Healthy Adults Clinical Trial
Official title:
Evaluation of the Susceptibility of Human Volunteers With Different Histo-Blood Group Antigens to Norovirus
Objectives: To evaluate the role of human histo-blood group antigens in susceptibility to
Norovirus infections.
Description of Study Design: Healthy volunteers with different blood types and low antibody
titers to the challenge strain will be challenged orally with a Norovirus in the CCCR
inpatient facility. Subjects with resistant (non-secretors) or susceptible (secretors (of
either A, B or O blood group)) to the challenge strain will be recruited. The challenge
study will be conducted in two groups of twenty, each with approximately ten secretors and
ten non-secretors. Three additional subjects per group will serve as alternates in the event
that any of the study subjects are unavailable or become ineligible at the time of the
inpatient study. Subjects will be monitored daily in the isolation facility for at least
five days following this challenge for daily clinical and virological evaluations. Subjects
will return to the investigational site for evaluation the day after discharge from the
inpatient unit and about 30 days (28-35 days) post challenge.
Study Endpoints: Norovirus infection as assessed by viral shedding, seroconversion and
clinical illness assessed by the duration and severity of symptoms
Noroviruses are single-stranded, positive-sense RNA viruses that cause acute gastroenteritis
in humans. The prototype Norwalk virus (NV) was identified in a large outbreak of acute
gastroenteritis in an elementary school in Norwalk, Ohio, in 1968. Since then, many strains
have been described and named by the locations of their first isolation. Genetically,
Noroviruses belong to one of four genera within Caliciviridae (CV). Phylogenetic analysis
has shown that the Norovirus genus is divided into five genogroups and each genogroup can be
further divided into genetic clusters; at least 30 genetic clusters of Noroviruses have been
identified.
Noroviruses have been recognized as the most important cause of non-bacterial epidemics of
acute gastroenteritis, affecting individuals of all ages, in both developing and developed
countries. Such outbreaks usually have high attack rates and have occurred in child care
centers, schools, restaurants, summer camps, hospitals, nursing homes, ships (both civilian
and military) as well as deployed military troops. The viruses are highly contagious and are
able to survive in the environment for extended periods of time. They are spread by contact
with environmental surfaces and person-to-person transmission. Noroviruses normally cause
moderate-to-severe diarrhea and the disease is often incapacitating and can be fatal in the
young and elderly. The most important public health concern is that Noroviruses can cause
large water- and food-borne outbreaks, resulting in the virus being classified as a Category
B agent.
Noroviruses have also been implicated in several military outbreaks. The "Desert Shield
virus" (DSV) isolated in US troops in the 1991 Gulf War was subsequently identified as a
Norovirus. Similarly the recently reported "mysterious" attacks of acute gastroenteritis
affecting the British troops in Afghanistan were also caused by a Norovirus. Large outbreaks
of Norovirus-associated gastroenteritis are common on US Navy ships, similar to those that
occurred on board cruise ship lines. Surveillance of acute gastroenteritis on board five US
Navy combat ships in 1998-1999 showed that all the ships experienced large outbreaks of
Norovirus acute gastroenteritis during their deployment in the Pacific and Indian Oceans,
following port visits. Because of the rapid spread of the disease, many departments and
units on board the ships were unable to function during the peak of the outbreaks.
Noroviruses are difficult to study because: 1) they are genetically and antigenically highly
diverse and multiple strains with distinct genetic identities co-circulate in the same
communities, making diagnosis and disease control extremely difficult; and 2) the virus
cannot be cultivated in cell culture and 3) no small animal model for studying Noroviruses
exists. The molecular cloning of the prototype Norwalk Virus (NV) in 1990 by one of the
co-investigators of this application has allowed rapid progress in studying Noroviruses and
other genera; however, many issues on Norovirus infection, pathogenesis, immunology and host
range remain unknown.
The discovery of Norovirus receptors provides new opportunities to evaluate the pathogenesis
and epidemiology of Noroviruses. A host genetic factor involving Norovirus infection was
originally suggested by many researchers before the cloning of Noroviruses in the 1990s
because about 20-30% of individuals who did not have antibodies against Noroviruses were
never infected following a challenge with NV, and in outbreaks, individuals who remained
healthy were clustered in families that had the same exposure to Noroviruses as the ill
families. Further, pre-existing antibodies against NV were not protective against NV
infection, while individuals who had high levels of antibodies against NV were more
susceptible to NV than individuals who did not have the antibodies. These observations
indicate that, in addition to immune responses, there must be another factor(s) that
controls the host-specificity of Norovirus infection.
We recently discovered that Noroviruses recognize human histo-blood group antigens as
receptors. Using recombinant capsid proteins from different Noroviruses representing
different genetic clusters, we have identified four binding patterns of Noroviruses to human
histo-blood group antigens, which are defined by the host Lewis, secretor and ABO blood
types. This finding provides a new approach to develop strategies to control the disease.
Specifically, if Noroviruses rely on the histo-blood group antigens on the surfaces of the
intestinal epithelial cells as receptors, a compound that inhibits the interaction between
the virus and receptors could be developed as an antiviral drug for Noroviruses. This
finding provides the basis for this protocol which seeks to confirm the relationship between
specific Norovirus susceptibility and specific histo-blood group antigen presence as well as
establish a model to evaluated future interventions (drugs and vaccines).
The specificity of the NV interaction with the sugar moieties of histo-blood group antigens
was shown by specific blocking of the binding by human milk from a secretor, by monoclonal
antibodies specific for secretor human blood-group antigens (HBGAs), by synthetic
oligosaccharide conjugates containing secretor antigens, and by treatment of the tissues
with a1,2 fucosidase. NV also binds to differentiated CaCo2 cells and differentiated CaCo2
cells express human histo-blood group antigens. Transfection of Chinese Hamster Ovary (CHO)
cells with a a1,2-linked fucosyl-transferase cDNA allowed attachment of NV virus-like
particles (VLPs). The bound rNV VLPs were internalized following incubation of the cells at
37oC.
To further investigate the association between secretor status and susceptibility to Norwalk
virus (NV), we collaborated with Dr. Christine Moe at Emory University's School of Medicine
on a volunteer challenge study. This study utilized the prototype NV, the first Norovirus
strain to be used for human challenge studies. Saliva samples from 77 NV-challenged
volunteers were tested for secretor status and for NV-binding. Fifty-five (71%) of the 77
volunteers were secretors. Among the 55 secretors, 34 (62%) were infected with NV following
challenge and saliva from 41 (75%) bound NV recombinant VLPs. None of the saliva samples
from the 22 non-secretor volunteers bound NV virus-like particles (VLPs) and none of them
became infected following NV challenge; strongly suggesting that the susceptibility to NV is
determined at least in part by the ability of the host to bind the norovirus strain.
More recently we performed a study to determine whether other strains of Noroviruses have a
similar pattern of host-specificity and have extended the binding patterns to 7 based on
examination of fourteen Noroviruses. The 7 patterns have been classified into two groups
according to their interactions with three major epitopes (A/B, H and Lewis) of HBGAs: the
A/B binding group and the Lewis-binding group. Strains in the A/B binding group recognize
the A and/or B and H antigens, but not the Lewis antigens, while strains in the
Lewis-binding group react only to the Lewis and/or H antigens. This classification also
resulted in a model of the Norovirus/HBGA interaction, in which a maximum of two binding
sites within a receptor binding interface are involved in NV/HBGA interaction. The A, B and
H side chains are responsible for binding by the A/B binding strains while the Lewis
epitopes are responsible for the Lewis binding strains. Phylogenetic analyses showed that
strains with identical or closely related binding patterns tended to be clustered, but
strains in both binding groups can be found in both genogroups I and II. Our results suggest
that Noroviruses have a wide spectrum of host range and human HBGAs play an important role
in Norovirus evolution.
Since human Noroviruses cannot be cultivated in vitro or infect animals, it is necessary to
perform human volunteer challenge studies to study the pathobiology of the infection. The
study will further the concept that Norovirus has a narrow host range which is fundamental
in the pathogenesis and immunology of Noroviruses. Additionally, we recently have identified
more than a dozen compounds that specifically block Norovirus attachment to their receptors.
The human challenge study should also establish a model that can be used in the evaluation
of these new compounds in regards to their capacity to block virus replication (anti-viral
drug). Furthermore, our study will re-evaluate whether acquired immunity is an independent
factor in Norovirus infections which may provide additional information in host immunity
potentially useful in vaccine development. Finally, the study will allow for banking of the
Norovirus challenge strain by collecting the diarrheal stools passed by the study subjects.
Banking of additional specimen, as mentioned above, is critical for future clinical trials
because the virus cannot be cultivated in vitro and must be isolated from humans infected
with the virus.
A specific challenge study would only use one challenge strain and any challenge strain used
in human clinical trials would have a separate IND and FDA approval prior to administration
to subjects.
;
Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Double Blind (Subject, Caregiver, Investigator, Outcomes Assessor)
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