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The Puzzle of Partial Immunity

For 40 years, scientists have labored to create a vaccine against malaria, inspired by the success of this approach against smallpox, yellow fever, and polio. However, unlike these other types of infections, malaria induces only partial immunity in those who contract the disease. After multiple bouts of the disease, a person develops enough immunity to prevent severe infection and mortality, but can still become ill. Moreover, even this limited immunity can be maintained only by frequent reinfection. Thus the ideal vaccine – one that could provide full and permanent protection from illness – would have to perform better than natural immunity, an ambitious goal for which there is no precedent. If researchers were to succeed in developing a vaccine that mimics naturally occurring immunity, it could save millions of children’s lives. It would not, however, eradicate malaria the way vaccines have eradicated smallpox.

No one knows the mechanism by which people eventually become partially immune to malaria. It may be related to the complexity of the parasite. Recent work has demonstrated that the malaria parasite expresses a repertoire of thousands of surface molecules, or antigens, which change constantly in the course of a single infection. The parasite therefore presents a moving target for the host immune system: by the time the host forms antibodies in response to one antigen, the parasite has already switched to a new one.

Despite these difficulties, scientists have come very close to developing vaccines that work. Their efforts have focused on the three major phases of the parasite life cycle. The first type of vaccine targets the sporozoite, the form in which the parasite enters the host’s body, in order to prevent it from establishing infection. A second, known as the Spf66 vaccine, seeks to destroy the parasite only after it has invaded the host’s red blood cells – an approach that could establish partial but not full immunity. And the third type targets the oocyst, a stage in the life cycle of the parasite that occurs only in the mosquito. The aim of this so-called altruistic vaccine is to block transmission from human to human via the mosquito. When a mosquito feeds on the blood of a vaccinated human, she ingests not only the parasite but also the antibodies specific to the target antigens. These antibodies will prevent the parasite from developing and multiplying in the mosquito and subsequently being passed on to other humans. This kind of vaccine would not protect the vaccinated person from contracting malaria, but vaccinating enough people in a given area could substantially reduce the number of infective bites residents receive.

All of these vaccines have shown promising results in animals, but none have worked well in humans. No one knows why the parasite operates differently in humans than in animals, and it is not clear when or how we will bridge this gap in our knowledge. A 1991 report on malaria prevention and control by the Institute of Medicine (IOM) summarized the results of the malaria vaccine program with cautious optimism. What we have learned from these initial studies may help in designing the next generation of vaccines, but despite the talents, hopes, and funds devoted to this solution, an effective vaccine for malaria remains exactly where it has been for the past 40 years: tantalizingly out of reach.

Given that an effective vaccine is years if not decades away, and that the best vaccine is likely to have only limited impact in preventing illness, we need to step back and reemphasize both prevention and control. One very promising way to prevent malaria is to use mosquito nets treated with a safe, biodegradable pyrethroid insecticide to protect sleeping children. In the early 1990s, four large-scale, randomized, controlled community trials were conducted in four African countries representing different malaria risks – Burkina Faso, Ghana, Kenya, and the Gambia – to determine the impact of using treated nets on mortality rates of children younger than five. The three-year trials, conducted under the auspices of the U.N. Development Programme (UNDP), WHO, and the World Bank, involved nearly half a million people and 20 research institutes and donors. The results were dramatic: children’s deaths from all causes dropped 15 percent in Burkina Faso, 17 percent in Ghana, 33 percent in Kenya, and 25 percent in the Gambia. (An earlier trial in the Gambia cut child mortality 63 percent, but that study was based on 100 percent compliance. The larger studies evaluated the bed nets under real-life conditions, in which compliance ranged from 20 percent to 90 percent.) The magnitude of the reduction in mortality indicates either that malaria is the most important cause of death in the age groups included in the trials or that preventing malaria in young children somehow helps reduce their likelihood of dying from other diseases. These results suggest that if bed nets were made widely available, they could save the lives of up to 500,000 African children each year.

Bed nets are not yet widely available in Africa, and those that are cost between $25 and $30 each – well beyond the reach of the average family. However, locally manufactured nets could cost as little as $5; a year’s supply of insecticide costs between 50 cents and $1. Although this sum is still high relative to annual cash income (between $300 and $400 in some regions), there is reason to believe that most African families could afford it. According to WHO, African families spend up to $65 (or one-fifth of their income) each year on antimalarial drugs, mosquito coils, and insect repellents to protect themselves from malaria, with limited effect. If these expenditures could be redirected to reasonably priced insecticide-impregnated bed nets, overall family expenditures would actually decline.

WHO is studying ways to promote and distribute insecticide-impregnated bed nets. Like insecticide spraying, distributing bed nets is a long-term commitment, so the key is to ensure that this intervention is sustainable. Rather than simply donating nets, international agencies should support local initiatives or otherwise work with local manufacturers to ensure that bed nets are available to all children at a cost their families can afford. WHO and other international agencies should also fund the research and development of new insecticides that can safely be used on bed nets, since sooner or later vector mosquitoes are likely to become resistant to the pyrethroid insecticides.

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Tagged: Biomedicine

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