Preventing Malaria by Vaccination

Abstract & Commentary

By Philip R. Fischer, MD, DTM&H, Dr. Fischer is Professor of Pediatrics, Department of Pediatric and Adolescent Medicine, Mayo Clinic, Rochester, MN., is Editor for Infectious Disease Alert.

Dr. Fischer reports no financial relationships relevant to this field of study. This article originally appeared in the December 2009 issue of Travel Medicine Advisor. It was edited by Frank Bia, MD, MPH, and peer reviewed by Mary-Louise Scully, MD.

Synopsis: New formulations of malaria vaccines show increasing efficacy in protecting both children in malaria-endemic areas and malaria-naïve adults without previous malaria exposure.

Source: Sacarlal J, et al. Long-term safety and efficacy of the RTS,S/AS02A malaria vaccine in Mozambican children. J Infect Dis 2009;200:329-336.

Nearly half of the world's population live in malaria-endemic geographic regions, and more than one million African children die of malaria each year. Vaccine development continues. The RTS,S vaccine includes a recombinant antigen that targets the pre-erythrocytic stage of P. falciparum. It is frequently coupled with the AS02A adjuvant system.

In previous studies, the RTS,S/AS02A vaccine has been shown to be protective against malaria in laboratory settings involving malaria-naïve adults. It also confers some protection against natural infection in semi-immune adults. The vaccine is safe in pre-school and school-aged children and prevents approximately 45% of malaria infection and 29% of clinical malaria over six months in children aged 1-4 years. At 21 months of follow-up after the initial vaccination, protection against clinical malaria was 35%. A subsequent study showed 66% protection against new malaria infection in African infants.

To build on that foundation, the currently reported study evaluated RTS,S/AS02A-vaccinated and control pre-school-aged children 45 months after initial vaccination in rural Mozambique. More than 2000 children were included in the study. Vaccine was given monthly for a total of three doses. More than 96% of vaccinated children were seropositive for circumsporozoite protein antibodies 45 months after vaccination. Vaccine efficacy was 31% in preventing a first episode of malaria and 38% in preventing severe malaria. These results provide optimism for sustained protective value of these vaccines and dispel some concern that childhood vaccination will lead to subsequently increased risks of natural infection in repeatedly exposed children.

Commentary

While still far from completely effective, use of currently tested malaria vaccines presumably could lead to the sparing of hundreds of thousands of lives each year in Africa. Recent data also show short-term effectiveness of a similar RTS,S vaccine when administered with routine childhood vaccines at 10, 14, and 18 weeks of age.1

Practitioners of travel medicine also are interested in protecting adults with short-term malaria exposures. In a comparison study of malaria-naïve adults, RTS,S/AS02A was compared with a vaccine incorporating a related liposome-based adjuvant, AS01B. Recipients of three vaccine doses over two months were challenged with malaria 2-3 weeks and five months after vaccination. RTS,S/AS01B protected 50% of recipients, while RST,S/AS02A protected 32%. Protection persisted through the five month re-challenge.2

Thus, advancing vaccine science is reaching the ability to protect up to half of vaccine recipients against malaria by using component vaccines. What would be the efficacy of using whole-organism vaccines?

Decades ago, it was found that malarial immunity could be achieved by allowing mosquitoes to inoculate subjects with irradiated sporozoites. Nonetheless, a heavy bite burden (1000 or more infected bites) was required to achieve this immunity.3 Fifteen healthy volunteers were exposed to biting mosquitoes monthly for three months while receiving prophylactic chloroquine. Ten volunteers were bitten by P. falciparum-infected mosquitoes, and five control subjects were exposed only to malaria-free mosquitoes. A month following subsequent discontinuation of chloroquine prophylaxis (two months after the last mosquito exposure), subjects were exposed to infected mosquitoes. None of the 10 subjects "vaccinated" by live parasites developed malaria, and all of the "unvaccinated" subjects developed malaria. This study suggests that human protection against malaria might potentially be achieved by prophylaxis-protected exposure to whole parasite vaccines.3

While waiting for further development of whole parasite and/or component vaccines, what else is new in the developing science of malaria protection? Bednets are known to be very effective in decreasing the burden of malaria in endemic regions, and a new study points at factors that are relevant to keeping local populations motivated to actually use the bednets.4 In addition, intermittent preventive therapy (IPT) of malaria in populations residing in endemic areas has been effective in decreasing the burden of malaria during pregnancy (IPTp) and infancy (IPTi). A new study suggests that artemisinin-based intermittent treatment also is effective in school-aged children.5

Ongoing studies in at-risk populations, such as children in developing countries and malaria-naïve adults, provide optimism that good protection might someday be available through some type of component vaccine or, perhaps, through a whole-sporozoite inoculation. How will we manage to assure that vaccines become available not only to travelers but to the masses of at-risk people around the world? As CC Campbell says, "millions of African children await the answer."6

References

  1. Abdulla S, et al. Safety and immunogenicity of RST,S/AS02D malaria vaccine in infants. N Engl J Med 2008;359:2533-2544.
  2. Kester KE, et al. RTS,S Vaccine Evaluation Group. Randomized, double-blind, phase 2a trial of falciparum malaria vaccines RTS,S/AS01B and RTS,S/AS02A in malaria-naive adults: Safety, efficacy, and immunologic associates of protection. J Infect Dis 2009;200:337-346.
  3. Roestenberg M, et al. Protection against a malaria challenge by sporozoite inoculation. N Engl J Med 2009;361:468-477.
  4. Toé LP, et al. Decreased motivation in the use of insecticide-treated nets in a malaria endemic area in Burkina Faso. Malar J. 2009;8:175.
  5. Barger B, et al. Intermittent preventive treatment using artemisinin-based combination therapy reduces malaria morbidity among school-aged children in Mali. Trop Med Int Health. 2009;14:784-791.
  6. Campbell CC. Malaria control — addressing challenges to ambitious goals. N Engl J Med 2009;361:522-523.