Cell-Mediated Immunity Generated in Response to a Purified Inactivated Vaccine for Dengue Virus Type 1

Dengue is the most prevalent arboviral disease afflicting humans, and a vaccine appears to be the most rational means of control. Dengue vaccine development is in a critical phase, with the first vaccine licensed in some countries where dengue is endemic but demonstrating insufficient efficacy in immunologically naive populations. Since virus-neutralizing antibodies do not invariably correlate with vaccine efficacy, other markers that may predict protection, including cell-mediated immunity, are urgently needed. Previously, the Walter Reed Army Institute of Research developed a monovalent purified inactivated virus (PIV) vaccine candidate against dengue virus serotype 1 (DENV-1) adjuvanted with alum. The PIV vaccine was safe and immunogenic in a phase I dose escalation trial in healthy, flavivirus-naive adults in the United States. From that trial, peripheral blood mononuclear cells obtained at various time points pre- and postvaccination were used to measure DENV-1-specific T cell responses. After vaccination, a predominant CD4+ T cell-mediated response to peptide pools covering the DENV-1 structural proteins was observed. Over half (13/20) of the subjects produced interleukin-2 (IL-2) in response to DENV peptides, and the majority (17/20) demonstrated peptide-specific CD4+ T cell proliferation. In addition, analysis of postvaccination cell culture supernatants demonstrated an increased rate of production of cytokines, including gamma interferon (IFN-γ), IL-5, and granulocyte-macrophage colony-stimulating factor (GM-CSF). Overall, the vaccine was found to have elicited DENV-specific CD4+ T cell responses as measured by enzyme-linked immunosorbent spot (ELISpot), intracellular cytokine staining (ICS), lymphocyte proliferation, and cytokine production assays. Thus, together with antibody readouts, the use of a multifaceted measurement of cell-mediated immune responses after vaccination is a useful strategy for more comprehensively characterizing immunity generated by dengue vaccines

Dengue-1 Envelope Protein Domain III along with PELC and CpG Oligodeoxynucleotides Synergistically Enhances Immune Responses

The major weaknesses of subunit vaccines are their low immunogenicity and poor efficacy. Adjuvants can help to overcome some of these inherent defects with subunit vaccines. Here, we evaluated the efficacy of the newly developed water-in-oil-in-water multiphase emulsion system, termed PELC, in potentiating the protective capacity of dengue-1 envelope protein domain III. Unlike aluminum phosphate, dengue-1 envelope protein domain III formulated with PELC plus CpG oligodeoxynucleotides induced neutralizing antibodies against dengue-1 virus and increased the splenocyte secretion of IFN-γ after in vitro re-stimulation. The induced antibodies contained both the IgG1 and IgG2a subclasses. A rapid anamnestic neutralizing antibody response against a live dengue virus challenge was elicited at week 26 after the first immunization. These results demonstrate that PELC plus CpG oligodeoxynucleotides broaden the dengue-1 envelope protein domain III-specific immune responses. PELC plus CpG oligodeoxynucleotides is a promising adjuvant for recombinant protein based vaccination against dengue virus

Immunogenicity, safety, and tolerability of a recombinant measles-virus-based chikungunya vaccine: a randomised, double-blind, placebo-controlled, active-comparator, first-in-man trial

International audienceBackgroundChikungunya is an emerging arthropod-borne disease that has spread from tropical endemic areas to more temperate climates of the USA and Europe. However, no specific treatment or preventive measure is yet available. We aimed to investigate the immunogenicity and safety of a live recombinant measles-virus-based chikungunya vaccine.MethodsWe did a randomised, double-blind, placebo-controlled, active-comparator, phase 1, dose-escalation study at one centre in Vienna, Austria. Healthy men and women aged 18–45 years with no comorbidities were randomly assigned, by computer-generated block randomisation (block size of 14), to receive either one of three escalating doses of the measles-virus-based candidate vaccine (low dose [1·5 × 104 median tissue culture infection doses (TCID50) per 0·05 mL], medium dose [7·5 × 104 TCID50 per 0·25 mL], or high dose [3·0 × 105 TCID50 per 1·0 mL]), or the active comparator—Priorix. Participants were additionally block-randomised to receive a booster injection on either day 28 or day 90 after the first vaccination. Participants and study investigators were masked to group allocation. The primary endpoint was the presence of neutralising anti-chikungunya antibodies on day 28, as assessed by 50% plaque reduction neutralisation test. Analysis was by intention to treat and per protocol. This trial is registered with EudraCT, number 2013-001084-23.FindingsBetween Nov 22, 2013, and Feb 25, 2014, we randomly assigned 42 participants to receive the low dose (n=12), the medium dose (n=12), or the high dose (n=12) of the measles-virus-based candidate vaccine, or Priorix (n=6), of whom 36 participants (86%; n=9, n=12, n=10, n=5, respectively) were included in the per-protocol population. The candidate vaccine raised neutralising antibodies in all dose cohorts after one immunisation, with seroconversion rates of 44% (n=4) in the low-dose group, 92% (n=11) in the medium-dose group, and 90% (n=10) in the high-dose group. The immunogenicity of the candidate vaccine was not affected by pre-existing anti-measles immunity. The second vaccination resulted in a 100% seroconversion for all participants in the candidate vaccine groups. The candidate vaccine had an overall good safety profile, and the rate of adverse events increased with vaccine dose and volume. No vaccination-related serious adverse events were recorded.InterpretationThe live recombinant measles-virus-based chikungunya vaccine had good immunogenicity, even in the presence of anti-vector immunity, was safe, and had a generally acceptable tolerability profile. This vaccine is the first promising measles-virus-based candidate vaccine for use in human beings

Route of inoculation and mosquito vector exposure modulate dengue virus replication kinetics and immune responses in rhesus macaques

© Public Library of Science. All rights reserved. Dengue virus (DENV) is transmitted by infectious mosquitoes during blood-feeding via saliva containing biologically-active proteins. Here, we examined the effect of varying DENV infection modality in rhesus macaques in order to improve the DENV nonhuman primate (NHP) challenge model. NHPs were exposed to DENV-1 via subcutaneous or intradermal inoculation of virus only, intradermal inoculation of virus and salivary gland extract, or infectious mosquito feeding. The infectious mosquito feeding group exhibited delayed onset of viremia, greater viral loads, and altered clinical and immune responses compared to other groups. After 15 months, NHPs in the subcutaneous and infectious mosquito feeding groups were re-exposed to either DENV-1 or DENV-2. Viral replication and neutralizing antibody following homologous challenge were suggestive of sterilizing immunity, whereas heterologous challenge resulted in productive, yet reduced, DENV-2 replication and boosted neutralizing antibody. These results show that a more transmission-relevant exposure modality resulted in viral replication closer to that observed in humans