What you see is not what you get: implications of the brevity of antibody responses to malaria antigens and transmission heterogeneity in longitudinal studies of malaria immunity

Background: A major handicap in developing a malaria vaccine is the difficulty in pinpointing the immune responses that protect against malaria. The protective efficacy of natural or vaccine-induced immune responses against malaria is normally assessed by relating the level of the responses in an individual at the beginning of a follow-up period and the individual's experience of malaria infection or disease during the follow-up. This approach has identified a number of important responses against malaria, but their protective efficacies vary considerably between studies. Hypothesis: It is likely that apart from differences in study methodologies, differences in exposure among study subjects within each study and brevity of antibody responses to malaria antigen are important sources of the variation in protective efficacy of anti-malaria immune responses mentioned above. Since malaria immunity is not complete, anyone in an area of stable malaria transmission who does not become asymptomatically or symptomatically infected during follow-up subsequent to treatment is most likely unexposed rather than immune. Testing the hypothesis: It is proposed that individuals involved in a longitudinal study of malaria immunity should be treated for malaria prior to the start of the study and only those who present with at least an asymptomatic infection during the follow-up should be included in the analysis. In addition, it is proposed that more closely repeated serological survey should be carried out during follow-up in order to get a better picture of an individual's serological status. Implications of the research: Failure to distinguish between individuals who do not get a clinical episode during follow-up because they were unexposed and those who are genuinely immune undermines our ability to assign a protective role to immune responses against malaria. The brevity of antibodies responses makes it difficult to assign the true serological status of an individual at any given time., i.e. those positive at a survey may be negative by the time they encounter the next infection

Does malaria suffer from lack of memory?

It is widely perceived that immunity to malaria is, to an extent, defective and that one component of this defective immune response is the inability to induce or maintain long-term memory responses. If true, this is likely to pose problems for development of an effective vaccine against malaria. In this article, we critically review and challenge this interpretation of the epidemiological and experimental evidence. While evasion and modulation of host immune responses clearly occurs and naturally acquired immunity is far from optimal, mechanisms to control blood-stage parasites are acquired and maintained by individuals living in endemic areas, allowing parasite density to be kept below the threshold for induction of acute disease. Furthermore, protective immunity to severe pathology is achieved relatively rapidly and is maintained in the absence of boosting by re-infection. Nevertheless, there are significant challenges to overcome. The need for multiple infections to acquire immunity means that young children remain at risk of infection for far too long. Persistent or frequent exposure to antigen seems to be required to maintain anti-parasite immunity (premunition). Lastly, pre-erythrocytic and sexual stages of the life cycle are poorly immunogenic, and there is little evidence of effective pre-erythrocytic or transmission-blocking immunity at the population level. While these problems might theoretically be due to defective immunological memory, we suggest alternative explanations. Moreover, we question the extent to which these problems are malaria-specific rather than generic (i.e. result from inherent limitations of the vertebrate immune system)