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Protecting Our Progeny
The Future of Vaccines
by Sir Gustav Nossal
From a public health viewpoint, there are three "future vaccines" of even greater interest: those against HIV/AIDS, malaria and tuberculosis. These are so important that each deserves some discussion. So far, an AIDS vaccine has eluded us, primarily because the human immunodeficiency virus has such devilishly clever tricks up its sleeve to foil the host's natural defense system. It chooses to live in and destroy one of the most important cells of the immune system, the so-called CD4+, or helper T cell. It also infects scavenger cells important in initiating immune responses. It can go underground in these cells, only to emerge much later. Being an RNA (ribonucleic acid) virus, it is subject to a very high rate of mutation, so that when the immune system does manage to polish off most of the virus, a mutant form with a different antigenic signature pops up, needing to be dealt with in turn. Finally, the active recognition sites on the grappling hooks that the virus uses to hang onto its target cell are skillfully hidden from the prying eyes of antibody molecules until the very moment of docking and entry.
Despite these challenges, progress is being made toward a vaccine. Stratagems have been devised to evoke antibodies that are broadly active against different subtypes of the virus. During the long latent period of the disease, while the patient is still well, the body's killer T cells do fight against the virus, keeping the total load in the body relatively low. If a vaccine can provoke those T cells into intense activity before infection occurs, the very small virus load entering the body might be destroyed completely.
We have good ideas about how to craft such a vaccine; it is now necessary to trial these one by one in the clinic, a process that is necessarily very slow. An alliance known as the International AIDS Vaccine Initiative (IAVI) has raised sizable funds to speed clinical trials, so that several different vaccine candidates can be assessed simultaneously. Much of this trial work will have to be conducted in developing countries, given their higher incidence of infection.
Targeting malaria
Malaria is the worst of the human parasitic diseases, killing between 1 million and 2 million people every year, chiefly in Africa. People living in endemic areas eventually develop partial immunity, such that they do not get attacks despite having parasites in their blood. If they move to a non-malarial area for several years, they gradually lose their immunity.
Here, scientists will have to do better than nature.
There are four susceptible points in the parasite's life cycle when it may be vulnerable. First, a motile form known as a sporozoite is introduced into the skin by the night-feeding female Anopheles mosquito. Within less than half an hour, sporozoites reach and enter liver cells. Up to that point, antibodies directed to the sporozoite surface might lead to their destruction. Once in the liver, the parasite multiplies, during the process shedding bits that will reach the surface of the cell. If a killer T cell recognizes these bits (called peptides or T cell epitopes), the affected liver cell is attacked and destroyed before it can release its progeny into the bloodstream. Infection is thus aborted.
But once the progeny (known as merozoites) are in the blood, they quickly attach to and infect red blood cells. They then multiply, rupture the red cell, and enter a new one. It is this blood-stage cycle that is responsible for the symptoms of the disease. In its transit from one red cell to the next, the merozoite is briefly susceptible to antibody.
Finally, some merozoite-infected red cells release gametocytes, sexual forms of the parasite, which can mature within the mosquito into male and female gametes. When these unite, the life cycle is completed. If one were to make antibodies to these gametocytes, one would not help the patient, but at a population level, transmission would be blocked, and eventually the disease might be brought under control.
Experimental vaccines incorporating each of these four sets of ideas have been shown to work in model systems. It is now a question of subjecting them to phased human trials. One of the many Gates Foundation programs, the Malaria Vaccine Initiative, is planning to do just that. So far, some partial success has been achieved in human trials with a sporozoite vaccine and a combination blood-stage antigen vaccine.
Attacking TB
Why do we need a tuberculosis vaccine other than the BCG (Bacillus Calmette- Guerin) vaccine? Simply because this live, attenuated bacterium can protect infants from tuberculosis but appears incapable of coping with the real problem, namely, pulmonary tuberculosis in adolescents and young adults. Though not as far advanced as it is for AIDS and malaria, research toward a new TB vaccine is exploring plenty of bright ideas, including both live attenuated and molecular approaches. A recently completed tubercle bacillus genome project is speeding the search. One of the biggest problems, not only with the "big three" but also with other vaccines, is the fact that pure protein molecules made by genetic engineering do not by themselves induce a strong immune response. For this we need immune-strengthening substances called adjuvants. Many are under development, but these tend to be toxic, and the search for more satisfactory adjuvants is intense.
Alternatively, we need new and craftier ways of delivering the vaccine. For example, we can take the gene for an important vaccine molecule (or antigen) and transplant it into a virus, then inject that virus, which will strongly alert the immune system. We can also inject DNA coding for antigens, which enters cells and then creates a factory where the body itself is manufacturing vaccine molecules over a considerable period. One highly promising strategy is known as prime-boost, in which a DNA vaccine is injected first and an engineered virus next. This has worked well in animal models of both HIV/AIDS and malaria.
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