Dengue

In Taiwan, people who aged 50 to 70 years accounted for over 40% among those who infected by dengue virus every year. Therefore, to understanding the immunogenicity and safety of TV005 vaccine among people aged 50 to 70 years is important for whether TV005 can be introduced into Taiwan as a major intervention to control dengue. This trial is a phase II, double-blind, multicenter, and placebo-controlled one. We plan to enroll 252 subjects whose age are 50 to 70 years at four study sites. One single-dose TV005 vaccine or placebo will be given subcutaneously. After vaccination, detailed data of the subjective symptoms, physical examination, laboratory examination, and titer of neutralization antibody from all subjects will be recorded. After completion of the present trial, we can clarify the immunogenicity and safety of TV005 among people aged 50 to 70 years.

tetravalent live attenuated dengue vaccine admixture TV005

rDEN1Δ30-1545
rDEN2/4Δ30(ME) -1495, 7163
rDEN3Δ30/31-7164
rDEN4Δ30-7132, 7163, 8308

0.5 ml
0.5 ml
0.5 ml
0.5 ml

1000
10000
1000
1000

Primary endpoint(s):
 To determine the safety of TV005 tetravalent live-attenuated dengue vaccine in persons aged 50 to 70 years by assessing the frequency of vaccine-related adverse events, graded by severity.
 To determine the immunogenicity of the TV005 tetravalent live attenuated dengue virus vaccine, as assessed by neutralizing antibody titers to DENV-1, DENV-2, DENV-3, and DENV-4 at 28, 56, 72, and 180 days after vaccination. Monovalent, bivalent, trivalent, and tetravalent seropositivity/seroconversion frequencies will be determined. DENV seropositivity is defined as a PRNT50 ≥ 1:10. Seroconversion is defined as a ≥ 4-fold rise in PRNT50.
*PRNT: plaque reduction neutralization titer

Secondary endpoints
 To assess the frequency, and quantity of vaccine viremia following vaccination for both vaccine and wild-type dengue.
 To determine the number of vaccines with recoverable DENV-1, DENV-2, DENV-3, and DENV-4 vaccine virus components or wild-type dengue virus during the first 14 days following vaccination. This is defined as recovery of vaccine virus from the blood or serum of a subject and/or by new seropositivity in a previously seronegative subject or seroconversion to DENV (> 4-fold rise in neutralizing antibody titers against DENV-1, DENV-2, DENV-3, or DENV-4) in a previously seropositive subject.
 To determine the effect of pre-existing DENV antibodies on recovery of vaccine virus from the blood or serum of a subject and/or seroconversion frequencies to DENV in the elderly.

Exploratory Objectives
 To determine the durability of the neutralizing antibody response, 1 year, 2 years and 3 years after vaccination using TV005.
 To evaluate cellular and innate immune responses to each DENV serotype tested. Selected CMI responses may include the following:
o The frequency of DENV specific T cells using intracellular cytokine staining (ICS) assay identifying cells expressing at least 2 of the followings activation markers (CD40L, IL-2, TNFα & IFNγ) upon a short term in vitro stimulation.
o The frequency of DENV specific memory B cells detected by B cell ELISPOT assays.
o Evaluation of the phenotype of peripheral blood mononuclear cells (PBMC) at primary infection with the TV005 vaccine.
 To evaluate more broadly the immunological response to vaccination by the use of additional cell-mediated immunity (CMI) and other immunological assays which may be performed if additional assay techniques are developed over the course of the study.
 To evaluate genome-wide transcription patterns by microarray that may be associated with immunological response to the vaccine or to clinical responses to the vaccine.

Inclusion Criteria
All of the following criteria must be fulfilled for a subject to qualify for inclusion in this study:
1) Man or non-pregnant / non-lactating woman in good general health as determined by
physical examination, laboratory screening, and review of medical history between the
ages of 50 years and 70 years at the time of enrollment into the study.
2) Residence in Taiwan for the 12 months duration with access to transportation to study
site.
3) Subjects who the investigator believes can and will comply with the requirements of the
protocol (e.g., completion of the diary cards, return for follow-up visits).
4) Subject who allow to access to their Medical Record.
5) Subjects who will remain available for the duration of the study, approximately 3 years
following the first vaccination.
6) Good general health as determined by physical examination, laboratory screening, and
review of medical history.
7) An informed consent form signed and dated by the subject.
8) If the subject is female, she must be of non-childbearing potential, i.e. surgically
sterilized or one year post-menopausal; or, if of childbearing potential, she must be
abstinent or have used adequate contraceptive precautions (i.e. intrauterine contraceptive
device; condom and spermicide combination, oral contraceptives or other equivalent
hormonal contraception, e.g. progestin implantable, cutaneous hormonal patch or
injectable contraceptives) for 30 days prior to vaccination, have a negative pregnancy test
prior to vaccination and must agree to continue such precautions for 90 days after
completion of the vaccination series.

Exclusion Criteria
A subject will be excluded from enrollment if any of the following criteria are met:
1) Pregnant or lactating female or female planning to become pregnant within 90 days of
receiving an investigational product or planning to discontinue abstinence or
contraceptive precautions within 90 days of receiving an investigational product.
2) Acute or chronic, clinically significant pulmonary, cardiovascular, hepatic, renal,
autoimmune, hematologic, or endocrine disease or functional defect, as determined by
history, physical examination, or screening tests.
3) History of any neurological, psychiatric, or behavioral disorder or seizures, with the
exception of a single febrile seizure in childhood.
4) Self-reported or suspected congenital or acquired immunodeficiency, or asplenia; or
receipt of immunosuppressive therapy such as anti-cancer chemotherapy or radiation
therapy within the preceding 6 months, or long-term systemic corticosteroid therapy
(prednisone or equivalent, ≥ 0.5 mg/kg/day or 20 mg/day, for more than 2 consecutive
weeks within the past 3 months). Inhaled and topical steroids are allowed.
5) HIV infection by screening and confirmatory assays, Hepatitis C virus (HCV) infection
by screening and confirmatory assays, or Hepatitis B virus (HBV) infection, by Hepatitis
B surface antigen (HBsAg) screening or, unwilling to allow HIV, HCV and HBV testing.
6) Screening laboratory values of hemoglobin <9.5 gm/dL in female adults or <11 gm/dL
in male adults, neutrophil <1,000 mm3
, platelet < 100,000/mm3
, Creatinine >1.5 mg/dL,
Bilirubin-T >1.5 times of upper limit, or ALT > 2 times of upper limit.
7) History of allergic disease/reaction likely to be exacerbated by any component of the
vaccine; or any history of a severe allergic reaction or anaphylaxis.
8) Current alcohol abuse or drug addiction that might interfere with the ability to comply
with trial procedures.
9) Any other condition that in the opinion of the investigator would jeopardize the safety or
rights of a subject participating in the trial or would render the subject unable to comply
with the protocol.
10) Planned administration of any vaccine not foreseen by the study protocol, during the
period starting from 30 days before the study vaccine and ending 30 days after study
vaccination; with the exceptions of the inactivated influenza vaccine or the inactivated
rabies vaccine (without administration of immunoglobulin) administered.
11) Use of any investigational or non-registered drug or vaccine other than the study vaccine
within 30 days preceding the study vaccine/placebo or planned use at any time during the
study period or history of having received any investigational dengue vaccine at any
previous time.
12) Administration of immunoglobulins and/or blood products within 90 days preceding the
study vaccine dose or planned administration at any time during the study period, which
might interfere with assessment of the immune response. Or administration of killed
vaccine within 14 days, or attenuated vaccine within 28 days.
13) A planned or anticipated move to a location that will prohibit participating in the trial for
the 12 month duration and unavailable for schedule visit during 2nd and 3rd year followup.
14) Potential volunteers who do not have easy access to a fixed or mobile telephone.
15) Any subject identified as a site employee of the Investigator or study clinic, with direct
involvement in the proposed study or other studies under the direction of that Investigator
or study clinic, as well as any family member (i.e., immediate, husband, wife and their
children, adopted or natural) of the clinic employees or the Investigator.