Mosquirix (RTS,S)

A Novel Vaccine for the Prevention of Plasmodium falciparum Malaria

Kyle J Wilby BSP ACPR, PharmD; Tim TY Lau PharmD ACPR FCSHP; Samuel E Gilchrist MSc (Pharm), PhD; Mary HH Ensom PharmD FASHP FCCP FCSHP FCAHS

Disclosures

The Annals of Pharmacotherapy. 2012;46(3):384-393. 

In This Article

Clinical Studies

Our search identified 5 randomized controlled trials[10–14] and 4 follow-up extension studies[15–18] assessing the effect of RTS,S with variations of either AS01 or AS02 on development of clinical disease in the field. Populations were limited to African infants and children. The studies are described below and results summarized in Table 1.

Phase 1 and 2 Trials

A double-blinded Phase 2b randomized controlled trial assessed safety and efficacy of RTS,S/AS02A against P. falciparum infection and disease in 2022 children living in Mozambique over 6.5 months after complete vaccination.[10] Included were 2 cohorts of children aged 1–4 years living in 2 separate areas. Each cohort was randomized to receive either 3 doses of RTS,S/AS02A (as 25 μg of RTS,S antigen in 250 μL of AS02A adjuvant) or 3 doses of control. For subjects <24 months, the control consisted of 2 doses of pneumococcal conjugate vaccine (Prevnar, Wyeth Lederle Vaccines) and 1 dose of Haemophilus influenzae type b (Hib) vaccine (GSK Biologicals); those 24 months and older received 3 doses of pediatric hepatitis B vaccine (GSK Biologicals). Vaccines were administered via intramuscular injection into the deltoid muscle, alternating the arms according to a 0-, 1-, and 2-month vaccination schedule. Cohort 1 (n = 1605; 803 RTS,S, 802 control) was passively surveyed for clinical disease and infection (fever and presence of P. falciparum asexual parasitemia >2500 parasites/μL) and cohort 2 (n = 417; 209 RTS,S, 208 control) was actively and passively surveyed for clinical disease and infection (fever and presence of P. falciparum asexual parasitemia >0 parasites/μL). Vaccine efficacy rates were adjusted for age, bed net use, distance from health facility, and geographic region.

Results were significantly in favor of RTS,S/AS02A, with vaccine efficacy of 29.9% (95% CI 11.0 to 44.8) for first episode of clinical disease and 28.6% (95% CI 10.4 to 43.1) for first episode of infection in cohort 1. For cohort 2, a vaccine efficacy rate of 45.0% (95% CI 31.4 to 55.9) was obtained for first episode of parasitemia >0 parasites/μL (measure of infection). Test results (proportionality of hazards with Schoenfeld residuals) for waning efficacy were not significant.[10]

A single-blind follow-up study assessed efficacy and safety of RTS,S/AS02A at 18 months following the third dose of vaccine.[15] Surveillance and monitoring methods were the same as previously reported.[10] Results, adjusted for age, bed net use, distance from health facility, and geographic region, were significantly in favor of RTS,S/AS02A, with vaccine efficacy of 35.3% (95% CI 21.6 to 46.6) for first episode of clinical disease and 31.8% (95% CI 18.1 to 43.1) for first episode of infection in cohort 1 (per-protocol analysis).[15] Intention-to-treat (ITT) results were similar (Table 1). The number of children with severe malaria was lower in the treatment group, yielding vaccine efficacy of 48.6% (95% CI 12.3 to 71.0). All-cause hospitalization rates were similar between groups and no interaction was found between age and vaccine efficacy.

An open-label follow-up study assessed efficacy and safety of RTS,S/AS02A at 45 months from the first dose of vaccine.[16] Definitions, methods, and adjustment of results were the same as described previously.[10,15] Results significantly favored RTS,S/AS02A, with vaccine efficacy of 30.5% (95% CI 18.9 to 40.4) for first episode of clinical disease and 31.9% (95% CI 22.2 to 40.4) for first episode of infection in cohort 1 (per-protocol analysis of months 2.5–45 of follow-up).[16] Vaccine efficacy for severe malaria remained significant (38.3% [95% CI 3.4 to 61.3]) and number of hospitalizations was insignificantly lower in the RTS,S/AS02A group (174 vs 194 admissions in control group; vaccine efficacy 22.2% [95% CI −3.8 to 41.7]). Analysis of vaccine efficacy at different time points showed lower rates in later months (16.8% over months 21–33 vs 11.8% over months 33–45), but no evidence of waning was detected by statistical methods.

A double-blind randomized controlled trial assessed safety and efficacy of RTS,S/AS01E in 894 Kenyan and Tanzanian children aged 5–17 months (mean 11.4) over 4.5–10.5 months (mean 7.9) of follow-up.[11] Subjects were randomized to receive 3 intramuscular doses (administered 1 month apart) of either RTS,S/AS01E or human diploid cell rabies vaccine (rabies vaccine BP, Sanofi-Pasteur). Subjects were monitored actively (by weekly home visits) and passively (by field workers and personnel in local health facilities). Active surveillance was delayed by 3 months at the Tanzanian site. The primary outcome was clinical episode of malaria (as defined above); secondary outcomes included development of any level of parasitemia and multiple episodes of malaria.

Altogether, 809 subjects completed per-protocol analysis (402 RTS,S/AS01E, 407 control). Results, including ITT analyses (447 RTS,S/AS01E, 447 control) were adjusted for age, insecticide-treated net use, distance from dispensary, and geographical location. In per-protocol analysis, vaccine efficacy was significant for first episode (53% [95% CI 28 to 69]) and multiple episodes (56% [95% CI 31 to 72]) of clinical malaria.[11]

A subsequent follow-up study reported results 12–15 months after vaccination.[17] Both sites were included in the 12-month analysis, but only the Kenyan site had data available for the 15-month analysis. All outcomes were defined as per the original study and results were adjusted for study center, age, village distance from health facility, and use of insecticide-treated bed nets. Results were significantly in favor of RTS,S/AS01E. Adjusted vaccine efficacy in perprotocol analysis for first clinical malaria episode was 39% (95% CI 20 to 54) at 12 months (both study sites) and 46% (95% CI 24 to 61) at 15 months; ITT analysis was similar (Table 1). Vaccine efficacy was also significantly in favor of RTS,S/AS01E for all episodes of clinical malaria at 12 (42% [95% CI 22 to 57]) and 15 (51% [95% CI 29 to 66]) months. Anti-CS antibody titers were measured throughout the study but no association was found between titer level and protection from clinical malaria 1 month following the third dose of vaccine. However, this association was significant when assessed at month 6.5 (HR for log increase in anti-CS antibody titer 0.43 [95% CI 0.2 to 0.8]). Vaccination with RTS,S/AS01E resulted in a geometric mean titer of anti-CS antibody of 539.6 enzyme-linked immunosorbant assay units (EU) per milliliter (95% CI 500.7 to 581.6) 1 month after the third vaccination. This level fell during the 4.5- to 10.5-month follow-up phase to 71.9 EU/mL (95% CI 66 to 79), but still remained above control group levels of 0.3 EU/mL (95% CI 0.2 to 0.3). Clinical effects of further declines in titer levels are unknown.

A Phase 2b, single-center, double-blind randomized controlled trial assessed RTS,S/AS02D in 340 infants in Bagamoyo, Tanzania, over a 9-month surveillance period in combination with the WHO Expanded Program on Immunization (EPI) vaccines.[12] The WHO EPI is an initiative that provides essential vaccines to children worldwide. Infants (mean age 7.8 weeks) were randomly assigned to receive 3 doses of RTS,S/AS02D (0.5 mL containing RTS,S 25 μg plus adjuvant) or hepatitis B vaccine (Engerix-B) via intramuscular injection in the left anterolateral thigh. Per the EPI immunization schedule, all subjects were also given a vaccine containing diphtheria and tetanus toxoids, whole-cell pertussis, and conjugated Hib (DTPw/Hib). Oral polio vaccine was provided at birth and administered with subsequent doses of DTPw/Hib. Primary outcomes were surveillance of adverse events and noninferiority of responses to EPI vaccines; the secondary efficacy outcome was development of clinical malaria (fever and asexual parasitemia of >500 parasites/μL). Subjects were monitored both actively and passively with home visits every 2 weeks. Vaccine efficacy for clinical disease was nonsignificant (43.2% [95% CI −47.1 to 78.0]). Vaccine efficacy for development of any infection (defined as first or only episode of parasitemia) was significantly in favor of RTS,S/AS02D (65.2% [95% CI 20.7 to 84.7]).

Results for analysis of EPI vaccine titers met prespecified criteria (<10% decrease in protective antibody levels to diphtheria, tetanus, Hib, and HBsAg or to rule out decrease by a factor of >1.5 in average antibody titers to whole-cell pertussis after vaccination) and responses were deemed noninferior when administered with RTS,S or control vaccine. The authors concluded that RTS,S/AS02D does not interfere with antibody responses to other immunizations and could conceivably be given as part of a routine vaccination schedule.[12]

A Phase 1/2b double-blind, randomized controlled trial assessed safety, immunogenicity, and efficacy of RTS,S/AS02D when administered to 214 infants at 10, 14, and 18 weeks of age.[13] Subjects were randomized to receive either RTS,S/AS02D (0.5 mL; 25 μg RTS,S plus adjuvant) or hepatitis B vaccine (Engerix-B, GSK Biologicals, Rixensart, Belgium). Patients also received DTPw/Hib at each visit as part of routine administration. Vaccines were administered in the right (DTPw/Hib) or left (study vaccines) anterolateral thighs. Outcomes were assessed through both active and passive detection of infection and clinical disease (fever plus asexual P. falciparum parasitemia of >500 parasites/μL). Other outcomes included safety, antibody titers, and incidence of infection (defined as detection of asexual P. falciparum ≥14 days after the third vaccine dose). Data were reported until 6 months from the first dose, which gave an approximate follow-up duration of 3 months.

Two hundred fourteen infants were randomized (ITT population) and 185 met the criteria for per-protocol population. Results were adjusted for distance from health facility and geographical location. Per-protocol vaccine efficacy for clinical malaria (65.8% [95% CI 25.3 to 84.4]) and infection (65.9% [95% CI 42.6 to 79.8]) was significantly in favor of RTS,S/AS02D. When assessed as ITT, the clinical malaria endpoint did not remain significant. When anti-CS antibody titers were assessed for effect in preventing infection, doubling titers resulted in a 6.4% (95% CI 10.8 to 1.8) reduction in risk of new infection and a 10 times increase resulted in 19.8% (95% CI 31.6 to 5.9) reduction.[13]

A follow-up study assessed outcomes in the same population at 12 months after the third vaccine dose (or 14 months after randomization).[18] Patients were monitored both actively and passively. Per-protocol analysis for clinical malaria resulted in nonsignificant vaccine efficacy of 33.0% (95% CI −4.3 to 56.9). Significant vaccine efficacy (41.9% [95% CI 13.7 to 60.9]) was reported for first episode of fever or history of fever (in the previous 24 hours) and parasitemia >0 parasites/μL.

These Phase 1 and 2 studies[10–13,15–18] demonstrate efficacy and safety of RTS,S in both infants and children. The vaccine efficacy rates of 30–53% are optimistically high, considering the complexity of the disease and difficulty in achieving high immunogenicity with the vaccine. While these rates show promise, translation to reductions in hospitalizations, complications, and mortality has yet to be established. Ongoing Phase 3 trials will hopefully address these issues and further characterize effects of RTS,S on reducing clinical episodes of malaria.

Phase 3 Trials

A Phase 3 randomized, double-blind, controlled trial reported preliminary results of efficacy, safety, and immunogenicity in 2 age groups of children (6–12 weeks and 5–17 months) from 7 countries in Africa after 14 months of follow-up from the first dose of vaccine.[14] Children in each age category were randomized to 1 of 3 groups: a group that received 3 doses of RTS,S (at 1-month intervals) and was scheduled to receive a booster dose 18 months after third dose; a second group receiving the same schedule without the booster; and a control group. Control vaccines were the meningococcal serogroup C conjugate vaccine (Menjugate, Novartis) for children 6–12 weeks of age and the rabies vaccine (VeroRab, Sanofi-Pasteur) for children 5–17 months. Primary efficacy outcome was development of clinical disease (fever and parasitemia >5000 parasites/μL) for each age category. Other outcomes included varying parasitemia threshold levels, severe malaria, adverse events, and anti-CS antibody titers. Patients were followed passively, but were encouraged to seek medical care for any illness.

This preliminary report presented vaccine efficacy results for only the older age category (5–17 months of age) at 14 months after the first dose of vaccine. Initial vaccine efficacy for severe malaria was reported for all patients (pooled age categories).[14] A subsequent publication will present vaccine efficacy and safety results at 32 months after first vaccine dose for all age categories.

Six thousand children in the 5- to 17-month age category were enrolled and 4296 included in per-protocol analysis. For the primary outcome of development of first or only episode of clinical disease, RTS,S demonstrated vaccine efficacy of 55.8% (97.5% CI 51.3 to 59.8) adjusted for age and distance to nearest health facility. Schoenfeld residuals showed that vaccine efficacy was not constant over time, with greater efficacy at the beginning of the follow-up period. Vaccine efficacy for all episodes in this population was 55.1% (95% CI 50.5 to 59.2). Results of ITT analyses were also significant (Table 1). Vaccine efficacy for severe malaria was 47.3% (95% CI 22.4 to 64.2) for children 5–17 months (n = 4296) and 34.8% (95% CI 16.2 to 49.2) for children 6 weeks to 17 months (n = 12,961). One month after the third vaccine dose, geometric mean antibody titer was 621 EU/mL (95% CI 592 to 652) in children who received RTS,S. No difference in mortality was demonstrated, but this may have been the result of extremely low rates of malaria-related mortality (6.6%).[14] It is possible that close monitoring and follow-up of patients contributed to reduction in overall mortality rates and more power is required to detect differences between the groups. These initial results confirm validity of efficacy rates observed in Phase 2 trials. Future analyses will determine whether vaccine response is sustainable over a 32-month follow-up period.

Limitations

The RTS,S vaccine studies[10–18] are generally well designed, but have notable limitations. The populations examined were limited to African infants and children, yet malaria affects a variety of populations, including those in Asia and South America. However, rates of P. falciparum are comparatively lower in these other regions,[19] and additional studies are required to assess overall efficacy of the vaccine before its administration and distribution in these areas, as it is ineffective against other malarial species (eg, P. vivax). These studies also had short follow-up periods; it is unclear how long the vaccine maintains its efficacy and whether regular booster doses will be required. Information from ongoing Phase 3 trials should assist in answering these questions. Lastly, published trials were not powered to address important clinical outcomes, such as hospitalizations or mortality. Adequately powered trials and follow-up studies are needed to determine whether significant reductions in morbidity and poor outcomes can be achieved.

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