Elsevier

Vaccine

Volume 27, Issue 1, 1 January 2009, Pages 2-9
Vaccine

Review
Reflections on early malaria vaccine studies, the first successful human malaria vaccination, and beyond

https://doi.org/10.1016/j.vaccine.2008.10.028Get rights and content

Abstract

Advances towards protective vaccines against malaria were made feasible by the development of a rodent model of mammalian malaria that allowed production of all stages of the malaria parasite for study. Investigations with sporozoites (the stage transmitted by mosquitoes in their saliva) demonstrated that immunization with radiation-attenuated sporozoites could produce a solid, sterile immunity, first shown in studies with mice and later with human volunteers. Protective immune mechanisms involve anti-sporozoite antibodies that immobilize sporozoites injected into the skin by mosquitoes, followed by CD4+ and CD8+ T-cells acting against liver stage parasites produced by sporozoites that have escaped antibody-based immunity and invaded hepatocytes. Two alternative approaches now being used in human trials are immunization with intact, attenuated sporozoites vs. immunization with “sub-unit” vaccines based on immunogenic components of sporozoites or liver stage parasites. In addition to immunization against these pre-erythrocytic stages, encouraging progress is being made on immunization against blood stage parasites and on immunization for production of transmission-blocking antibodies. There is reason to be optimistic that one or more of the approaches will work on a large scale, and that a multi-stage vaccine may be able to combine several of these approaches in a sequential immunological assault against the malaria parasite as it progresses through its stages.

Introduction

A recent review on vaccination against malaria in “Vaccine” [1] described the disease burden posed by malaria and the need for a vaccine that can protect against this devastating disease. It concluded that the most advanced and well-documented vaccine candidates rely on protective immunity induced by the circumsporozoite protein (CSP) found at the surface of the sporozoite, the stage injected by the mosquito to initiate the disease. One approach to vaccination has been the use of intact, attenuated sporozoites to induce a sterile immunity generated by protective anti-CSP antibodies acting against mosquito-injected sporozoite challenges [2], together with CD4+ and CD8+ T-cells that recognize and act against hepatocytes invaded by sporozoites [3]. This attenuated sporozoite approach was first successfully carried out by injection of X-irradiated sporozoites of the rodent malaria parasite Plasmodium berghei into mice [4] and soon followed by allowing X-irradiated mosquitoes to inject sporozoites of the human malaria parasite P. falciparum into human volunteers [5]. A compendium of human vaccination trials with this approach has shown >90% of volunteers to be completely protected against challenge by bite of infected mosquitoes [6]. Plans by this group are underway to attempt to vaccinate large numbers of humans by syringe injection of purified, irradiated P. falciparum sporozoites [7].

A second approach attempts to use “sub-unit” vaccines based on immunogenic components of sporozoites or liver stage parasites. The review [1] noted that there are multiple such vaccine candidates and concluded that the most advanced candidate is RTS,S. This includes a polypeptide corresponding to amino acids 207–395 of the CSP from the human malaria parasite, P. falciparum, fused to the hepatitis B surface antigen and expressed in the form of virus-like particles in yeast cells [8]. A recent trial testing this vaccine on infants in a highly endemic area of Mozambique concluded that the adjusted vaccine efficacy was 65.9% [9], although this interpretation of the actual degree of efficacy remains controversial [10].

Thus, in view of the great interest in vaccines that appear to act against CSP on the surface of the sporozoite and on the infected hepatocyte, it is constructive to review the history of how this immunogen came to be identified. As a co-investigator in the initial successful immunization study with mice [4] and the sole survivor of the group that conducted the first successful vaccination study with humans [5], here is a highly personal and selective history of what led up to these studies and how they have since advanced.

Section snippets

Early history

Isaac Newton, in a letter to Robert Hooke wrote: “If I have seen further it is by standing on the shoulders of giants.” All of us who have been privileged to work on developing a vaccine against malaria are part of a lineage of researchers, and can trace our debt to those upon whose shoulders we stand. We, in turn, can hope to make contributions that will enable others to reach a shared goal: a practical, protective vaccine for malaria.

This is a personal history; thus, permit me to name some

The search for research “models” of malaria

Human malaria does not lend itself easily, however, to basic research in immunology. A laboratory model for in vivo study of mammalian malaria (preferably in rodents) had long been a dream of malariologists. Up through the 1940s, several avian models were available. I must confess that my favorite has always been P. lophurae, both because this became William Trager's parasite of choice (and his work with it over many years led inexorably to his ultimate success in culturing of P. falciparum)

The emergence of rodent malaria as a research model

The issue was resolved with the description of a rodent malaria parasite, P. berghei, in central Africa by a Belgian physician (Ignace Vinke) and entomologist (Marcel Lips) in 1948 [21]. As often occurs with important discoveries, these workers had not been searching for what they ultimately found. Vincke spent the years of World War II doing malaria surveys in the former Belgian Congo (now the Democratic Republic of the Congo). In 1942 he observed sporozoites in the salivary glands of the

Initiation of immunization studies with rodent malaria

By 1967, our immunization studies had begun. By immunizing mice via intravenous injection of sporozoites obtained from dissected-out mosquito salivary glands and then attenuated by X-irradiation, almost total protection against subsequent challenge with viable sporozoites was achieved [39]. Over the next 2 years the fundamental characteristics of this protection were established, including such things as its species and stage-specificity [40], the humoral component of its action [41], [42] and

The first human trial

After the initial successes with immunization of mice against sporozoites, as well as with simians (squirrel monkeys) [54], it seemed timely to move toward trial studies with human volunteers. Sporozoites obtained directly from dissected-out mosquito salivary glands, however, could not ethically be injected IV into humans, as had been done with rodents. An alternative approach was suggested from studies on mosquito-borne viruses. Serological surveys, done after epidemics of infections with

Attempts at in vitro production of sporozoites

The next question to be faced was how to go from the obviously impractical approach of mosquito injection of irradiated sporozoites to a more practical large-scale vaccination protocol with purified sporozoites. In the mid-1970s, armed with ignorance, the answer seemed to be to try to develop culture procedures to raise large numbers of sporozoites without mosquitoes. An important stimulus was the encouragement provided by the 1976 success in continuous culturing of P. falciparum blood stages

Acknowledgements

I thank Irwin Sherman, Steve Hoffman and Hope Vanderberg for careful readings and constructive comments on a draft manuscript of this paper. The author's work is funded by Public Health Service grant # AI63530 from the NIH Institute of Allergy and Infectious Diseases.

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    This paper was adapted from a talk given by the author to the International Conference on Malaria Vaccines for the World in September 2007 at the Royal Society of Medicine in London.

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