Rotavirus Vaccines: Mind Your Ps and Gs

Rotavirus Vaccines: Mind Your Ps and Gs 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[8] or G2P[4]. The most common serotypes circulating when the vaccines were developed included G1P[8], G2P[4], G3P[8], G4P[8], and G9P[8]. 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[8], other circulating G1P[8] strains are homotypic (both proteins the same), G3P[8] are partly heterotypic (1 protein different), and G2P[4] are fully heterotypic (both G and P proteins different). With at least 27 known G and 35 known P proteins [1] and 70 different G-P combinations identified in humans [2], 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 [3]. 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[8] in the states using RotaTeq whereas G2P[4] and an equine-like G3P[8] [5] dominated in the states using Rotarix. While these genotypes have been reported previously, for example G2P[4] has been reported in Brazil [6] and Belgium [7] 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[4], a fully heterotypic virus. The rationale for this predominance may be that although Rotarix has high G2P[4] efficacy, it may be somewhat lower and with a shorter duration compared to that against homotypic G1P[8] strains [3, 8]. However, in a 2014 meta-analysis [3] 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[8] strains. This is a bit more difficult to understand, as 1 of the viruses in RotaTeq contains P[8]. However, the emergence of this strain has been noted in several countries after vaccine introduction, for example in Nicaragua [9] and the United States [10]. 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 [11]. However, similar to the above-mentioned rationale for Rotarix, the vaccine effectiveness of RotaTeq vaccine against G12P[8] strains in the United States is good (83%) and provided significant protection against G12P[8] strains, but it is slightly lower than that for other common rotavirus genotypes (87%–89%) [11]. In the evaluation of serotype prevalence that spanned the years 2008 to 2013 in the United States [10], which is a predominantly but not exclusively RotaTeq country, a change from G3P[8] to G12P[8] was also detected. This would agree with the Australian findings from RotaTeq states. The US report [10] also noted a similar increase in the diversity of strains compared to the prevaccine era, with the sporadic appearance of unusual strains including G8P[4] and G2P[8], G3P[24], G2P[8], G3P[4], G3P[6], G2P[14], G4P[6], and G9P[4]. 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 [12]. 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[4], and the most likely strain to cause infection in Rotateq states is G12P[8], 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. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. Matthijnssens J, Ciarlet M, McDonald SMet al.   Uniformity of rotavirus strain nomenclature proposed by the Rotavirus Classification Working Group (RCWG). Arch Virol  2011; 156: 1397– 413. Google Scholar CrossRef Search ADS PubMed  2. Bányai K, László B, Duque Jet al.   Systematic review of regional and temporal trends in global rotavirus strain diversity in the pre rotavirus vaccine era: insights for understanding the impact of rotavirus vaccination programs. Vaccine  2012; 30( Suppl 1): A122– 30. Google Scholar CrossRef Search ADS PubMed  3. Leshem E, Lopman B, Glass Ret al.   Distribution of rotavirus strains and strain-specific effectiveness of the rotavirus vaccine after its introduction: a systematic review and meta-analysis. Lancet Infect Dis  2014; 14: 847– 56. Google Scholar CrossRef Search ADS PubMed  4. Dóró R, László B, Martella Vet al.   Review of global rotavirus strain prevalence data from six years post vaccine licensure surveillance: is there evidence of strain selection from vaccine pressure? Infect Genet Evol  2014; 28: 446– 61. Google Scholar CrossRef Search ADS PubMed  5. Cowley D, Donato CM, Roczo-Farkas S, Kirkwood CD. Emergence of a novel equine-like G3P[8] inter-genogroup reassortant rotavirus strain associated with gastroenteritis in Australian children. J Gen Virol  2016; 97: 403– 10. Google Scholar CrossRef Search ADS PubMed  6. Nakagomi T, Cuevas LE, Gurgel RGet al.   Apparent extinction of non-G2 rotavirus strains from circulation in Recife, Brazil, after the introduction of rotavirus vaccine. Arch Virol  2008; 153: 591– 3. Google Scholar CrossRef Search ADS PubMed  7. Matthijnssens J, Zeller M, Heylen Eet al.  ; RotaBel study group. Higher proportion of G2P[4] rotaviruses in vaccinated hospitalized cases compared with unvaccinated hospitalized cases, despite high vaccine effectiveness against heterotypic G2P[4] rotaviruses. Clin Microbiol Infect  2014; 20: O702– 10. Google Scholar CrossRef Search ADS PubMed  8. Correia JB, Patel MM, Nakagomi Oet al.   Effectiveness of monovalent rotavirus vaccine (Rotarix) against severe diarrhea caused by serotypically unrelated G2P[4] strains in Brazil. J Infect Dis  2010; 201: 363– 9. Google Scholar CrossRef Search ADS PubMed  9. Bucardo F, Mercado J, Reyes Y, González F, Balmaseda A, Nordgren J. Large increase of rotavirus diarrhoea in the hospital setting associated with emergence of G12 genotype in a highly vaccinated population in Nicaragua. Clin Microbiol Infect  2015; 21: 603.e1– 7. Google Scholar CrossRef Search ADS   10. Bowen MD, Mijatovic-Rustempasic S, Esona MDet al.   Rotavirus strain trends during the postlicensure vaccine era: United States, 2008-2013. J Infect Dis  2016; 214: 732– 8. Google Scholar CrossRef Search ADS PubMed  11. Payne DC, Boom JA, Staat MAet al.   Effectiveness of pentavalent and monovalent rotavirus vaccines in concurrent use among US children <5 years of age, 2009-2011. Clin Infect Dis  2013; 57: 13– 20. Google Scholar CrossRef Search ADS PubMed  12. Ladhani SN, Collins S, Djennad Aet al.   Rapid increase in non-vaccine serotypes causing invasive pneumococcal disease in England and Wales, 2000-17: a prospective national observational cohort study. Lancet Infect Dis  2018; 18: 441– 51. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png The Journal of Infectious Diseases Oxford University Press

Rotavirus Vaccines: Mind Your Ps and Gs

Loading next page...
 
/lp/ou_press/rotavirus-vaccines-mind-your-ps-and-gs-CzqVbfJ19S
Publisher
Oxford University Press
Copyright
© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.
ISSN
0022-1899
eISSN
1537-6613
D.O.I.
10.1093/infdis/jiy203
Publisher site
See Article on Publisher Site

Abstract

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[8] or G2P[4]. The most common serotypes circulating when the vaccines were developed included G1P[8], G2P[4], G3P[8], G4P[8], and G9P[8]. 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[8], other circulating G1P[8] strains are homotypic (both proteins the same), G3P[8] are partly heterotypic (1 protein different), and G2P[4] are fully heterotypic (both G and P proteins different). With at least 27 known G and 35 known P proteins [1] and 70 different G-P combinations identified in humans [2], 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 [3]. 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[8] in the states using RotaTeq whereas G2P[4] and an equine-like G3P[8] [5] dominated in the states using Rotarix. While these genotypes have been reported previously, for example G2P[4] has been reported in Brazil [6] and Belgium [7] 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[4], a fully heterotypic virus. The rationale for this predominance may be that although Rotarix has high G2P[4] efficacy, it may be somewhat lower and with a shorter duration compared to that against homotypic G1P[8] strains [3, 8]. However, in a 2014 meta-analysis [3] 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[8] strains. This is a bit more difficult to understand, as 1 of the viruses in RotaTeq contains P[8]. However, the emergence of this strain has been noted in several countries after vaccine introduction, for example in Nicaragua [9] and the United States [10]. 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 [11]. However, similar to the above-mentioned rationale for Rotarix, the vaccine effectiveness of RotaTeq vaccine against G12P[8] strains in the United States is good (83%) and provided significant protection against G12P[8] strains, but it is slightly lower than that for other common rotavirus genotypes (87%–89%) [11]. In the evaluation of serotype prevalence that spanned the years 2008 to 2013 in the United States [10], which is a predominantly but not exclusively RotaTeq country, a change from G3P[8] to G12P[8] was also detected. This would agree with the Australian findings from RotaTeq states. The US report [10] also noted a similar increase in the diversity of strains compared to the prevaccine era, with the sporadic appearance of unusual strains including G8P[4] and G2P[8], G3P[24], G2P[8], G3P[4], G3P[6], G2P[14], G4P[6], and G9P[4]. 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 [12]. 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[4], and the most likely strain to cause infection in Rotateq states is G12P[8], 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. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed. References 1. Matthijnssens J, Ciarlet M, McDonald SMet al.   Uniformity of rotavirus strain nomenclature proposed by the Rotavirus Classification Working Group (RCWG). Arch Virol  2011; 156: 1397– 413. Google Scholar CrossRef Search ADS PubMed  2. Bányai K, László B, Duque Jet al.   Systematic review of regional and temporal trends in global rotavirus strain diversity in the pre rotavirus vaccine era: insights for understanding the impact of rotavirus vaccination programs. Vaccine  2012; 30( Suppl 1): A122– 30. Google Scholar CrossRef Search ADS PubMed  3. Leshem E, Lopman B, Glass Ret al.   Distribution of rotavirus strains and strain-specific effectiveness of the rotavirus vaccine after its introduction: a systematic review and meta-analysis. Lancet Infect Dis  2014; 14: 847– 56. Google Scholar CrossRef Search ADS PubMed  4. Dóró R, László B, Martella Vet al.   Review of global rotavirus strain prevalence data from six years post vaccine licensure surveillance: is there evidence of strain selection from vaccine pressure? Infect Genet Evol  2014; 28: 446– 61. Google Scholar CrossRef Search ADS PubMed  5. Cowley D, Donato CM, Roczo-Farkas S, Kirkwood CD. Emergence of a novel equine-like G3P[8] inter-genogroup reassortant rotavirus strain associated with gastroenteritis in Australian children. J Gen Virol  2016; 97: 403– 10. Google Scholar CrossRef Search ADS PubMed  6. Nakagomi T, Cuevas LE, Gurgel RGet al.   Apparent extinction of non-G2 rotavirus strains from circulation in Recife, Brazil, after the introduction of rotavirus vaccine. Arch Virol  2008; 153: 591– 3. Google Scholar CrossRef Search ADS PubMed  7. Matthijnssens J, Zeller M, Heylen Eet al.  ; RotaBel study group. Higher proportion of G2P[4] rotaviruses in vaccinated hospitalized cases compared with unvaccinated hospitalized cases, despite high vaccine effectiveness against heterotypic G2P[4] rotaviruses. Clin Microbiol Infect  2014; 20: O702– 10. Google Scholar CrossRef Search ADS PubMed  8. Correia JB, Patel MM, Nakagomi Oet al.   Effectiveness of monovalent rotavirus vaccine (Rotarix) against severe diarrhea caused by serotypically unrelated G2P[4] strains in Brazil. J Infect Dis  2010; 201: 363– 9. Google Scholar CrossRef Search ADS PubMed  9. Bucardo F, Mercado J, Reyes Y, González F, Balmaseda A, Nordgren J. Large increase of rotavirus diarrhoea in the hospital setting associated with emergence of G12 genotype in a highly vaccinated population in Nicaragua. Clin Microbiol Infect  2015; 21: 603.e1– 7. Google Scholar CrossRef Search ADS   10. Bowen MD, Mijatovic-Rustempasic S, Esona MDet al.   Rotavirus strain trends during the postlicensure vaccine era: United States, 2008-2013. J Infect Dis  2016; 214: 732– 8. Google Scholar CrossRef Search ADS PubMed  11. Payne DC, Boom JA, Staat MAet al.   Effectiveness of pentavalent and monovalent rotavirus vaccines in concurrent use among US children <5 years of age, 2009-2011. Clin Infect Dis  2013; 57: 13– 20. Google Scholar CrossRef Search ADS PubMed  12. Ladhani SN, Collins S, Djennad Aet al.   Rapid increase in non-vaccine serotypes causing invasive pneumococcal disease in England and Wales, 2000-17: a prospective national observational cohort study. Lancet Infect Dis  2018; 18: 441– 51. Google Scholar CrossRef Search ADS PubMed  © The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices)

Journal

The Journal of Infectious DiseasesOxford University Press

Published: May 22, 2018

There are no references for this article.

You’re reading a free preview. Subscribe to read the entire article.


DeepDyve is your
personal research library

It’s your single place to instantly
discover and read the research
that matters to you.

Enjoy affordable access to
over 18 million articles from more than
15,000 peer-reviewed journals.

All for just $49/month

Explore the DeepDyve Library

Search

Query the DeepDyve database, plus search all of PubMed and Google Scholar seamlessly

Organize

Save any article or search result from DeepDyve, PubMed, and Google Scholar... all in one place.

Access

Get unlimited, online access to over 18 million full-text articles from more than 15,000 scientific journals.

Your journals are on DeepDyve

Read from thousands of the leading scholarly journals from SpringerNature, Elsevier, Wiley-Blackwell, Oxford University Press and more.

All the latest content is available, no embargo periods.

See the journals in your area

DeepDyve

Freelancer

DeepDyve

Pro

Price

FREE

$49/month
$360/year

Save searches from
Google Scholar,
PubMed

Create lists to
organize your research

Export lists, citations

Read DeepDyve articles

Abstract access only

Unlimited access to over
18 million full-text articles

Print

20 pages / month

PDF Discount

20% off