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After a rocky start with the initial licensure and subsequent withdrawal of Rotashield because of an association with intussusception, 2 newer rotavirus vaccines, Rotarix (monovalent) and RotaTeq (pentavalent), have enjoyed a remarkable success. They are now licensed in over 100 countries and have markedly reduced the number of deaths, hospitalizations, and medical visits wherever they have been studied. Rotavirus strains are often classified according to the 2 surface capsid proteins, G (VP7) and P (VP4), that induce neutralizing antibodies. The G protein is a glycoprotein important for attachment to host cells, whereas the P protein’s name derives from its being cleaved by a protease into 2 fragments that enhance infectivity. G and P proteins are further designated numerically to define specific serotypes, for example G1P or G2P. The most common serotypes circulating when the vaccines were developed included G1P, G2P, G3P, G4P, and G9P. However, it is apparent that the epidemiology of rotavirus includes regular changes in the circulating strains, as well as the identity of the dominant strain, even in the absence of vaccines. Therefore, it has been a challenge to determine the effects of the vaccines on the background of natural variation. Strains can be thought of as homotypic, partly heterotypic, and fully heterotypic to the vaccines based on the G and P proteins. Thus, when compared to, for example G1P, other circulating G1P strains are homotypic (both proteins the same), G3P are partly heterotypic (1 protein different), and G2P are fully heterotypic (both G and P proteins different). With at least 27 known G and 35 known P proteins  and 70 different G-P combinations identified in humans , the opportunity for the introduction of new strains is high. New strains may emerge from animal reservoirs either as complete viruses or as reassortants; the rotavirus’ segmented genome allows exchange of genome segments. New strains can also arise from newly mutated genes in circulating types. In any case, new strains may enter into circulation that would not be controlled to the same extent as the strains that circulated when the vaccines were developed. Therefore, surveillance systems are necessary to identify the possible emergence of new strains/types, and to monitor the effects of selective vaccine pressure on strain diversity. Surveillance systems were established in many countries [2–4]. In fact, at least 82 studies of rotavirus strain surveillance have been published since vaccine introduction . However, among all the varied systems, the Australian system is unique in that both monovalent and pentavalent vaccines are administered and there is a clear geographic distinction in where they are used. This provides an opportunity to observe the selective pressure that might be applied by each vaccine, with built-in controls from nearby States and Territories that use the alternative vaccine. Indeed, we are indebted to the groups who have used this system over the last decades to help determine the natural variation in strain circulation and the possible effect of vaccination on rotavirus epidemiology. The Australian rotavirus surveillance program has evaluated the circulating rotavirus genotypes in Australia since 1997. These reports appear yearly in the Communicable Diseases Intelligence journal. In a report published in the current issue of the Journal of Infectious Diseases, Roczo-Farkas et al confirmed and extended the findings from previous studies that also described a greater diversity of rotavirus genotypes after the introduction of rotavirus vaccines. A strength of the study includes the long duration of observations and the large size: 13051 rotavirus-positive samples, including 9301 from the prevaccine era and 3750 from the postvaccine era. Further, 2179 were from RotaTeq states and 1571 from Rotarix states. Specifically, the authors noted the dominance of G12P in the states using RotaTeq whereas G2P and an equine-like G3P  dominated in the states using Rotarix. While these genotypes have been reported previously, for example G2P has been reported in Brazil  and Belgium  following the introduction of Rotarix, the question remained whether the new dominant strains were due to selective vaccine pressure or natural variation. The comparison between Rotarix states and RotaTeq states suggests that there is selective pressure from Rotarix that leads to a dominance of G2P, a fully heterotypic virus. The rationale for this predominance may be that although Rotarix has high G2P efficacy, it may be somewhat lower and with a shorter duration compared to that against homotypic G1P strains [3, 8]. However, in a 2014 meta-analysis  Leshem et al concluded that the introduction of rotavirus vaccines did not alter the usual strain variation that would indicate selective vaccine pressure. They attributed this to the broad efficacy of both vaccines against multiple serotypes. In fact, levels of serum neutralizing antibodies induced by the G and P proteins have not correlated well with protection, whereas the level of total antirotavirus IgA, which may be nonserotype specific, has correlated better. The comparison between states in the current report also suggested that the selective pressure of Rotateq led to a prevalence of G12P strains. This is a bit more difficult to understand, as 1 of the viruses in RotaTeq contains P. However, the emergence of this strain has been noted in several countries after vaccine introduction, for example in Nicaragua  and the United States . Some have speculated that the emergence and persistence of G12 strains was due to the presence of a population that was immunologically naive to this genotype . However, similar to the above-mentioned rationale for Rotarix, the vaccine effectiveness of RotaTeq vaccine against G12P strains in the United States is good (83%) and provided significant protection against G12P strains, but it is slightly lower than that for other common rotavirus genotypes (87%–89%) . In the evaluation of serotype prevalence that spanned the years 2008 to 2013 in the United States , which is a predominantly but not exclusively RotaTeq country, a change from G3P to G12P was also detected. This would agree with the Australian findings from RotaTeq states. The US report  also noted a similar increase in the diversity of strains compared to the prevaccine era, with the sporadic appearance of unusual strains including G8P and G2P, G3P, G2P, G3P, G3P, G2P, G4P, and G9P. The evolution of strains for many pathogens is influenced by selective immune pressure. This is most evident for influenza, where changes in circulating strains require annual reevaluation of vaccine strain selection. The selective pressure of vaccines is perhaps best illustrated by the replacement of pneumococcal types after introduction of pneumococcal conjugate vaccine (PCV), requiring the addition of multiple new types to the original PCV . However, studies of rotavirus epidemiology demonstrate that the immunity induced by rotavirus vaccines is more broadly protective than either influenza or pneumoccocus. So, although the most likely viruses to cause breakthrough infections after Rotarix may be G2P, and the most likely strain to cause infection in Rotateq states is G12P, the overall effectiveness remains high. The broad cross-protection may be due to other cross-reactive T- or B-cell epitopes in the G protein or other nonstructural proteins. Changes in rotavirus strain circulation have occurred after the introduction of rotavirus vaccines, but, to date, the broad effectiveness of the current vaccines appears to have limited the emergence of new strains that are resistant to vaccine-induced immunity. Nevertheless, continued vigilance by worldwide surveillance networks is warranted to ensure that this protection persists. Notes Acknowledgments. I would like to thank Christopher Harrison, MD, Children’s Mercy, Kansas City for review and helpful suggestions. Potential conflicts of interest. D. I. B. receives funding from the National Institutes of Health as one of the Vaccine and Treatment Evaluation centers (contract number HHSN272200800006C, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH), D. B. was one of the developers of the vaccine that lead to Rotarix. The author has submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. 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The Journal of Infectious Diseases – Oxford University Press
Published: May 22, 2018
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