Impact of rotavirus vaccination: the importance of monitoring strains

Abstract

Future MicrobiologyVol. 4, No. 10 EditorialFree AccessImpact of rotavirus vaccination: the importance of monitoring strainsJon R Gentsch, Umesh D Parashar & Roger I GlassJon R Gentsch† Author for correspondenceDivision of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA. Search for more papers by this authorEmail the corresponding author at jrg4@cdc.gov, Umesh D ParasharDivision of Viral Diseases, National Center for Immunization and Respiratory Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USASearch for more papers by this author & Roger I GlassFogarty International Center, NIH, Bethesda, MD, USA. Search for more papers by this authorEmail the corresponding author at glassr@mail.nih.govPublished Online:8 Dec 2009https://doi.org/10.2217/fmb.09.105AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit In an article in this issue of Future Microbiology, Matthijnssens et al. review recent data on the impact of the two new rotavirus vaccines, RotaTeq™ and Rotarix™, on disease burden and highlight the importance of monitoring the effect of vaccination on rotavirus strains [1]. The authors point out that data becoming available from postlicensure studies in the USA, Australia and elsewhere suggest that vaccine usage has caused a substantial reduction of rotavirus gastroenteritis cases and hospitalizations [2,3]. While these vaccine effectiveness (VE) results are highly encouraging, Matthijnssens et al. remind readers that the long-term impact of immunization with rotavirus vaccines on strain evolution has not been studied and suggest that the large diversity of rotavirus serotypes, distinct from those of the two vaccines, and the potential for rapid viral evolution through genetic reassortment [4–6] could challenge the effectiveness of the two vaccines through the emergence of strains that evade immunity. Consequently, the authors believe it will be important to continue surveillance during the postintroduction period to monitor strains.Immunity to rotavirus is thought to have both serotype-specific (homotypic) and cross-reactive (heterotypic) components. For example, challenge studies in piglets demonstrate that primary infection elicits predominantly serotype-specific protection against both VP4 (P) and VP7 (G) antigens (for a review see [7]). Similarly, in a study of natural rotavirus infection, children who developed threshold levels of neutralizing antibodies to serotype G3 were subsequently protected against re-infection with the same serotype, suggesting that protection was homotypic. Protection elicited in recipients of a serotype G3 vaccine also appeared to be largely homotypic, as indicated by much higher efficacy against human G3 than non-G3 strains. Repeat rotavirus infections acquired naturally, or by vaccination, broaden protective immunity to include multiple serotypes, as indicated by development of cross-neutralizing antibodies and cross-reactive epitope-blocking antibodies specific for the VP4 and VP7 serotype antigens, suggesting that a stronger heterotypic response is generated during re-infection [7].Consistent with this, experiments in animals and human vaccine trials demonstrate heterotypic protection between vaccines and challenge strains. The vaccine trials and follow-up studies conducted with two new rotavirus vaccines demonstrated heterotypic protection against strains having one (G9P[8] versus Rotarix and RotaTeq) or two (G2P[4] versus Rotarix) distinct serotype antigens compared with the vaccines [8–11]. While the VP7 and VP4 serotype antigens are thought to be important for development of immunity against rotavirus infection, other viral proteins, such as VP6 and NSP4, may also be involved [12,13]. Thus, if rotavirus strains that escape immunity arise in vaccinated populations, it may be through selection of strains that are distinct in a variety of homotypic and cross-reactive sites on VP4 and VP7, as well as perhaps other proteins.While noting the importance of surveillance, the authors also suggest that it will be challenging to distinguish between changes occurring as a result of natural fluctuations in genotype prevalence that have occurred over time in different regions of the world and those that could be mediated by population immunity to the vaccines. Examples of such natural variation in the prevaccine era include the emergence of serotype G9 from the mid-1990s to become a globally important strain, the probable emergence of G12 in this decade and cyclic fluctuation of common serotypes such as G2 [5,6,14,15]. As the authors describe, the post-vaccine era has already seen examples of the challenge. Notably, after Brazil started routine immunization with the monovalent serotype G1P[8] vaccine Rotarix in 2006, a dramatic increase and predominance of G2P[4] strain has been observed in Brazil over the past 2–3 years following vaccine introduction. This observation has led researchers to hypothesize that the reported lower efficacy of Rotarix against fully heterotypic G2P[4] could have resulted in a selective advantage over other serotypes, resulting in an increase in G2P[4] prevalence, although the authors acknowledged the possibility that natural strain shifts might also explain this phenomenon [16,17]. Studies documenting a similar increase of G2P[4] during 2006 in countries that had not introduced a vaccine, as well as a trend of increasing G2 prevalence on the continent before vaccine introduction, suggest this was more likely due to natural fluctuation in prevalence of this strain [14,18]. Furthermore, a study conducted in a region of Brazil with high prevalence of G2P[4] over three consecutive years (2005–2007) showed good VE of Rotarix against G2P[4] strains [19]. Nevertheless, the observed predominance of G2P[4] strains in Brazil over multiple years is rather unusual and warrants further monitoring.Since vaccine introduction, VE and associated strain surveillance studies are also being conducted in several other high- and low-income countries. In Australia, where both RotaTeq and Rotarix vaccines were introduced in July 2007, individual states use one or the other but not both vaccines [20]. The Australian state of Queensland has reported 45% (2007) and 43% (2008) declines in rotavirus-positive tests in the first year and a half following vaccine introduction [21]. The use of either Rotarix or RotaTeq, but not both, by individual states within Australia presents a unique opportunity to detect possible vaccine-mediated changes in strains. For example, if a stable long-term serotype change only occurs in states using one of the vaccines it may be indicative of immune selection and may correlate with trends of severe acute gastroenteritis cases. Between 2007 and 2008, Kirkwood and coworkers have demonstrated that states using Rotarix have a higher prevalence of serotypes G2 and G9 while states using RotaTeq have increased prevalence of G3 [20]. Nonetheless, these investigators concluded that it was too soon to discriminate these patterns from natural fluctuations seen in Australia every 2–3 years [22].In the USA, the New Vaccine Surveillance Network (NVSN) has conducted active, population-based surveillance for acute rotavirus gastroenteritis and rotavirus strains in three US counties since 2006 [23]. During 2008, 2 years after licensure of RotaTeq in the USA, an 80% reduction in hospitalizations and emergency room visits was observed compared with 2006 and 2007, in agreement with the large decline in rotavirus activity detected by national laboratory surveillance and other studies [2,3]. Similarly to Australian states using RotaTeq, US laboratory surveillance data show an increase in G3P[8] strains concomitant with vaccine introduction [20,24]. While these findings are intriguing, a study conducted at a large pediatric hospital in Houston, TX, USA, during a season when the majority of rotavirus cases were caused by G3P[8] strains showed a high VE of RotaTeq [25]. Thus, additional years of surveillance will be required to determine if this trend towards increasing G3 prevalence is long lasting and associated with any impact on disease.Conducting VE and strain-monitoring studies in lower income country settings may be particularly important because the large variety of strains that often have unique serotype antigens and are sometimes more prevalent than strains considered globally common may offer the stiffest challenge to vaccines [5,6]. Continuation of ongoing studies such as those in Brazil and El Salvador where Rotarix is used in national immunization programs, and Nicaragua where RotaTeq is currently being donated by the manufacturer for the routine childhood immunization schedule, will be invaluable to assess potential strain changes over time. In Brazil and El Salvador, temporal studies of VE and strain variation can help test the early hypothesis that Rotarix use results in selection of strains bearing heterotypic serotype antigens compared with the vaccine. For Nicaragua, RotaTeq usage has not been accompanied by an increase in serotype G3 to date [26], unlike the findings in the USA and some parts of Australia [20]. Thus, continuation of studies in Nicaragua may give key information on potential selection of G3 by RotaTeq. Finally, studies to follow-up the recently completed Rotarix vaccine trial in Malawi, where vaccine efficacy was a relatively low 49%, could provide important information on VE in a country that has a highly unusual strain profile, including a variety of prevalent rotaviruses with two distinct serotype antigens compared with Rotarix [27]. While efficacy in the Malawi trial was relatively low compared with trials in high-income countries, no significant differences were seen in efficacy against common strains compared with strains with novel serotypes, suggesting that Rotarix provided broad heterotypic protection [28].We agree wholeheartedly with Matthijnssens et al. that strain surveillance should continue long term in countries adopting rotavirus vaccines to assess the impact of rotavirus immunization programs on viral serotypes. To discriminate between natural fluctuations in rotavirus serotypes that occur periodically and changes driven by immunity to rotavirus vaccines, Matthijnssens et al. proposed monitoring strains in separate groups of vaccinated and unvaccinated children during the same time period within the same region of one country [1]. While such an approach may be important to determine if vaccines cause changes in circulating strains, the more critical question is whether observed differences are accompanied by significant reductions in VE and resurgence in severe cases of rotavirus acute gastroenteritis, which may indicate selection of rotaviruses that have circumvented vaccine immunity. Answering these questions will require long-term monitoring of VE in conjunction with active surveillance for rotavirus gastroenteritis and strains. In addition to assessing prevalence of different strains before and after vaccine implementation, these investigations will permit evaluation of strain-specific disease incidence over several seasons and assessment of strain-specific VE through epidemiologic studies will allow full understanding of the impact of vaccination on rotavirus strains. Studies of VE and strains being conducted in several developed as well as low-income countries or related studies should continue for several years after substantial uptake of vaccines has occurred, since it may take a period of time for strains that evade immunity to become sufficiently common to have an impact on VE, even in a setting where population immunity is high. If strains that evade immunity to rotavirus vaccines are detected it will be important to perform full genomic and antigenic characterization in an attempt to identify potential mutations or reassorted genes associated with their virulence phenotype. Such studies may be critical in identifying correlates of protection that could be valuable in designing improved vaccines in the future.DisclosureThe findings and conclusions in this report are those of the authors and do not necessarily represent the views of Centers for Disease Control and Prevention.Financial & competing interests disclosureThe 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. 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This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.No writing assistance was utilized in the production of this manuscript.PDF download