Sub-Saharan Africa, from the Indian Ocean to the Atlantic, commands rightful attention as the world's main hotbed of HIV infection and AIDS.
The same vast region has been for centuries the principal focus of an even more deadly pandemic - malaria - which takes the lives of some 2 million to 3 million people each year, mostly the very young. The East African Republic of Kenya is afflicted with both infections - AIDS and malaria.
The latest effort to contrive an effective preventive vaccine against malaria got its start among inhabitants of Western Kenya. Many adults in that population have developed immunity to the death-dealing malarial parasite, Plasmodium falciparum, which is delivered by the bite of anopheles mosquitoes.
Vaccinologist Altaf Lal, at the Centers for Disease Control (CDC) in Atlanta, is chief of the Molecular Vaccine Section in the Division of Parasitic Diseases. He is senior author of a report in the current Proceedings of the National Academy of Sciences (PNAS), dated Feb. 16, on "Immunogenicity and in vitro protective efficacy of a recombinant multistage Plasmodium falciparum candidate vaccine."
"The work started in Western Kenya," Lal told BioWorld Today, "where we investigated the genetic diversity of falciparum, and the immune responses in individuals who were naturally exposed to malaria and developed clinical immunity against infection and disease. Based on those studies," he recounted, "back at CDC we selected the components that went into our multicomponent candidate vaccine."
Lal explained that "in malarial endemic regions, especially in Sub-Saharan Africa, malaria is a disease of young children and pregnant women. As children age, they develop a capability to limit the parasitemia. It's a function of age and exposure."
Immunity Without Vaccination Comes Naturally
"This transition begins at 5 years of age," he went on, "and by the time teen-age years and adult age set in, individuals are fairly well protected against clinical manifestations of the illness. They develop certain levels of immunity that tend to suppress high-level parasitemias. So they acquire natural immunity as a result of exposure to malarial infection. That is what we are trying to simulate in our candidate vaccine."
A so-so police force may station one car at a location where it knows the suspect is likely to touch base. But a superior law-enforcement agency stakes out each and every site its quarry visits regularly - home, place of work, favorite bar.
P. falciparum, the malarial parasite, is superior, too. Its complex life cycle so far has outwitted every attempt over the past two decades at a vaccine to effectively immunize people at risk for infection. Many attempts have singled out a single stage in the parasite's multistage passage from mosquito bite to bloodstream, to liver to red blood cells, and back to mosquito. The three way stations on this round trip bear the names sporozoite (liver stop), merozoite (red blood cell stage) and gametocyte (ingested by mosquito).
Each of these stages carries a numerous set of antigenic epitopes that are vaccine targets for the immune system's B cells (which make antibodies), proliferative T cells and killer T cells. Lal and his co-authors, he related, "constructed a synthetic gene that encodes for 12 B-cell, 6 T-cell proliferative, and three cytotoxic T lymphocyte epitopes." These targets are specific for the several stages in the parasite's life cycle.
"What we have," Lal pointed out, "is a gene we created that expresses in baculovirus a multivalent protein in vitro, with which we immunize. It's not a DNA vaccine, but a protein vaccine," totaling 42 kiloDaltons in size.
The vaccine consisted of that protein together with one of five assorted adjuvants designed to kick-start the immunization process.
"Each of the stages in malaria," Lal pointed out, "has a different set of antigens. For instance, the sporozoite antigens are not expressed in the liver stage; liver-stage antigens may or may not be expressed in the blood stage; blood-stage antigens won't be expressed in the mosquito stage. Within each stage there are a variety of antigens, and each antigen will have T-cell determinants, and B-cell determinants on them.
"The key in our vaccine development," he went on, "is understanding the complexity of this whole immune response, identifying those critical B-cell epitopes that induce antibodies that are crucial for host-parasite infection. If you can induce those, you can block those host-parasite interactions."
So Far, Rabbits; Monkeys Next; People Maybe
Lal's laboratory at CDC has developed a collaborative relationship with Protein Sciences Corp. in Meriden, Conn. That firm is producing the good manufacturing practice vaccine prototype. "We are working on a time line," Lal said, "to initiate vaccine trials in monkeys in March of this year. We anticipate the data will be available in six to nine months, and based on those results we will then make a decision whether to proceed with human trials or not."
Meanwhile, rabbits immunized with four shots of the multicomponent vaccine attained "high-level and long-lasting antibody responses." These peaked after the fourth immunization, and stayed high until the 14th to 16th week. The rabbits' antibody titers did best with sporozoite-stage antigens, less well with merozoite, and least well with gametocytes.
In the event of a parasite developing resistance to the vaccine, or if one or another of its target epitopes "broke through" - faltered in humans - the CDC vaccinologist pointed out, "the advantage in a multicomponent vaccine, the way we and others are designing them, enables us to change the construct pretty much at will. Within a few months we can develop a re-engineered epitope, which would incorporate the breakthroughs or resistance the parasites may be telling us."
Lal emphasized the word candidate. "While we are optimistic," he observed, "that this vaccine has given us all the right information so far, and we are moving ahead aggressively, I don't want anybody out there getting a wrong sense that we already have a vaccine."