Date: 2015-04-24
Type of information: Publication of results in a medical journal
phase: 3
Announcement: publication of results in the Lancet
Company: PATH Malaria Vaccine Initiative (MVI), GSK (UK), Agenus (USA - MA)
Product: RTS,S/AS01
Action
mechanism: vaccine. RTS,S aims to trigger the immune system to defend against Plasmodium falciparum malaria parasite when it first enters the human host’s bloodstream and/or when the parasite infects liver cells. It is designed to prevent the parasite from infecting, maturing, and multiplying in the liver, after which time the parasite would re-enter the bloodstream and infect red blood cells, leading to disease symptoms. In the Phase III efficacy trial, RTS,S is administered in three doses, one month apart. A booster dose administered 18 months after the third dose is also being studied in the trial.
The vaccine, based on a protein first identified in the laboratory of Drs Ruth and Victor Nussenzweig at New York University, was invented, developed, and manufactured in laboratories at GSK Vaccines in Belgium in the late 1980s and initially tested in US volunteers as part of a collaboration with the US Walter Reed Army Institute of Research.
Disease: malaria
Therapeutic area: Infectious diseases - Parasitic diseases
Country: 7 African countries (Burkina Faso, Gabon, Ghana, Kenya, Malawi, Mozambique, Tanzania)
Trial
details: The trial includes 11 African research centers in seven African countries with GSK and the PATH Malaria Vaccine Initiative (MVI), with grant funding from the Bill & Melinda Gates Foundation to MVI. The trial, started in March 2009 and concluded in January 2014, enrolled 15,459 participants, in two age categories: children (aged 5-17 months at first vaccination) and infants (aged 6-12 weeks at first vaccination). The study is sponsored by GSK Biologicals SA, the vaccine developer and manufacturer, and funded by both GSK Biologicals SA and the PATH Malaria Vaccine Initiative (MVI). The study was designed by the Clinical Trials Partnership Committee (CTPC), consisting of representatives of all research sites, study sponsor and study funders. All authors were involved in data collection. All data were analyzed following a pre-defined analysis plan.
Latest
news: * On April 24, 2015, GSK announced that final results from a large-scale Phase III trial of the RTS,S malaria vaccine candidate, including the impact of a booster dose, published in The Lancet, show that the vaccine candidate helped protect children and infants from clinical malaria for at least three years after first vaccination. The latest results demonstrated that vaccination with RTS,S, followed by a booster dose of RTS,S administered 18 months after the primary schedule, reduced the number of cases of clinical malaria in children (aged 5-17 months at first vaccination) by 36% to the end of the study1 (over an average follow-up of 48 months across trial sites) and in infants (aged 6-12 weeks at first vaccination) by 26% to the end of the study (over an average follow-up of 38 months across trial sites). Efficacy decreased over time in both age groups. Without the booster dose, the 3-dose primary schedule reduced clinical malaria cases by 28% in children and 18% in infants to the study end. The efficacy of RTS,S was evaluated in the context of existing malaria control measures, such as insecticide treated bed nets, which were used by approximately 80% of the children and infants in the trial. For children in the 5-17 month age category who received a booster dose 18 months after the primary schedule, an average of 1,774 cases of clinical malaria were prevented for every 1,000 children vaccinated across the trial sites, over an average of 48 months of follow-up. For infants aged 6-12 weeks at first vaccination with RTS,S, who received a booster dose, 983 cases of clinical malaria, on average, were prevented for every 1,000 infants vaccinated across trial sites over an average of 38 months of follow-up. More cases were averted in areas of higher malaria transmission. In the absence of a booster dose, 1,363 cases of clinical malaria were prevented, on average, for every 1,000 children aged 5-17 months at first vaccination and 558 cases for every 1,000 infants aged 6-12 weeks at first vaccination to the end of the study Statistically significant efficacy against severe malaria to the end of the study period was observed only in children who received the booster dose. There was indication of increased risk for severe malaria in children who did not receive the booster dose, compared to those in the control group. Safety: RTS,S continued to display an acceptable safety and tolerability profile during the entire study period. The incidence of fever in the week after vaccination was higher in children who received RTS,S than in those receiving control vaccine. In some children who experienced fever, the febrile reaction was accompanied by generalized convulsions, but all those affected fully recovered within seven days. The meningitis signal previously reported remains in the older age category, including two cases reported after the booster dose of RTS,S. This could be a chance finding, as comparisons were made across groups for many different diseases, and because some of these cases happened years after vaccination without any obvious relationship to vaccination. The occurrence of meningitis will be followed closely during Phase IV studies, if RTS,S is licensed. The European Medicines Agency (EMA) is currently reviewing the regulatory application for RTS,S through the Art. 58 procedure initiated in July 2014. A positive opinion from the EMA’s Committee for Medicinal Products for Human Use, together with a potential policy recommendation from the World Health Organisation (anticipated by the end of 2015), would be the basis for licensure applications to National Regulatory Authorities in sub-Saharan African countries. If positive, these regulatory decisions would help pave the way for the introduction of RTS,S through African national immunisation programmes. If RTS,S is approved, GSK has committed to making the vaccine available at a not-for-profit price. * On July 29, 2014, results of this phase 3 trial have been published in PLOS Medicine. The effect of vaccination diminished over time, but protection against clinical malaria remained evident 18 months after vaccination. In the new report, the RTS,S Clinical Trials Partnership* update estimates of vaccine efficacy (the reduction in the risk of malaria in participants who received the vaccine compared to those who received a comparator vaccine) and calculate the number of cases of malaria that the vaccine prevented in a phase 3, randomized, controlled clinical trial of the malaria vaccine RTS,S/AS01 given to young infants and children in Africa. * On November 9, 2012, Agenus, a developer of therapeutic vaccines for cancer and infectious diseases, has announced the second complete set of results from the Phase 3 trial of GSK RTS,S malaria vaccine candidate (also known as Mosquirix™), which contains Agenus’ QS-21 Stimulon adjuvant, were published online in the New England Journal of Medicine and announced at the International Vaccines for Africa Conference in Cape Town, South Africa. QS-21 Stimulon is a component of AS01, one of GSK’s proprietary adjuvant systems used in RTS,S.
The study included 6,537 infants aged 6–12 weeks and 8,923 children aged 5–17 months who were randomly assigned to receive three doses of RTS,S/AS01 or comparator vaccine. During 18 months following vaccination, the researchers report vaccine efficacy of 45% [95% confidence interval (CI): 41%–49%, intention-to-treat analysis] in children age 5-17 months, and 27% vaccine efficiency [95% CI: 21%–33%, intention-to-treat analysis] in infants age 6-12 weeks. In both age groups, vaccine efficacy was highest in the first 6 months after vaccination. Across all 11 study sites, RTS,S/AS01 averted an average of 829 (range 37 to 2365) cases of clinical malaria per 1,000 children vaccinated, and 449 (Range -10 to 1402) cases in infants vaccinated, over 18 months following vaccination.
Safety analyses found overall serious adverse events (SAE) to occur less often in children age 5-17 months who received the vaccine [18.6% (95% confidence interval 17.6%–19.6%), compared with 22.7% (95% CI 21.2%–24.3%) in children who received a comparator vaccine]. In infants age 6-12 weeks overall SAE were not found to differ significantly with immunization. As noted in earlier reports, more meningitis cases were reported as SAE in participants who received the malaria vaccine than in those who received a comparator immunization (16 cases among the 5,949 children in the RTS,S/AS01 vaccine group and one case among the 2,974 children in the control group; and nine cases among 4,358 young infants in the RTS,S/AS01 group and three among 2,179 young infants in the control group) and no causal relationship to the vaccine has been established. Going forward the study will analyze further efficacy and safety results following administration of a booster immunization given to study participants just after the time period analyzed in the current report. The authors note that "Translated to the population at risk of malaria, reductions in clinical cases on this scale as a result of vaccination with RTS,S/AS01 would have a major public health impact."
The RTS,S Clinical Trials Partnership (2014) Efficacy and Safety of the RTS,S/AS01 Malaria Vaccine during 18 Months after Vaccination: A Phase 3 Randomized, Controlled Trial in Children and Young Infants at 11 African Sites. PLoS Med 11(7): e1001685. doi:10.1371/journal.pmed.1001685. * On October 7, 2013, results from a large-scale Phase III trial, have been presented at a Multilateral Initiative on Malaria Pan African Conference in Durban. The results show that the malaria vaccine candidate, RTS,S, continued to protect young children and infants from clinical malaria up to 18 months after vaccination. Based on these data, GSK now intends to submit, in 2014, a regulatory application to the European Medicines Agency (EMA). The World Health Organization (WHO) has indicated that a policy recommendation for the RTS,S malaria vaccine candidate is possible as early as 2015 if it is granted a positive scientific opinion by EMA.
These latest results demonstrated that over 18 months of follow-up, RTS,S was shown to almost halve the number of malaria cases in young children (aged 5-17 months at first vaccination) and to reduce by around a quarter the malaria cases in infants (aged 6-12 weeks at first vaccination). Vaccine efficacy was also assessed separately at each of the trial sites, which represent a wide range of malaria transmission settings; efficacy was found to be statistically significant at all sites in young children and at four sites in infants.
The efficacy and public health impact of RTS,S were evaluated in the context of existing malaria control measures, such as insecticide treated bed nets, which were used by 78% of children and 86% of infants in the trial. In these latest results over 18 months of follow-up, children aged 5-17 months at first vaccination with RTS,S experienced 46% fewer cases of clinical malaria, compared to children immunised with a control vaccine. An average of 941 cases of clinical malaria were prevented over 18 months of follow-up for every 1,000 children vaccinated in this age group, noting that a child can contract more than one case of malaria. Severe malaria cases were reduced by 36%; 21 cases of severe malaria were prevented over 18 months of follow-up for every 1,000 children vaccinated. Malaria hospitalisations were reduced by 42%.
Infants aged 6-12 weeks at first vaccination with RTS,S had 27% fewer cases of clinical malaria.
Over 18 months of follow-up, 444 cases of clinical malaria were prevented for every 1,000 infants vaccinated. The reduction of severe malaria cases and malaria hospitalisations by 15% and 17%, respectively, were not statistically significant. Overall, vaccine efficacy declined over time: Previous results from one year follow-up of the Phase 3 trial showed that efficacy of RTS,S was 56% against clinical malaria and 47% against severe malaria for the 5-17 month-old age group and 31% against clinical malaria and 37% against severe malaria in the 6-12 week-old age group.
RTS,S continued to display an acceptable safety and tolerability profile during the 18 month follow-up. Apart from the meningitis signal previously reported2, no other safety signal was identified. The occurrence of meningitis will be followed closely during the remainder of the trial. Further data from 32 months follow-up and the impact of a fourth ‘booster’ dose given 18 months after the initial three doses are expected to become available in 2014.
In this trial, infants (aged 6-12 weeks at first vaccination) receiving the RTS,S vaccine candidate experienced one-third fewer episodes of both clinical and severe malaria and experienced similar reactions to the injection when compared to those who received the control meningococcal C conjugate vaccine. Insecticide-treated bed nets were used by 86% of the trial participants demonstrating that RTS,S provided protection beyond existing malaria control interventions.
When administered with standard childhood vaccines in the Phase 3 study, efficacy of the RTS,S vaccine candidate against clinical and severe malaria in infants aged 6 to 12 weeks was 31% (clinical) and 37% (severe) over 12 months of follow-up after the third vaccine dose. Results published in the New England Journal of Medicine in November 2011 showed that efficacy against clinical and severe disease in children 5-17 months of age at the time of first vaccination was higher and demonstrated that clinical and severe malaria cases were reduced by approximately half. Both co-primary endpoints in the large ongoing efficacy trial were met.
Follow-up for this trial will continue and should provide more data for analyses to better understand the different findings between the age categories and insights into RTS,S’ efficacy in areas with differences in malaria prevalence. Longer-term efficacy data of the vaccine during 30 months of follow-up after the third dose, and the impact of a booster dose, are expected to be available at the end of 2014.
There was no increase in overall reporting of serious adverse events6 (SAEs) between the infants vaccinated with the RTS,S malaria vaccine candidate and infants in the control group, which received a comparator vaccine. Side effects following vaccination primarily included local injection site reactions, which were less frequent in RTS,S vaccinations compared to the DTP-HepB/Hib vaccine; and fever, which was more frequent in RTS,S than the control vaccine group (following 30.6% versus 21.1% of vaccine doses, respectively).
Two new cases of meningitis were reported in the 6-12 week-old infant age category in addition to the 9 reported last year; one in the RTS,S group and one in the control vaccine group. Further analysis revealed a bacterial cause of the meningitis in 7 of the 11 cases.
