E D I TO R I A L CO M M E N TA RY
Unexpected Benefits of Immunization: Rotavirus Vaccines Reduce Childhood Seizures Geoffrey A. Weinberg Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York
(See the Major Article by Payne et al on pages 173–7.)
Keywords.
rotavirus vaccine; vaccine effectiveness; childhood seizures.
Received 23 September 2013; accepted 26 September 2013; electronically published 20 November 2013. Correspondence: Geoffrey A. Weinberg, MD, Division of Infectious Diseases and Pediatric HIV Program, Department of Pediatrics, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, Box 690, Rochester, NY 14642 ([email protected]). Clinical Infectious Diseases 2014;58(2):178–80 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/cid/cit681
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been well documented, and even a reduction in the intensity and occurrence of seasonality of infection has been noted [4–14]. In addition, adverse effects such as intussusception (associated with the older rhesus-based tetravalent rotavirus vaccine) have not been problematic with the newer vaccines [15–18]. In this issue of Clinical Infectious Diseases, Payne and colleagues present a new, rather unexpected benefit of rotavirus vaccination—that full vaccination is associated with a significant decrease (roughly a 20% reduction) in the risk of seizures requiring hospitalization or ED care in the first year after vaccination is completed. They utilized the Vaccine Safety Datalink (VSD) project data to calculate the relative incidence of seizures during a 55-week interval after either full rotavirus vaccination (3 doses of RV5 vaccine or 2 doses of RV1 vaccine, although >99% of vaccinated children received RV5, likely because of earlier market introduction) or no rotavirus vaccination, for infants born in March 2006 through November 2009. The incidence risk ratio of first-ever seizure in fully rotavirus-vaccinated children, compared with nonvaccinated children matched by age, sex, time of vaccination, and VSD site, was 0.816 (95% confidence interval [CI], .729–.914); that for all seizures was 0.790 (95% CI, .714–.875).
EDITORIAL COMMENTARY
Several intriguing features of this simple but elegant analysis are worth noting. First, why would vaccination against rotavirus, primarily known as an important pathogen of acute gastroenteritis in young children, have anything to do with seizures in infancy? In fact, it has long been known, but not always generally appreciated, that rotavirus infection is not simply limited to the intestine. Encephalopathy (as defined by lethargy out of proportion to that expected with simple dehydration, along with abnormal cerebrospinal fluid or neuroimaging studies), and seizures have all been noted in young children suffering from acute rotavirus gastroenteritis, with seizure rates (afebrile or febrile) of approximately 2%–7% of medically attended children [19–23]. In addition, rotavirus antigen, nucleic acid, and cultivatable virus has been detected in the sera, and nucleic acid in the cerebrospinal fluid, of rotavirusinfected children [21, 23–25]. Thus, it is biologically plausible that rotavirus vaccination might reduce seizures. Second, even if biologically plausible, it might be unexpected that one could actually detect a change in seizure incidence, given that many other causes of both febrile (eg, human herpes virus 6 infection) and afebrile (eg, epilepsy, birth asphyxia, perhaps other infections [22]) seizures occur in early childhood, and
Downloaded from http://cid.oxfordjournals.org/ at Carleton University on March 16, 2015
The introduction of universal infant immunization against rotavirus, with either pentavalent human-bovine reassortant vaccine (RotaTeq [RV5], Merck and Company, Whitehouse Station, New Jersey), licensed by the Food and Drug Administration (FDA) in February 2006, or monovalent human rotavirus vaccine (Rotarix [RV1], GlaxoSmithKline Biologicals, Rixensart, Belgium), licensed by the FDA in April 2008, has been extraordinarily successful. In the prevaccine era, rotavirus infection led to 25 000–50 000 hospitalizations, nearly 400 000 emergency room visits, and 400 000 medical care visits of children in the United States, in addition to nearly 600 000 deaths worldwide [1–3]. Within 6 years of universal immunization, substantial declines in the rates of rotavirus-associated hospitalizations, emergency department (ED) and office visits, and gastroenteritis-related telephone triage calls all have
to unseen confounders not controlled in this type of database analysis. For example, perhaps children receiving rotavirus vaccine were more likely to receive antipyretics before or after immunization, possibly reducing the risk of seizures with fever, and inflating the protective effect of vaccination. On the whole, however, many of the confounders are likely to be of lesser effect, making the estimate of Payne et al reasonably robust. Another unique feature of this study concerns the VSD itself, which so often has been used to study adverse events surrounding vaccination [26]. In this work, the VSD was used to define the degree of protection against an unusual complication of the vaccine-preventable disease itself. This description of a “beneficial event,” rather than an “adverse event,” might suggest a new paradigm for future VSD studies. Finally, in a cost-conscious modern world, Payne and colleagues allude to a potential cost savings from the protection against seizures in the first year of life by rotavirus vaccination, assuming that their findings are correct, of $7 million or more. In a recent cost analysis from the New Vaccine Surveillance Network, a population-based, active surveillance system with laboratory confirmation of infection, it was estimated that the annual cost savings of universal rotavirus vaccination by the years 2008–2009 was $187 million [27]. Although this hospitalization- and EDcost analysis did not specifically analyze rotavirus-induced seizures, an atypical presentation of rotavirus infection (defined as having associated encephalopathy, sepsis, shock, or intussusception) indeed was associated with increased medical care costs [27], likely corroborating the simple cost estimates of Payne et al. In summary, the VSD database has been used by Payne et al in a novel manner, that is, to find an uncommon but important, and biologically plausible, “beneficial effect”—namely, that universal infant rotavirus immunization protects against childhood seizures in the
first year after vaccination, and in doing so may save the healthcare system several million dollars annually. As market share of the RV1 vaccine increases, it might be useful to repeat the analysis, to ensure that the same medical benefits and cost savings accrue as shown in this work for RV5. Work such as this not only is interesting scientifically, but provides yet another reason to strongly promote universal rotavirus immunization. In addition, the work provides as an opportunity to reflect on the fact that sometimes, unexpected effects of vaccination are beneficial and are a cause for celebration, rather than the more commonly publicized concern for unexpected adverse effects. Note Potential conflicts of interest. Author certifies no potential conflicts of interest. 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. Cortese MM, Parashar UD; Centers for Disease Control and Prevention. Prevention of rotavirus gastroenteritis among infants and children: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2009; 58 (RR-2):1–25. 2. Tate JE, Patel MM, Steele AD, et al. Global impact of rotavirus vaccines. Expert Rev Vaccines 2010; 9:395–407. 3. Payne DC, Staat MA, Edwards KM, et al. Active, population-based surveillance for severe rotavirus gastroenteritis in children in the United States. Pediatrics 2008; 122: 1235–43. 4. Tate JE, Haynes A, Payne DC, et al. Trends in national rotavirus activity before and after introduction of rotavirus vaccine into the national immunization program in the United States, 2000 to 2012. Pediatr Infect Dis J 2013; 32:741–4. 5. Payne DC, Boom JA, Staat MA, et al. Effectiveness of pentavalent and monovalent rotavirus vaccines in concurrent use among US children
Unexpected Benefits of Immunization: Rotavirus Vaccines Reduce Childhood Seizures Geoffrey A. Weinberg Department of Pediatrics, University of Rochester School of Medicine and Dentistry, Rochester, New York
(See the Major Article by Payne et al on pages 173–7.)
Keywords.
rotavirus vaccine; vaccine effectiveness; childhood seizures.
Received 23 September 2013; accepted 26 September 2013; electronically published 20 November 2013. Correspondence: Geoffrey A. Weinberg, MD, Division of Infectious Diseases and Pediatric HIV Program, Department of Pediatrics, University of Rochester School of Medicine and Dentistry, 601 Elmwood Ave, Box 690, Rochester, NY 14642 ([email protected]). Clinical Infectious Diseases 2014;58(2):178–80 © The Author 2013. Published by Oxford University Press on behalf of the Infectious Diseases Society of America. All rights reserved. For Permissions, please e-mail: journals. [email protected]. DOI: 10.1093/cid/cit681
178
•
CID 2014:58 (15 January)
•
been well documented, and even a reduction in the intensity and occurrence of seasonality of infection has been noted [4–14]. In addition, adverse effects such as intussusception (associated with the older rhesus-based tetravalent rotavirus vaccine) have not been problematic with the newer vaccines [15–18]. In this issue of Clinical Infectious Diseases, Payne and colleagues present a new, rather unexpected benefit of rotavirus vaccination—that full vaccination is associated with a significant decrease (roughly a 20% reduction) in the risk of seizures requiring hospitalization or ED care in the first year after vaccination is completed. They utilized the Vaccine Safety Datalink (VSD) project data to calculate the relative incidence of seizures during a 55-week interval after either full rotavirus vaccination (3 doses of RV5 vaccine or 2 doses of RV1 vaccine, although >99% of vaccinated children received RV5, likely because of earlier market introduction) or no rotavirus vaccination, for infants born in March 2006 through November 2009. The incidence risk ratio of first-ever seizure in fully rotavirus-vaccinated children, compared with nonvaccinated children matched by age, sex, time of vaccination, and VSD site, was 0.816 (95% confidence interval [CI], .729–.914); that for all seizures was 0.790 (95% CI, .714–.875).
EDITORIAL COMMENTARY
Several intriguing features of this simple but elegant analysis are worth noting. First, why would vaccination against rotavirus, primarily known as an important pathogen of acute gastroenteritis in young children, have anything to do with seizures in infancy? In fact, it has long been known, but not always generally appreciated, that rotavirus infection is not simply limited to the intestine. Encephalopathy (as defined by lethargy out of proportion to that expected with simple dehydration, along with abnormal cerebrospinal fluid or neuroimaging studies), and seizures have all been noted in young children suffering from acute rotavirus gastroenteritis, with seizure rates (afebrile or febrile) of approximately 2%–7% of medically attended children [19–23]. In addition, rotavirus antigen, nucleic acid, and cultivatable virus has been detected in the sera, and nucleic acid in the cerebrospinal fluid, of rotavirusinfected children [21, 23–25]. Thus, it is biologically plausible that rotavirus vaccination might reduce seizures. Second, even if biologically plausible, it might be unexpected that one could actually detect a change in seizure incidence, given that many other causes of both febrile (eg, human herpes virus 6 infection) and afebrile (eg, epilepsy, birth asphyxia, perhaps other infections [22]) seizures occur in early childhood, and
Downloaded from http://cid.oxfordjournals.org/ at Carleton University on March 16, 2015
The introduction of universal infant immunization against rotavirus, with either pentavalent human-bovine reassortant vaccine (RotaTeq [RV5], Merck and Company, Whitehouse Station, New Jersey), licensed by the Food and Drug Administration (FDA) in February 2006, or monovalent human rotavirus vaccine (Rotarix [RV1], GlaxoSmithKline Biologicals, Rixensart, Belgium), licensed by the FDA in April 2008, has been extraordinarily successful. In the prevaccine era, rotavirus infection led to 25 000–50 000 hospitalizations, nearly 400 000 emergency room visits, and 400 000 medical care visits of children in the United States, in addition to nearly 600 000 deaths worldwide [1–3]. Within 6 years of universal immunization, substantial declines in the rates of rotavirus-associated hospitalizations, emergency department (ED) and office visits, and gastroenteritis-related telephone triage calls all have
to unseen confounders not controlled in this type of database analysis. For example, perhaps children receiving rotavirus vaccine were more likely to receive antipyretics before or after immunization, possibly reducing the risk of seizures with fever, and inflating the protective effect of vaccination. On the whole, however, many of the confounders are likely to be of lesser effect, making the estimate of Payne et al reasonably robust. Another unique feature of this study concerns the VSD itself, which so often has been used to study adverse events surrounding vaccination [26]. In this work, the VSD was used to define the degree of protection against an unusual complication of the vaccine-preventable disease itself. This description of a “beneficial event,” rather than an “adverse event,” might suggest a new paradigm for future VSD studies. Finally, in a cost-conscious modern world, Payne and colleagues allude to a potential cost savings from the protection against seizures in the first year of life by rotavirus vaccination, assuming that their findings are correct, of $7 million or more. In a recent cost analysis from the New Vaccine Surveillance Network, a population-based, active surveillance system with laboratory confirmation of infection, it was estimated that the annual cost savings of universal rotavirus vaccination by the years 2008–2009 was $187 million [27]. Although this hospitalization- and EDcost analysis did not specifically analyze rotavirus-induced seizures, an atypical presentation of rotavirus infection (defined as having associated encephalopathy, sepsis, shock, or intussusception) indeed was associated with increased medical care costs [27], likely corroborating the simple cost estimates of Payne et al. In summary, the VSD database has been used by Payne et al in a novel manner, that is, to find an uncommon but important, and biologically plausible, “beneficial effect”—namely, that universal infant rotavirus immunization protects against childhood seizures in the
first year after vaccination, and in doing so may save the healthcare system several million dollars annually. As market share of the RV1 vaccine increases, it might be useful to repeat the analysis, to ensure that the same medical benefits and cost savings accrue as shown in this work for RV5. Work such as this not only is interesting scientifically, but provides yet another reason to strongly promote universal rotavirus immunization. In addition, the work provides as an opportunity to reflect on the fact that sometimes, unexpected effects of vaccination are beneficial and are a cause for celebration, rather than the more commonly publicized concern for unexpected adverse effects. Note Potential conflicts of interest. Author certifies no potential conflicts of interest. 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. Cortese MM, Parashar UD; Centers for Disease Control and Prevention. Prevention of rotavirus gastroenteritis among infants and children: recommendations of the Advisory Committee on Immunization Practices (ACIP). MMWR Recomm Rep 2009; 58 (RR-2):1–25. 2. Tate JE, Patel MM, Steele AD, et al. Global impact of rotavirus vaccines. Expert Rev Vaccines 2010; 9:395–407. 3. Payne DC, Staat MA, Edwards KM, et al. Active, population-based surveillance for severe rotavirus gastroenteritis in children in the United States. Pediatrics 2008; 122: 1235–43. 4. Tate JE, Haynes A, Payne DC, et al. Trends in national rotavirus activity before and after introduction of rotavirus vaccine into the national immunization program in the United States, 2000 to 2012. Pediatr Infect Dis J 2013; 32:741–4. 5. Payne DC, Boom JA, Staat MA, et al. Effectiveness of pentavalent and monovalent rotavirus vaccines in concurrent use among US children
