Influenza, Human Clinical Trial
Official title:
Safety and Efficacy of Intradermal Trivalent Influenza Vaccination in Institutionalized Older Adults
Influenza is associated with significant morbidity and mortality. Institutionalized older
adults (age>65) is the group associated with highest risk of complications. Influenza
vaccines are the cornerstone of influenza prevention but one systematic review has found
that there is no statistically significant difference against laboratory confirmed
influenza. A major reason is immune senescence in older adults which result in weaker
response towards vaccines when compared with young adults. Intradermal administration of
vaccine has been suggested to improve immune response due to the abundance of
immunostimulatory cells, such as dendritic cells in the dermis. Intradermal administration
of influenza vaccine has been shown to have comparable or superior efficacy compared with
intramuscular administration in the >60-year old population and the rates of adverse events
post-vaccination were also comparable between them. The immunogenicity of intradermal
administration has also been shown to be better in immunocompromised patients, including
community dwelling older adults. In addition, intradermal vaccination has good acceptability
and safety profile in different countries, so it has been licensed in Hong Kong and
worldwide. However, there is little study regarding the efficacy of intradermal vaccination
of influenza in institutionalized older adults, investigators therefore would like to
perform a prospective, randomized study to compare the safety and immunogenicity between
conventional full dose intramuscular immunization and full dose intradermal immunization of
the trivalent influenza vaccine in institutionalized older adults.
The hypothesis is that full dose intradermal trivalent influenza vaccination is as effective
as full-dose standard intramuscular injection in terms of seroconversion and seroprotection
rate in institutionalized older adults. Finding of this study will be important in the
vaccination of institutionalized older adults and immunocompromised patients as intradermal
vaccine may induce a better immune response against influenza infection.
This is a prospective, randomized, parallel-group single centre trial in the Queen Mary
Hospital and Fung Yiu King Hospital. Investigators aim to recruit 100 subjects who would be
qualified for the Hospital Authority (HA)/ Centre for Health Protection (CHP) Mass
Vaccination Program for Trivalent influenza vaccine (TIV). These patients include
Institutionalized older adult patients at the age of 65 or above.
After informed consent (allow patient one week to consider) subjects will be randomly
assigned into 2 groups to receive the following vaccines: Group 1: the full-dose (1 dose)
standard TIV (15ug hemagglutinin TIV) delivered intramuscularly using a conventional needle,
Group 2: a full-dose (1 dose) intradermal injection (15ug hemagglutinin TIV) delivered with
the Intanza 15 at day 0. All TIV vaccines used in this study will be either of Vaxigrip®
(Group 1) or Intanza® Intradermal (Group 2), Sanofi-Pasteur and provided by the Hospital
Authority or the University of Hong Kong. Baseline HI to the TIV will be measured at day 0.
Patients fulfilling the inclusion criteria will be screened from the Community Geriatric
Assessment Team (CGAT) of Fung Yiu King Hospital by the investigators. Before commencing,
patients would be allowed to have one week to consider joining the study. Meanwhile,
investigators would also take 5ml of serum from the participant to test for the baseline TIV
antibody. Principal Investigator is experienced in administering intramuscular injections
and he would be responsible for refilling the low-dose intradermal injection in a sterile
technique. The microneedle device used in this study comprises an array of three 0.6 mm
microneedles, made up of silicon crystal, and bonded to the tip of a plastic adapter, which
can be mounted on any standard syringe. During injection, the microneedle device was lightly
pushed against the shoulder so that the microneedles penetrated the outmost layer of skin.
The entire vaccine dose will then be injected causing a blanched bleb to appear.
Intramuscular injection of conventional full-dose vaccine is given in the usual way with the
prefilled syringe. Principal Investigator will be responsible for subject bleeding, serum
separation, storing in doublet copies, freezing and archiving, according to HKU protocols.
MN and HI analysis (see below) shall be conducted by the HKU Laboratory according to the
following protocols:
Microneutralization antibody assay (MN) NT will be performed inside a type II Biosafety
Cabinet in a Biosafety Containment level III facility. NT will be performed in 96-well
microtiter plates seeded with MDCK cells. Two fold serial dilutions of paired serum (pre-
and post-vaccination) will be tested in duplicates against 100 TCID50 of the following 3
viruses: A/California/7/2009 (H1N1)pdm09-like virus; an A/Victoria/361/2011 (H3N2)-like
virus; and a B/Wisconsin/1/2010-like virus in the presence of L-1-tosylamide-2-phenylethyl
chloromethyl ketone (TPCK)-treated trypsin (TPCK-trypsin; Sigma). A corresponding set of
cell controls with sera but without virus inoculation will be used as controls. The cells
will be scored for the inhibition of the cytopathic effect (CPE) at 72~96 hours. The titer
of neutralization antibody is defined as the maximum dilution of serum at which the
percentage of CPE is less than or equal to 50%.
HI assay Serum samples will be tested for Hemagglutination inhibition (HI) antibody against
the following: A/California/7/2009 (H1N1)pdm09-like virus; an A/Victoria/361/2011
(H3N2)-like virus; and a B/Wisconsin/1/2010-like virus using reference antigens (WHO
influenza reagent kit provided by the World Health Organization influenza Collaborating
Centre, CDC, Atlanta, Georgia, USA. HAI antibody assays will be performed by standard
microtiter techniques after removal of non-specific inhibitors in serum with receptor
destroying enzyme (RDE) (1:3), incubation overnight at 37 degree C followed by
heat-inactivation at 56 degree C for 30 minutes. All serum samples from each subject will be
tested for each of the test antigens. Serial two-fold dilutions of RDE-treated serum from
1:10 will be titrated against 4 hemagglutinin units of reference antigens using 0.25% turkey
erythrocytes. A doublet backup of each serum sample would be prepared and frozen in two
separately located freezers at -20ºC for potential future analysis and/or validation.
Outcome measures:
Primary outcome:
a. Change from baseline (day 0 of vaccination )in neutralization antibody titre against
influenza at day 21 and day 180 of vaccination
Secondary outcomes:
a. Adverse effects at day 0-7
;
Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Prevention
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