Adenovirus-5-Vectored P. falciparum Vaccine Expressing CSP and AMA1. Part B: Safety, Immunogenicity and Protective Efficacy of the CSP Component

Background: A protective malaria vaccine will likely need to elicit both cell-mediated and antibody responses. As adenovirus vaccine vectors induce both these responses in humans, a Phase 1/2a clinical trial was conducted to evaluate the efficacy of an adenovirus serotype 5-vectored malaria vaccine against sporozoite challenge.\ud \ud Methodology/Principal Findings: NMRC-MV-Ad-PfC is an adenovirus vector encoding the Plasmodium falciparum 3D7 circumsporozoite protein (CSP). It is one component of a two-component vaccine NMRC-M3V-Ad-PfCA consisting of one adenovector encoding CSP and one encoding apical membrane antigen-1 (AMA1) that was evaluated for safety and immunogenicity in an earlier study (see companion paper, Sedegah et al). Fourteen Ad5 seropositive or negative adults received two doses of NMRC-MV-Ad-PfC sixteen weeks apart, at 1x1010 particle units per dose. The vaccine was safe and well tolerated. All volunteers developed positive ELISpot responses by 28 days after the first immunization (geometric mean 272 spot forming cells/million[sfc/m]) that declined during the following 16 weeks and increased after the second dose to levels that in most cases were less than the initial peak (geometric mean 119 sfc/m). CD8+ predominated over CD4+ responses, as in the first clinical trial. Antibody responses were poor and like ELISpot responses increased after the second immunization but did not exceed the initial peak. Pre-existing neutralizing antibodies (NAb) to Ad5 did not affect the immunogenicity of the first dose, but the fold increase in NAb induced by the first dose was significantly associated with poorer antibody responses after the second dose, while ELISpot responses remained unaffected. When challenged by the bite of P. falciparum-infected mosquitoes, two of 11 volunteers showed a delay in the time to patency compared to infectivity controls, but no volunteers were sterilely protected.\ud \ud Significance: The NMRC-MV-Ad-PfC vaccine expressing CSP was safe and well tolerated given as two doses, but did not provide sterile protection

Addressing climate change with behavioral science: a global intervention tournament in 63 countries

Effectively reducing climate change requires marked, global behavior change. However, it is unclear which strategies are most likely to motivate people to change their climate beliefs and behaviors. Here, we tested 11 expert-crowdsourced interventions on four climate mitigation outcomes: beliefs, policy support, information sharing intention, and an effortful tree-planting behavioral task. Across 59,440 participants from 63 countries, the interventions’ effectiveness was small, largely limited to nonclimate skeptics, and differed across outcomes: Beliefs were strengthened mostly by decreasing psychological distance (by 2.3%), policy support by writing a letter to a future-generation member (2.6%), information sharing by negative emotion induction (12.1%), and no intervention increased the more effortful behavior—several interventions even reduced tree planting. Last, the effects of each intervention differed depending on people’s initial climate beliefs. These findings suggest that the impact of behavioral climate interventions varies across audiences and target behaviors

Pooled analysis of WHO Surgical Safety Checklist use and mortality after emergency laparotomy

Background The World Health Organization (WHO) Surgical Safety Checklist has fostered safe practice for 10 years, yet its place in emergency surgery has not been assessed on a global scale. The aim of this study was to evaluate reported checklist use in emergency settings and examine the relationship with perioperative mortality in patients who had emergency laparotomy. Methods In two multinational cohort studies, adults undergoing emergency laparotomy were compared with those having elective gastrointestinal surgery. Relationships between reported checklist use and mortality were determined using multivariable logistic regression and bootstrapped simulation. Results Of 12 296 patients included from 76 countries, 4843 underwent emergency laparotomy. After adjusting for patient and disease factors, checklist use before emergency laparotomy was more common in countries with a high Human Development Index (HDI) (2455 of 2741, 89.6 per cent) compared with that in countries with a middle (753 of 1242, 60.6 per cent; odds ratio (OR) 0.17, 95 per cent c.i. 0.14 to 0.21, P <0001) or low (363 of 860, 422 per cent; OR 008, 007 to 010, P <0.001) HDI. Checklist use was less common in elective surgery than for emergency laparotomy in high-HDI countries (risk difference -94 (95 per cent c.i. -11.9 to -6.9) per cent; P <0001), but the relationship was reversed in low-HDI countries (+121 (+7.0 to +173) per cent; P <0001). In multivariable models, checklist use was associated with a lower 30-day perioperative mortality (OR 0.60, 0.50 to 073; P <0.001). The greatest absolute benefit was seen for emergency surgery in low- and middle-HDI countries. Conclusion Checklist use in emergency laparotomy was associated with a significantly lower perioperative mortality rate. Checklist use in low-HDI countries was half that in high-HDI countries.Peer reviewe

Mortality of emergency abdominal surgery in high-, middle- and low-income countries

Background: Surgical mortality data are collected routinely in high-income countries, yet virtually no low- or middle-income countries have outcome surveillance in place. The aim was prospectively to collect worldwide mortality data following emergency abdominal surgery, comparing findings across countries with a low, middle or high Human Development Index (HDI). Methods: This was a prospective, multicentre, cohort study. Self-selected hospitals performing emergency surgery submitted prespecified data for consecutive patients from at least one 2-week interval during July to December 2014. Postoperative mortality was analysed by hierarchical multivariable logistic regression. Results: Data were obtained for 10 745 patients from 357 centres in 58 countries; 6538 were from high-, 2889 from middle- and 1318 from low-HDI settings. The overall mortality rate was 1⋅6 per cent at 24 h (high 1⋅1 per cent, middle 1⋅9 per cent, low 3⋅4 per cent; P < 0⋅001), increasing to 5⋅4 per cent by 30 days (high 4⋅5 per cent, middle 6⋅0 per cent, low 8⋅6 per cent; P < 0⋅001). Of the 578 patients who died, 404 (69⋅9 per cent) did so between 24 h and 30 days following surgery (high 74⋅2 per cent, middle 68⋅8 per cent, low 60⋅5 per cent). After adjustment, 30-day mortality remained higher in middle-income (odds ratio (OR) 2⋅78, 95 per cent c.i. 1⋅84 to 4⋅20) and low-income (OR 2⋅97, 1⋅84 to 4⋅81) countries. Surgical safety checklist use was less frequent in low- and middle-income countries, but when used was associated with reduced mortality at 30 days. Conclusion: Mortality is three times higher in low- compared with high-HDI countries even when adjusted for prognostic factors. Patient safety factors may have an important role. Registration number: NCT02179112 (http://www.clinicaltrials.gov)

A Novel MVA-Based Multiphasic Vaccine for Prevention or Treatment of Tuberculosis Induces Broad and Multifunctional Cell-Mediated Immunity in Mice and Primates.

Bacille Calmette-Guérin (BCG) vaccination of new born babies can protect children against tuberculosis (TB), but fails to protect adults consistently against pulmonary TB underlying the urgent need to develop novel TB vaccines. Majority of first generation TB vaccine candidates have relied on a very limited number of antigens typically belonging to the active phase of infection. We have designed a multi-antigenic and multiphasic vaccine, based on the Modified Vaccinia Ankara virus (MVA). Up to fourteen antigens representative of the three phases of TB infection (active, latent and resuscitation) were inserted into MVA. Using three different strains of mouse (BALB/c, C57BL/6 and C3H/HeN), we show that a single vaccination results in induction of both CD4 and CD8 T cells, displaying capacity to produce multiple cytokines together with cytolytic activity targeting a large array of epitopes. As expected, dominance of responses was linked to the mouse haplotype although for a given haplotype, responses specific of at least one antigen per phase could always be detected. Vaccination of non-human primates with the 14 antigens MVA-TB candidate resulted in broad and potent cellular-based immunogenicity. The remarkable plasticity of MVA opens the road to development of a novel class of highly complex recombinant TB vaccines to be evaluated in both prophylactic and therapeutic settings

MVATG18377 induces multiple cytokines-producing T cells in C57BL/6 mice.

<p>Cells from MVATG18377-immunized C57BL/6 mice were stimulated with antigen peptide pools or an irrelevant E7 peptide (Irr). Results are presented as (<b>A</b>) the percentage of IFNγ⁺, IFNγ⁺TNFα⁺ or IFNγ⁺TNFα⁺IL2⁺ cell subsets among total CD4 T cells or (<b>B</b>) percentage of IFNγ⁺, TNFα⁺ or IFNγ⁺TNFα⁺ cell subsets among total CD8 T cells. Plain bars represent response from individual mice and hatched bars represent median response for each cell subset. Cut-off value (dotted line, 0.02%) is represented for both CD4⁺ and CD8⁺ T cell responses. Only antigens with median value above the cut-off value are represented. For these antigens, only cell subgroups with a percentage above the cut-off value are represented. No response was detected in MVATGN33.1-immunized mice (data not shown). For each cell population, background signal obtained in unstimulated cell condition was subtracted. Pie charts represent a more global analysis for each responder antigen. All analyzed single (IFNγ⁺, TNFα⁺ and IL2⁺), double (IFNγ⁺TNFα⁺, IFNγ⁺IL2⁺ and TNFα⁺IL2⁺) or triple (IFNγ⁺TNFα⁺IL2⁺) cytokine producer cells are included under the corresponding color codes. Results are representative of two independent experiments.</p

ELISpot analysis of IFNγ responses specific of MVATG18377-encoded Mtb antigens in different strains of mice.

<p>(<b>A</b>) BALB/c, (<b>B</b>) C57BL/6 and (<b>C</b>) C3H/HeN mice were immunized once with either MVATGN33.1 (light grey) or MVATG18377 (dark grey). Results are shown as the number of IFNγ-producing T cells (spots-forming cells) per 10⁶ splenocytes following stimulation with either peptide pools specific of each of the 14 antigens or the irrelevant GLL peptide (Irr). For long sequence antigens (Rv2029, Rv2626, Rv1733, Rv0111, RpfB-RpfD, Ag85B, Rv3478 and Rv1807), only results obtained with the peptide pool leading to the highest response are shown. Full bars represent individual mice and hatched bars represent median values of each group. The experimental cut-off value (dotted line) is represented for each mouse strain: 51 spots/10⁶ cells for BALB/c, 56 spots/10⁶ cells for C57BL/6 and 72 spots/10⁶ cells for C3H/HeN mice. Results are representative of two independent experiments.</p

MVATG18377 induces multiple cytokines-producing T cells in BALB/c mice.

<p>Cells from MVATG18377-immunized BALB/c mice were stimulated with antigen peptide pools or an irrelevant E7 peptide (Irr) and IFNγ, IL2 and TNFα intracellular cytokine staining was measured by flow cytometry. Results are presented as (<b>A</b>) the percentage of IFNγ⁺, IFNγ⁺TNFα⁺ or IFNγ⁺TNFα⁺IL2⁺ cell subsets among total CD4 T cells or (<b>B</b>) percentage of IFNγ⁺, TNFα⁺ or IFNγ⁺TNFα⁺ cell subsets among total CD8 T cells. Plain bars represent response from individual mice and hatched bars represent median response for each cell subset. Cut-off value (dotted line, 0.02%) is represented for both CD4⁺ and CD8⁺ T cell responses. Only antigens with median values above the cut-off value are represented. For these antigens, only cell subgroups with a percentage above the cut-off value are represented. No response was detected in MVATGN33.1-immunized mice (data not shown). For each cell population, background signal obtained in unstimulated cell condition was subtracted. Pie charts represent a more global analysis for each responder antigen. All analyzed single (IFNγ⁺, TNFα⁺ and IL2⁺), double (IFNγ⁺TNFα⁺, IFNγ⁺IL2⁺ and TNFα⁺IL2⁺) or triple (IFNγ⁺TNFα⁺IL2⁺) cytokine producer cells are included under the corresponding color codes. Results are representative of two independent experiments.</p

Schematic representation of the antigen fusions of MVATG18377.

<p>Three antigen fusions were inserted in the deletion III of MVA vector. The first fusion is constituted by the fusion of Rv2029, Rv2626, Rv1733 and Rv0111 proteins and is placed under the control of p7.5K promoter. The second fusion contains a fusion of RpfB-RpfD, Ag85B, TB10.4 and ESAT-6 proteins and its expression is driven by the pH5R promoter. The third fusion is constituted by the fusion of Rv0569, Rv1813, Rv3407, Rv3478 and Rv1807 proteins and is placed under the control of pB2R promoter. SF, signal peptide of the F protein of measles virus. SR, signal peptide of the glycoprotein precursor of rabies virus ERA strain. TMR, membrane-anchoring peptide derived from the rabies glycoprotein of PG strain.</p