Malaria vaccine based upon the addition of a MSA1 peptide

Details Malaria vaccine based upon the addition of a MSA1 peptide Malaria vaccine based upon the addition of a MSA1 peptide

1998-11-27

2003-04-22

Nguyen, Dave Trong (Department: 1632)

Drug, bio-affecting and body treating compositions

Whole live micro-organism, cell, or virus containing

Genetically modified micro-organism, cell, or virus

C514S04400A, C435S320100, C435S069100, C435S325000, C435S455000

Reexamination Certificate

active

06551586

ABSTRACT:

FIELD OF THE INVENTION
The present invention relates to novel DNA constructs comprising a vector linked to a DNA segment which encodes a protein containing a signal protein at its N-terminus and an anchor sequence at its C-terminus.
More particularly, the present invention relates to vaccines which are useful for the prevention and treatment of malaria caused by
Plasmodium falciparum
in humans.
This work was supported by a DARPA grant. The government retains certain rights in the invention.
BACKGROUND OF THE INVENTION
Preventing or treating malaria has long been a challenging health problem, particularly in developing countries, and the rapid development of drug resistance in the parasite has enhanced the need for the development of a malaria vaccine. Although there has been steady progress over the last decade, several problems still must be overcome, including selection of an appropriate delivery system vehicle and antigen carrier.
Although malaria was believed to have subsided after World War II, recent outbreaks suggest that the disease is on the rise. Malaria is again the leading cause of morbidity/mortality globally and presents an increasing threat in at risk environments. Estimates are that 300 million new cases of malaria occur each year, with mortality of approximately 1% of infected individuals. Prophylactic medications used to prevent the disease have been rendered ineffective by the emergence of drug-resistant strains of the parasite worldwide. Complete vector protection is simply not possible and all attempts to eradicate the relevant species of mosquito have failed.
Four species of
protozoa
of the genus Plasmodium are found in man. The four species include:
Plasmodium vivax, Plasmodium malariae, Plasmodium falciparum
and
Plasmodium ovale
. Of these,
Plasmodium falciparum
produces the most pathogenic of the malarias and often results in death. It is responsible for about half of the human cases of malaria found worldwide.
In malaria, the disease is such that infection followed by recovery does not confer meaningful protection to the individual despite a significant antibody response to several of the parasite proteins. The conventional wisdom has been that the parasite either does not possess antigens suitable for the development of a protective response or has evolved mechanisms which allow it to escape the host immune system. Because recent evidence has shown that immune protection is possible using irradiated sporozoites, the latter hypothesis described above is the more reasonable explanation.
The life cycle of the malaria parasite provides several stages at which interference could lead to cessation of the infective process. Included among these stages is the invasion of the erythrocyte by the merozoite. The merozoite represents a potentially attractive target (and perhaps the only target) from which a vaccine may be produced, because the free merozoite, although it has a limited lifetime (one to two hours) occurs earlier in the life cycle of malaria, and the emergence of later stage sexual forms, which are responsible for transmission of the disease, depends upon the erythrocytic stage.
The general life cycle of malaria parasites is the same for human and other animal malaria parasites, thus allowing model studies to be conducted on a rodent species with accurate translation to the human parasite. For example, the rodent malaria parasite strain
Plasmodium berghei
Anka has a pathology very similar to the FCR-3 strain of
Plasmodium falciparum
(a well studied variant of the human parasite). In addition, the blood stage of the human parasite can be grown in the laboratory (in human red cells) thus affording a system for studying the effects of antibodies/inhibitors on the invasion process, and the erythrocytic phase.
In the life cycle of the malaria parasite, a human becomes infected with malaria from the bite of a female Anopheles mosquito. The mosquito inserts its probe into a host and in so doing, injects a sporozoite form of
Plasmodium falciparum
, present in the saliva of the mosquito.
The sporozoites which have been injected into the human host are cleared into a number of host tissue cells, including liver parenchyma cells (hepatocytes) and macrophages. This phase is known as the exoerythrocytic cycle because at this point in the life cycle the organism has not yet entered red blood cells. After entering hepatocytes, sporozoites undergo a transformation into trophozoites, which incubate and undergo schizogony, rupture and liberate tissue merozoites. This process takes approximately 7-10 days and, depending upon species, may repeat itself several times, during which time the host feels no effects. In
Plasmodium falciparum
, this repetition does not occur. After the incubation period, the liver or other tissue cells burst open and release numerous merozoites into the bloodstream.
Shortly thereafter, certain of these blood borne merozoites invade red blood cells, where they enter the erythrocytic phase of the life cycle. Within the red blood cells, young plasmodia have a red nucleus and a ring-shaped, blue cytoplasm. The plasmodium divides into merozoites, which may break out of the red blood cell, enter other erythrocytes and repeat the multiplication process. This period lasts approximately 48 hours.
During this same 48 hour period of the erythrocytic cycle, male and female gametocytes are formed in the red blood cells. These gametocytes also burst out of the red blood cells along with the merozoites. It is during this period that the human host experiences the symptoms associated with malaria. The merozoites which burst forth from the red blood cells live for only a few hours in the bloodstream. The gametocytes live for several days or more in the host's bloodstream.
The gametocytes are capable of mating only in the mosquito. Thus, in order for
Plasmdium falciparium
to produce sporozoites for infecting a second human host, a mosquito must first bite a human host carrying gametocytes. These gametocytes mature into macrogametes, mate in the mosquito's stomach and produce a zygote. The zygote (ookinete) is active and moves through the stomach or the midgut wall. Under the lining of the gut, the ookinete becomes rounded and forms a cyst called an oocyst, in which hundreds of sporozoites develop. Sporozoites thereafter invade the entire mosquito and many of them enter the salivary glands where they are in a favorable position to infect the next host when the mosquito feeds on its blood. The life cycle thereafter simply repeats itself in another human host.
During the life cycle of
Plasmdium falciparium
, inhibition of invasion of the erythrocyte by the merozoite may be a key to developing an effective vaccine for malaria. Once the parasite has gained entry into the red cell, exposure to the immune system is gone.
In the past, live vaccinia virus was used as a vaccine to eradicate smallpox successfully, and a recombinant vaccinia virus expressing viral antigens has been shown to induce a strong antibody response in immunized animals, conferring protection against disease (Arita, I.,
Nature
, 1979, 279, 293-298). Furthermore, it has been shown in animal models that co-presentation of potential immunogens with highly immunogenic vaccinia virus proteins can elicit a strong immune response against that specific immunogen (Moss and Flexner,
Annals of the New York Academy of Sciences
, 86-103; Mackett and Smith,
J. Gen. Virol
., 1986, 67, 2067-2082; Houard, et al.,
J. Gen. Virol
., 1995, 76, 421-423; Fujii, et al.,
J. Gen. Virol
., 1994, 75, 1339-1344; Rodrigues, et al.
J. Immunol
., 1994, 153, 4636-4648). Therefore, the utilization of live recombinant vaccinia virus as a vaccine might overcome many problems of antigen expression and delivery presently encountered in the preparation of recombinant proteins in
E. coli
, yeast or insect expression systems. A panel of transfer vectors have been constructed that allow insertion of foreign genes into several sites within the 180 kb vaccinia virus genome (Earl and Moss,
Current Protoco

Affiliated with

Also associated with

Rating

Malaria vaccine based upon the addition of a MSA1 peptide does not yet have a rating. At this time, there are no reviews or comments for this patent.

If you have personal experience with Malaria vaccine based upon the addition of a MSA1 peptide, we encourage you to share that experience with our LandOfFree.com community. Your opinion is very important and Malaria vaccine based upon the addition of a MSA1 peptide will most certainly appreciate the feedback.

Rate now

Comments { 0 }

Profile ID: LFUS-PAI-O-3009022