Vaccines against malaria Hill, Adrian V. S.
Philosophical transactions of the Royal Society of London. Series B. Biological sciences,
10/2011, Letnik:
366, Številka:
1579
Journal Article
Recenzirano
Odprti dostop
There is no licenced vaccine against any human parasitic disease and Plasmodium falciparum malaria, a major cause of infectious mortality, presents a great challenge to vaccine developers. This has ...led to the assessment of a wide variety of approaches to malaria vaccine design and development, assisted by the availability of a safe challenge model for small-scale efficacy testing of vaccine candidates. Malaria vaccine development has been at the forefront of assessing many new vaccine technologies including novel adjuvants, vectored prime-boost regimes and the concept of community vaccination to block malaria transmission. Most current vaccine candidates target a single stage of the parasite's life cycle and vaccines against the early pre-erythrocytic stages have shown most success. A protein in adjuvant vaccine, working through antibodies against sporozoites, and viral vector vaccines targeting the intracellular liver-stage parasite with cellular immunity show partial efficacy in humans, and the anti-sporozoite vaccine is currently in phase III trials. However, a more effective malaria vaccine suitable for widespread cost-effective deployment is likely to require a multi-component vaccine targeting more than one life cycle stage. The most attractive near-term approach to develop such a product is to combine existing partially effective pre-erythrocytic vaccine candidates.
Recombinant adenoviruses are among the most promising tools for vaccine antigen delivery. Recently, the development of new vectors has focused on serotypes to which the human population is less ...exposed in order to circumvent pre-existing anti vector immunity. This study describes the derivation of a new vaccine vector based on a chimpanzee adenovirus, Y25, together with a comparative assessment of its potential to elicit transgene product specific immune responses in mice. The vector was constructed in a bacterial artificial chromosome to facilitate genetic manipulation of genomic clones. In order to conduct a fair head-to-head immunological comparison of multiple adenoviral vectors, we optimised a method for accurate determination of infectious titre, since this parameter exhibits profound natural variability and can confound immunogenicity studies when doses are based on viral particle estimation. Cellular immunogenicity of recombinant E1 E3-deleted vector ChAdY25 was comparable to that of other species E derived chimpanzee adenovirus vectors including ChAd63, the first simian adenovirus vector to enter clinical trials in humans. Furthermore, the prevalence of virus neutralizing antibodies (titre >1:200) against ChAdY25 in serum samples collected from two human populations in the UK and Gambia was particularly low compared to published data for other chimpanzee adenoviruses. These findings support the continued development of new chimpanzee adenovirus vectors, including ChAdY25, for clinical use.
Recent genome-wide studies have reported novel associations between common polymorphisms and susceptibility to many major infectious diseases in humans. In parallel, an increasing number of rare ...mutations underlying susceptibility to specific phenotypes of infectious disease have been described. Together, these developments have highlighted a key role for host genetic variation in determining the susceptibility to infectious disease. They have also provided insights into the genetic architecture of infectious disease susceptibility and identified immune molecules and pathways that are directly relevant to the human host defence.
Highlights • Inserting tPA leader sequence enhanced humoral responses of ChAdOx1 MERS. • ChAdOx1 MERS elicited cellular immunity and neutralising antibodies. • ChAdOx1 MERS responses were boosted by ...MVA MERS. • Immunogenicity of a single dose of ChAdOx1 MERS was equivalent to 2 doses of MVA MERS. • In MVA, F11 promoter enhanced cellular, but not humoral, immunogenicity, comparing to mH5 promoter.
Over a century since Ronald Ross discovered that malaria is caused by the bite of an infectious mosquito it is still unclear how the number of parasites injected influences disease transmission. ...Currently it is assumed that all mosquitoes with salivary gland sporozoites are equally infectious irrespective of the number of parasites they harbour, though this has never been rigorously tested. Here we analyse >1000 experimental infections of humans and mice and demonstrate a dose-dependency for probability of infection and the length of the host pre-patent period. Mosquitoes with a higher numbers of sporozoites in their salivary glands following blood-feeding are more likely to have caused infection (and have done so quicker) than mosquitoes with fewer parasites. A similar dose response for the probability of infection was seen for humans given a pre-erythrocytic vaccine candidate targeting circumsporozoite protein (CSP), and in mice with and without transfusion of anti-CSP antibodies. These interventions prevented infection more efficiently from bites made by mosquitoes with fewer parasites. The importance of parasite number has widespread implications across malariology, ranging from our basic understanding of the parasite, how vaccines are evaluated and the way in which transmission should be measured in the field. It also provides direct evidence for why the only registered malaria vaccine RTS,S was partially effective in recent clinical trials.
Protection against liver-stage malaria relies on the induction of high frequencies of antigen-specific CD8⁺ T cells. We have previously reported high protective levels against mouse malaria, albeit ...short-lived, by a single vaccination with adenoviral vectors coding for a liver-stage antigen (ME.TRAP). Here, we report that prime-boost regimens using modified vaccinia virus Ankara (MVA) and adenoviral vectors encoding ME.TRAP can enhance both short- and long-term sterile protection against malaria. Protection persisted for at least 6 months when simian adenoviruses AdCh63 and AdC9 were used as priming vectors. Kinetic analysis showed that the MVA boost made the adenoviral-primed T cells markedly more polyfunctional, with the number of gamma interferon (INF-γ), tumor necrosis factor alpha (TNF-α), and interleukin-2 (IL-2) triple-positive and INF-γ and TNF-α double-positive cells increasing over time, while INF-γ single-positive cells declined with time. However, IFN-γ production prevailed as the main immune correlate of protection, while neither an increase of polyfunctionality nor a high integrated mean fluorescence intensity (iMFI) correlated with protection. These data highlight the ability of optimized viral vector prime-boost regimens to generate more protective and sustained CD8⁺ T-cell responses, and our results encourage a more nuanced assessment of the importance of inducing polyfunctional CD8⁺ T cells by vaccination.
Previous work with small-animal laboratory models of tuberculosis has shown that vaccination strategies based on heterologous prime-boost protocols using Mycobacterium bovis bacillus Calmette-Guérin ...(BCG) to prime and modified vaccinia virus Ankara strain (MVA85A) or recombinant attenuated adenoviruses (Ad85A) expressing the mycobacterial antigen Ag85A to boost may increase the protective efficacy of BCG. Here we report the first efficacy data on using these vaccines in cattle, a natural target species of tuberculous infection. Protection was determined by measuring development of disease as an end point after M. bovis challenge. Either Ad85A or MVA85A boosting resulted in protection superior to that given by BCG alone: boosting BCG with MVA85A or Ad85A induced significant reduction in pathology in four/eight parameters assessed, while BCG vaccination alone did so in only one parameter studied. Protection was particularly evident in the lungs of vaccinated animals (median lung scores for naïve and BCG-, BCG/MVA85A-, and BCG/Ad85A-vaccinated animals were 10.5, 5, 2.5, and 0, respectively). The bacterial loads in lymph node tissues were also reduced after viral boosting of BCG-vaccinated calves compared to those in BCG-only-vaccinated animals. Analysis of vaccine-induced immunity identified memory responses measured by cultured enzyme-linked immunospot assay as well as in vitro interleukin-17 production as predictors of vaccination success, as both responses, measured before challenge, correlated positively with the degree of protection. Therefore, this study provides evidence of improved protection against tuberculosis by viral booster vaccination in a natural target species and has prioritized potential correlates of vaccine efficacy for further evaluation. These findings also have implications for human tuberculosis vaccine development.
Certain infectious agents are recognised causes of cancer and other chronic diseases. To understand the pathological mechanisms underlying such relationships, here we design a Multiplex Serology ...platform to measure quantitative antibody responses against 45 antigens from 20 infectious agents including human herpes, hepatitis, polyoma, papilloma, and retroviruses, as well as Chlamydia trachomatis, Helicobacter pylori and Toxoplasma gondii, then assayed a random subset of 9695 UK Biobank participants. We find seroprevalence estimates consistent with those expected from prior literature and confirm multiple associations of antibody responses with sociodemographic characteristics (e.g., lifetime sexual partners with C. trachomatis), HLA genetic variants (rs6927022 with Epstein-Barr virus (EBV) EBNA1 antibodies) and disease outcomes (human papillomavirus-16 seropositivity with cervical intraepithelial neoplasia, and EBV responses with multiple sclerosis). Our accessible dataset is one of the largest incorporating diverse infectious agents in a prospective UK cohort offering opportunities to improve our understanding of host-pathogen-disease relationships with significant clinical and public health implications.
Intracellular pathogens contribute to a significant proportion of infectious disease morbidity and mortality worldwide. Increasing evidence points to a major role for host genetics in explaining ...inter-individual variation in susceptibility to infectious diseases. A number of monogenic disorders predisposing to infectious disease have been reported, including susceptibility to intracellular pathogens in association with mutations in genes of the interleukin-12/interleukin-23/interferon-γ axis. Common genetic variants have also been demonstrated to regulate susceptibility to intracellular infection, for example the CCR5Δ32 polymorphism that modulates human immunodeficiency virus-1 (HIV-1) disease progression. Genome-wide association study approaches are being increasingly utilized to define genetic variants underlying susceptibility to major infectious diseases. This review focuses on the current state-of-the-art in genetics and genomics as pertains to understanding the genetic contribution to human susceptibility to infectious diseases caused by intracellular pathogens such as tuberculosis, leprosy, HIV-1, hepatitis, and malaria, with a particular emphasis on insights from recent genome-wide approaches. The results from these studies implicate common genetic variants in novel molecular pathways involved in human immunity to specific pathogens.
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