CNS infection safety signal of RTS,S/AS01 and possible association with rabies vaccine

Abstract

A key concern for the RTS,S/AS01 malaria vaccine is the higher meningitis incidence in children aged 5–17 months who were given the intervention than in age-matched controls,1RTS,S Clinical Trials PartnershipEfficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial.Lancet. 2015; 386: 31-45Summary Full Text Full Text PDF PubMed Scopus (808) Google Scholar with 11 cases in the R3R group (who were given three doses of RTS,S/AS01 plus a booster dose), ten cases in the R3C group (who were given three doses of RTS,S/AS01 plus a comparator vaccine), and one case in the control group (who were given four doses of a comparator vaccine). Characteristics of the meningitis safety signal include disease development up to roughly 1100 days after doses 1, 2, and 3, and 500 days after dose 4; signal absence in infants aged 6–12 weeks; occurrence of cases in eight of 11 trial sites;1RTS,S Clinical Trials PartnershipEfficacy and safety of RTS,S/AS01 malaria vaccine with or without a booster dose in infants and children in Africa: final results of a phase 3, individually randomised, controlled trial.Lancet. 2015; 386: 31-45Summary Full Text Full Text PDF PubMed Scopus (808) Google Scholar, 2Smith P on behalf of the Joint Technical Expert Group (JTEG)JTEG's summary of RTS,S/AS01 clinical trial data.http://www.who.int/immunization/sage/meetings/2015/october/Smith_Malaria_Review_RTS_S_AS01_print.pdfGoogle Scholar and low incidence (relative to baseline) in the control group, rather than high incidence (relative to baseline) in the intervention group.3WHOEstimating meningitis hospitalization rates for sentinel hospitals conducting surveillance of invasive bacterial vaccine-preventable diseases.Wkly Epidemiol Rep. 2013; 88: 471PubMed Google Scholar Additionally, more cerebral malaria cases were reported in children aged 5–17 months in the R3R and R3C groups (43 cases) than in the control group (10 cases). Calculations again suggest that, compared with baseline, cerebral malaria incidence was lower than expected in the control group, rather than higher than expected in the intervention group.4Roca-Feltrer A Carneiro I Armstrong Schellenberg JRM Estimates of the burden of malaria morbidity in Africa in children under the age of 5 years.Trop Med Int Health. 2008; 13: 771-783Crossref PubMed Scopus (69) Google Scholar Interpretation of these findings has so far focused on three possibilities: first, a chance finding, since meningitis was one of dozens of adverse events monitored; second, systematic bias despite the randomised, blinded trial design; and third, an adverse effect from the RTS,S/AS01 vaccine—eg, through effects on the blood–brain barrier or choroid plexus. The third hypothesis would unify the meningitis and cerebral malaria signals into an overall CNS infection signal and explain some epidemiological findings. However, it would not explain the signal absence in infants aged 6–12 weeks or the relatively low incidence in children aged 5–17 months in the control group. A fourth possibility exists. Unlike young infants, who received the meningococcal conjugate vaccine, older controls received rabies vaccine. The hypothesis that rabies vaccine provided non-specific protection against CNS disease, rather than that RTS,S/AS01 increased risk, is consistent with the main epidemiological features of the safety signal. Indirect vaccine effects have been reported previously—eg, reduced childhood mortality after immunisation with live measles virus.5Aaby P Jensen H Samb B et al.Differences in female-male mortality after high-titre measles vaccine and association with subsequent vaccination with diphtheria-tetanus-pertussis and inactivated poliovirus: reanalysis of West African studies.Lancet. 2003; 361: 2183-2188Summary Full Text Full Text PDF PubMed Scopus (175) Google Scholar Although the absence of a biological mechanism for rabies vaccine to reduce CNS infection risk undermines such a hypothesis, if proven the implications would be profound for trial design, understanding of non-specific vaccine effects, and rabies vaccine use. Therefore, we recommend accelerated research, including studies of animal and human responses to rabies vaccine and, if results are consistent with our hypothesis, randomised trials of rabies vaccine use. BDG works for Agence de Médecine Preventive, which receives grants from GlaxoSmithKline for work on malaria and malaria vaccines. AF reports grants and personal fees from GlaxoSmithKline, Sanofi-Pasteur MSD, Novartis, Pfizer, and Alios; and personal fees from Takeda, all of which are outside the submitted work and paid to his employers. DCW declares no competing interests.