| Volunteer studies at the Vaccine Trial Centre |
| Sine
its establishment, many vaccine studies have been conducted at the Vaccine Trial Centre. A. Cholera vaccines (against O1 serotype) By Principal in Investigator - Dr. Sricharoen Migasena The initial series of four studies were supported by the WHO-CDD programme to evaluate the current oral cholera vaccine candidates. The studies include: * Safety and immunogenicity of B-sub-unit./ whole cell cholera vaccine. * Dose-finding study for procholeragenoid and compared immunogenicity of procholeragenoid and B-sub-unit. * Safety and immunogenicity of live oral cholera vaccine candidate CVD103. * Establishment of a challenge dose of V. cholerae N16961. Following the initial phase, other cholera vaccine candidates, both non-living antigen vaccine and live attenuated mutant vaccine studies were conducted here. These vaccines include Pasteur oral cholera or Dodin vaccine that consists of isolated antigenic fractions from V. cholerae El Tor, Ogawa, and Inaba. CVD 103 HgR is a genetically engineered attenuated V. cholerae, O1, and S. typhi Ty21a/V. cholerae Inaba Hybrid Vaccine. Reactogenicity, acceptability, dose findings, dose schedules for optimum immune response, immunogenicity in terms of serology and local (gut) immunity were also evaluated as well as challenge studies to evaluate the efficacy of vaccines for partial or complete protection form illness. All above studied vaccines were found safe and acceptable to volunteers. No severe side effects attributed to the vaccine were reported. B. Rotavirus Vaccine Apart form cholera vaccines, rotavirus candidate vaccine is another diarrhoeal diseases vaccine being tested. Studies on antibody responses and interaction between tetravalent rotavirus vaccine and oral poliovirus vaccine (OPV) were performed in collaboration with paediatricians at Phramongkutklao Hospital (The Royal Thai Army Hospital). The objectives of the study were (a) to establish whether simultaneous administration of OPV and tetravalent rotavirus vaccine results in impaired seroconversion to an individual component of either vaccine (poliovirus serotypes 1, 2, 3, rotavirus serotypes (VP7) 1, 2, 3 & 4). (b) to investigate whether mutual interference can be overcome by giving multiple doses (2 or 3) of the vaccine. The project was supported by CDD programme of WHO. The study was a randomised double-blind placebo-controlled for each of the vaccines. C. Poliomyelitis Vaccine (OPC vs. IPV) The project entitled "A comparative trial of oral polio vaccine (OPV), inactivated polio vaccine (IPV), and simultaneously administered OPV and IPV in Thai infants" was a multi-centred study in three different countries namely Gambia, Oman, and Thailand. The project was supported by the EPI Programme of the World Health Organization. The study was performed in collaboration with paediatricians at Phramongkutklao Hospital. The study was a prospective randomised double blind comparative trial of OPV/IPV and combined OPV and IPV in Thai infants. The objectives of the study was whether three doses of IPV alone given at one month interval in early infancy gives adequate serological response and whether simultaneous administration of OPV and IPV gives better humoral antibody than OPV alone and better acquired immunity than IPV alone. D. Malaria Vaccines (Phase I/II) Many malaria vaccine candidates have been planned for the study at the VTC by various groups of investigators for many years, but unfortunately, the studies elsewhere did no show promising results. In 1992, the first malaria vaccine was studied at the VTC in collaboration with Armed Forces Research Institute of Medical Sciences (AFRIMS) and Walter Reed Army Institute of Research (WRAIR). The project "Evaluation of the safety and immunogenicity of a falciparum sporozoite vaccine (RTS,S/' D-MPL) in malaria naive and experienced Thai adults" was studied at the VTC itself for the naive group and the team moved to malaria endemic area, Pong Nam Ron, Chanthaburi Province for the experienced Thai adults group. A total of 30 adult Thai male volunteers, 15 malaria-naive and 15 malaria malaria-experienced individuals, received two doses of the vaccine (at 0th and 8th weeks). Each dose of vaccine was well tolerated in both groups; the major reaction noted was tenderness at the site of infection one and two days after each dose. Peak antibody levels to the repeat region of CSP was seen at two weeks after the first dose in both groups, but no boosting was observed after the second dose. In contrast, antibodies to the carboxy terminal region of CSP increased after each dose. Interestingly, five of 14 malaria naive and seven of 15 malaria experienced volunteers developed cytotoxic T-lymphocyte activity against a T-cell epitope in the carboxy terminal region of CSP. The results of this study indicate that the RTS,S/alum/3D-MPL vaccine was safe and immunogenic in adult Thai males and when compared to results of a similar trial in American volunteers, suggest that ethic differences may play a role in the immune response to this investigational malaria vaccine. In late 1993, another malaria vaccine study was scheduled at the VTC. The title of the study was "Phase I Safety and Immunogenicity Testing of a Multistage Plasmodium falciparum vaccine, SPf66, at Mahidol University Vaccine Trial Centre" The study was conducted in malaria-naive Thai adults. Three doses of vaccine were given sub-cutaneously at deltoid region at 0,1 and 6 months. Only minor local reactions were observed. There were no significant post-immunisation changes in biochemical, haematological, or urological parameters. Vaccine immunogenicity was assessed by standard ELISA using SPf66 as a capture antigen. Eight of 11 volunteers seroconverted after three doses. Preliminary experiments showed that seven of 11 volunteers developed T cells capable of recognising SPf66 in vitro as measured in proliferative assays. A positive correlation exists between antibody response and lympho-proliferative results. In conclusion, cGMP-SPf66 proved safe and immunogenic in this Phase I study. E. Varicella Vaccine The project entitled "Seroepidemiological survey of varicella-zoster infection in Thai population" was initiated to determine first, the seroprevalence of infection with Varicella Zoster virus in various age groups the relationship between serological background and various epidemiological and demographic factors. At the same time, in collaboration with paediatrician at Phramongkutklao Hospital, a study entitled "Comparative assessment of the immunogenicity and reactogenicity of three different antigenic mass content of live attenuated Varicella vaccine in 9-36 months old Thai children" was performed. The study was supported by SmithKline Beecham Biologicals, Belgium. F. Measles Vaccine Since 1990, the Global Advisory Group to the Expanded Programme on Immunization (EPI) of WHO endorsed the immunisation of measles vaccine in infants. Alternate routes of administering measles vaccine, both by aerosol and intranasally, have been successful in immunising young children. Such alternate routes are attractive because of the ease of administration, the ability of non-medical personnel to give the vaccine, child acceptance, parental preference, and because alternate routes avoid transmission risks of hepatitis B and HIV associated with injections They may also produce superior mucosal immunity, which may be of some importance in interrupting circulation of the wild measles virus in communities. Therefore, the project entitle "A pilot trial of Edminston-Zagreb measles vaccination by intranasal and subcutaneous routes in young children" is performed in collaboration with paediatricians at Phramongkutklao Hospital. The objectives of the study are to evaluate seroresponse rates in children after administration of Edmonston-Zagreb (EZ) vaccine by intranasal and subcutaneous routes at 6 month of age. Reactogenicity is compared among study groups following both vaccination sessions. The project is supported by The Task Force of Child Survival and Development. G. New Cholera Vaccine (O139) A series of cholera O139 studies were scheduled in 1995-1996by the support of Global Programme on Vaccine (GPV) of the World Health Organization. The first study was to identify the optimal doses of Vibrio cholerae O139 to be used in subsequent efficacy challenge studies. The second was to assess the clinical tolerance as well as immune responses to a killed whole cell Vibrio cholerae O139 vaccine and to determine its protective efficacy by a challenge study. The third was to assess the clinical tolerance as well as immune responses to an attenuated Vibrio cholerae O139 vaccine-the Bengal 3 strain and to determine its protective efficacy by a challenge study as presented in the abstract entitled. "Validation of a Human Volunteer Challenge Model Using Frozen Bacteria of the New between North American and Trial2 Volunteers" By Dr. Punnee Pitisuttithum |
| H.
HIV - I Vaccine Trial I. Monovalent AIDSVAXtm MN Vaccine Trial |
| A vaccine to protect humans from HIV-1 infection is urgently needed. A prototype candidate HIV-1 vaccine consisting of a genetically engineered gp120 protein which accurately imitates the outer envelope glycoprotein of HIV-I MN strain has been produced by Genentech Inc., (South San Francisco, CA, USA) and has been studied in the United States. Therefore, at the beginning of 1995, the VTC in collaboration with the Bangkok Metropolitan Administration (BMA) and the Virology Division of the Faculty of Medicine, Siriraj hospital launched the HIV candidate vaccine trial entitled "Evaluation of safety and immunogenicity (phase I/II) of MN rgp120/HIV-1 alum-adjuvant candidate vaccine in recovering intravenous drug users in Bangkok, Thailand" to determine its safety and immunogenicity. The financial support came from Global Programme on AIDS (GPA) of the World Health Organization and Genentech, Inc., USA. The first dose of vaccine was given on the 21 February 1995. This preventive vaccine will be given at four doses, 0, 1, 6 and 12 months. The interim analysis after the third dose at 6.5 months showed that the vaccine was safe and immunogenic. |
| II. Bivalent B/E HIV-I Vaccine Trial |
| There
is considerable genetic variation among HIV-1 strains isolated from different
geographical locations worldwide. Therefore, evaluation of candidate vaccines
that are composed of antigens commonly circulated in a given location
and population and that have been demonstrated safe and immunologically
active in preclinical studies is a reasonable strategy. HIV-1 isolates
routinely recovered from newly infected individuals in Thailand are of
subtypes B and E, with E viruses predominating. Therefore the VTC/FTM,
Armed Forces Research Institute of Medical Sciences (AFRIMS) in Bangkok,
Research Institute for Health Sciences (RIHES) in Chiang Mai, and the
Faculty of Medicine, Siriraj Hospital (Thai AIDS Vaccine Evaluation Group)
launched the interesting AIDS vaccine trial entitled. * A Phase I/II, Double-blind, Placebo-controlled Study of the Chiron Vaccines HIV Thai E gp120/MF59 Vaccine Administered Alone or Combined with the Chiron Biocine HIV SF2 gp120 Antigen in Healthy HIV-Seronegative Thai adults. Current Principal Investigator at VTC. - Dr. Punnee Pitisuttithum At the same time, a Phase I/II AIDSVAXTM B/E Vaccine was started in late 1998. This trial was extremely important before the decision was made to proceed to phase III efficacy trial of AIDSVAXTM B/E Vaccine in Thailand. Early in the investigation of HIV-1, antibodies that could neutralise HIV-1 and found that, similar to other viruses, these antibodies were directed to the envelope protein gp120 of the virus. These findings led to the development of AIDSVAXTM based on the gp120 protein. AIDSVAXTM vaccine consists of highly purified glycoproteins produced in Chinese Hamster Ovary (CHO) cells by recombinant DNA technology. The data from a Phase I/II trial of AIDSVAX? B/E vaccine both in Thailand and U.S.A. showed that the vaccine is highly safe and immunogenic. There are two projects of AIDSVAXTM B/E vaccine as follows: * A phase I/II trial to evaluation the safety and immunogenicity of AIDSVAXTM B/E vaccine in Bangkok, Thailand. Principal Investigator-Dr.Punnee Pitisuttithum Preliminary result of this study showed that AIDSVAXTM B/E appeared to be highly safe and immunogenic in human. Interim analysis of this study had led to the decision to move on to a phase III trial to determine the efficacy AIDSVAX? B/E in March 1999 * A Phase III Trial to Determine the efficacy of AIDSVAXTM the efficacy of AIDSVAXTM B/E vaccine in Intravenous Drug Users in Bangkok, Thailand. It is a collaborative study with Bangkok Metropolitan Administration, HIV/AIDS Collaboration ( US CDC, Atlanta, and the Thai Ministry of Public Health). This phase III trial is a randomised, double blind, placebo-controlled trial among 2,500 HIV-negative IDU attending 17 BMA drug treatment clinics. As part of the Thai national requirement to strengthen the infrastructure of the country, the first state-of-art Data Management Unit (DMU) in Asia was established by VaxGen Inc. at the Faculty using the DataFax (Clinical DataFax Systems Inc., Hamilton, Ontario, Canada) technology. This technology allows the quality control (QC) and quality assurance (QA) on data management to be 'real-time', because the Case-Report Form (CRF) can be transmitted via facsimiles from 17 clinics instead of key-punching the data. Real-time QA and QC could then be established. The establishment of the DMU is probably the first time in Thailand that clinical trial data for licensing purpose is practised in Thailand. A Faculty's VTC team is also responsible for the Good Clinical Practice (GCP) of this important trial. |
| III. Prime-boost Concept Vaccine |
| While
gp120 antigens elicit a strong humoral response, they have usually not
induced an anti-HIV CD8+ specific CTL response. In contrast, live recombinant
vaccinia-virus constructs encoding HIV-I genes can infect mammalian cells
causing them to express HIV-I proteins. Aventis Pasteur has developed
a recombinant canarypox virus (ALVAC) that can express foreign genes.
In mammalian cells, canarypox undergoes an abortive cycle of replication
and does not produce infectious progeny. This suggests that ALVAC will
not disseminate or be transmitted to unvaccinated contacts. Aventis Pasteur
has utilised the ALVAC construct to express genes from rabies, measles,
cytomegalovirus and Japanese encephalitis virus, and clinical trials with
these constructs have demonstrated safety and immunogenicity. No serious
adverse events attributable to the ALVAC vaccine have been reported in
over 800 subjects receiving an ALVAC construct (Aventis Pasteur unpublished
data). Recombinant canarypox constructs elicit moderate to strong CD8+
restricted CTL in human volunteers, presumably due to antigen processing
via the MHC class I pathway. Although ALVAC constructs generally elicit
both antibody and CTL responses, the level of antibody can be significantly
boosted by administration of a soluble protein antigen. So the Thai AIDS
Vaccine Evaluation Group launched the project entitled. * A Phase I/II Trial of Pasteur Merieux Connaught Live Recombinant ALVAC-HIV (vCP1521) Priming With VaxGen gp120 B/E (AIDSVAXTM B/E) Boost in Thai HIV Seronegative Adults was started in March 2000. VTC Principal Investigator - Dr. Punnee Pitisuttithum I. Tetravalent Live - attenuated Dengue Vaccines Dengue vaccine development efforts have proceeded slowly with many months and years of testing before a suitable candidate vaccine could be identified. No known, reliable in vitro markers of attenuation for dengue virus exist, nor is there a proven animal model for predicting attenuation of dengue virus for humans. Over the past 20 years, many live-attenuated dengue candidate vaccines have been evaluated in humans; many of which were found to be poor vaccines due to either under-attenuation (i.e. the vaccines made the volunteers too ill) or over-attenuation (i.e. the vaccines did not induce an adequate immune response). The Mahidol University group from Thailand successfully developed candidate live-attenuated vaccines for dengue serotype 1,2, and 4 viruses in primary dog kidney cells and for serotype 3 in primary green monkey kidney cells. These vaccines have been tested as monovalent, bivalent, trivalent, and tetravalent vaccines in several dozen Thai volunteers, and were found safe and immunogenic in both Thai children and adults. The four attenuated strains were then transferred to Aventis Pasteur for scaling up to industrial manufacture. Two trials of Aventis Pasteur Tetravalent Live-attenuated Dengue Vaccine have been performed at the Faculty of Tropical Medicine, Mahidol University during 1998-2000. These studies are randomised double blind trials. * Safety and Immunogenicity of Tetravalent Live-attenuated Dengue Vaccine Formulations in Thai Adult Volunteers. The objective of the study is to determine the safety and immunogenicity of the Aventis Pasteur Tetravalent Live-attenuated Dengue Vaccine seven formulations given in 2 doses (six months apart) in Thai adult volunteers Principal Investigator: Assoc. Prof. Pornthep Chanthavanich Department of Tropical Paediatrics * Safety and Immunogenicity of Tetravalent Live-attenuated Dengue Vaccine Formulations in Thai Children The objective of the study is to determine the safety and immunogenicity of two formulations of the Aventis Pasteur Tetravalent Live-attenuated Dengue Vaccine Thai children aged 5-12 years Principal Investigator: Prof. Arunee Sabchareon Department of Tropical Paediatrics |