Prime-boost vaccination with recombinant protein and adenovirus-vector expressing Plasmodium vivax circumsporozoite protein (CSP) partially protects mice against Pb/Pv sporozoite challenge.

Vaccine development against Plasmodium vivax malaria lags behind that for Plasmodium falciparum. To narrow this gap, we administered recombinant antigens based on P. vivax circumsporozoite protein (CSP) to mice.

Vaccine Containing the Three Allelic Variants of the Circumsporozoite Antigen Induces Protection in Mice after Challenge with a Transgenic Rodent Malaria Parasite.

is the most common species that cause malaria outside of the African continent. The development of an efficacious vaccine would contribute greatly to control malaria. Recently, using bacterial and adenoviral recombinant proteins based on the circumsporozoite protein (CSP), we demonstrated the possibility of eliciting strong antibody-mediated immune responses to each of the three allelic forms of CSP (PvCSP).

Human CD8+ T cells mediate protective immunity induced by a human malaria vaccine in human immune system mice.

A number of studies have shown that CD8+ T cells mediate protective anti-malaria immunity in a mouse model. However, whether human CD8+ T cells play a role in protection against malaria remains unknown. We recently established human immune system (HIS) mice harboring functional human CD8+ T cells (HIS-CD8 mice) by transduction with HLA-A∗0201 and certain human cytokines using recombinant adeno-associated virus-based gene transfer technologies.

Human immune system mice immunized with Plasmodium falciparum circumsporozoite protein induce protective human humoral immunity against malaria.

In this study, we developed human immune system (HIS) mice that possess functional human CD4+ T cells and B cells, named HIS-CD4/B mice. HIS-CD4/B mice were generated by first introducing HLA class II genes, including DR1 and DR4, along with genes encoding various human cytokines and human B cell activation factor (BAFF) to NSG mice by adeno-associated virus serotype 9 (AAV9) vectors, followed by engrafting human hematopoietic stem cells (HSCs). HIS-CD4/B mice, in which the reconstitution of human CD4+ T and B cells resembles to that of humans, produced a significant level of human IgG against Plasmodium falciparum circumsporozoite (PfCS) protein upon immunization.

Immunogenicity of a prime-boost vaccine containing the circumsporozoite proteins of Plasmodium vivax in rodents.

Plasmodium vivax is the most widespread and the second most prevalent malaria-causing species in the world. Current measures used to control the transmission of this disease would benefit from the development of an efficacious vaccine. In the case of the deadly parasite P.

Antibodies to Plasmodium circumsporozoite protein (CSP) inhibit sporozoite's cell traversal activity.

Plasmodium sporozoites are deposited in the skin of the mammalian host by Anopheles mosquitoes. To continue the life cycle, the sporozoites have to invade the host's hepatocytes, where they transform into exoerythrocytic forms (EEFs) inside a parasitophorous vacuole. During their route from the skin to the liver, the parasites traverse the capillary epithelium in the dermis to enter the blood circulation, and cross the endothelium of liver sinusoids to enter the parenchyma.

TLR5-dependent immunogenicity of a recombinant fusion protein containing an immunodominant epitope of malarial circumsporozoite protein and the FliC flagellin of Salmonella Typhimurium.

Recently, we described the improved immunogenicity of new malaria vaccine candidates based on the expression of fusion proteins containing immunodominant epitopes of merozoites and Salmonella enterica serovar Typhimurium flagellin (FliC) protein as an innate immune agonist. Here, we tested whether a similar strategy, based on an immunodominant B-cell epitope from malaria sporozoites, could also generate immunogenic fusion polypeptides. A recombinant His6-tagged FliC protein containing the C-terminal repeat regions of the VK210 variant of Plasmodium vivax circumsporozoite (CS) protein was constructed.

Identification of non-CSP antigens bearing CD8 epitopes in mice immunized with irradiated sporozoites.

Immunization of BALB/c mice with irradiated sporozoites (IrSp) of Plasmodium yoelii can lead to sterile immunity. The circumsporozoite protein (CSP) plays a dominant role in protection. Nevertheless after hyper-immunization with IrSp, complete protection is obtained in CSP-transgenic BALB/c mice that are T-cell tolerant to the CSP and cannot produce antibodies [CSP-Tg/JhT(-/-)].

Breakthroughs towards a malaria vaccine.

Since the 1960s, the scientist Ruth Nussenzweig, C.V. Starr Professor at New York University School of Medicine, has been working to develop an antimalarial vaccine.

The Plasmodium eukaryotic initiation factor-2alpha kinase IK2 controls the latency of sporozoites in the mosquito salivary glands.

Sporozoites, the invasive form of malaria parasites transmitted by mosquitoes, are quiescent while in the insect salivary glands. Sporozoites only differentiate inside of the hepatocytes of the mammalian host. We show that sporozoite latency is an active process controlled by a eukaryotic initiation factor-2alpha (eIF2alpha) kinase (IK2) and a phosphatase.

Immunogenicity and protective efficacy of a recombinant yellow fever vaccine against the murine malarial parasite Plasmodium yoelii.

The live-attenuated yellow fever vaccine (YF17D) is one of the safest and most effective vaccines available today. Here, YF17D was genetically altered to express the circumsporozoite protein (CSP) from the murine malarial parasite Plasmodium yoelii. Reconstituted recombinant virus was viable and exhibited robust CSP expression.

A bicomponent Plasmodium falciparum investigational vaccine composed of protein-peptide conjugates.

There is yet no licensed vaccine against malaria, a serious human disease affecting mostly children, with an annual death rate of about one million. Plasmodia, the malaria-causing parasites, have two obligatory hosts: mammals or birds, in which they multiply asexually, and mosquitoes with sexual multiplication. The most common and serious type of malaria is caused by Plasmodium falciparum.

From the circumsporozoite protein to the RTS, S/AS candidate vaccine.

The RTS,S/AS01(E) malaria vaccine candidate has recently entered Phase 3 testing. Reaching this important milestone is the culmination of more than 20 years of research and development by GlaxoSmithKline and partners and collaborators. The vaccine has been developed to protect young children and infants living in Sub-Saharan Africa against clinical and severe disease caused by Plasmodium falciparum infection.

The circumsporozoite protein is an immunodominant protective antigen in irradiated sporozoites.

Malaria infection starts when mosquitoes inject sporozoites into the skin. The parasites enter the blood stream and make their way to the liver where they develop into the exo-erythrocytic forms (EEFs). Immunization with irradiated sporozoites (IrSp) leads to robust protection against malaria infection in rodents, monkeys and humans by eliciting antibodies to circumsporozoite protein (CS) that inhibit sporozoite infectivity, and T cells that destroy the EEFs.

Antigen targeting to dendritic cells elicits long-lived T cell help for antibody responses.

Resistance to several prevalent infectious diseases requires both cellular and humoral immune responses. T cell immunity is initiated by mature dendritic cells (DCs) in lymphoid organs, whereas humoral responses to most antigens require further collaboration between primed, antigen-specific helper T cells and naive or memory B cells. To determine whether antigens delivered to DCs in lymphoid organs induce T cell help for antibody responses, we targeted a carrier protein, ovalbumin (OVA), to DCs in the presence of a maturation stimulus and assayed for antibodies to a hapten, (4-hydroxy-3-nitrophenyl) acetyl (NP), after boosting with OVA-NP.

Safety and enhanced immunogenicity of a hepatitis B core particle Plasmodium falciparum malaria vaccine formulated in adjuvant Montanide ISA 720 in a phase I trial.

Highly purified subunit vaccines require potent adjuvants in order to elicit optimal immune responses. In a previous phase I trial, an alum formulation of ICC-1132, a malaria vaccine candidate comprising hepatitis B core (HBc) virus-like particle containing Plasmodium falciparum circumsporozoite (CS) protein epitopes, was shown to elicit Plasmodium falciparum-specific antibody and cellular responses. The present study was designed as a single-blind, escalating-dose phase I trial to evaluate the safety and immunogenicity of single intramuscular doses of ICC-1132 formulated in the more potent water-in-oil adjuvant Montanide ISA 720 (ICC-1132/ISA 720).

Yellow fever 17D as a vaccine vector for microbial CTL epitopes: protection in a rodent malaria model.

The yellow fever vaccine 17D (17D) is safe, and after a single immunizing dose, elicits long-lasting, perhaps lifelong protective immunity. One of the major challenges facing delivery of human vaccines in underdeveloped countries is the need for multiple injections to achieve full efficacy. To examine 17D as a vector for microbial T cell epitopes, we inserted the H-2K(d)-restricted CTL epitope of the circumsporozoite protein (CS) of Plasmodium yoelii between 17D nonstructural proteins NS2B and NS3.

Induction of protective immunity against malaria by priming-boosting immunization with recombinant cold-adapted influenza and modified vaccinia Ankara viruses expressing a CD8+-T-cell epitope derived from the circumsporozoite protein of Plasmodium yoelii.

We immunized mice with an attenuated (cold-adapted) influenza virus followed by an attenuated vaccinia virus (modified vaccinia virus Ankara), both expressing a CD8(+)-T-cell epitope derived from malaria sporozoites. This vaccination regimen elicited high levels of protection against malaria. This is the first time that the vaccine efficacy of a recombinant cold-adapted influenza virus vector expressing a foreign antigen has been evaluated.

Levels of circumsporozoite protein in the Plasmodium oocyst determine sporozoite morphology.

The sporozoite stage of the Plasmodium parasite is formed by budding from a multinucleate oocyst in the mosquito midgut. During their life, sporozoites must infect the salivary glands of the mosquito vector and the liver of the mammalian host; both events depend on the major sporozoite surface protein, the circumsporozoite protein (CS). We previously reported that Plasmodium berghei oocysts in which the CS gene is inactivated do not form sporozoites.

Delayed-type hypersensitivity in volunteers immunized with a synthetic multi-antigen peptide vaccine (PfCS-MAP1NYU) against Plasmodium falciparum sporozoites.

During the testing of the safety and immunogenicity of an adjuvanted, synthetic Plasmodium falciparum CS multiple antigen peptide (MAP) vaccine, we investigated the potential for using cutaneous delayed-type hypersensitivity (DTH) reactions as a correlate of immune response. We evaluated 27 of our volunteers for DTH reactions to intradermal inoculation (0.02 ml) of several concentrations of the MAP vaccine and adjuvant control solutions.

Surface expression of an immunodominant malaria protein B cell epitope by yellow fever virus.

The yellow fever 17D virus (YF17D) has several characteristics that are desirable for the development of new, live attenuated vaccines. We approached its development as a vector for heterologous antigens by studying the expression of a humoral epitope at the surface of the E protein based on the results of modelling its three-dimensional structure. This model indicated that the most promising insertion site is between beta-strands f and g, a site that is exposed at the external surface of the virus.