Childhood meningitis in the conjugate vaccine era: a prospective cohort study.

Bacterial conjugate vaccines have dramatically changed the epidemiology of childhood meningitis; viral causes are increasingly predominant, but the current UK epidemiology is unknown. This prospective study recruited children under 16 years of age admitted to 3 UK hospitals with suspected meningitis. 70/388 children had meningitis-13 bacterial, 26 viral and 29 with no pathogen identified. Group B Streptococcus was the most common bacterial pathogen. Infants under 3 months of age with bacterial meningitis were more likely to have a reduced Glasgow Coma Score and respiratory distress than those with viral meningitis or other infections. There were no discriminatory clinical features in older children. Cerebrospinal fluid (CSF) white blood cell count and plasma C-reactive protein at all ages, and CSF protein in infants <3 months of age, distinguished between bacterial meningitis and viral meningitis or other infections. Improved diagnosis of non-bacterial meningitis is urgently needed to reduce antibiotic use and hospital stay.

Safety and immunogenicity of heterologous prime-boost immunisation with Plasmodium falciparum malaria candidate vaccines, ChAd63 ME-TRAP and MVA ME-TRAP, in healthy Gambian and Kenyan adults.

BACKGROUND: Heterologous prime boost immunization with chimpanzee adenovirus 63 (ChAd63) and Modified vaccinia Virus Ankara (MVA) vectored vaccines is a strategy recently shown to be capable of inducing strong cell mediated responses against several antigens from the malaria parasite. ChAd63-MVA expressing the Plasmodium falciparum pre-erythrocytic antigen ME-TRAP (multiple epitope string with thrombospondin-related adhesion protein) is a leading malaria vaccine candidate, capable of inducing sterile protection in malaria naïve adults following controlled human malaria infection (CHMI). METHODOLOGY: We conducted two Phase Ib dose escalation clinical trials assessing the safety and immunogenicity of ChAd63-MVA ME-TRAP in 46 healthy malaria exposed adults in two African countries with similar malaria transmission patterns. RESULTS: ChAd63-MVA ME-TRAP was shown to be safe and immunogenic, inducing high-level T cell responses (median >1300 SFU/million PBMC). CONCLUSIONS: ChAd63-MVA ME-TRAP is a safe and highly immunogenic vaccine regimen in adults with prior exposure to malaria. Further clinical trials to assess safety and immunogenicity in children and infants and protective efficacy in the field are now warranted. TRIAL REGISTRATION: Pactr.org PACTR2010020001771828 Pactr.org PACTR201008000221638 ClinicalTrials.gov NCT01373879 NCT01373879 ClinicalTrials.gov NCT01379430 NCT01379430.

ChAd63-MVA-vectored blood-stage malaria vaccines targeting MSP1 and AMA1: assessment of efficacy against mosquito bite challenge in humans.

The induction of cellular immunity, in conjunction with antibodies, may be essential for vaccines to protect against blood-stage infection with the human malaria parasite Plasmodium falciparum. We have shown that prime-boost delivery of P. falciparum blood-stage antigens by chimpanzee adenovirus 63 (ChAd63) followed by the attenuated orthopoxvirus MVA is safe and immunogenic in healthy adults. Here, we report on vaccine efficacy against controlled human malaria infection delivered by mosquito bites. The blood-stage malaria vaccines were administered alone, or together (MSP1+AMA1), or with a pre-erythrocytic malaria vaccine candidate (MSP1+ME-TRAP). In this first human use of coadministered ChAd63-MVA regimes, we demonstrate immune interference whereby responses against merozoite surface protein 1 (MSP1) are dominant over apical membrane antigen 1 (AMA1) and ME-TRAP. We also show that induction of strong cellular immunity against MSP1 and AMA1 is safe, but does not impact on parasite growth rates in the blood. In a subset of vaccinated volunteers, a delay in time to diagnosis was observed and sterilizing protection was observed in one volunteer coimmunized with MSP1+AMA1-results consistent with vaccine-induced pre-erythrocytic, rather than blood-stage, immunity. These data call into question the utility of T cell-inducing blood-stage malaria vaccines and suggest that the focus should remain on high-titer antibody induction against susceptible antigen targets.

Phase Ia clinical evaluation of the safety and immunogenicity of the Plasmodium falciparum blood-stage antigen AMA1 in ChAd63 and MVA vaccine vectors.

BACKGROUND: Traditionally, vaccine development against the blood-stage of Plasmodium falciparum infection has focused on recombinant protein-adjuvant formulations in order to induce high-titer growth-inhibitory antibody responses. However, to date no such vaccine encoding a blood-stage antigen(s) alone has induced significant protective efficacy against erythrocytic-stage infection in a pre-specified primary endpoint of a Phase IIa/b clinical trial designed to assess vaccine efficacy. Cell-mediated responses, acting in conjunction with functional antibodies, may be necessary for immunity against blood-stage P. falciparum. The development of a vaccine that could induce both cell-mediated and humoral immune responses would enable important proof-of-concept efficacy studies to be undertaken to address this question. METHODOLOGY: We conducted a Phase Ia, non-randomized clinical trial in 16 healthy, malaria-naïve adults of the chimpanzee adenovirus 63 (ChAd63) and modified vaccinia virus Ankara (MVA) replication-deficient viral vectored vaccines encoding two alleles (3D7 and FVO) of the P. falciparum blood-stage malaria antigen; apical membrane antigen 1 (AMA1). ChAd63-MVA AMA1 administered in a heterologous prime-boost regime was shown to be safe and immunogenic, inducing high-level T cell responses to both alleles 3D7 (median 2036 SFU/million PBMC) and FVO (median 1539 SFU/million PBMC), with a mixed CD4(+)/CD8(+) phenotype, as well as substantial AMA1-specific serum IgG responses (medians of 49 µg/mL and 41 µg/mL for 3D7 and FVO AMA1 respectively) that demonstrated growth inhibitory activity in vitro. CONCLUSIONS: ChAd63-MVA is a safe and highly immunogenic delivery platform for both alleles of the AMA1 antigen in humans which warrants further efficacy testing. ChAd63-MVA is a promising heterologous prime-boost vaccine strategy that could be applied to numerous other diseases where strong cellular and humoral immune responses are required for protection. TRIAL REGISTRATION: ClinicalTrials.gov NCT01095055.

Synergistic inhibition of HIV-1 infection by combinations of soluble polyanions with other potential microbicides.

Several polyanionic compounds with potential for use as topically applied microbicides to prevent HIV-1 sexual transmission, such as PRO 2000, are currently in phase III clinical efficacy trials. Microbicidal formulations may well comprise combinations of inhibitors to increase potency, reduce dose and minimize problems of HIV-1 resistance. We have therefore evaluated in vitro, the anti-HIV-1 activity of two leading polyanionic microbicides combined with other antiretroviral agents with microbicidal potential. Dextran sulfate (DS) and PRO 2000 were combined with the neutralizing antibody IgG1b12, the peptide-based fusion inhibitor T20, the CCR5 antagonist TAK779 and the cyanobacterial protein cyanovirin-N. Anti-HIV-1 activity was assessed in a single cycle replication assay using pseudoviruses carrying a luciferase reporter gene and the envelope glycoproteins from HIV-1 isolates JR-FL (R5) and HxB2 (X4), against both immortalized and primary CD4+ cell targets. The data were analyzed for synergy using Calcusyn software. Results indicate that PRO 2000 and DS can act synergistically with most inhibitors tested, although the degree of synergy depends on inhibitor concentration and combination. These data provide a rational basis for testing of microbicide combinations in vivo.