New combination could lead to malaria vaccine progress

July 2007

The combination of two different candidate malaria vaccines into one regimen has led to a significant increase in immune responses in a study of rhesus macaques at the Walter Reed Army Institute of Research.

Although rhesus macaques do not contract falciparum malaria, they have been reliably predictive of subsequent clinical vaccine trials.

The Army–led research team showed a 16-fold increase in T cell responses in the animals receiving the combination over RTS,S/AS01B alone. These same responses have been associated with increased malaria protection in previous human trials. This finding may put the prime-boost combination at the front of the pipeline for malaria vaccine research.

Clinical research on RTS,S (Rixensart, GlaxoSmithKline) began in 1992, when a human trial of the first RTS,S prototype failed. Since then, RTS,S, formulated with AS02A has been the only vaccine candidate that has shown human protection in both a challenge model and in field trials in children. RTS,S–based efforts focus the immune system to target antibodies to intercept the invading parasite before it enters the liver and to target T cells to eliminate the parasite within the liver. A recent RTS,S improvement is its formulation with a new adjuvant, AS01B, a vaccine termed “RTS,S/AS01B.”

The most recent development, a prime–boost regimen involving an adenovirus expressing the circumsporozoite protein designated Ad35CS (Leiden, Crucell Holland) followed by two doses of RTS,S/AS01B, was described by a team led by Ann Stewart, DVM, PhD, senior scientist at the Walter Reed Army Institute of Research.

“We think this is incredibly positive and a strong ‘go signal’ to proceed to clinical trials,” said Col. Gray Heppner, MD, director of the division of malaria vaccine development at the Walter Reed Army Institute of Research. “This is a lesson in persistence, dedication and, above all else, teamwork. The story on RTS,S is that we didn’t give up on it. We worked closely with industry and overseas partners and the Malaria Vaccine Initiative. Together, we have demonstrated that adjuvanted RTS,S does protect healthy adult volunteers against infection and children at risk of malaria in Africa.”

For the present combination study, Stewart and colleagues worked in collaboration with GlaxoSmithKline (the producer of RTS,S/AS01B) and Crucell Holland (the adenovirus producer). The results appeared in Infection and Immunity.

The researchers had previously found that the higher the antibody and the higher the magnitude of the T cell response, the more likely patients are to be protected. Hence, the interest in the significant increases in T cell responses induced by the combination of RTS,S/AS01B and Ad35CS in the present prime-boost trial.

Partnerships for licensure

In 1996, RTS,S/AS02A showed increased protection in a human challenge study at the Walter Reed Army Institute of Research. In that study, six of seven people were completely protected against malaria.

In 1999 to 2000, RTS,S/AS02A was then taken to Gambia for an MRC–sponsored study where it showed reduced malaria rates in healthy adult men. In 2003 to 2005, a trial of RTS,S/A02A was then conducted in children in Mozambique by a partnership of CISM, GlaxoSmithKline, the University of Barcelona and the Malaria Vaccine Initiative at PATH. The participating children showed an unprecedented 48% reduction in severe malaria for 18 months. Due in part to this success, the Malaria Vaccine Initiative at PATH and GlaxoSmithKline committed more than $100 million for multicenter, phase–3 trials of adjuvanted RTS,S starting in 2008. By 2008, the lead RTS,S formulation will enter phase–3, multicenter licensure trials in Africa, and could be licensed within the next five years.

“The mission of the Department of Defense malaria vaccine program is protection for the military, but the greater public health need is always a consideration,” Heppner said. “Of course, there is tremendous spillover benefit of all of our research. Prime-boost vaccination is exciting because we think we’ve got something much more immunogenic and potentially much more beneficial both to the military and to the global population in need. If all goes well, an improved vaccine could be available by 2015.”

For more information:

• Stewart VA, McGrath SM, Dubois PM, et al. Priming with adenovirus 35-circumsporozoite protein (CS) vaccine followed by RTS,S/AS01B boosting significantly improves immunogenicity to Plasmodium falciparum CS compared to that with either malaria vaccine alone. Infect Immun. 2007;75:2283-2290.