Chikungunya fever (CHIKF) is a mosquito-borne disease caused by Chikungunya virus (CHIKV). This virus is considered a priority pathogen to the UK government, the US National Institute of Allergy and ...Infectious Diseases (NIAID) and the US military personnel, due to the potential of CHIKV to cause major outbreaks. Nearly all CHIKV infections are symptomatic, often incapacitating and patients experience severe joint pain and inflammation that can last for more than one year with 0.4-0.5% fatality rates. Mother-to-child transmission has also been described. Despite this re-emerging disease has been documented in more than 100 countries in Europe, Oceania, Africa, Asia, the Caribbean, South and North America, no licensed vaccine is yet available to prevent CHIKF. Nevertheless, various developments have entered phase I and II trials and are now viable options to fight this incapacitating disease. This review focuses on the development of CHIKV vaccines that have reached the stage of clinical trials since the late 1960s up until 2018.
SARS‐CoV‐2 infection is causing a pandemic disease that is reflected in challenging public health problems worldwide. Human leukocyte antigen (HLA)‐based epitope prediction and its association with ...disease outcomes provide an important base for treatment design. A bioinformatic prediction of T cell epitopes and their restricted HLA Class I and II alleles was performed to obtain immunogenic epitopes and HLA alleles from the spike protein of the severe acute respiratory syndrome coronavirus 2 virus. Also, a correlation with the predicted fatality rate of hospitalized patients in 28 states of Mexico was done. Here, we describe a set of 10 highly immunogenic epitopes, together with different HLA alleles that can efficiently present these epitopes to T cells. Most of these epitopes are located within the S1 subunit of the spike protein, suggesting that this area is highly immunogenic. A statistical negative correlation was found between the frequency of HLA‐DRB1*01 and the fatality rate in hospitalized patients in Mexico.
Highlights
First HLA association study for COVID‐19 in Mexico
An epitope prediction for HLA Class I and II provided a list of highly immunogenic epitopes from the S protein of SARS‐CoV2 with potential use for vaccine development.
A multi‐level approach revealed a correlation of HLA‐DRB1*01 frequency with fatality in Mexican hospitalized patients at ecological level.
Dengue and Zika viruses are closely related mosquito-borne flaviviruses responsible for major public health problems in tropical and sub-tropical countries. The genomes of both, dengue and zika ...viruses encodes 10 genes that are translated into three structural proteins (C, prM, and E) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B, and NS5). The non-structural protein 1 (NS1) is a highly conserved glycoprotein of approximately 48-50 KDa. In infected cells, NS1 is found as a homodimer associated with intracellular membranes and replication complexes, serving as a scaffolding protein in virus replication and morphogenesis. NS1 is secreted efficiently from infected cells as a hexamer and is found in patient's sera during the acute phase of the disease. NS1 detection in sera is a valuable diagnostic marker and immunization with NS1 has been shown to protect animal models from lethal challenges with dengue and Zika viruses. Nevertheless, soluble NS1 has been associated with severe dengue and anti-NS1 antibodies have been reported to cross-react with host platelets and endothelial cells and thus presumably contribute to pathogenesis. Due to the implications of NS1 in arbovirus pathogenesis and its relevance as vaccine candidate, we discuss the dual role that anti-NS1 antibodies may play in protection and disease and the challenges that need to be overcome to develop safe and effective NS1-based vaccines against dengue and Zika.
Newly emerging viruses, primarily zoonotic or vector-borne, pose a persistent threat to public health and have led to outbreaks of global concern ....Newly emerging viruses, primarily zoonotic or ...vector-borne, pose a persistent threat to public health and have led to outbreaks of global concern ....
Immunogenicity is considered one important criterion for progression of candidate vaccines to further clinical evaluation. We tested this assumption in an infection and vaccination model for malaria ...pre‐erythrocytic stages. We engineered Plasmodium berghei parasites that harbour a well‐characterised epitope for stimulation of CD8+ T cells, either as an antigen in the sporozoite surface‐expressed circumsporozoite protein or the parasitophorous vacuole membrane associated protein upregulated in sporozoites 4 (UIS4) expressed in exo‐erythrocytic forms (EEFs). We show that the antigen origin results in profound differences in immunogenicity with a sporozoite antigen eliciting robust, superior antigen‐specific CD8+ T‐cell responses, whilst an EEF antigen evokes poor responses. Despite their contrasting immunogenic properties, both sporozoite and EEF antigens gain access to antigen presentation pathways in hepatocytes, as recognition and targeting by vaccine‐induced effector CD8+ T cells results in high levels of protection when targeting either antigen. Our study is the first demonstration that poorly immunogenic EEF antigens do not preclude their susceptibility to antigen‐specific CD8+ T‐cell killing, which has wide‐ranging implications on antigen prioritisation for next‐generation pre‐erythrocytic malaria vaccines.
Synopsis
Key benchmarks for malaria vaccine design were investigated. Antigen immunogenicity and accessibility were studied with results indicating the proof‐of‐concept that a poorly immunogenic exo‐erythrocytic form (EEF) antigen is comparably vulnerable as a strongly immunogenic sporozoite antigen to targeting by vaccine‐induced effector CD8+ T cells.
Contrasts in immunogenicities are brought about by antigen origin in malaria pre‐erythrocytic stages, with a sporozoite surface antigen evoking strong and superior antigen‐specific CD8+ T cell responses, whilst an EEF vacuolar antigen eliciting inferior responses.
Antigen presentation pathways in hepatocytes are accessed by both sporozoite surface and EEF vacuolar antigens, notwithstanding their disparate immunogenicities.
Recognition by vaccine‐induced, antigen‐specific effector CD8+ T cells leads to high levels of protection when targeting either antigen.
EEF antigens were demonstrated to have marginal impacts on the level of CD8+ T cell responses to whole sporozoite immunisation.
Key benchmarks for malaria vaccine design were investigated. Antigen immunogenicity and accessibility were studied with results indicating the proof‐of‐concept that a poorly immunogenic exo‐erythrocytic form (EEF) antigen is comparably vulnerable as a strongly immunogenic sporozoite antigen to targeting by vaccine‐induced effector CD8+ T cells.
Malaria remains one the world's most deadly infectious diseases, with almost half a million deaths and over 150 million clinical cases each year. An effective vaccine would contribute enormously to ...malaria control and will almost certainly be required for eventual eradication of the disease. However, the leading malaria vaccine candidate, RTS,S, shows only 30-50% efficacy under field conditions, making it less cost-effective than long-lasting insecticide treated bed nets. Other subunit malaria vaccine candidates, including TRAP-based vaccines, show no better protective efficacy. This has led to increased interest in combining subunit malaria vaccines as a means of enhancing protective efficacy. Mathematical models of the effect of combining such vaccines on protective efficacy can help inform optimal vaccine strategies and decision-making at all stages of the clinical process. So far, however, no such model has been developed for pre-clinical murine studies, the stage at which all candidate antigens and combinations begin evaluation. To address this gap, this paper develops a mathematical model of vaccine combination adapted to murine malaria studies. The model is based on simple probabilistic assumptions which put the model on a firmer theoretical footing than previous clinical models, which rather than deriving a relationship between immune responses and protective efficacy posit the relationship to be either exponential or Hill curves. Data from pre-clinical murine malaria studies are used to derive values for unknowns in the model which in turn allows simulations of vaccine combination efficacy and suggests optimal strategies to pursue. Finally, the ability of the model to shed light on fundamental biological variables of murine malaria such as the blood stage growth rate and sporozoite infectivity is explored.
Zika virus (ZIKV) emerged on a global scale and no licensed vaccine ensures long-lasting anti-ZIKV immunity. Here we report the design and comparative evaluation of four replication-deficient ...chimpanzee adenoviral (ChAdOx1) ZIKV vaccine candidates comprising the addition or deletion of precursor membrane (prM) and envelope, with or without its transmembrane domain (TM). A single, non-adjuvanted vaccination of ChAdOx1 ZIKV vaccines elicits suitable levels of protective responses in mice challenged with ZIKV. ChAdOx1 prME ∆TM encoding prM and envelope without TM provides 100% protection, as well as long-lasting anti-envelope immune responses and no evidence of in vitro antibody-dependent enhancement to dengue virus. Deletion of prM and addition of TM reduces protective efficacy and yields lower anti-envelope responses. Our finding that immunity against ZIKV can be enhanced by modulating antigen membrane anchoring highlights important parameters in the design of viral vectored ZIKV vaccines to support further clinical assessments.
Infections with dengue virus (DENV) and Zika virus (ZIKV) can induce cross-reactive antibody responses. Two immunodominant epitopes-one to precursor membrane protein and one to the fusion loop ...epitope on envelope (E) protein-are recognized by cross-reactive antibodies
that are not only poorly neutralizing, but can also promote increased viral replication and disease severity via Fcγ receptor-mediated infection of myeloid cells-a process termed antibody-dependent enhancement (ADE)
. ADE is a significant concern for both ZIKV and DENV vaccines as the induction of poorly neutralizing cross-reactive antibodies may prime an individual for ADE on natural infection. In this report, we describe the design and production of covalently stabilized ZIKV E dimers, which lack precursor membrane protein and do not expose the immunodominant fusion loop epitope. Immunization of mice with ZIKV E dimers induces dimer-specific antibodies, which protect against ZIKV challenge during pregnancy. Importantly, the ZIKV E-dimer-induced response does not cross-react with DENV or induce ADE of DENV infection.
Variable efficacy against some dengue serotypes and risk of antibody-dependent enhancement in subgroups of vaccine recipients continue to be a concern with leading vaccine candidates.4,5 Esper Kallas ...and colleagues6 report safety and immunogenicity results from a phase 2 trial of the live-attenuated dengue vaccine Butantan-DV tested in 300 volunteers in a two-step, double-blind, randomised placebo-controlled trial. Future efficacy results of an ongoing phase 3 trial are needed to confirm whether the in-vitro neutralising antibody response observed will translate to a balanced protective efficacy against dengue; although these results using the functional PRNT50 assay are promising, the assay has some limitations.8 The authors also showed that after vaccination, cellular immune responses were induced in addition to increased antibody titres. 94% of vaccine recipients had dengue-specific IFNγ responses after one dose of vaccine. IFNγ production in CD8-positive T cells was detected at 91 days despite the use of a flow cytometry technique that is regarded as less sensitive than the ex-vivo IFNγ ELISpot assay.9 These results are important for a field that has historically focused on antibody assays, but which could benefit from the assessment of T-cell responses.10 Assessment of T-cell induction might be particularly important in a vaccine that has an advantage of using the non-structural DENV regions from three dengue serotypes, resulting in a broader anti-dengue response and thus potentially contributing to protection.
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