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Laboratory of Malaria Immunology and Vaccinology

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Asexual Blood-Stage Vaccines

AMA1

AMA1 has been shown in several studies to be a promising malaria vaccine candidate. Immunization of mice or monkeys with either purified or recombinant forms of AMA1 protected these animals against rodent and simian malaria, respectively. There is mounting evidence to suggest that this protection is antibody mediated; passive transfer of antibodies raised in both mice and rabbits against refolded P. chabaudi AMA1 protected mice against challenge with Plasmodium chabaudi. Monoclonal antibodies raised against both P. falciparum AMA1 and Pk66, the P. knowlesi homologue of AMA1, inhibit merozoite growth in vitro. Human and animal anti-AMA1 antibodies also inhibit merozoite growth in vitro.

Some of the most convincing evidence for the potential of AMA1 as a vaccine candidate has come from LMIV’s study involving the stringent Aotus vociferans model system. Immunization of these New World monkeys with recombinant P. falciparum AMA1-FVO expressed in P. pastoris provided significant protection against challenge with homologous P. falciparum parasites, and the level of protection in these experiments correlated with the anti-AMA1 antibody levels.

The major challenges in the development of an AMA1-based vaccine will be addressing antigenic polymorphism, longevity of the immune response, and vaccination in the context of ongoing infection.

AMA1-C1/Alhydrogel

AMA1-C1 is the combination of two divergent polymorphic forms of the protein formulated with a single adjuvant. Alhydrogel, an aluminum hydroxide gel, was chosen as the primary vaccine adjuvant platform because of its extensive safety record when used with other recombinant proteins in many age groups and populations. Alhydrogel formulations of blood-stage vaccine candidates generate a substantial immune response in animal studies and are safe. Although Alhydrogel is generally well tolerated in humans, it is a relatively weak adjuvant for antibody induction to many antigens. Aluminum-based adjuvants mainly stimulate a Th2-type immune response characterized by increased antibody titers without affecting cell-mediated immunity.

There have been four human clinical trials to date using the recombinant AMA1-C1/Alhydrogel vaccine. The outcome of a Phase I trial in malaria-naïve U.S. adults was sufficient to progress to safety evaluations in semi-immune adults in Mali. This formulation has advanced to begin collection of safety, immunogenicity, and biologic impact data in the context of malaria exposure in Malian children (Phase I/II study). An additional, small U.S. Phase I trial was also initiated to observe the B-cell and T-cell immune responses to vaccination with this formulation.

AMA1-C1/Alhydrogel+CPG 7909

Alhydrogel-based vaccines may be significantly improved by addition of a second adjuvant, CPG 7909. The combination of adjuvants, Alhydrogel+CPG 7909, has provided some of the highest antibody levels observed in animal models to date for AMA1, and the antibody levels correlated with the inhibition of parasite growth in vitro. Thus, the LMIVhas pursued clinical development of AMA1-C1/Alhydrogel+CPG 7909.

Although no significant safety issues have been identified thus far in U.S. Phase I clinical trials of malarial antigens formulated with Alhydrogel+CPG 7909, the induction of autoimmune disease with the use of this DNA analogue remains a concern. LMIV is proceeding with caution as clinical evaluation moves into the field, monitoring specific laboratory markers of autoimmune disease (anti-dsDNA and urine for blood and protein) and clinical evidence of autoimmunity.

AMA1-C1/ISA 720

In an alternative approach to achieve higher and longer-lasting antibody responses, AMA1-C1 formulated with an experimental water-in-oil adjuvant, Montanide ISA 720, is being evaluated. In animal studies, AMA1-C1/ISA 720 has been found to enhance and prolong the specific antibody response when compared to AMA1-C1/Alhydrogel. A Phase I clinical trial of this formulation will begin in 2007.

BSAM-1

BSAM-1 is tetravalent vaccine containing two polymorphic forms for each of the two proteins, AMA1 and MSP142. (MSP142 is another major antigen candidate for blood-stage vaccines.) Multiple different blood-stage parasite proteins are included to increase the likelihood that 1) the vaccinee will produce an adequate immune response, and 2) that the resulting immune response may be additive or synergistic as a consequence of targeting two distinct proteins simultaneously.

Preclinical evaluations of BSAM-1/Alhydrogel and BSAM-1/Alhydrogel+CPG 7909 in mice, rats, and rabbits have shown these formulations to be safe and immunogenic. In these studies, the immunogenicity of the BSAM-1 formulations was compared to the immunogenicity of the individual components (AMA1-C1 or MSP142-C1) prepared at the comparable dose and formulation. Within the BSAM-1/Alhydrogel formulations, no immunologic inhibition was detected; the anti-AMA1 or anti-MSP142 antibody responses generated in response to BSAM-1 vaccination were comparable to those induced by vaccination with either AMA1-C1/Alhydrogel or MSP142-C1/Alhydrogel. When CPG 7909 was added to the BSAM-1 formulation, the result was a significant increase in the overall antibody production. Clinical safety evaluation of this formulation will begin in 2007.

MSP1

MSP1 is synthesized as a ~200 kilodalton (kDa) polypeptide. MSP1 is processed, at or just prior to merozoite release from the red blood cell, into smaller fragments that form a noncovalently associated complex. The 42 kDa C-terminal fragment of MSP1 (MSP142) is responsible for tethering the complex to the surface of the merozoite; secondary processing of MSP142 at the time of merozoite invasion of red blood cells is essential for parasite invasion. The MSP142 molecule can be divided into dimorphic and conserved regions.

MSP142 proteins formulated with Alhydrogel and Alhydrogel+CPG 7909 have undergone clinical testing. In humans, there was minimal evidence of strain specificity in the antibody response to the dimorphic forms of this protein. In contrast, the analysis of specific T-cell responses showed the importance of the dimorphic region.

A substantial enhancement in specific antibody responses was observed when MSP142 was formulated with Alhydrogel+CPG 7909 as compared to Alhydrogel alone. However, only low-level in vitro parasite growth inhibition was observed, and biologically relevant inhibition is likely to require much higher levels of antibody.

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Last Updated June 12, 2007