The Elusive Malaria Vaccine: Miracle or Mirage?

Irwin W. Sherman

American Society for Microbiology 2009
A book review by Danny Yee © 2011
The Elusive Malaria Vaccine is a detailed history of more than a century of immunological research into malaria, and specifically of the search for a malaria vaccine. Sherman has been a participant in this research himself and draws not only on the published research but on "behind the scenes" knowledge of people and personalities, dead ends, funding sources, scandals, and so forth.

The approach is only roughly chronological, as it follows separate approaches to finding a vaccine, tracing the work done by individual researchers and research groups. So it can be hard to follow the flow of events, with discoveries and ideas naturally cropping up in different contexts.

The story begins with an account of the hunt for an infectious agent, starring Laveran, Ross, and Grassi. This led to the identification of the Plasmodium parasite and its transmission by Anopheles mosquitoes.

A seven page chapter gives a brief account of malaria as a disease and the drugs available for treatment, but Sherman doesn't duplicate the clinical literature on malaria (though a few pointers into that might have been useful). There's also a general account of the human immune system, keeping malaria in view, which is helpful for non-specialists. And a brief history of early vaccination covers Jenner and smallpox, Pasteur and anthrax, and a range of different vaccines.

Work on malaria in the first half of the twentieth century mostly involved bird and monkey malarias: P. relictum in sparrows and canaries, P. lophurae and P. gallinaceum in chickens, and P. knowlesi in rhesus monkeys. There were some limited successes:

"protection could be achieved after vaccination with the various stages of the parasite, although in most cases this required the use of an adjuvant. Protection against reinfection was stage specific and more often than not was nonsterilizing. ... the protective antigens had still not been identified."

A global malaria eradication campaign was launched in 1955, but by the 1960s it was clearly failing, bringing renewed interest in finding a vaccine. There was proof that

"humans repeatedly exposed to malaria-infected mosquitoes could develop an immunity capable of restricting clinical illness and parasite blood density and that this immunity could be passively transferred to nonimmune individuals (children) via gamma globulin".
Vaccine research led to improved understanding of immunity and antigenic variation and some practical results, mostly in the rhesus monkey-P. knowlesi model, but these failed to identify antigens, relied on powerful adjuvants, and were not obviously extendable to humans.

One key was finding an animal host for human malaria.

"Quentin Geiman at Stanford University reported that the night owl monkey, Aotus trivirgatus, from Colombia, would support the development of P. falciparum. This was a significant breakthrough in malaria research, as now a small primate host would be available for chemotherapy and immunity studies."

And in vitro cultivation was achieved in 1976.

"the impact of continuous cultivation of P. falciparum would be phenomenal, allowing for the sequencing of the P. falciparum genome, allowing the identification and isolation of blood and insect stage antigens, and providing a means for identifying vaccine candidates."
These inspired a USAID program to test vaccine candidates in owl monkeys. Less positive was USAID's refusal to listen to scientists skeptical about a practical malaria vaccine for humans, resulting in some dubious funding awards and several cases of fraud and malfeasance.

The search for a blood stage antigen was propelled by developments in molecular genetics, notably monoclonal antibodies, recombinant methods, and PCR. P. falciparum was sequenced in 2002. Sherwin describes the discovery of MSP-1 protein, "the first and most abundant merozoite surface protein", which became one of the most popular vaccine targets.

"In 2005, according to WHO, there were 93 candidate malaria vaccines in development. Of these, 26 were based principally on MSP-1. By 2006, the total number of candidate vaccines was 23, of which 6 were based on MSP-1. And by November 2007, as a result of failures during safety and immunogenicity trials in volunteers in a nonacademic setting, the number of vaccines had been reduced and three of the remaining five MSP-1 projects had been terminated."

One sidetrack was Manuel Elkin Patarroyo's 1987 claim to have made a synthetic, multiantigenic vaccine SPf66; this was abandoned by 1996, after exhaustive field trials failed to show an effect.

Turning to attempts to block transmission, Sherwin describes the basic epidemiology behind the Ross-MacDonald "malaria equation". This led to attempts to reduce the reproductive ratio below the critical level: notably the failed eradication program in the 1960s and more recent approaches centred on insecticide-treated bed nets. Another possibility is a vaccine that, rather than preventing the disease, blocks its transmission, targeting either gamete or zygote/ookinate antigens; some candidates here have progressed to consideration for clinical trials.

"During the 24 h of development within the mosquito midgut, malaria parasites are outside of cells and are bathed with the constituents of the blood meal. Thus, the midgut stages are accessible to the immune factors of the vertebrate host"

In approaches targeting the blood stages a key protein was PfEMP1, expressed on the surface of infected red blood cells and the site of considerable antigenic variation. Blocking merozoite entry into red blood cells was another approach. Pregnant women are particularly vulnerable to malaria, as a result of sequestration of infected erythrocytes in the placenta, and there is the possibility of targeting a vaccine specifically at pregnancy malaria.

Attempts to use attenuated or killed sporozoites as a vaccine have a long history. Much of this work has targeted the circumsporozoite protein: a vaccine RTS,S, coupled with surface antigen protein from hepatitis B virus, has been tested and is in preparation for licensing in 2011. And a company (Sanaria) has been set up just to develop an attenuated sporozoite vaccine, but some malariologists still think a vaccine may be decades away. Other approaches involve DNA-based vaccines and virus vectors, or attempts to use gene knockout to produce attenuated sporozoites that would stop development at the liver stage.

Our direct knowledge of human immunity largely comes from the use of malaria as a therapy for treating late-stage syphilis and from natural immunity, which appears to involve an antibody-independent T-cell mechanism. Much of Sherman's own work has been on red blood cell antigens and natural immunity.

There are several reasons why a vaccine for malaria (or indeed for any eukaryotic parasite) has remained elusive, among them the complexity of the Plasmodium genome compared to viruses or even bacteria, the complexity of its life-cycle, the lack of good animal models, and the variability of blood stage antigens. Sherman briefly touches on current prospects and the practical problems that will remain even if a vaccine is found.

These accounts of research careers and research programs are set in a biographical matrix which sometimes goes into involved background detail. As an example, there is a page-long paragraph describing the first twenty years of Richard Rossan's career, that starts:

"Richard Rossan (born in 1929) had his first encounter with malaria parasites during the summer of 1949 at the University of Illinois, Champaign-Urbana, while taking an Introductory Protozoology course taught by Richard Kudo, a world-famous protozoologist. Coincident with being awarded an M.S. degree in 1951, Rossan received a draft notice due to the Korea conflict. He opted for a 4-year commitment in the U.S. Navy, a decision that was to affect his entire research career. ...

Most researchers don't get an entire page, but many are covered, making for a lot of biographical detail. There's also some coverage of the politics and funding of individual research groups. Much of this material — where various researchers did their undergraduate degrees, what they did in retirement, and other minutiae — will probably only interest other researchers within the field, and perhaps the historians and sociologists studying them.

The "accessible to a general audience" on the back cover blurb is a real stretch, but Sherman does offer enough support for a reader with no more than school biology to follow at least the gist of the science. And there's certainly plenty of fascinating material in that, and in the historical background.

Some extra structure could have made The Elusive Malaria Vaccine more accessible. The more narrowly biographical detail could have been separated out into "boxes" on individual researchers, for example, making the core threads following research programmes easier to follow. A glossary would be useful. And the solitary figure, showing the life cycle of P. falciparum, could have been augmented, perhaps with a timeline of events, a chart of connections between different researchers, and a chart of the history of clinical trials for different candidate vaccines, to make just a few suggestions.

Those after more general books on malaria have a good selection of alternatives, both popular and scholarly, but The Elusive Malaria Vaccine offers a unique focus on the immunological research.

May 2011

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%T The Elusive Malaria Vaccine: Miracle or Mirage?
%A Sherman, Irwin W.
%I American Society for Microbiology
%D 2009
%O hardcover, references, index
%G ISBN-13 9781555815158
%P 391pp