Does Preventing Rotavirus Infections Through Vaccination Also Protect Against Naturally Occurring Intussusception Over Time?
0 Kaiser Permanente Vaccine Study Center, Kaiser Permanente , Oakland, California
1 US Centers for Disease Control and Prevention , Atlanta , Georgia
Does Preventing Rotavirus
Vaccination Also Protect
Against Naturally Occurring Intussusception Over Time?
TO THE EDITOR—Intestinal
intussusception is an uncommon event (incidence
approximately 30 per 100 000 per year
in US infants) in which one part of the
intestine folds into another. The
condition is usually considered idiopathic, but
numerous case reports link
intussusception to enteric pathogens, notably
adenovirus. Several case reports have linked
wild-type rotavirus to intussusception,
although evidence for this link is
In 1999, a previous rotavirus vaccine
(Rotashield) was found to be associated
with intussusception  and was
withdrawn from the US market. Currently, 2
rotavirus vaccines are routinely
administered to US infants: RotaTeq and Rotarix.
Large clinical trials (>60 000 children
each) found no statistical association
between vaccination and intussusception
within 42 days following any dose [3,
4]. Nonetheless, with the accumulation of
study power over time, recent
postlicensure rotavirus vaccine safety assessments
in the United States [5, 6] report a modest
but significant risk of intussusception.
One could postulate that if vaccines
based on 3 different live-attenuated
rotavirus vaccine strains (rhesus in
Rotashield, bovine-human reassortants in
RotaTeq, and human rotavirus in
Rotarix) are statistically associated with
intussusception, then the wild-type rotavirus
(naturally nonattenuated and most
virulent) could also plausibly be associated with
intussusception. We studied a vaccine
probe hypothesis: If wild-type rotavirus
infection is causally associated with
intussusception, then the prevention of such
infections through vaccination could
conceivably protect against intussusception
during time periods after vaccination.
To assess whether children protected
by rotavirus vaccine were at lower risk
for intussusception in the first year after
completing their full vaccine series, we
retrospectively analyzed a cohort of
children born after rotavirus vaccine
licensure (February 2006) and enrolled in
the Vaccine Safety Datalink (VSD), a
collaboration of managed care organizations
capturing medical visits and vaccination
data on more than 9 million individuals.
Intussusception cases had ICD9-CM
code 560.0 (intussusception) and 543.9
(other and unspecified diseases of
appendix) in VSD hospitalization or
emergency room automated data files. Based
on previously published results, VSD’s
positive predictive value for these
ICD9-CM codes was 75% . We calculated
rates of intussusception from 4 to 55
weeks following last rotavirus vaccination
among children receiving a full course of
rotavirus vaccinations, limiting our
analysis to those children having at least 1 other
recommended vaccine. A time-to-event
analysis using a Cox proportional hazards
model accounted for gender, age at last
vaccine dose, seasonality, VSD site, and
index year of intussusception event.
Our cohort contained VSD data on
186 488 children receiving a full course
of rotavirus vaccines and 64 089 children
receiving none. We found 50 cases of
intussusception among the vaccinated
children (0.027%) and 22 cases among
the children receiving no rotavirus
vaccine (0.034%). Compared with children
receiving no rotavirus vaccine, the
incidence of intussusception among the
vaccinated children was not statistically
different (incidence rate ratio = 0.94 [95%
confidence interval (CI), .50, 1.75]).
Previous analyses conducted before
and after introduction of Rotashield 
suggested that rotavirus vaccine receipt
perhaps triggered “early-onset”
intussusceptions among children biologically
predisposed to experience this condition,
which would then be followed by a period
of compensatory, decreased risk later in
infancy. A similar finding was suggested
during a prelicensure randomized clinical
trial of Rotarix, whereupon the relative
risk of intussusception decreased from
0.56 (95% CI, .25, 1.24) for the 0–100
day postvaccination interval to 0.28
(95% CI, .10, .81) during the 0–1 year
postvaccination interval .
Our findings, derived from a
well-powered sample having good clinical and
vaccine exposure accuracy, indicate that the
risk of naturally occurring
intussusception was not modified by rotavirus
vaccination during the period of 1 month to 1
year following vaccination.
1. Mansour AM , El Koutby M , El Barbary MM , et al. Enteric viral infections as potential risk factors for intussusception . J Infect Dev Ctries 2013 ; 7 : 28 - 35 .
2. Murphy TV , Gargiullo PM , Massoudi MS , et al. Intussusception among infants given an oral rotavirus vaccine . N Engl J Med 2001 ; 344 : 564 - 72 .
3. Vesikari T , Matson DO , Dennehy P , et al. Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine . N Engl J Med 2006 ; 354 : 23 - 33 .
4. Dennehy PH , Goveia MG , Dallas MJ , et al. The integrated phase III safety profile of the pentavalent human-bovine (WC3) reassortant rotavirus vaccine . Int J Infect Dis 2007 ; 11 : S36 - 42 .
5. Weintraub ES , Baggs J , Duffy J , et al. Risk of intussusception after monovalent rotavirus vaccination . New Engl J Med 2014 ; 370 : 513 - 9 .
6. Yih WK , Lieu TA , Kulldorf M , et al. Intussusception risk after rotavirus vaccination in US infants . New Engl J Med 2014 ; 370 : 503 - 12 .
7. Shui IM , Baggs J , Patel MM , et al. Risk of intussusception following administration of a pentavalent rotavirus vaccine in US infants . JAMA 2012 ; 307 : 598 - 604 .
8. Simonsen L , Morens DM , Elixhauser A , et al. Effect of rotavirus vaccination programme on trends in admission of infants to hospital for intussusception . Lancet 2001 ; 358 : 1224 - 9 .
9. Macias M , Lopez P , Velazquez FR , et al. The rotavirus vaccine RIX4414 (Rotarix) is not associated with intussusception in one year old infants . In: 45th Annual Interscience Conference on Antimicrobial Agents and Chemotherapy; Washington, DC: 17 December 2005 .
Correspondence: Daniel C. Payne , PhD, MSPH, Centers for Disease Control and Prevention, 1600 Clifton Rd, NE, MS-A34 , Atlanta, GA 30333 ().
Clinical Infectious Diseases ® 2015 ; 60 ( 1 ) :163-4 Published by Oxford University Press on behalf of the Infectious Diseases Society of America 2014 . This work is written by (a) US Government employee(s) and is in the public domain in the US .