After 40 years, RTS,S nears the finish line

27 Jun 2011

Patrick Adams

Source: TropIKA.net

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As it undergoes the final phase of testing, RTS,S/AS01, the world’s most clinically-advanced malaria vaccine, is generating excited talk about an imminent rollout.

Indeed, the World Health Organization (WHO) has indicated that if Phase III results confirm the level of safety and efficacy demonstrated in previous trials, a recommendation on the vaccine could be made by 2015. That would pave the way for governments in endemic countries--including the seven in which trials are underway--to decide on approval, adoption and implementation of the new tool.

But RTS,S isn’t just a vaccine. The culmination of more than 40 years of research, it’s a testament to the power of globe-spanning partnerships to solve public health problems—and it has lessons for every future challenge, no matter how big or small.

The story of RTS,S officially begins in 1960s with the identification of the circumsporozoite protein in the laboratory of New York University’s Victor Nussenzweig. But as Nussenzweig himself points out, it was his wife Ruth Nussenzweig who first demonstrated that a malaria vaccine was possible; in 1967, she and colleagues successfully immunized mice with X-irradiated sporozoites of Plasmodium berghei (1).

From there, the Nussenzweigs went on to show that immunization with radiation-attenuated sporozoites could confer complete sterile protection against malaria in animals and humans. (2,3) “It was obvious that a vaccine was possible,” says Victor Nussenzweig. But how exactly that might be achieved wasn’t at all clear.

According to Nussenzweig, the vaccine’s development went through three distinct phases. First there was the afterglow of the CS findings and the sense of possibility that research ushered in. But then, after two major trials--one of a peptide vaccine by Hoffman-LaRoche and another of a recombinant vaccine by the US Army—failed to demonstrate protection, RTS,S languished. (4,5) The result, says Nussenzweig, was “neglect for many years.”

Nevertheless, scientists at Walter Reed Army Institute of Research (WRAIR) and what is now GlaxoSmithKline (GSK) Biologicals continued their collaborative work on the vaccine’s development. “A critical hurdle was to increase the immune response,” wrote Christian Loucq, director of the PATH Malaria Vaccine Initiative (MVI), in a recent paper in Health Affairs. (6)

Established in 1999 through a grant from the Bill & Melinda Gates Foundation, MVI was just a year old when it partnered with GSK to share the vaccine’s future development costs. MVI agreed to fund the clinical development plan (CDP)

“Key to success here was the decision by GlaxoSmithKline scientists, led by Joe Cohen, to include in the malaria vaccine a component of the company’s hepatitis B vaccine,” he said, adding that “later the company scientists also added a proprietary adjuvant system” intended to enhance the body’s immune response.

Yet in the case of RTS,S, collaboration has gone far beyond the chemical makeup of the vaccine. “Just as it takes a village to raise a child, it has taken a huge number of stakeholders around the world to reach this point,” wrote Loucq, who went on to describe “the pivotal roles played by collaborations of non-profit organizations, pharmaceutical companies, private and public donors, and countries whose citizens would benefit most directly from a vaccine.”

One of those is an MVI-supported project by the Swiss Tropical and Public Health Institute. Using cost-of-illness data recently collected in Ghana, Nigeria and Uganda, scientists at Swiss TPH are developing an epidemiological and economic model to calculate cost effectiveness estimates for malaria vaccines in those and, soon, other endemic countries. The model is designed to be used by funders and policymakers to determine approximately how many cases could be averted by the use of a vaccine in a given transmission setting and alongside other malaria control interventions.

Meanwhile, a collaborative undertaking by PATH, WHO and African ministries of health led to the development of the Malaria Vaccine Decision-Making Framework (DMF). First drafted in 2006, the strategic planning tool is intended to facilitate effective cooperation between governments and other stakeholders in making a decision on a malaria vaccine within three years of licensure. To date, every country in sub-Saharan Africa has contributed to the DMF’s creation or begun the process of implementing a country-specific DMF.

There’s also the work undertaken by the Malaria Clinical Trials Alliance (MCTA). The latter, a project of the INDEPTH network based in Ghana, aims to facilitate site preparation for the conduct of clinical trials of malaria interventions while also promoting sustainable development of clinical trials sites in resource-poor settings. With PATH’s support, MCTA has helped to strengthen research capacity at RTS,S trial sites—by building and refurbishing facilities, strengthening ties with local communities and enabling African scientists to participate in international conferences.

And, as Loucq points out, the development of RTS,S has laid the foundation for a novel approach to the development of future malaria vaccines with higher efficacy than RTS,S—first by boosting immunity, then targeting other antigens of the parasite, and lastly blocking the parasite’s entry into red blood cells: “This strategy requires coordinated investments in identifying and prioritizing new targets on the parasite, developing delivery mechanisms or platforms to reach these targets, and creating better tools to evaluate the potential success of vaccine approaches.”

The Malaria Vaccine Technology Road Map published by the WHO in 2006 stated that the malaria community’s first landmark goal is to “by 2015, develop and license a first-generation malaria vaccine that has a protective efficacy of more than 50% against severe malaria and death and lasts longer than one year.” Thanks to partnerships and the innovations they’ve made possible, they may very well achieve that.

“The lesson of RTS,S,” says Nussenzweig, “is that the success of a single component modern vaccine needs to be based on a solid rationale, must have the support of the pharmaceutical industry and requires a large investments in human resources and money.” While RTS,S is still not the ideal vaccine, he says, “a molecular target has been defined and improvement is likely.”

References

Nussenzweig RS et al. (1967) Protective immunity produced by the injection of x-irradiated sporozoites of plasmodium berghei. Nature 14;216:160-2. Available from: http://www.ncbi.nlm.nih.gov/pubmed/6057225
Nussenzweig RS, Vanderberg J, Most H & Orton C. Immunity in simian malaria induced by irradiated sporozoites. J Parasitol 1970; 56: 350–351. Available from:
8 Clyde DF, Most H, McCarthy V & Vanderberg JP. Immuniza- tion of man against sporozoite-induced falciparum malaria. Am J Med Sci 1973; 266: 169–177.
Etlinger HM et al (1991) Ability of recombinant or native proteins to protect monkeys against heterologous challenge with Plasmodium falciparum. Infect Immun 59(10):3498-503. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1894356
Stoute JA et al (1997) A preliminary evaluation of a recombinant circumsporozoite protein vaccine against Plasmodium falciparum malaria, RTS,S Malaria Vaccine Evaluation Group. N Engl J Med. 9;336:86-91. Available from: http://www.ncbi.nlm.nih.gov/pubmed/8988885
Loucq C et al (2011) Producing a successful malaria vaccine: innovation in the lab and beyond. Health Affairs 30:(6)1065-1072. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21653958