RESUMO
There is an urgent need for a malaria vaccine that can prevent severe disease in young children and adults. Despite earlier work showing an immunological mechanism for preventing infection and reducing disease severity, there is currently no reliable vaccine that can provide durable protection. In part, this may reflect a limited number of ways that the host can respond to the NANP repeat sequences of circumsporozoite protein (CSP) in the parasite. In addition, it may reflect antigenic escape by the parasite from protective antibodies. To be successful, a vaccine must protect against repeated exposure to infected mosquitoes in endemic areas. We have created a series of live viral vectors based on the rubella vaccine strain that express multiple tandem repeats of NANP, and we demonstrate immunogenicity in a rhesus macaque model. We tested the vectors in a sequential immunization strategy. In the first step, the animals were primed with CSP-DNA vaccine and boosted with rubella/CSP vectors. In the second step, we gave rubella/CSP vectors again, followed by recombinant CSP protein. Following the second step, antibody titers were comparable to adult exposure to malaria in an endemic area. The antibodies were specific for native CSP protein on sporozoites, and they persisted for at least 1½ years in two out of three macaques. Given the safety profile of rubella vaccine in children, these vectors could be most useful in protecting young children, who are at greatest risk of severe malarial disease.
Assuntos
Macaca mulatta/imunologia , Vacinas Antimaláricas/imunologia , Malária Falciparum/imunologia , Plasmodium falciparum/imunologia , Proteínas de Protozoários/imunologia , Vacina contra Rubéola/imunologia , Sequência de Aminoácidos , Animais , Anticorpos Antiprotozoários/imunologia , Ensaio de Imunoadsorção Enzimática/métodos , Imunofluorescência/métodos , Humanos , Imunidade/imunologia , Imunização/métodos , Vacinas Antimaláricas/administração & dosagem , Malária Falciparum/parasitologia , Malária Falciparum/prevenção & controle , Plasmodium falciparum/genética , Plasmodium falciparum/metabolismo , Proteínas de Protozoários/genética , Proteínas de Protozoários/metabolismo , Vacina contra Rubéola/genética , Vacina contra Rubéola/metabolismo , Fatores de Tempo , Vacinas de DNA/administração & dosagem , Vacinas de DNA/imunologiaRESUMO
Anti-retroviral therapy (ART) has been highly successful in controlling HIV replication, reducing viral burden, and preventing both progression to AIDS and viral transmission. Yet, ART alone cannot cure the infection. Even after years of successful therapy, ART withdrawal leads inevitably to viral rebound within a few weeks or months. Our hypothesis: effective therapy must control both the replicating virus pool and the reactivatable latent viral reservoir. To do this, we have combined ART and immunotherapy to attack both viral pools simultaneously. The vaccine regimen consisted of DNA vaccine expressing SIV Gag, followed by a boost with live attenuated rubella/gag vectors. The vectors grow well in rhesus macaques, and they are potent immunogens when used in a prime and boost strategy. We infected rhesus macaques by high dose mucosal challenge with virulent SIVmac251 and waited three days to allow viral dissemination and establishment of a reactivatable viral reservoir before starting ART. While on ART, the control group received control DNA and empty rubella vaccine, while the immunotherapy group received DNA/gag prime, followed by boosts with rubella vectors expressing SIV gag over 27 weeks. Both groups had a vaccine "take" to rubella, and the vaccine group developed antibodies and T cells specific for Gag. Five weeks after the last immunization, we stopped ART and monitored virus rebound. All four control animals eventually had a viral rebound, and two were euthanized for AIDS. One control macaque did not rebound until 2 years after ART release. In contrast, there was only one viral rebound in the vaccine group. Three out of four vaccinees had no viral rebound, even after CD8 depletion, and they remain in drug-free viral remission more than 2.5 years later. The strategy of early ART combined with immunotherapy can produce a sustained SIV remission in macaques and may be relevant for immunotherapy of HIV in humans.
Assuntos
Síndrome da Imunodeficiência Adquirida/terapia , Fármacos Anti-HIV/uso terapêutico , Vacinas contra a SAIDS/administração & dosagem , Síndrome de Imunodeficiência Adquirida dos Símios/terapia , Vírus da Imunodeficiência Símia/imunologia , Síndrome da Imunodeficiência Adquirida/sangue , Síndrome da Imunodeficiência Adquirida/imunologia , Síndrome da Imunodeficiência Adquirida/virologia , Animais , Terapia Combinada/métodos , Modelos Animais de Doenças , Esquema de Medicação , Quimioterapia Combinada/métodos , Produtos do Gene gag/genética , Produtos do Gene gag/imunologia , Vetores Genéticos/administração & dosagem , Vetores Genéticos/genética , Humanos , Macaca mulatta , Plasmídeos/administração & dosagem , Plasmídeos/genética , Vírus da Rubéola/imunologia , Vacinas contra a SAIDS/genética , Síndrome de Imunodeficiência Adquirida dos Símios/sangue , Síndrome de Imunodeficiência Adquirida dos Símios/imunologia , Síndrome de Imunodeficiência Adquirida dos Símios/virologia , Vírus da Imunodeficiência Símia/genética , Vírus da Imunodeficiência Símia/isolamento & purificação , Fatores de Tempo , Resultado do Tratamento , Vacinas Atenuadas/administração & dosagem , Vacinas de DNA/administração & dosagem , Vacinas de DNA/genética , Latência Viral/efeitos dos fármacos , Latência Viral/imunologia , Replicação Viral/efeitos dos fármacos , Replicação Viral/imunologiaRESUMO
The hypodermoclysis technique of subcutaneous infusion has many benefits for long-term care patients and staff. Minor complications associated with the procedure are easily remedied, and studies have proved its effectiveness. Hypodermoclysis provides an easy-to-use, safe, and cost-effective alternative to intravenous hydration for the elderly long-term care patient.
