Background

The circumsporozoite protein on the sporozoite is considered to be the principal antigen responsible for these antibodies. In previous trials, however, circumsporozoite vaccines have not been found to be sufficiently immunogenic. In this trial, the authors report on a recombinant circumsporozoite vaccine (consisting of the circumsporozoite protein fused to hepatitis B surface antigen), in three different formulations with three different adjuvants. 

Methods

Healthy volunteers, without prior exposure to malaria and without significant medical problems. 

Vaccine

The RTS,S vaccine, a recombinant polypeptide produced by yeast cells and consisting of two components:

• RTS is a polypeptide chain consisting of part of the circumsporozoite protein fused to HBsAg.
• S is the HBsAg polypeptide alone.

The vaccines were administered i.m. at 0, 4 and 28 weeks. Thus, there were three vaccines, each vaccine to be given in three doses. 

Follow-up and measurements

Patients were monitored clinically at days 1, 2, 7 and 14 after each vaccination.

Blood samples were obtained for the evaluation of humoral immunity on the day of each vaccination, and at days 1 and 14 thereafter. Humoral immunity was evaluted by determining antibodies to circumsporozoite protein (total IgG levels and IgG subclass levels) and by an indirect fluorescence antibody assay to air dried sporozoite. Antibodies to HBsAg were also determined.

Blood was obtained for the evaluation of cellular immunity (proliferative and cytolytic assays) before the first vaccination and after the third one.

Challenge with malaria

22 subjects who had received all three vaccine doses and 6 unimmunized controls were challenged with falciparum malaria. This involved five bites from laboratory-bred Anopheles mosquitos that had been infected with sporozoites. Follow-up included frequent blood-smear examinations and treatment as needed if infection developed. 

Results

46 subjects, men and women (mean age 31, range 18-45), were randomized to one of the three vaccines in roughly equal numbers. The first dose was well tolerated (mild local discomfort).

41 subjects went on to receive the second dose. Reactions to vaccines 2 and 3 were more severe after the second dose (mainly constitutional symptoms).

27 subjects received the third vaccine dose. The reasons for not completing all three doses were mainly scheduling problems or noncompliance. Because of the severity of the reaction after the second dose, two subjects (one for vaccine 2 and one for vaccine 3) were not given the third dose and the remainder received a reduced dose.

Of the 27 subjects who received all three doses, 22 agreed to undergo sporozoite challenge (8 given vaccine 1 and 7 given vaccines 2 and 3). 

Immunogenicity

Antibodies to circumsporozoite developed in all three vaccine groups, but were higher in subjects who received vaccines 2 and 3. Similarly, subjects who had been HBsAb negative before vaccination seroconverted, but antibody response was higher in groups 2 and 3. 

Vaccine efficacy

Sporozoite challenge in 6 unimmunized controls produced parasitemia in all 6 after 11-13 days. 7 out of the 8 subjects given vaccine 1 became parasitemic (12.6 days after exposure). 5 of the 7 subjects given vaccine 2 became parasitemic (after 15.2 days). Only 1 out of the 7 subjects given vaccine 3 developed malaria, for a relative risk of infection of 0.14 (95% CI 0.02 to 0.88).

Antibody titers were higher in subjects who were protected. Measurements of cellular immunity did not clearly predict protection, however. 

Authors' discussion

Although these results are very encouraging, they are preliminary, and many more studies of safety and efficacy will be needed, particularly in the field, in the setting of repeated exposure to multiple strains of plasmodium. 

Editorial