CpG oligonucleotides induce strong humoral but only weak CD4+ T cell responses to protein antigens in rhesus macaques in vivo
ABSTRACT Oligonucleotides containing CpG motifs (CpG ODN) are strong adjuvants for humoral immune responses but data on cellular immune responses in primates are scarce. Rhesus macaque blood contained similar numbers of plasmacytoid dendritic cells and B cells, the key sensors of CpG ODN, as human blood, and these cells were activated by CpG-A and CpG-B in vitro. In vivo, both ODNs induced equal plasma levels of interferon-inducible protein 10 and similarly enhanced antibody responses following i.m. injections of the ODNs, protein antigen, and aluminium hydroxide into rhesus macaques, whereas antigen-specific CD4(+) T cell responses were only slightly increased by CpG ODN.
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ABSTRACT: The goal for an effective malaria transmission-blocking vaccine (TBV) is to induce immunity against the stages of the parasite that infect mosquitoes so that malaria transmission can be reduced or halted. Malaria trans-mission is generally spatially confined to an infectious source, thus a TBV used in a community can effec-tively suppress malaria transmission to others. Anti-bodies induced by TBVs target antigens on the surface of sexual and mosquito midgut stages of the malaria parasite and antibodies interfere with the develop-ment of the parasites in the midgut of the mosquito. Proteins synthesized in the gametocytes (pre-fertiliza-tion antigens, in Plasmodium falciparum: Pfs230 and Pfs48/45) and in the zygotes-ookinetes (post-fertilization antigens, in P. falciparum: Pfs25 and Pfs28) represent some of the key target antigens for the development of TBVs. All the four proteins contain multiple cysteine-rich sequences and the epitopes recognized by transmis-sion-blocking antibodies are reduction-sensitive con-formational in nature. The inability to express properly folded proteins has frustrated a protein-based TBV development approach and DNA-based vaccine con-structs were envisaged to overcome the conformational problem in recombinant proteins. Indeed studies in mice and monkeys have firmly established the value of DNA-based TBV approach. Although immunogenic in larger animals, delivery of DNA-based TBVs needs to be further optimized to elicit a strong and long lasting functional immune response. This DNA vaccine plat-form can also facilitate evaluation of a cocktail of pre-and post-fertilization antigens in pre-clinical setting prior to the development of an ideal and effective TBV for clinical trials in human volunteers. MALARIA continues to remain among the top three infec-tious organisms (malaria, TB and HIV) affecting billions of people globally. More than a century has passed since the discovery of the causative agent of malaria 1 and the role of mosquito in malaria transmission 1 , and an esti-mated 300–500 million people living in more than 100 countries in various regions of the world currently still suffer from clinical malaria annually. While there are four species of the Plasmodium parasites that cause malaria in humans, malaria caused by P. falciparum results in an es-timated 1 million deaths per year, 90% of which in Africa alone, mostly children under the age of five. Extreme poverty, political instability, deteriorating socioeconomic conditions, environmental degradation, population migra-tions and inadequate health care infrastructure are just some of the many reasons implicated in our inability to control malaria. While drugs, insecticide-treated bed-nets and other mosquito vector control interventions are used to control or reduce the impact of malaria, widespread prevalence of drug resistance in the parasites and insecti-cide resistance in the vectors have essentially resulted in the current worsening global malaria situation. A safe, ef-fective and affordable malaria vaccine is expected to pro-vide a long-lasting approach to prevent infection, reduce disease severity, prevent death and interrupt transmission. The complex life cycle of the malaria parasite is ac-companied by extensive developmental changes in the parasites in the vertebrate host and in the mosquito vector that carry out parasite transmission. Successful cyclic transmission process ensures continuous evolution of ge-netic diversity in the parasite population and the spread of anti-malarial drug resistance. Various asexual and sexual stages of the malaria parasite provide numerous targets for mounting an immunological attack by vaccines. For instance, the sporozoite stages of the parasite inoculated during mosquito blood feeding initiate the infection in the liver and have been shown to be excellent targets for hu-moral and cellular immunity during their exoerythrocytic life cycle. Asexual stages developing within erythrocyte are associated with clinical malaria including pathogenic effects and death and are targets of protective immune mecha-nisms mediated by antibodies and a number of cytokines. These asexual stages are also intimately associated with a well-described phenomenon of antigenic variation, which is proving to be a big hurdle toward asexual stage vaccine development. Likewise, erythrocytic sexual stages and mosquito midgut stages of the parasites have been shown to be effective targets of transmission-blocking antibodies.
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ABSTRACT: Acute shortages of Indian origin Rhesus macaques significantly hinder HIV/AIDS research. Cellular immune responses are particularly difficult to study because only a subset of animals possess MHC class I (MHC I) alleles with defined peptide-binding specificities. To expand the pool of nonhuman primates suitable for studies of cellular immunity, we defined 66 MHC I alleles in Cynomolgus macaques (Macaca fascicularis) of Chinese, Vietnamese, and Mauritian origin. Most MHC I alleles were found only in animals from a single geographic origin, suggesting that Cynomolgus macaques from different origins are not interchangeable in studies of cellular immunity. Animals from Mauritius may be particularly valuable because >50% of these Cynomolgus macaques share the MHC class I allele combination Mafa-B*430101, Mafa-B*440101, and Mafa-B*460101. The increased MHC I allele sharing of Mauritian origin Cynomolgus macaques may dramatically reduce the overall number of animals needed to study cellular immune responses in nonhuman primates while simultaneously reducing the confounding effects of genetic heterogeneity in HIV/AIDS research.The Journal of Immunology 10/2005; 175(8):5230-9. DOI:10.4049/jimmunol.175.8.5230 · 5.36 Impact Factor