RESUMO
The RV144 HIV-1 vaccine trial (Thailand, 2003 to 2009), using immunogens genetically matched to the regional epidemic, demonstrated the first evidence of efficacy for an HIV-1 vaccine. Here we studied the molecular evolution of the HIV-1 epidemic from the time of immunogen selection to the execution of the efficacy trial. We studied HIV-1 genetic diversity among 390 volunteers who were deferred from enrollment in RV144 due to preexisting HIV-1 infection using a multiregion hybridization assay, full-genome sequencing, and phylogenetic analyses. The subtype distribution was 91.7% CRF01_AE, 3.5% subtype B, 4.3% B/CRF01_AE recombinants, and 0.5% dual infections. CRF01_AE strains were 31% more diverse than the ones from the 1990s Thai epidemic. Sixty-nine percent of subtype B strains clustered with the cosmopolitan Western B strains. Ninety-three percent of B/CRF01_AE recombinants were unique; recombination breakpoint analysis showed that these strains were highly embedded within the larger network that integrates recombinants from East/Southeast Asia. Compared to Thai sequences from the early 1990s, the distance to the RV144 immunogens increased 52% to 68% for CRF01_AE Env immunogens and 12% to 29% for subtype B immunogens. Forty-three percent to 48% of CRF01_AE sequences differed from the sequence of the vaccine insert in Env variable region 2 positions 169 and 181, which were implicated in vaccine sieve effects in RV144. In conclusion, compared to the molecular picture at the early stages of vaccine development, our results show an overall increase in the genetic complexity of viruses in the Thai epidemic and in the distance to vaccine immunogens, which should be considered at the time of the analysis of the trial results.
Assuntos
Surtos de Doenças , Evolução Molecular , Variação Genética , Infecções por HIV/epidemiologia , HIV-1/genética , Sequência de Bases , Citometria de Fluxo , Genótipo , Infecções por HIV/genética , Humanos , Funções Verossimilhança , Modelos Genéticos , Dados de Sequência Molecular , Filogenia , Análise de Sequência de DNA , Tailândia/epidemiologia , Vacinas Virais/genéticaRESUMO
BACKGROUND: The Thai Phase III Trial of ALVAC-HIV and AIDSVAX B/E showed an estimated vaccine efficacy (VE) of 31% to prevent acquisition of human immunodeficiency virus (HIV). Here we evaluated the effect of vaccination on disease progression after infection. METHODS: CD4(+) T-cell counts and HIV viral load (VL) were measured serially. The primary analysis evaluated vaccine efficacy (VEP) as the percent reduction (vaccine vs placebo) in cumulative probability of a primary composite endpoint of clinical and CD4(+) count components at prespecified time points after infection. Secondary analyses of biomarker-based endpoints were assessed using marginal mean and linear mixed models. RESULTS: There were 61 endpoints in the modified intent-to-treat cohort (mITT; n = 114). There was no evidence for efficacy at 30, 42, 54, and 60 months in the mITT and per protocol (n = 90) cohorts. Estimated VEP (mITT) was15.8% (-21.9, 41.8) at 60 months postinfection. There was weak evidence of lower VL and higher CD4(+) count at 60 and 66 months in the vaccine group. Lower mucosal VL was observed among vaccine recipients, primarily in semen (P = .04). CONCLUSIONS: Vaccination did not affect the clinical course of HIV disease after infection. A potential vaccine effect on the genital mucosa warrants further study.
Assuntos
Vacinas contra a AIDS/imunologia , Infecções por HIV/virologia , HIV-1/imunologia , Vacinas Virais/imunologia , Vacinas contra a AIDS/administração & dosagem , Adulto , Terapia Antirretroviral de Alta Atividade/métodos , Contagem de Linfócito CD4 , Progressão da Doença , Feminino , Seguimentos , Infecções por HIV/imunologia , Infecções por HIV/patologia , Infecções por HIV/prevenção & controle , HIV-1/patogenicidade , Humanos , Modelos Lineares , Masculino , Estudos Prospectivos , Assunção de Riscos , Sêmen/virologia , Tailândia , Fatores de Tempo , Vacinação , Vagina/virologia , Carga Viral , Vacinas Virais/administração & dosagem , Adulto JovemRESUMO
Cynomolgus monkeys, as animal models of scrub typhus, are typically infected with Orientia tsutsugamushi by intradermal inoculation. However, the clinical and histological features at the O. tsutsugamushi inoculation sites, akin to "eschars" at chigger inoculation sites in humans, have not been fully characterized. We intradermally inoculated one medial thigh of six cynomolgus monkeys with semi-purified O. tsutsugamushi (Karp). Within 7 days, two animals developed scrub typhus-like eschars and four had dusky plaques, accompanied by inguinal lymphadenopathy. Biopsies of eschars and an enlarged regional lymph node resembled human disease and stained positively for O. tsutsugamushi by Giemsa, anti-Karp fluorescent antibody, or streptavidin alkaline phosphatase. O. tsutsugamushi-specific IgM and IgG antibody levels measured in both of two monkeys rose steadily after infection. This pilot study shows that cynomolgus intradermally inoculated with O. tsutsugamushi replicate the localized cutaneous pathogenesis of human scrub typhus infections, strengthening the value of this animal model.
Assuntos
Macaca fascicularis/microbiologia , Doenças dos Macacos/patologia , Orientia tsutsugamushi/fisiologia , Tifo por Ácaros/patologia , Pele/patologia , Animais , Anticorpos Antibacterianos/sangue , Modelos Animais de Doenças , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Injeções Intradérmicas , Linfonodos/microbiologia , Doenças Linfáticas/etiologia , Doenças Linfáticas/microbiologia , Doenças Linfáticas/patologia , Masculino , Projetos Piloto , Tifo por Ácaros/complicações , Tifo por Ácaros/imunologiaRESUMO
We assessed the prophylactic efficacy of azithromycin (250 mg/day) against malaria in 276 adults in western Thailand in a randomized, double-blind, placebo-controlled trial. After antimalarial suppressive treatment, volunteers were randomized in a 2:1 ratio to either the azithromycin or placebo, respectively. Study medication was given for an average of 74 days. The azithromycin group (n = 179) had five endpoint parasitemias (1 Plasmodium vivax and 4 P. falciparum), and the placebo group (n = 97) had 28 endpoint parasitemias (21 P. vivax, 5 P. falciparum, and 2 mixed infections). Adverse events and compliance and withdrawal rates were similar in both groups. The protective efficacy (PE) of azithromycin was 98% for P. vivax (95% confidence interval [CI] = 88-100%). There were too few cases to reliably estimate the efficacy of azithromycin for P. falciparum (PE =71%, 95% C =-14-94%). We conclude that daily azithromycin was safe, well-tolerated, and had a high efficacy for the prevention of P. vivax malaria.
Assuntos
Antimaláricos/uso terapêutico , Azitromicina/uso terapêutico , Malária Vivax/prevenção & controle , Parasitemia/prevenção & controle , Adulto , Animais , Antimaláricos/administração & dosagem , Azitromicina/administração & dosagem , Quimioprevenção , Método Duplo-Cego , Feminino , Humanos , Malária Vivax/epidemiologia , Malária Vivax/parasitologia , Masculino , Parasitemia/epidemiologia , Parasitemia/parasitologia , Plasmodium vivax/efeitos dos fármacos , Tailândia/epidemiologia , Resultado do TratamentoRESUMO
The development of HIV research laboratories at the Armed Forces Research Institute of Medical Sciences (AFRIMS), Royal Thai Army Medical Department in supporting of HIV-1 vaccine trials in Thailand was implemented in 1991. The collaboration between AFRIMS, Royal Thai Army Medical Department, and the US Military HIV Research Program with the ultimate goal to conduct the HIV-1 vaccine trial phase III. The HIV serology lab was set up for surveillance program in military recruits. Then, there was a need to strengthen more on the existing laboratories by training personnel to cope with the confidentiality of the lab results, specimen processing and data management which are critical. Later on, the necessary laboratory for measuring of vaccine immunogenicity was developed, such as lymphoproliferation assay. Additionally, a molecular biology lab was also developed. The HIV research laboratory management must include an ability to deal with some problems, such as late specimen receiving, fluctuating of power supply, technical staffs maintained. Good laboratory practices and safety must be strictly implemented. Communication network among facilities also played an important role in HIV laboratory strengthening at AFRIMS.
Assuntos
Academias e Institutos/organização & administração , Pesquisa Biomédica , Infecções por HIV , Medicina Militar , Humanos , TailândiaRESUMO
We measured plasma tafenoquine concentrations in Thai soldiers given a monthly regimen of tafenoquine to determine whether these concentrations adequately suppressed malarial infections on the Thai-Cambodian border. After receiving a treatment course of artesunate and doxycycline, 104 male soldiers were administered a loading dose of tafenoquine (400 mg daily for 3 days), followed by tafenoquine monthly (400 mg every 4 weeks) for 5 months. Consecutive monthly mean (+/- standard deviation) trough plasma tafenoquine concentrations were 223+/-41, 127+/-29, 157+/-51, 120+/-24, and 88+/-20 ng/mL. Only 1 soldier developed malaria during the study. At the time of malaria diagnosis, his plasma tafenoquine concentration was 40 ng/mL, which was approximately 3-fold lower than the trough concentrations of the other soldiers. Although low tafenoquine concentrations appear to be uncommon, additional investigations are needed to determine the relationship between plasma tafenoquine concentrations and suppression of malaria.
Assuntos
Aminoquinolinas/sangue , Antimaláricos/sangue , Adulto , Artemisininas/sangue , Artesunato , Quimioprevenção , Método Duplo-Cego , Doxiciclina/sangue , Humanos , Masculino , Pessoa de Meia-Idade , Militares , Sesquiterpenos/sangue , TailândiaRESUMO
We compared the performance of 2 commercially available dipstick assays, 2 enzyme-linked immunosorbent assays (ELISAs), and an indirect immunofluorescent antibody (IFA) assay for the diagnosis of scrub typhus, using the indirect immunoperoxidase (IIP) test as the reference standard. The dipstick assays were the Integrated Diagnostics (Baltimore, MD) Dip-S-Ticks Scrub Recombinant (r56) dipstick test (INDX assay) and the PanBio (Brisbane, Australia) Scrub Typhus IgM and IgG Rapid Immunochromatographic test (PanBio assay). One of the ELISAs used pooled cell lysates of Karp, Kato, and Gilliam strain Orientia tsutsugamushi as antigen (pooled-antigen ELISA), and the other used a recombinant r56 protein as the antigen (recombinant ELISA). With a panel of 123 positive and 227 negative sera, sensitivity and specificity of the assays were as follows: INDX assay, IgG, 60% and 95%, IgM, 60% and 97%; PanBio assay, IgG, 94% and 96%, IgM, 83% and 93%; IFA (1:400 cutoff), IgG, 91% and 96%, IgM, 85% and 98%; pooled-antigen ELISA, IgG (1:1600 cutoff), 97% and 89%, IgM (1:400 cutoff), 94% and 91%; recombinant ELISA, IgG (1:1600 cutoff), 97% and 92%, IgM (1:400 cutoff), 93% and 94%. Because of its excellent performance and use of a standardized, commercially available antigen, the recombinant ELISA is suitable for use in a diagnostic laboratory, where it may be able to replace the IFA and IIP assays. In contrast, the PanBio dipstick assay was easy to perform and did not require sophisticated equipment, making it suitable for use in rural areas where more sophisticated diagnostic tests such as the ELISA and IFA may not be available.
Assuntos
Anticorpos Antibacterianos/análise , Imunoglobulina G/análise , Imunoglobulina M/análise , Orientia tsutsugamushi/imunologia , Tifo por Ácaros/diagnóstico , Tifo por Ácaros/imunologia , Ensaio de Imunoadsorção Enzimática , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Masculino , Reprodutibilidade dos Testes , Saúde da População Rural , Tifo por Ácaros/epidemiologia , Sensibilidade e Especificidade , Testes Sorológicos , Tailândia/epidemiologiaRESUMO
Murine typhus and scrub typhus are important human rickettsial diseases in Thailand. Small mammals, including many species of rodents and shrews, serve as the reservoir host of rickettsial diseases. Rickettsia typhi can be transmitted to humans by fleas causing murine typhus, while infection with Orientia tsutsugamushi causing scrub typhus in humans is transmitted by chiggers. The prevalence of rickettsial infection depends on the geographic area. The seroprevalence of antibody to R. typhi and O. tsutsugamushi was studied in commensal rodents and shrews trapped in markets in the Bangkok Metropolitan Area (BMA). R. typhi and O. tsutsugamushi antigen prepared in the yolk sac of embryonated eggs were used to determine the specific antibody in trapped animals' sera by using fluorescein isothiocyanate (FITC)-anti rat immunoglobulins as a second antibody. Antibody to R. typhi was found in 25 (5%) of 500 sera tested and no antibody to O. tsutsugamushi was detected. R. typhi antibody titer ranged from 40-1280 and was found in Rattus norvegicus (4.2%), Rattus rattus (0.4%), Rattus exulans (0.2%), and Mus musculus (0.2%) trapped in 8 of 47 markets in the BMA. R. typhi antibody was commonly found in R. norvegicus. The authors concluded that murine typhus is an important rickettsial disease and R. norvegicus is an important reservoir species of rodents found in markets of the BMA.
Assuntos
Infecções por Rickettsia/epidemiologia , Doenças dos Roedores/epidemiologia , Animais , Anticorpos Antibacterianos/análise , Muridae , Ratos , Infecções por Rickettsia/veterinária , Tifo por Ácaros/epidemiologia , Tifo por Ácaros/veterinária , Estudos Soroepidemiológicos , Tailândia/epidemiologia , Tupaiidae , Tifo Endêmico Transmitido por Pulgas/epidemiologia , Tifo Endêmico Transmitido por Pulgas/veterinária , Saúde da População UrbanaRESUMO
Described herein is the clinical presentation of a patient from Bangkok, with fever, petechial rash, history of a tick bite, and a diagnosis of spotted fever rickettsiosis.
Assuntos
Infecções por Rickettsia/epidemiologia , Infecções por Rickettsia/microbiologia , Adulto , Antibacterianos/uso terapêutico , Anticorpos Antibacterianos/sangue , Doxiciclina/uso terapêutico , Humanos , Imunoglobulina G/sangue , Imunoglobulina M/sangue , Masculino , Infecções por Rickettsia/sangue , Infecções por Rickettsia/tratamento farmacológico , TailândiaRESUMO
Human spotted fever rickettsiosis was detected molecularly by 2 real-time polymerase chain reaction (PCR) assays performed on DNA extracted from a Thai patient's serum sample. Sequences of PCR amplicons from 5 rickettsial genes used for multilocus sequence typing were 100% identical with those deposited with GenBank for Rickettsia honei TT-118.
Assuntos
Técnicas de Amplificação de Ácido Nucleico/métodos , Infecções por Rickettsia/sangue , Rickettsia/genética , Adulto , Humanos , Masculino , Biologia Molecular/métodos , Rickettsia/isolamento & purificação , Infecções por Rickettsia/diagnóstico , Infecções por Rickettsia/fisiopatologia , TailândiaRESUMO
We assessed monthly doses of tafenoquine for preventing Plasmodium vivax and multidrug-resistant P. falciparum malaria. In a randomized, double-blind, placebo-controlled study, 205 Thai soldiers received either a loading dose of tafenoquine 400 mg (base) daily for 3 days, followed by single monthly 400-mg doses (n = 104), or placebo (n = 101), for up to 5 consecutive months. In volunteers completing follow-up (96 tafenoquine and 91 placebo recipients), there were 22 P. vivax, 8 P. falciparum, and 1 mixed infection. All infections except 1 P. vivax occurred in placebo recipients, giving tafenoquine a protective efficacy of 97% for all malaria (95% confidence interval [CI], 82%-99%), 96% for P. vivax malaria (95% CI, 76%-99%), and 100% for P. falciparum malaria (95% CI, 60%-100%). Monthly tafenoquine was safe, well tolerated, and highly effective in preventing P. vivax and multidrug-resistant P. falciparum malaria in Thai soldiers during 6 months of prophylaxis.
Assuntos
Aminoquinolinas/uso terapêutico , Antimaláricos/uso terapêutico , Malária Falciparum/prevenção & controle , Malária Vivax/prevenção & controle , Plasmodium falciparum/efeitos dos fármacos , Administração Oral , Animais , Método Duplo-Cego , Esquema de Medicação , Resistência a Múltiplos Medicamentos , Seguimentos , Humanos , Militares , Tailândia , Resultado do TratamentoRESUMO
ALVAC-HIV (vCP1521) and AIDSVAX B/E were evaluated in a phase 1/2 trial of human immunodeficiency virus (HIV)-negative Thai adults. Of 133 volunteers enrolled, 122 completed the trial. There were no serious vaccine-related adverse events, nor were there intercurrent HIV infections. Lymphoproliferative responses to glycoprotein 120 E were induced in 63% of the volunteers, and HIV-specific CD8 cytotoxic T lymphocyte responses were induced in 24%. Antibody responses increased in frequency and magnitude in association with the dose level of AIDSVAX B/E. Binding and neutralizing antibodies to the MN strain were induced in 100% and 98%, respectively, of the volunteers receiving 600 microg of AIDSVAX B/E, and such antibodies to E strains were induced in 96% and 71%, respectively, of these volunteers. This vaccine combination was well tolerated and was immunogenic, meeting milestones for advancement to phase 3 evaluation.