A Malaria Vaccine That Works. . . Somewhat
Abstract & Commentary
Synopsis: The RTS,S/AS02A vaccine, a pre-erythrocytic vaccine based upon the Plasmodium falciparum circumsporozote surface antigen was recently proven to be safe, well tolerated, and immunogenic in this phase IIb proof-of-concept efficacy study done in Mozambican children.
Sources: Alonso PL, et al. Efficacy of the RTS,S/AS02A Vaccine Against Plasmodium falciparum Infection and Disease in Young African Children: Randomized Controlled Trial. Lancet. 2004;364:1411-1420; Van de Perre P, et al. Vaccine Efficacy; Winning a Battle (Not War) Against Malaria. Lancet. 2004;363:1380-1383; Vogel G. A Complex New Vaccine Shows Promise. Science. 2004;306:587-588; Wilson ME. Malaria Vaccine Trial: Modest Protection, Good Progress. Current Infect Dis Reports. 2005;7:31-32.
There is no doubt that an effective malaria vaccine is very much needed, and it doesn’t have to be perfect. Attempts to develop an efficacious malaria vaccine have been ongoing for about 50 years, but with little promise of success. No wonder. The global figures for malaria morbidity and mortality are truly staggering. Half the world’s population is exposed to malaria infections. There are approximately 500 million new acute malaria episodes on an annual basis, with somewhere between 1 and 3 million deaths occurring largely in children under the age of 5 years and mostly in Africa. The risk of death from malaria begins to decrease after age 2-3 years, and one important goal is to produce a vaccine that can be administered to infants who are approximately 2 months of age. In 2000, GlaxoSmithKline Biologicals and the Malaria Vaccine Initiative (MVI) Programme for Appropriate Technology in Health (PATH) entered into partnership aimed at fostering malaria vaccine development. The Malaria Vaccine Initiative is based in Rockville, MD, having been created in 1999 by the Bill and Melinda Gates Foundation for this purpose.
Of the candidate vaccines under development, RTS,S/AS02A is one of the most complicated and advanced. Previous studies have shown that malaria-naïve adult volunteers exposed to P. falciparum infected mosquitoes were protected against infection by P. falciparum sporozotes using this recombinant vaccine directed against the pre-erythrocytic stage of the malarial parasite. It had also protected semi-immune individuals from natural infection in The Gambia. In Phase I, during studies of Gambian children age 1-11, the RTS,S vaccine was found to be safe, well tolerated, and immunogenic. A pediatric vaccine studied in Mozambican children age 1- 4 was found to be similar.
This Phase IIb, double-blind, randomized, controlled trial was published in Lancet during October 2004. Phase IIb studies are performed to demonstrate efficacy against experimental challenge with organisms in the pre-erythrocytic phase of the malaria cycle and, either prevent or ameliorate natural infections. This study had been performed during the rainy season in the Manhica District of southern Mozambique. The estimated risk of malaria exposure can be illustrated by an entomological inoculation rate of 38 infected bites per person per year. The primary objective was to measure the vaccine’s efficacy against clinical episodes of P. falciparum malaria in children age 1-4 years, following their first vaccination series over a 6-month period of surveillance that began 14 days after dose 3.
RTS,S/AS02A and control vaccine were administered intramuscularly into the deltoid muscle at 0, 1, and 2 months. Half of the adult dose was used, ie 250-µL volume containing 25µg of RTS,S. RTS,S is a fused hybrid molecule consisting of 2 polypepetides: a circumsporozote protein expressed in Saccharomyces cerevisiae, fused to the surface antigen of hepatitis B virus (HbsAg). The AS02A adjuvant is an oil-in-water emulsion containing the immunostimulants, monophosphoryl lipid A and saponin-derived QS21.
In 2001, children aged 12-24 months had already received their hepatitis B immunizations. Control vaccine for children younger than 24 months, therefore, included 2 doses of the pneumococcal conjugate vaccine at first and third vaccinations, and 1 dose of Haemophilus influenzae type B vaccine at the second vaccination. For older children, control vaccine was pediatric hepatitis B vaccine. Careful blinded vaccine labeling and administration were necessary, and this was performed by a vaccination team not involved in any other study procedures. Participants were observed after each vaccination, as well as at home visits for the following 3 days. Unsolicited adverse experiences were recorded for 30 days after every dose. Beginning 60 days after the third dose, study children were visited at home once a month.
There were 2 cohorts of children described in this study. The first cohort of 1605 was followed by a system of passive surveillance, in addition to antibody determinations. If febrile illness occurred, they were evaluated for both malaria and other diseases, then appropriately treated. The second cohort of 417 lived in an area where malaria transmission was more intense, and they had to be cleared of their parasitemia between the second and third doses of experimental or control vaccines. These children were followed via active surveillance every 2 weeks for 2.5 months, and then monthly until 6.5 months after the last vaccine dose. Blood smears were evaluated for the presence of malaria parasites and the density of any parastiemia.
Comment By Maria D. Mileno, MD& Frank J. Bia, MD, MPH
The malaria vaccine successfully produced anticircumsporozoite antibody titers that were determined both before and after vaccination. Pre-vaccination anticircumsporozoite antibody titers were low in study children (natural infections), however, RTS,S induced specific antibody titers following vaccine dose 3, even resulting in persistent, albeit 75% lower titers, at 6 months. Still, they remained above baseline values. The vaccine was more immunogenic in children than it had previously been shown to be in adults, and particularly for the children who were ages 12-24 months. The vaccine also produced high levels of antibodies against HBsAg. When parasitemia prevalence was determined in a study survey at 6.5 months, it was found to be 37% lower in the vaccine group, although the densities of parasitemia were similar in the vaccine and control groups. What about actual malaria prevention? In the first cohort, the efficacy for prevention of all clinical episodes of malaria was about 27%, and for episodes of severe malaria it was about 58%. Among children between the ages of 1 and 2, the results were even more promising, with a 77% reduction in the chance for severe malaria in this small but important group within the study. There were 123 clinical episodes in the RTS,S vaccine group and 159 in the control group. In terms of severity, 11 of 745 children had at least 1 severe episode of malaria, compared with 21 of 745 children in the control group. The 4 deaths felt to be attributable to malaria, all occurred in the control group. Fewer children with malaria required hospital admission in the RTS,S group, when compared with controls (42 vs 62). In the second cohort, the vaccine was shown to be 45% effective in extending the time to first infection.
The global burden of disease from malaria continues to grow despite improvements in eradication efforts. Emergence of widespread resistance to available and affordable antimalarial agents also has made it difficult to treat patients in endemic regions. The most vulnerable groups include infants and pregnant women, as well as non-immune individuals traveling into endemic areas.
Although complete protection against malaria infection was not demonstrated, this vaccine promises to decrease the burden of malaria significantly, with its implementation in the most desperately affected regions of the world. These results also offer the hope that protective immunity may now be generated against what has been an immunologically elusive pathogen. Other work presented during sessions of the recent ASTMH meetings in Miami Beach, FL suggests that malaria vaccines, which target the gametocyte, will make an impact on malaria in endemic communities as well. As for travelers, advise them to hang onto their DEET and bed nets for now.
Be aware that the vaccine costs may come in at about $10-20 (US) per dose. Whereas travelers might find that acceptable it could be a significant problem to solve in the parts of Africa where the vaccine is most needed. Also, it is not known how HIV-infected vaccinees will respond, and the interaction between HIV and malaria is of particular significance for pregnant women and their newborns.