VIRAL IMMUNOLOGY
Volume 31, Number 2, 2017 Vaccines That Work
ª Mary Ann Liebert, Inc.
Pp. 1–5
DOI: 10.1089/vim.2017.0121
Challenges to Developing a Rotavirus Vaccine
Paul A. Offit
Abstract
Rotavirus is the most important cause of gastroenteritis worldwide. In developing countries, the virus is a major
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cause of death in infants and young children. In the United States, before the licensure of vaccines, rotavirus
infections accounted for *2.7 million cases of gastroenteritis annually. Here are described the history and
challenges surrounding the development of a rotavirus vaccine.
Keywords: rotavirus, vaccine development, gastroenteritis
R otaviruses are the most important cause of gastro-
enteritis throughout the world. Symptoms include high
fever, vomiting, and diarrhea progressing, in severe cases, to
dehydration, shock, and death (15).
In developed countries, where standards of hygiene in the
home and sanitation in the country are high, rotavirus is the
most common cause of infant diarrhea (6). Virtually all
children are infected by 2 to 3 years of age. In the United
States, before the availability of rotavirus vaccines, rotavirus
accounted for *2.7 million cases of gastroenteritis, 500,000
physician visits, 55,000 to 70,000 hospital admissions, and
20–60 deaths per year (18,23). The high rate of hospital
admissions for dehydration is caused by the virus’s pro-
pensity to cause diarrhea, fever, and, most importantly,
frequent, severe, and persistent vomiting, making it difficult
to rehydrate the child orally (35).
In developing countries, rotavirus infections are one of
the most common causes of death in infants and young
children. Before the availability of rotavirus vaccines, the
World Health Organization (WHO) estimated that between
480,000 and 640,000 infants and young children died every
year—about 2,000 children every day—from dehydration
caused by rotavirus (1,28,37,40).
Although oral rehydration therapy in the developing
world has helped to decrease the number of severe and fatal
infections (1), the continuing mortality of rotavirus under-
lined the need for a safe and effective vaccine.
In 1978, Drs. Stanley Plotkin and Fred Clark, with
funding from Pasteur-Mérieux-Connaught (PMC; Sanofi
Pasteur today), established a rotavirus research team at the
Children’s Hospital of Philadelphia (CHOP). I joined that
team in 1981. Dr. Plotkin was able to convince PMC to fund
the project because rotavirus was an important disease
Division of Infectious Diseases, The Children’s Hospital of Philadelphia, The Perelman School of Medicine at the University of
Pennsylvania, Philadelphia, Pennsylvania.
1
and Lessons Learned
worldwide, a rotavirus vaccine would likely be licensed for
universal use in U.S. infants (making higher profits likely),
and Dr. Plotkin had enormous credibility with vaccine
makers, having successfully researched and developed a
rubella vaccine and directed clinical trials of a human-cell-
based rabies vaccine.
In 1983, several years after the rotavirus team at CHOP
was formed, Bishop et al. provided the first evidence that a
vaccine to prevent rotavirus was possible (5). Bishop found
that children infected with rotavirus during the first month of
life were protected against moderate-to-severe disease
caused by reinfection; these children were not, however,
protected against mild disease. Conversely, children not
infected during the first month of life were susceptible to
severe rotavirus gastroenteritis. Bishop’s findings were later
replicated in children infected during the first few years of
life (3,16,38,41). The Bishop study set a limit on what could
be expected from a rotavirus vaccine; a realistic goal would
be to keep children out of the hospital and out of the morgue
but not to prevent reinfection or even mild disease caused by
reinfection.
Bishop’s findings were consistent with previous obser-
vations that effector functions at mucosal surfaces are short
lived; for example, rotavirus-specific secretory immuno-
globulin A (sIgA) is not typically detected at the intestinal
mucosal surface 1 year after symptomatic infection (14,25).
Although mucosal, virus-specific sIgA at the time of expo-
sure can protect against all rotavirus disease, protection against
moderate-to-severe disease but not mild disease is most
likely mediated by virus-specific sIgA produced by memory
rotavirus-specific B cells in the intestinal lamina propria
(26). Because it takes several days for memory B cells to be
activated and to differentiate to antibody-producing plasma
 2 OFFIT
cells, modification and not complete protection against
disease results.
Before the first rotavirus vaccine could be developed,
several important questions about rotavirus pathogenesis
and immunogenesis had to be addressed. These questions
were answered using both large (calves, sheep, horses, and
pigs) and small (mice) animal models. Researchers found
the following:

Species-specific strains of rotavirus infect the young of
many mammalian and some avian species (32).
 Species barriers were high. For example, bovine rota-
viruses caused diarrhea in calves but not in babies and
human rotaviruses caused diarrhea in babies but not in
calves (32).
 Rotaviruses replicated primarily in mature villous epi-
thelial cells of the small intestine; although rotaviruses
have been detected in the bloodstream, neither viremia
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nor replication at sites distant to the small intestine was
an important part of viral pathogenesis (31). Therefore,
protection against rotavirus disease depended on in-
ducing an immune response active at the intestinal
mucosal surface. Because sIgA resists degradation by
acids and proteases, it is the critical immunoglobulin
present at the intestinal mucosal surface. Monomeric
IgG in serum, because it lacks secretory piece, is not
transported through the polymeric immunoglobulin
receptor—which is located at the base of villous epi-
thelial cells—to the intestinal mucosal surface. There-
fore, the goal of a rotavirus vaccine was to induce high
titers of intestinal virus-specific sIgA.
 The most effective way to induce rotavirus-specific
sIgA at the intestinal mucosal surface and high fre-
quencies of virus-specific memory B and T cells in the
intestinal lamina propria was by oral inoculation; par-
enteral inoculation was less effective (30).

Although human and animal rotaviruses include a va-
riety of distinguishable serotypes, studies in animals
and children showed that heterotypic immunity existed
(21).
For these reasons, our first attempt at a rotavirus vaccine
centered on oral inoculation with a bovine rotavirus strain
that was distinct from known human serotypes.
This source of our first rotavirus vaccine was a calf
with diarrhea in Chester County, Pennsylvania in 1981. This
virus was serially passaged 12 times in African green
monkey kidney cells at The Wistar Institute. Because this
was the third of several strains isolated, it was called Wistar
Calf 3 (WC3) (13). In an initial double-blinded, placebo-
controlled, efficacy trial performed in suburban Philadel-
phia, three doses of WC3 were given by mouth at 2, 4, and 6
months of age resulting in a 76% reduction in all rotavirus
infections and 100% protection against moderate-to-severe
disease (12). These findings were not, however, reproduced
in subsequent efficacy trials conducted in Cincinnati and
Bangui, Central African Republic, where protection against
disease was insignificant (4,17). Heterotypic protection,
which was induced by antibodies directed against outer
capsid proteins, appeared to be inconsistent. Therefore, the
WC3 vaccine was abandoned as a vaccine candidate.
It was back to the drawing board. The goal at this point
was to determine which rotaviral genes coded for proteins
that evoked virus-neutralizing antibodies and which rota-
viral genes determined viral virulence. With this informa-
tion in hand, the plan was to create a series of reassortant
rotavirus strains that retained the attenuated virulence
characteristics of WC3 (which had been shown to be safe in
clinical trials) but did not include rotaviral genes associated
with viral virulence. Again, animal models were used to
determine the genetic basis of rotavirus virulence and ro-
tavirus neutralization phenotype.
Animal model studies revealed the following:
 At least four rotavirus genes (VP3, VP4, VP7, and
NSP4) determined viral virulence. Inclusion of all four
genes was necessary to confer pathogenicity (20).
 Both rotaviral surface proteins (VP4 and VP7) inde-
pendently evoked rotavirus-specific neutralizing anti-
bodies (19,29). Rotaviruses, therefore, were similar to
the influenza viruses, where two viral surface proteins
determine neutralization phenotype. Rotavirus surface
protein VP4 was responsible for viral cell binding.
Because cleavage of VP4 by intestinal proteases was
required for cell entry, VP4 serotypes were termed P
types. Because rotavirus surface protein VP7 is a gly-
coprotein, VP7 serotypes were termed G types. Global
surveillance has led to the characterization of at least
37 P genotypes and 27 G serotypes in humans and,
because rotavirus has a segmented genome, gene re-
assortment could theoretically lead to almost 200 dif-
ferent P and G combinations. However, although >60
P-G combinations have been found in humans, five
strains (P[8], G1; P[4], G2; P[8], G3; P[8], G4; and
P[8], G9) are associated with 80% to 90% of the
childhood rotavirus disease burden globally (32).
With this information in hand, five bovine–human re-
assortant rotavirus strains that included the attenuating
genes of WC3 and either the P or G genes from prevalent
human rotavirus serotypes were created. Unfortunately, at
this stage, PMC abandoned the project and Dr. Plotkin left
CHOP. Fred Clark and I then presented what we had done to
scientists at three vaccine makers: Merck, Glaxo-Smith-
Kline, and Wyeth. Merck was willing to evaluate our bo-
vine–human reassortant rotaviruses as a vaccine. A formal
working relationship was established in 1992.
Unfortunately, an event that occurred in 1998 dramati-
cally changed the landscape of how future rotavirus vaccine
trials would be conducted.
On August 31, 1998, the first animal–human reassortant
rotavirus vaccine for use in infants was licensed in the
United States. The vaccine (Rotashield), which was devel-
oped by researchers at the National Institutes of Health
(NIH) in collaboration with Wyeth Laboratories, was given
by mouth to infants at 2, 4, and 6 months of age and con-
tained one simian rotavirus and three simian–human re-
assortant rotaviruses (7). The simian rotavirus strain, rhesus
rotavirus (RRV), was similar to human serotype G3. The
other three viruses were reassortants containing 10 genes
from RRV and 1 gene (gene segment 8 or 9) from human
rotaviruses of serotypes G1, G2, or G4. The choice of simian
and simian–human rotaviruses for use as a vaccine for infants
was based on inclusion of the attenuated virulence charac-
teristics of the nonhuman strain RRV, and inclusion of human
rotavirus genes that encoded surface protein vp7. Rotashield
 CHALLENGES TO DEVELOPING A ROTAVIRUS VACCINE
replicated less efficiently in the human intestine than in
natural human rotaviruses, evoked virus-specific neutraliz-
ing antibodies against human G types 1–4, and was even-
tually shown to afford excellent protection against challenge
in prospective, placebo-controlled studies (2,22,33,34,36).
In August 1998, Rotashield was licensed for use in U.S.
infants. Although Rotashield had been shown to be safe in a
10,000-child, prospective, placebo-controlled, prelicensure
study, a rare adverse event appeared postlicensure (although
several cases of this adverse event had also been seen both
in the vaccine and placebo group prelicensure).
About 1 year after licensure, after Rotashield had been
administered to about 1 million infants in the United States,
15 cases of intussusception after its use were reported to the
Vaccine Adverse Events Reporting System (8). Intussuscep-
tion occurs when a segment of the small intestine—typically
around the ileocecal junction—telescopes into itself causing a
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blockage. When this occurs, severe intestinal bleeding or
entrance of intestinal bacteria into the bloodstream can result
in sepsis. In July of 1999, the Centers for Disease Control and
Prevention (CDC) temporarily suspended the use of Rota-
shield, pending the results of a case–control analysis. Sub-
sequent studies found that Rotashield was a rare cause of
intussusception in children—about 1 case of intussusception
for every 10,000 children vaccinated (24,27).
Because Rotashield was found to cause intussusception,
both the CDC and the American Academy of Pediatrics
withdrew their recommendation in October 1999 (9).
Although Rotashield was withdrawn from use, several
investigators argued, reasonably, that even in U.S. children
natural infection was still far more likely to cause hospi-
talization and death than immunization. Nonetheless, the
manufacturer withdrew Rotashield for U.S. use.
More tragic was the loss of Rotashield for the developing
world. Because the United States was no longer using Ro-
tashield, health officials in the developing world argued that
if the vaccine was unsafe for U.S. children, then it was also
unsafe for their children, even though the benefit-to-risk
ratio was dramatically different. As a result, Rotashield, a
vaccine that had the capacity to save as many as 2,000 lives
a day, went unused. Seven years passed before the next
rotavirus vaccine became available.
The cause of intussusception after administration of Ro-
tashield remains unknown.
The problem with the first rotavirus vaccine did not end
attempts to make a safer vaccine, but it did increase the size
and expense of prelicensure trials. Now the task was not
simply to rule out relatively uncommon side effects pre-
licensure, but rather to rule out rare events prelicensure.
Merck struggled with the cost of this development project,
which would soon exceed $1 billion. The argument that
most persuaded Merck at this point, when it became clear
that a Phase III trial would be large, was that Glaxo-Smith-
Kline, a competitor, was also moving forward with its own
rotavirus vaccine (a live attenuated human strain). Another
limitation and expense to making a rotavirus vaccine was
that no clear immunological correlate of protection had been
found. Neither virus-specific binding nor neutralizing anti-
bodies in the serum or at the intestinal mucosal surface was
predictive of protection. Based on animal model studies, the
correlate most likely predictive of protection was the fre-
quency of virus-specific B and T cells in the intestinal
3
lamina propria (26). However, these data could have only
been provided by performing intestinal biopsies on other-
wise healthy children—an impossibility.
Although it took about 10 years to do the basic science
research required to construct the bovine–human rotavirus
strains that became a vaccine, it took 16 years to do the
research of development, which included small Phase I and
Phase II studies for safety and efficacy to prove that each of
the strains needed to be in the final formulation (proof-of-
concept studies), to determine the correct dose of each strain
(dose-ranging studies), to prove that the shelf life of the
vaccine was compatible with distribution in the developing
world (real-time stability studies), and to design a conve-
nient plastic squirt vial that allowed for easy inoculation of a
fully liquid product (32). One of the biggest hurdles was de-
ciding how to mass-produce the vaccine. GlaxoSmithKline’s
(GSK’s) microcarrier technology was probably the most effi-
cient way to mass-produce live attenuated rotavirus vaccines.
Merck did not have this technology, eventually settling on
Nunc cell factories. This, too, was one of the many go-no-go
decisions that stalled the vaccine.
The Merck bovine–human rotavirus vaccine, RotaTeq, is
a live, oral vaccine that contains five bovine–human re-
assortant strains. The bovine strain WC3 is the backbone
virus for the vaccine. The four human strains reassorted into
the WC3 backbone include human serotypes G1, G2, G3, or
G4 (derived from outer capsid protein VP7) as well as P1A
(derived from outer capsid protein VP4) (11).
The efficacy of RotaTeq against all rotavirus gastroen-
teritis was evaluated in a Phase III trial of >70,000 infants
(39). This trial, which was a placebo-controlled, 11 country,
4-year, prospective study, cost about $350 million. The
original study, which was designed in collaboration with
the Food and Drug Administration, was a 40,000-child,
placebo-controlled trial. But intussusception is a relatively
rare event. Background rates are low. Therefore, the trial
continued, adding increments of 10,000 children beyond the
original 40,000 until statistical differences between the in-
cidence of intussusception in the vaccine and control group
were reached. During this time, as 10s of millions of dollars
were added to the expense of the trial, Merck struggled to
decide whether it wanted to continue to pursue this vaccine.
RotaTeq was effective. Protection against rotavirus
disease of any severity was 74%, against severe rotavirus
disease 98%, against rotavirus-associated hospitalizations
96%, against emergency visits 94%, against office visits
87%, and against hospitalizations of any etiology 59%; the
last finding proving the importance of rotavirus as a cause of
severe gastroenteritis in children. One year after vaccina-
tion, the efficacy of RotaTeq was 63% against all rotavirus
diseases and 88% against severe disease (39).
The large Phase III trial also showed that RotaTeq neither
caused nor prevented intussusception. Within 14 days of
inoculation, 1 case occurred in the vaccine group and 1 in
the placebo group; within 42 days of inoculation, 6 cases in
the vaccine group and 5 in the placebo group; and within 1
year of inoculation, 12 cases in the vaccine group and 15 in
the placebo group (39).
In February 2006, the Advisory Committe on Immuniza-
tion Practices (ACIP) recommended routine immunization
of U.S. infants with three doses of RotaTeq to be administered
by mouth at 2, 4, and 6 months of age (7). Since licensure,
 4 OFFIT
rotavirus vaccines have caused an approximate 90% decrease
in the incidence of clinically significant rotavirus disease in the
United States (10). Furthermore, the introduction of rotavirus
vaccines into the United States has not increased the overall
incidence of intussusception. Globally, as of May 2016, 81
countries, including 38 low-income countries, have im-
plemented rotavirus vaccines as part of their national immu-
nization programs.
Author Disclosure Statement
No competing financial interests exist.
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Address correspondence to:
Dr. Paul A. Offit
Division of Infectious Diseases
The Children’s Hospital of Philadelphia
The Perelman School of Medicine
at the University of Pennsylvania
Philadelphia, PA 19104
E-mail: offit@email.chop.edu