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The results of the phase I/IIb trial of GSK’s RTS,S/AS02 malaria vaccine have been published in Lancet and the results are promising. The RTS,S vaccine is a fusion of the recombinant Hepatitis B surface antigen with the central tandem repeat and C-terminal regions of the Pf circumsporozoite protein formulated with a proprietary adjuvant AS02. The vaccine had previously been tested on adults and children aged 1 to 4 years with some evidence of short-term protection (efficacy in the latter group was 30% for first clinical malaria episode and 60% for severe malaria followed through 18 months).
Object: Phase I/IIb study on safety, immunogenicity, and efficacy of RTS,S/AS02 in infants administered at 10, 14, 18 weeks of age
Study design: 214 infants residing in a high transmission area with intense malaria surveillance and control activities.
Exclusion criteria: Children whose mother had Hepatitis B, HIV, those not receiving oral polio virus vaccine and BCG vaccine at least 1 week before study vaccination and those receiving other pre-study vaccinations.
Arms: Pf vaccine candidate (RTS/AS02, GSK) vs. hepatitis B vaccine (Engerix, GSK). Both arms received DTPw/HiB and OPV on day 0, 30, and 60. Study vaccines were administered intramuscularly on day 14, 44, and 74. Vaccination team was not blinded to treatment but was not involved in any other part of the study.
Anti-HbsAg and anti-circumsporozoite antibodies were measured at baseline and after the third dose of the study vaccines. Antibodies against Hib and B. pertussis were also measured.Blood smears were preformed at regular intervals and at onset of malaria symptomatology. All children with a positive smear received first line treatment. All children were cleared presumptively with amodiaquine and S/P 2 weeks before the final study vaccine dose. The children with negative smears were followed with active detection qoweek for 12 weeks and passive detection as pre-defined symptomatology arose (fever to 37.5, h/o fever in last 24 hours, pallor).
Primary endpoint: safety during first 6 months (intention to treat)
Secondary endpoints: immunogenicity analyses and vaccine efficacy (per protocol cohort)
Study definition for clinical malaria: axillary temp > 37.5 with an asexual parasitemia of Pf of 500/ul.
Results:
Safety: comparable between RTS,S and Engerix, with pain being the most common (80-90%, comparable between all vaccines), followed by irritability (40-50%, comparable between all vaccines). There were no vaccine-related serious adverse evetns. Four deaths occurred, one in the RTS,S group, and were attributed to septic shock (1) and gastroenteritis/severe dehydration (3).
Immunogeniticty: Antibody levels to HbsAg were much higher in the RTS,S group (geometric mean 10,082) than in the Engerix-B grou (392) 30 days after the third dose. Antibody levels to Circumsporozoite were higher in the RTS,S group than in the Engerix B group but decreased in the RTS,S group from 200 at 30 days post-third dose to 59 at 106 days post-third dose.
Efficacy: 22 new infections in the RTS,S group and 46 new infections in the Engerix B group for a crude vaccine efficacy of 62.2%, p=0.0002 over a 3 month follow-up period (month 6 of study). However, efficacy based on intention to treat throughout the entire study period (0 to 6 months) was only 35.5% (p=0.093). On average, the group without malaria infection had high anti-circumsporozoite antibody levels (208 vs. 132, p=0.026). Doubling the anti-CS antibody titers was associated with a 6.4% risk reduction (10.8-1.8, p=0.007).
Comments: This was only a Phase I/IIB study and its primary outcome is safety. The initial results are promising, but the follow up of only 3 months post-vaccination precludes any definitive assessment on the true efficacy of RTS,S in infants. This is important in light of the fact that the anti-CS antibody titers seem to diminish rapidly after the third dose and that the authors showed how protection against falciparum malaria seemed to be associated with higher titers. It is often thought that malaria vaccines would benefit from boosting from abortive natural infections. Perhaps this could be examined indirectly by examining the anti-CS antibody titers in RTS,S and Engerix vaccinated individuals who were infected by Pf during the study. If the antibody titers remained similar to the infant’s baseline pre-infection, it can be assumed that boosting did not occur and it was a failure of a long-lived humoral response. Because this study was designed with intense malaria surveillance (as rightfully, it should), it ultimately cannot assess if the vaccine can prevent severe, life threatening malaria since disease progression is aborted at the early stages. In this short and limited study, there were no malaria related deaths in 214 infants. This is a testament of how malaria control and surveillance can be so effective and would, if resources were available, be the ideal solution.
The exclusion of HIV mothers from the study also makes the study less practical in light of the increasing prevalence of HIV in malaria-endemic countries. One must assume that a phase III study will aim to include infants born to HIV+ mothers.
Reference: The Lancet 2007; 370:1543-1551
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