other recently published studies from this region found vaccine effectiveness in similar ranges by child mortality stratum: 80% in Japan [24] (low child mortality), 60% in the Philippines [25] (high child mortality).

Safety
In randomized controlled trials, rotavirus vaccines have been well tolerated [26][27][28][29][30][31]; a Cochrane review of available data found no increase in serious adverse events associated with Rotarix, RotaTeq, or Rotavac [32 && ]. However, one consideration with all live-attenuated, oral rotavirus vaccines is the potential risk of intussusception, a rare but serious cause of bowel obstruction in which one portion of the intestine invaginates into another portion, in some cases necessitating surgery. The first rotavirus vaccine, RotaShield, was withdrawn from the US market in 1999 after it was found to be associated with risk of intussusception [33]. Further, the natural incidence of intussusception peaks during the same ages as rotavirus vaccination is given in many countries [34]. Although currently available rotavirus vaccines did not show an association with intussusception during clinical trials, the rarity of this outcome makes it difficult to evaluate without extremely large numbers of participants.
Postmarketing surveillance in high-income and middle-income countries has detected a temporally limited but significant increase in the risk of intussusception in the 1-7 days following administration of Rotarix or RotaTeq [35][36][37][38][39][40], on the order of 1 to 6 excess cases per 100 000 infants vaccinated. However, results from high-income and middle-income countries may not be fully generalizable to low-income and lower middle-income countries, which demonstrate important differences in access to healthcare as well as rotavirus vaccine effectiveness, as previously discussed. Further, the baseline incidence and epidemiology of intussusception may also vary by country. Lastly, it cannot be assumed that the risk profile will be the same across all rotavirus vaccines.
Recent data from an intussusception surveillance network in seven Rotarix-using African countries showed no significant increase in intussusception risk following rotavirus vaccination [41 Given the importance of this research question, the wide variability in intussusception epidemiology by geography, and the possibility that associations could vary by vaccine product, ongoing investigation is necessary. In this vein, surveillance is ongoing in two multicountry networks: postintroduction intussusception surveillance is currently underway in several African countries using RotaTeq [45], whereas baseline (preintroduction) and postintroduction intussusception surveillance is ongoing in several Asian countries, including in India (for the newly prequalified vaccines) [46,47]. Results from these evaluations will be helpful in further understanding the risk-benefit profile of rotavirus vaccines globally.

NEWLY WHO-PREQUALIFIED ROTAVIRUS VACCINES
The availability of more affordable rotavirus vaccines will be an important part of ensuring continued coverage into the future. In 2018, two new rotavirus vaccines were prequalified by WHO: Rotavac and ROTASIIL. These vaccines will soon be available for use globally, but are currently only in routine use in India. This section will, thus, focus on the safety and efficacy data available from randomized controlled trials.

Rotavac (Bharat Biotech)
Rotavac is a monovalent G9P [11] naturally attenuated, live oral rotavirus vaccine. A randomized, double-blind, placebo-controlled trial evaluated the safety and efficacy of this vaccine in more than 6500 infants enrolled from three sites in India [30]. Infants were randomized to receive either vaccine or placebo at a target schedule of 6-7, at least 10, and at least 14 weeks of age, and were followed up to 2 years of age for adverse events and gastroenteritis. Infants received routine immunizations as regularly scheduled (i.e. on the same day as the study vaccine). The estimated efficacy of Rotavac against severe rotavirus gastroenteritis requiring hospitalization or supervised rehydration was 56% (95% CI: 37-70%) in the first year of life [30] and 49% (95% CI: 17-68%) in the second year of life [48]. The occurrence of adverse events was not significantly higher in the vaccine group as compared with the placebo group; however, there was insufficient power to evaluate an association with intussusception [30,48]. In a noninterference trial (also randomized, double-blind, and placebo-controlled), no difference was seen in the immune response to pentavalent or OPV vaccines when comparing Rotavac recipients to placebo recipients [49].

ROTASIIL (Serum Institute of India)
ROTASIIL, a pentavalent bovine-human reassortant live attenuated oral vaccine, has the unique feature of being heat-stable in its lyophilized form, retaining stability for up to 18 months at 40 8C [50]. This vaccine was evaluated in two randomized, double-blind, placebo-controlled trials: one in Niger [51] and one in India [29]. In each trial, infants were randomized to receive either vaccine or placebo at a target schedule of 6, 10, and 14 weeks of age, in coordination with any other vaccines recommended by the Expanded Program on Immunization (EPI) schedule. In Niger, the vaccine was transported and stored centrally at up to 25 8C until distribution to health centers, at which time it was stored at ambient temperature. In both trials, children were followed for serious adverse events and episodes of acute gastroenteritis; primary analyses were conducted after a target number of cases had been reached. In Niger, the vaccine efficacy against severe rotavirus gastroenteritis was 67% [95% CI: 50-78%; per-protocol analysis at the time of primary analysis (event-driven cut-off)], and no significant differences in adverse event rates were noted in the vaccine as compared with the placebo group, though the study was not powered to evaluate differences in the risk of intussusception [28,51]. In India, the vaccine efficacy against severe rotavirus gastroenteritis in the first year of life was 33% (95% CI: 12-49%; per-protocol analysis). The proportion of infants experiencing adverse events was similar in the vaccine and placebo populations; however, the study was not powered to detect significant differences in the risk of intussusception [29]. No evidence was found of interference with routinely administered EPI vaccines [52].

Current usage of Rotavac and ROTASIIL in India
Both Rotavac and ROTASIIL are being introduced on a phased basis in India. As of 2019, Rotavac has been introduced into the Expanded Program on Immunization (EPI) schedule in 10 states: 4 in 2016, 5 in 2017, and 1 in 2018 [53]. Approximately 50 million doses have been procured by the Ministry of Health and Family Welfare so far [54]. In 2018, ROTASIIL was introduced into one state, and over one million doses have been distributed since then [55]. Postmarketing studies to evaluate the safety of the vaccines with respect to intussusception and the vaccine effectiveness are underway, and the expansion of routine use of both vaccines is anticipated with country-wide rollout projected by late 2019. www.co-infectiousdiseases.com

Rotavin-M1 (POLYVAC)
Nationally licensed vaccines can play an important role in broadening the affordability and availability of rotavirus vaccination, particularly in countries with the desire and ability to pursue local manufacture. For instance, in Vietnam, the government has made a concerted effort to foster the development and local manufacture of vaccines, to enable selfsufficiency [56]. Rotavirus-focused efforts led to the development of Rotavin-M1, a live, attenuated, frozen oral vaccine derived from a human rotavirus strain (G1P [8]) isolated from a child hospitalized for diarrhea in Nha Trang, Vietnam [56,57]. This vaccine was shown to be well tolerated and immunogenic (73% seroconversion) in a trial of Vietnamese infants [57]. Rotavin-M1 has been licensed on this immunogenicity data in Vietnam since 2012 and is available in the private market, with a two-dose schedule at 2 and 4 months of age. This vaccine is currently being introduced into the EPI schedule on a pilot basis in selected districts of two provinces: Nam Dinh and Thua Thien Hue. Vaccine effectiveness and impact evaluations are ongoing. A phase III immunogenicity trial of a liquid, nonfrozen presentation of the vaccine is being planned [58].

Lanzhou lamb rotavirus vaccine (Lanzhou Institute of Biological Products)
The Lanzhou lamb rotavirus vaccine (LLR) is a live, attenuated oral vaccine based on a lamb rotavirus strain (G10P [15]) first isolated in 1985, and is licensed exclusively in China [59,60]. LLR has been available in China since 2000, and more than 60 million doses have been distributed [61]; however, the vaccine is not part of the country's national immunization program, and consequently, coverage is relatively low [62]. Further, coverage is highly variable by geography. LLR is recommended to be given once annually for children 2 months to 3 years of age. Although no efficacy data are available, as no placebo-controlled phase III trials were performed for this vaccine, several case-control studies have estimated vaccine effectiveness against rotavirus gastroenteritis. These studies, from different time periods and different geographies, generated vaccine effectiveness estimates ranging from 35 to 77% [59,[63][64][65]. More recently, an ecological analysis suggested that the incidence of rotavirus gastroenteritis among young children was reduced in districts with higher as compared with lower rotavirus vaccine coverage [62]. Further research could be useful in evaluating the performance of and optimal schedule for this vaccine.

ROTAVIRUS VACCINE PIPELINE
Several rotavirus vaccine candidates are in the pipeline [66], including further development of licensed products or strains, as well as new strategies to overcome some of the challenges associated with live, attenuated, oral infant vaccines (Fig. 2). This section will provide a brief overview of products actively under development.

RV3-BB
The candidate that is furthest along in development is RV3-BB (PT BioFarma, Bandung, Indonesia), an oral vaccine based on a naturally attenuated neonatal strain of G3P [6] rotavirus and initially developed by the Murdoch Children's Research Institute [67 && ]. RV3-BB, because of its ability to replicate in the newborn gut even in the presence of maternal antibodies, is intended to be given on a neonatal schedule with the goal of providing early protection against rotavirus [67 && ]. The most recent data for this vaccine is from a Phase 2b, randomized, placebo-controlled trial that took place in Indonesia from 2013 to 2016. Full-term infants (N ¼ 1649) were randomly assigned to one of three arms: placebo, neonatal schedule (0-5 days, 8-10, and 14-16 weeks of age), or infant schedule (8-10, 14-16, and 18-20 weeks of age); all infants received either placebo or vaccine, according to their trial arm, at each of the four time points. Infants were followed up to 18 months of age for severe rotavirus gastroenteritis. The per-protocol vaccine efficacy against severe rotavirus was 94% (56-99%) at 12 months of age for infants receiving vaccine on the neonatal schedule, and 77% (31-92%) at 12 months of age for infants receiving vaccine on the infant schedule. Immune responses were also noted in both groups, and the vaccine was well tolerated in both vaccine groups [67 && ]. Further, no evidence was noted of interference by or with OPV in the neonatal schedule group [68]. This vaccine is being further evaluated in a dose ranging study in African neonates and infants [69]. Biofarma are currently driving clinical development, with the aim to introduce the vaccine into the Indonesian national immunization program by 2021 and eventually pursue a product for the global market.

Nonreplicating rotavirus vaccines
Another strategy currently being investigated is the development of parenterally administered rotavirus vaccines. Such vaccines could have the potential to overcome some of the challenges associated with oral vaccines, such as interference by neutralizing antibodies present in breast milk, and other barriers associated with reduced efficacy [70 & ]. Further, parentally administered vaccines could be combined with other infant immunizations. One such nonreplicating rotavirus vaccine (NRRV) under development is the subunit vaccine P2-VP8-P [8], most recently assessed in South African toddlers and infants [71]. During a dose-escalation phase, 90 toddlers and infants were randomized to receive vaccine or placebo; doses of 30 and 60 mg were tolerated and selected for further study in an expanded group of 114 infants, again randomized to receive vaccine or placebo. The vaccine was well tolerated, and vaccinated infants demonstrated strong IgG response (>98% seroconversion) compared with placebo (9% seroconversion) [71]. More recently, a trivalent subunit vaccine (VAC 041, P2-VP8-P[4]P[6]P [8]) was studied using a similar design [72]. Strong IgG responses were demonstrated, and neutralizing antibody response to several strains of rotavirus was also noted.
There is also a VP6 subunit vaccine under development that incorporates norovirus virus-like particles (VLPs) to form a combination vaccine [73][74][75][76]. This candidate has demonstrated good immunoresponse in mice models [75,76]. An inactivated www.co-infectiousdiseases.com rotavirus vaccine (IRV) has also been developed by CDC for parenteral administration [77]. This candidate, based on a G1P [8] strain, has been trialed in mice, rats, rabbits, and pig models and demonstrated heterotypic neutralizing antibody response [78,79]. Systemic and mucosal immunity were shown in mice after administration by injection and by microneedle patch [77]. Further, this candidate was efficacious against oral rotavirus challenge in piglets [80]. A combined inactivated polio vaccine (IPV)-IRV product is also under development with this same strain, and has been tested in mice, with no evidence of interference of the immune response to either component [81]. Other early-stage candidates include an inactivated G1P [8] strain isolated from a hospitalized Chinese infant [82] and a truncated VP4 based on the LLR strain [83].

CONCLUSION
Now, with four WHO-prequalified oral rotavirus vaccines available, and several more products nationally licensed or in development, we are at an unprecedented time of choice in the history of rotavirus vaccines. However, rotavirus disease remains a large burden worldwide, and numerous countries have yet to introduce rotavirus vaccines into their national schedules. Rotavirus vaccines have a proven track record of impact, balanced with a favorable risk-benefit profile. With new products in the pipeline, and several countries poised to introduce vaccines formerly available only in a single market, we look forward to the continuation of an exciting era in the use of rotavirus vaccines.

Acknowledgements
None. Disclaimer: The findings and conclusions of this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention (CDC). Names of specific vendors, manufacturers, or products are included for public health and informational purposes; inclusion does not imply endorsement of the vendors, manufacturers, or products by the Centers for Disease Control and Prevention or the US Department of Health and Human Services.
Financial support and sponsorship None.

Conflicts of interest
There are no conflicts of interest.

REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as: & of special interest && of outstanding interest