• No results found

Sibling Transmission of Vaccine-Derived Rotavirus (RotaTeq) Associated With Rotavirus Gastroenteritis

N/A
N/A
Protected

Academic year: 2020

Share "Sibling Transmission of Vaccine-Derived Rotavirus (RotaTeq) Associated With Rotavirus Gastroenteritis"

Copied!
6
0
0

Loading.... (view fulltext now)

Full text

(1)

(RotaTeq) Associated With Rotavirus Gastroenteritis

abstract

Although rotavirus vaccines are known to be shed in stools, transmis-sion of vaccine-derived virus to unvaccinated contacts resulting in symptomatic rotavirus gastroenteritis has not been reported to our knowledge. We document here the occurrence of vaccine-derived rota-virus (RotaTeq [Merck and Co, Whitehouse Station, NJ]) transmission from a vaccinated infant to an older, unvaccinated sibling, resulting in symptomatic rotavirus gastroenteritis that required emergency de-partment care. Results of our investigation suggest that reassortment between vaccine component strains of genotypes P7[5]G1 and P1A[8]G6 occurred during replication either in the vaccinated infant or in the older sibling, raising the possibility that this reassortment may have increased the virulence of the vaccine-derived virus. Both chil-dren remain healthy 11 months after this event and are without under-lying medical conditions.Pediatrics2010;125:e438–e441

AUTHORS:Daniel C. Payne, PhD, MSPH,aKathryn M.

Edwards, MD,bMichael D. Bowen, PhD,cErin Keckley, RN,b

Jody Peters, MS,bMathew D. Esona, PhD,cElizabeth N.

Teel, BS,cDiane Kent, RN,bUmesh D. Parashar, MBBS,

MPH,aand Jon R. Gentsch, PhDc

aEpidemiology Branch andcGastroenteritis and Respiratory

Viruses Laboratory Branch, Division of Viral Diseases, National Center for Immunization and Respiratory Disease, Centers for Disease Control and Prevention, Atlanta, Georgia; and

bDepartment of Pediatrics, Division of Infectious Diseases,

Vanderbilt University Medical Center, Nashville, Tennessee

KEY WORDS

rotavirus, acute gastroenteritis, RotaTeq, rotavirus vaccine, WC3, sibling transmission, horizontal transmission, shedding, reassortant, New Vaccine Surveillance Network, NVSN

ABBREVIATIONS

ACIP—Advisory Committee on Immunization Practices REST—RotaTeq Efficacy and Safety Trial

AGE—acute gastroenteritis

CDC—Centers for Disease Control and Prevention ED— emergency department

RT-PCR—reverse transcription-polymerase chain reaction

The findings and conclusions in this report are those of the authors and do not necessarily represent the views of the Centers for Disease Control and Prevention.

www.pediatrics.org/cgi/doi/10.1542/peds.2009-1901

doi:10.1542/peds.2009-1901

Accepted for publication Nov 20, 2009

Address correspondence to Daniel C. Payne, PhD, MSPH, Centers for Disease Control and Prevention, 1600 Clifton Rd, NE, MS-A47, Atlanta, GA 30333. E-mail: dvp6@cdc.gov

PEDIATRICS (ISSN Numbers: Print, 0031-4005; Online, 1098-4275).

Copyright © 2010 by the American Academy of Pediatrics

(2)

The orally administered, live, attenu-ated, pentavalent human-bovine (WC3 strain) reassortant rotavirus vaccine, RotaTeq (Merck and Co, Whitehouse Station, NJ),1 was licensed by the US

Food and Drug Administration and rec-ommended by the Advisory Committee on Immunization Practices (ACIP) for universal immunization of US infants in 2006.2 In the pivotal prelicensure

RotaTeq Efficacy and Safety Trial (REST), into which ⬎70 000 infants were enrolled, the vaccine was found to be safe and 98% efficacious in pre-venting severe G1–G4 rotavirus gastro-enteritis.3,4By October 2009,28

mil-lion doses (Barbara Kuter, PhD, Merck and Company, personal communication, November 6, 2009) of RotaTeq had been distributed throughout the United States with a continued record of safety and ef-fectiveness during the postlicensure pe-riod.5–9Transmission of RotaTeq strains

to unvaccinated contacts was not evalu-ated in the pivotal clinical trials and, to our knowledge, has not been reported during the postlicensure period.

CASE REPORT

During active, prospective population-based surveillance for acute gastroen-teritis (AGE) in the Centers for Disease Control and Prevention (CDC)-funded New Vaccine Surveillance Network,10a

male child aged 30 months was identi-fied with AGE that required emergency department (ED) care in January 2009, approximately 48 to 60 hours after the onset of vomiting and subsequent diar-rhea. The child had been referred to the ED for evaluation and rehydration by his primary care provider. The child was alert at ED admission and had a blood pressure of 133/88, pulse rate of 120 beats per minute, respiratory rate of 24 respirations per minute, 95% ox-ygen saturation, and a maximum tem-perature of 100.7°F. Abdominal exami-nation revealed a nontender and nondistended abdomen. The patient received intravenous fluid and

ondan-setron (Zofran) for the prevention of nausea and vomiting and was dis-charged from the ED.

Following New Vaccine Surveillance Network protocols, epidemiologic data and a whole stool specimen were col-lected in the ED. Past medical history revealed that the child had achieved full gestational age, had a birth weight of 6 lbs 5 oz, was breastfed for 1 to 3 months, was growing and developing well, and was not taking medications. The patient had never received rotavirus vaccine but was up-to-date on all other vaccinations. His only hospitalization since birth occurred at 4 months of age, when abdominal distention was noted and he was diagnosed with an ileocolic intussusception that required manual reduction during surgery.

The stool sample obtained at the ED visit was positive according to a

Rota-clone enzyme immunoassay, with

an optical density (OD) of 1.811 (Rotaclone-positive OD ⬎ 0.15). The specimen was sent to the CDC for routine surveillance confirmation by reverse transcription-polymerase chain reaction (RT-PCR) and nucleotide se-quencing to determine the G and P ge-notypes (defined by the VP7andVP4

genes, respectively).11–14TheVP7gene

open-reading frame and a 650-base

pair (bp) fragment of the VP4

gene were 100% identical to cognate gene fragments from the correspond-ing viruses in RotaTeq and closely re-lated to wild-type human P[8]G1 strains (95.7%–98.3% similarity for

VP4 and 92.8%–99.2% similarity for

VP7) (Jelle Matthijnssens, PhD, Daniel Joelsson, BS, Donald J. Warakomski, BS, MsC, Tingyi Zhou, MD, Marc van Maanen, PhD, Pamela K. Mathis, BS, Todd S. Ranheim, PhD, Max Ciarlet, PhD. written communication, 2009). Subsequent analysis revealed that partial sequences of other genes (NSP1, 313 bp;NSP2, 177 bp;NSP3, 421 bp,NSP4, 131 bp;NSP5, 229 bp;VP1, 879

bp; VP3, 500 bp; VP6, 368 bp) were 100% identical to the WC3 cognate genes of RotaTeq. In addition, a partial gene sequence ofVP2(541 bp) exhib-ited 99.7% identity with the WC3 se-quence of RotaTeq. The P[8] and G1 components of the vaccine are found in 2 separate strains. Analyses by RT-PCR detected no additional rotavirus se-rotypes. These results suggest that the unvaccinated 30-month-old child was shedding a P[8]G1 vaccine-virus reas-sortant of RotaTeq, a reassortment also detected among 2 subjects during a clin-ical trial of a prototype quadrivalent for-mulation of the vaccine.15

Electron microscopy performed on the sample revealed sporadic rotavirus-like particles that represented empty or bro-ken capsids. Results of tests for other viral agents by real-time RT-PCR (norovi-rus genogroups I, II, and IV, sapovi(norovi-rus, astrovirus) or real-time PCR (adenovirus group F) and for bacterial agents ( Sal-monella,Shigella,Campylobacter, Esch-erichia coli0157, other entericE coli, and

Vibrio spp.) by cultivation techniques were all negative.

An investigation into possible sources of RotaTeq exposure for the child revealed that he did not attend day care, but he did have a 2-month-old male sibling who had received his first dose of RotaTeq ap-proximately 10 days before the older child’s onset of AGE symptoms and was the likely source of the vaccine virus. The younger sibling was asymptomatic. Med-ical chart review and consultation with the primary care provider 11 months af-ter the ED visit indicated no diagnosed immunologic dysfunction or further hos-pitalization for either child.

DISCUSSION

We describe the first identified post-licensure occurrence of RotaTeq vaccine-derived rotavirus transmis-sion from a vaccinated infant to an older, unvaccinated sibling that re-sulted in symptomatic rotavirus

gas-CASE REPORTS

PEDIATRICS Volume 125, Number 2, February 2010 e439

at Viet Nam:AAP Sponsored on August 29, 2020

www.aappublications.org/news

(3)

active surveillance catchment popula-tion of ⬎141 000 children younger than 5 years old, which suggests that it is not a common phenomenon.

Evaluating the incidence and charac-teristics of vaccine-virus shedding is important for oral, live vaccines such as RotaTeq. However, transmission of shed vaccine virus to unvaccinated contacts was not evaluated in the RotaTeq REST and was not observed in studies that assessed the transmis-sion of RotaTeq from recipients to subjects administered placebo.16–18

Among a subset of subjects from the REST, 8.9% (n⫽32) of 360 vaccine re-cipients shed the vaccine virus after dose 1, none did so after dose 2, and a single subject (0.3%) shed virus after dose 3. Shedding was reported from 1 to 15 days after vaccination with the first dose.1In another study, shedding

was evaluated among 134 vaccine re-cipients 4 to 6 days after each vaccine dose by using plaque assays and elec-tropherotyping. RotaTeq antigen was detected from the stools of 12.7% (n

17) of dose 1 vaccine recipients but from none of the 109 and 99 subjects evaluated after doses 2 and 3, respec-tively.3 A postlicensure study of 103

vaccinated children with stool speci-mens collected 1 to 9 days after the first dose of RotaTeq demonstrated a cumulative shedding rate higher than that observed in the clinical trials. Ro-tavirus antigen was detected by en-zyme immunoassay from 21.4% of the subjects, with highest shedding occur-ring 6 to 8 days after vaccine dose 1. The shed virus was viable, as indicated by ability to cultivate vaccine virus from fecal specimens, with titers rang-ing from 1⫻101 to 1107

plaque-forming units per mL after passage.19

In another clinical study of an earlier, quadrivalent formulation that con-tained 4 of the 5 strains of currently

from stools of 6.8% (n⫽12) of vaccine recipients for up to 15 days after dose 1. Of the infants shedding vaccine vi-rus, 2 shed a recombinant rotavirus having both P1A (corresponding to ge-notype P[8]) and G1 human surface proteins on a WC3 bovine rotavirus backbone.15The detection of the same

strain in our case suggests that reas-sortment between vaccine strains of genotypes P7[5]G1 and P1A[8]G6 oc-curred during intestinal replication in either the vaccinated infant or in the older sibling. This finding raises the possibility that the vaccine-derived re-assortant may have increased the vir-ulence, a hypothesis that requires con-firmation. If the reassortment event did take place in the vaccinated infant, the presence of AGE symptoms only in the 30-month-old sibling may reflect greater susceptibility to infection from this reassortant in the absence of pro-tective maternal antibodies.

RotaTeq contains 5 live, attenuated, ro-tavirus strains, each developed by ge-netic reassortment in which a single gene coding the surface proteins of the common human strains (G1–G4, P8) was introduced into a backbone of 9 or 10 genes from the bovine parent strain (2 vaccine strains have a human rotavirus VP3 gene).20 Consequently,

the vaccine strains with predomi-nantly bovine genes are not well adapted to replicate efficiently in the human intestine. In contrast, the oth-er ACIP-approved rotavirus vaccine, Rotarix (GlaxoSmithKline Biologicals [Rixensart, Belgium]),21 has a single

(P[8]G1) strain with all 11 human genes. These biological differences are reflected in the distinctive patterns of viral shedding observed among in-fants vaccinated with the 2 products. Vaccine virus is shed in 9% to 21% of RotaTeq recipients, predominantly 6 to 8 days after the first dose. Vaccine

vi-compared with 0% to 3% of placebo recipients.22 Furthermore, although

shedding did not occur later than 15 days after the first dose with RotaTeq, 24% of infants continued to shed rotavi-rus antigen in stools collected 30 days after receiving the first dose of Rotarix.23

Thus, theoretically, the potential for (nonreassortant) vaccine-virus trans-mission to contacts may be greater for Rotarix than for RotaTeq. Horizontal transmission of Rotarix among twins in the Dominican Republic was detected among⬃18.8% (95% confidence inter-val: 10.9%–29.2%) of the infants where 1 sibling received placebo, and the other received Rotarix.24

Horizontal transmission of vaccine vi-rus has been established for other live, attenuated vaccines, such as varicella-zoster vaccine25 and oral poliovirus

vaccine.26During the early stages of its

introduction, the ability of oral polio-virus vaccine to indirectly vaccinate immunologically susceptible contacts was believed to be important in inter-rupting poliovirus circulation and in in-ducing herd immunity.27

Although neither child described in this report was known to have any un-derlying medical conditions, the Rota-Teq manufacturer’s package insert1

and the current ACIP recommenda-tions28 caution against vaccinating

infants with close, immunodeficient contacts or those having contact with children receiving immunosuppres-sive therapy. Cases of vaccine-acquired rotavirus infection have been infrequently reported in the lit-erature among children with severe combined immunodeficiency.29

(4)

CONCLUSIONS

Reassortment between RotaTeq vac-cine strains of genotypes P7[5]G1 and P1A[8]G6 occurred during intes-tinal replication, and transmission occurred to an unvaccinated, older

sibling, which caused symptomatic rotavirus gastroenteritis that re-quired ED medical care.

ACKNOWLEDGMENTS

We acknowledge the work of Dr Jan Vinje and Ms Nicole Gregoricus (CDC)

for performing the norovirus, sapo-virus, astrosapo-virus, and adenovirus laboratory testing; Dr Charles Hum-phrey (CDC) for conducting electron microscopy analysis; and Dr Cheryl Bopp (CDC) for performing bacterial cultivation laboratory tests.

REFERENCES

1. RotaTeq (rotavirus vaccine, live, oral, pen-tavalent) [package insert]. Rockville, MD: Merck; 2006

2. Parashar UD, Alexander JP, Glass RI; Advi-sory Committee on Immunization Practices, Centers for Disease Control and Prevention. Prevention of rotavirus gastroenteritis among infants and children. MMWR Recomm Rep.2006;55(RR-12):1–13 3. Vesikari T, Matson DO, Dennehy P, et al.

Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vac-cine.N Engl J Med.2006;354(1):23–33 4. Vesikari T, Itzler R, Matson DO, et al. Efficacy

of a pentavalent rotavirus vaccine in reduc-ing rotavirus-associated health care utiliza-tion across three regions (11 countries).Int J Infect Dis.2007;11(suppl 2):S29 –S35 5. Belongia E, Irving S, Shui I, et al. Rapid cycle

analysis of pentavalent rotavirus (RotaTeq) vaccine safety in the Vaccine Safety Datal-ink population: preliminary results. Paper presented at: meeting of the Advisory Com-mittee on Immunization Practices; June 25, 2008; Atlanta, GA

6. World Health Organization. Global Advisory Committee on Vaccine Safety, 17–18 De-cember 2008. Wkly Epidemiol Rec.2009; 84(5):37– 40

7. Boom JA. Effectiveness of pentavalent rota-virus vaccine in United States clinical prac-tice. Paper presented at: meeting of the Advisory Committee on Immunization Practices; October 23, 2008; Atlanta, GA

8. Centers for Disease Control and Prevention. Delayed onset and diminished magnitude of rotavirus activity: United States, November 2007–May 2008.MMWR Morb Mortal Wkly Rep.2008;57(25):697–700

9. Clark HF, Lawley D, Mallette LA, et al. Decline in cases of rotavirus gastroenteritis pre-senting to the Children’s Hospital of Phila-delphia after introduction of a pentavalent rotavirus vaccine.Clin Vaccine Immunol.

2009;16(3):382–386

10. Payne DC, Staat MA, Edwards KM, et al. Ac-tive, population-based surveillance for se-vere rotavirus gastroenteritis in children in

the United States.Pediatrics.2008;122(6): 1235–1243

11. Das BK, Gentsch JR, Cicirello HG, et al. Char-acterization of rotavirus strains from new-borns in New Delhi, India.J Clin Microbiol.

1994;32(7):1820 –1822

12. Freeman MM, Kerin T, Hull J, et al. Enhance-ment of detection and quantification of ro-tavirus in stool using a modified real-time RT-PCR assay. J Med Virol. 2008;80(8): 1489 –1496

13. Gentsch JR, Glass RI, Woods P, et al. Identifi-cation of group A rotavirus gene 4 types by polymerase chain reaction.J Clin Microbiol.

1992;30(6):1365–1373

14. Esona MD, Steele D, Kerin TK, et al. Determi-nation of the G and P types of previously non-typeable rotavirus strains from the Af-rican Rotavirus Network from 1996 –2004: identification of unusual G types.J Infect Dis.2010; In press

15. Clark HF, Bernstein DI, Dennehy PH, et al. Safety, efficacy, and immunogenicity of a live, quadrivalent human-bovine reassor-tant rotavirus vaccine in healthy infants.

J Pediatr.2004;144(2):184 –190

16. Clark HF, Borian FE, Bell LM, et al. Protective effect of WC3 vaccine against rotavirus diar-rhea in infants during a predominantly se-rotype I rotavirus season.J Infect Dis.1988; 158(3):570 –587

17. Clark HF, Burke CJ, Volkin DB, et al. Safety, immunogenicity and efficacy in healthy in-fants of G1 and G2 human reassortant rota-virus vaccine in a new stabilizer/buffer liq-uid formulation.Pediatr Infect Dis J.2003; 22(10):914 –920

18. Block SL, Vesikari T, Goveia MG, et al; Pen-tavalent Rotavirus Vaccine Dose Confir-mation Efficacy Study Group. Efficacy, im-munogenicity, and safety of a pentavalent human-bovine (WC3) reassortant rotavi-rus vaccine at the end of shelf life. Pedi-atrics.2007;119(1):11–18

19. Yen C, Jakob K, Peckham X, et al. Detection of fecal shedding of rotavirus vaccine in in-fants following their first dose of pentava-lent rotavirus vaccine. Paper presented at:

annual meeting of the Pediatric Academic Societies; May 4, 2009; Baltimore, MD

20. Angel J, Franco MA, Greenberg HB. Rotavi-rus vaccines: recent developments and fu-ture considerations. Nat Rev Microbiol.

2007;5(7):529 –539

21. Anderson EJ. Rotavirus vaccines: viral shed-ding and risk of transmission.Lancet Infect Dis.2008;8(10):642– 649

22. McCormack PL, Keam SJ, Bernstein DI, et al. Rotavirus vaccine RIX4414 (Rotarix): a re-view of its use in the prevention of rotavirus gas-troenteritis.Paediatr Drugs.2009;11(1):75–88 23. Phua KB, Quak SH, Lee BW, et al. Evaluation

of RIX4414, a live, attenuated rotavirus vaccine, in a randomized, double-blind, placebo-controlled phase 2 trial involving 2464 Singaporean infants.J Infect Dis.2005; 192(suppl 1):S6 –S16

24. Han HH. Summary of human rotavirus vac-cine Rotarix: safety and efficacy trials. Paper presented at: the Vaccines for Enteric Disease Conference; September 10, 2009; Malaga, Spain

25. Otsuka T, Gomi Y, Inoue N, et al. Transmission of varicella vaccine virus, Japan.Emerg Infect Dis.2009;15:1702–1703

26. Centers for Disease Control and Prevention. Update on vaccine-derived polioviruses: worldwide, January 2008 –June 2009.

MMWR Morb Mortal Wkly Rep.2009;58(36): 1002–1006

27. Alexander LN, Seward JF, Santibanez TA, et al. Vaccine policy changes and epidemi-ology of poliomyelitis in the United States.

JAMA.2004;292(14):1696 –1701

28. Cortese MM, Parashar UD; Centers for Dis-ease Control and Prevention. Prevention of rotavirus gastroenteritis among infants and children: recommendations of the Advi-sory Committee on Immunization Practices (ACIP).MMWR Recomm Rep.2009;58(RR-2):1–26 29. Patel NC, Hertel PM, Estes MK, et. al. Vaccine-acquired rotavirus infection in two infants with severe combined immunodeficiency. Paper presented at: meeting of the Ameri-can Academy of Allergy Asthma & Immunol-ogy. March 17, 2009; Washington, DC

CASE REPORTS

PEDIATRICS Volume 125, Number 2, February 2010 e441

at Viet Nam:AAP Sponsored on August 29, 2020

www.aappublications.org/news

(5)

DOI: 10.1542/peds.2009-1901 originally published online January 25, 2010;

2010;125;e438

Pediatrics

Gentsch

Mathew D. Esona, Elizabeth N. Teel, Diane Kent, Umesh D. Parashar and Jon R.

Daniel C. Payne, Kathryn M. Edwards, Michael D. Bowen, Erin Keckley, Jody Peters,

Services

Updated Information &

http://pediatrics.aappublications.org/content/125/2/e438

including high resolution figures, can be found at:

References

http://pediatrics.aappublications.org/content/125/2/e438#BIBL

This article cites 22 articles, 5 of which you can access for free at:

Subspecialty Collections

_sub

http://www.aappublications.org/cgi/collection/vaccine:immunization

Vaccine/Immunization

b

http://www.aappublications.org/cgi/collection/infectious_diseases_su

Infectious Disease

following collection(s):

This article, along with others on similar topics, appears in the

Permissions & Licensing

http://www.aappublications.org/site/misc/Permissions.xhtml

in its entirety can be found online at:

Information about reproducing this article in parts (figures, tables) or

Reprints

http://www.aappublications.org/site/misc/reprints.xhtml

(6)

DOI: 10.1542/peds.2009-1901 originally published online January 25, 2010;

2010;125;e438

Pediatrics

Gentsch

Mathew D. Esona, Elizabeth N. Teel, Diane Kent, Umesh D. Parashar and Jon R.

Daniel C. Payne, Kathryn M. Edwards, Michael D. Bowen, Erin Keckley, Jody Peters,

Rotavirus Gastroenteritis

Sibling Transmission of Vaccine-Derived Rotavirus (RotaTeq) Associated With

http://pediatrics.aappublications.org/content/125/2/e438

located on the World Wide Web at:

The online version of this article, along with updated information and services, is

by the American Academy of Pediatrics. All rights reserved. Print ISSN: 1073-0397.

the American Academy of Pediatrics, 345 Park Avenue, Itasca, Illinois, 60143. Copyright © 2010 has been published continuously since 1948. Pediatrics is owned, published, and trademarked by Pediatrics is the official journal of the American Academy of Pediatrics. A monthly publication, it

at Viet Nam:AAP Sponsored on August 29, 2020

www.aappublications.org/news

References

Related documents

An additional quality control study, aiming to compare the laboratory serum potassium results of samples processed via two methods (utilizing routine transport or centrifugation on

This work attempts to solve the problem of instability that results from disruptions in accessing the active wireless resources in a mobile wireless

Green Building Index (GBI) is the green rating tool recognized by the Malaysian construction industry to promote sustainability in the built environment.. It is developed

Gestational diabetes mellitus diagnosed with a 2-h 75-g oral glucose tolerance test and adverse pregnancy outcomes. Validation of normative data for 75 g oral

Synthesis of silver nanoparticles (AgNPs) using the marine alga Gracilaria parvispora extract is clearly shown here.. Transmission electron microscopy (TEM) revealed that

Abstract: Cerebral autosomal-dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) is the most common monogenic form of hereditary cere-

Data pre-processing is considered a significant and crucial initial step in data analysis and data mining projects, as the output of this stage is inputted to

LCnMOS, a technique to tackle the leakage problem in logic gate circuits, uses single additional leakage control transistor, driven by the output from the pull up and pull