Is death the only important measure of vaccine success? Given that the diagnosis of malaria is presumptive in most cases and verbal autopsy is used to attribute cause of death, is the trial to substantiate vaccine efficacy justified?
In the past decade, the rapid rise in the incidence of malaria has been so alarming that it is considered a re-emerging disease. In 2006 alone, an estimated 250-300 million cases resulted in almost a million deaths worldwide. Many of those who die are children: malaria kills one child every 30 seconds. Countries in tropical Africa account for more than 90% of the total malaria incidence and for the great majority of malaria deaths. Factors that contribute to the worsening global malaria situation include the spread of drug-resistant strains, frequent civil unrest in Africa forcing resettlement in endemic areas, gross inadequacy of funds for implementing vector control programs and providing basic health care, and changing rainfall patterns. Since malaria is concentrated in the world’s poorest countries, which lack well-developed and accessible health care infra- structures, most people needing rapid diagnosis and treatment for malaria don’t get it even though the cost per patient may be extremely low by the standards of high-income countries. Historically, vaccines are one of the most cost-effective and sustainable ways to control infectious diseases. Consequently, much malaria research is focused on developing an effective vaccine. Current efforts are concentrating on DNA technologies that might induce an immune response to the different stages of malaria infection. To be effective, any intervention, whether preventive or curative, must be inexpensive and relatively easy to administer and maintain. A North American university is in the process of designing trials to test a multi-stage DNA vaccine. Preliminary studies in the United States of America have been encouraging; immunization of human research participants shows evidence of a strong immune response, and experimental challenge studies in North American volunteers are being initiated. Larger-scale field studies, for Phases II and III, are being planned due to the acute need to find an effective vaccine as soon as possible. If the vaccine were found to be efficacious in malaria-endemic areas, it could potentially save millions of lives. A country in sub-Saharan Africa where malaria is endemic has expressed interest in participating in the vaccine research effort. The African and North American investigators begin to work together to design a study protocol to assess the vaccine’s efficacy for reducing deaths due to malaria in chil- dren younger than 5 years, and particularly in infants. It is thought that the vaccine might work in two possible ways: first, it might prevent vaccinated individuals from getting malaria at all. Second, it might not prevent the acquisition of malaria, but it might prevent those who become infected from becoming seriously ill and/or dying; that is, vaccinated children might get a milder case of malaria. One of the districts in the country, whose total population is approximately 150 000, has put together a very effective epidemiological surveillance system. Trained community health workers visit each home in every village in the district every three months and record all births, deaths, major illnesses, marriages, and migrations. A centralized, computerized, record keeping system is regularly updated on the basis of the community health worker reports. At the same time, most of the villages in this district are remote and only four health posts serve the entire population. Furthermore, in addition to the high malaria burden (18% of annual income lost due to the disease), trained health care workers, lab facilities, and medicines are in extremely short supply. Children younger than 5 years in the study area suffer an average of six bouts of malaria a year; and fatally afflicted children and infants often die less than 72 hours after developing symptoms The investigators plan on randomly selecting potential partic- ipants (children less than 5 years old) for the vaccine trial from the database gathered by the community health workers. A study vaccination team will visit each home, explain the study, and obtain informed consent from the appropriate caregiver and administer the vaccine or placebo, in double-blind fash- ion, to those children whose parents agree to participate. The risks of vaccination are minor, and the potential benefit is prevention of morbidity or mortality due to malaria. The team will then leave the village without implementing any other interventions. The data on subsequent illness and death due to malaria will be collected passively by using the information from the centralized data base that is already in place, as well as active surveillance regularly conducted by the community health workers. The impact on the existing health care structure will be minimal. Since there is no clearly defined immunological marker to measure protective immunity against malaria, and since mortality is by far the most important outcome variable to measure, the study will look at deaths (and, to the extent that health records and verbal autopsies allow, deaths due to malaria) as a study endpoint. Practically, this means that in the absence of a surrogate marker for mortality, the investigators cannot interfere with the “natural” consequences of malaria transmission in the study villages. Yet, the study investigators are aware that due to the presence of the study itself and with relatively little expense, all or nearly all deaths from malaria in the study population could be avoided. If they identified and treated all cases of malaria in the study population, however, they cannot measure the efficacy of the vaccine, which, of course, is the entire reason for the study.
- Is death the only important measure of vaccine success? Given that the diagnosis of malaria is presumptive in most cases and verbal autopsy is used to attribute cause of death, is the trial to substantiate vaccine efficacy justified?
- Sometimes ethical considerations can affect study design. In this study, how does the ethical obligation of improving malaria care and treatment affect the study design?
- The case study does not indicate that any provision has been made for an ethical review by the country where the research is being conducted. If the North American partners insist that the review conducted in the United States of America is adequate, what should the host country do? In the host country, who has the ethical obligation to ensure review by a local committee – researchers, government health staff, public health authorities, regulatory bodies, or others? If the host country does not have the capacity to provide ethical oversight, what options are available?
