Shigellosis is a mild-to-severe diarrheal infection, caused by the genus
, and is responsible for significant morbidity and mortality worldwide. We evaluated the safety and immunogenicity of an ...investigational
vaccine (1790GAHB) based on generalized modules for membrane antigens (GMMA) in Kenya, a
-endemic country. This phase 2a, observer-blind, controlled randomized study (NCT02676895) enrolled 74 healthy adults aged 18-45 years, of whom 72 were vaccinated. Participants received, in a 1:1:1 ratio, two vaccinations with the 1790GAHB vaccine at doses of either 1.5/25 μg of O antigen (OAg)/protein (group 1.5/25 μg) or 5.9/100 μg (group 5.9/100 μg) at day (D) 1 and D29, or vaccination with a quadrivalent meningococcal vaccine at D1 and tetanus, diphtheria, and acellular pertussis vaccine at D29 (control group). Solicited and unsolicited adverse events (AEs), serious AEs (SAEs), and AEs of special interest (neutropenia and reactive arthritis) were collected. Anti-
lipopolysaccharide (LPS) serum immunoglobulin G (IgG) geometric mean concentrations (GMC) were evaluated at D1, D29, and D57 and compared to anti-
LPS antibody levels in convalescent patients naturally exposed to
. The percentages of participants with seroresponse were also calculated. The most frequently reported solicited local and systemic AEs across all groups were pain and headache, respectively. Only one case of severe systemic reaction was reported (severe headache after first vaccination in group 5.9/100 μg). Seven and three episodes of neutropenia, assessed as probably or possibly related to vaccination respectively, were reported in the investigational and control groups, respectively. No other SAEs were reported. Despite very high baseline anti-
LPS serum IgG levels, the 1790GAHB vaccine induced robust antibody responses. At D29, GMC increased 2.10- and 4.43-fold from baseline in groups 1.5/25 and 5.9/100 μg, respectively, whereas no increase was observed in the control group. Antibody titers at D57 were not statistically different from those at D29. Seroresponse was 68% at D29 and 90% at D57 in group 1.5/25 μg, and 96% after each vaccination in group 5.9/100 μg. The 1790GAHB vaccine was well tolerated and highly immunogenic in a population of African adults, regardless of the GMMA OAg/protein content used.
is the second most deadly diarrheal disease among children under five years of age, after rotavirus, with high morbidity and mortality in developing countries. Currently, no vaccine is widely ...available, and the increasing levels of multidrug resistance make
a high priority for vaccine development. The single-component candidate vaccine against
(1790GAHB), developed using the GMMA technology, contains the O antigen (OAg) portion of lipopolysaccharide (LPS) as active moiety. The vaccine was well tolerated and immunogenic in early-phase clinical trials. In a phase 1 placebo-controlled dose escalation trial in France (NCT02017899), three doses of five different vaccine formulations (0.06/1, 0.3/5, 1.5/25, 3/50, 6/100 µg of OAg/protein) were administered to healthy adults. In the phase 1 extension trial (NCT03089879), conducted 2-3 years following the parent study, primed individuals who had undetectable antibody levels before the primary series received a 1790GAHB booster dose (1.5/25 µg OAg/protein). Controls were unprimed participants immunized with one 1790GAHB dose. The current analysis assessed the functionality of sera collected from both studies using a high-throughput luminescence-based serum bactericidal activity (SBA) assay optimized for testing human sera. Antibodies with complement-mediated bactericidal activity were detected in vaccinees but not in placebo recipients. SBA titers increased with OAg dose, with a persistent response up to six months after the primary vaccination with at least 1.5/25 µg of OAg/protein. The booster dose induced a strong increase of SBA titers in most primed participants. Correlation between SBA titers and anti-
LPS serum immunoglobulin G levels was observed. Results suggest that GMMA is a promising OAg delivery system for the generation of functional antibody responses and persistent immunological memory.
Capture strategies for the brown marmorated stink bug, Halyomorpha halys (Hemiptera: Pentatomidae), are challenging. Here we developed and evaluated a multimodal trap which combines visual and ...olfactory stimuli. Visual stimuli consisted of LEDs emitting UV-A and visible light. Olfactory stimuli were comprised of the synthetic aggregation pheromone and odours from trapped H. halys individuals. Stink bug attraction at different wavelengths was evaluated in laboratory two-choice bioassays, and different prototypes of the trap were tested in 2021 in natural, agricultural, and urban settings. Traps with a combination of UV-A and blue or green visible wavelengths provided higher H. halys attraction (up to ~8-fold) compared to traditional sticky or small pyramidal traps. The concurrent presence of synthetic pheromone and LED had a synergistic effect on H. halys positive phototaxis. Further development and implementation of the multimodal trap is discussed for prospective use in attract-and-kill or push–pull strategies.
The investigational
vaccine (1790GAHB) based on GMMA (generalized modules for membrane antigens) is immunogenic, with an acceptable safety profile in adults. However, pre-vaccination anti-
...lipopolysaccharide (LPS) antibody levels seemed to impact vaccine-related immune responses. This phase 1, open-label, non-randomized extension study (ClinicalTrials.gov: NCT03089879) evaluated immunogenicity of a 1790GAHB booster dose in seven adults with undetectable antibodies prior to priming with three 1790GAHB vaccinations 2-3 years earlier (boosted group), compared to one dose in 28 vaccine-naïve individuals (vaccine-naïve group). Anti-
LPS serum IgG geometric mean concentrations and seroresponse (increase of ≥25 EU or ≥50% from baseline antibody ≤ 50 EU and ≥50 EU, respectively) rates were calculated at vaccination (day D1), D8, D15, D29, D85. Safety was assessed. Geometric mean concentrations at D8 were 168 EU (boosted group) and 32 EU (vaccine-naïve group). Response peaked at D15 (883 EU) and D29 (100 EU) for the boosted and vaccine-naïve groups. Seroresponse rates at D8 were 86% (boosted group) and 24% (vaccine-naïve group) and increased at subsequent time points. Across both groups, pain (local) and fatigue (systemic) were the most frequent solicited adverse events (AEs). Unsolicited AEs were reported by 57% of boosted and 25% of vaccine-naïve participants. No deaths, serious AEs, or AEs of special interest (except one mild neutropenia case, possibly vaccination-related) were reported. One 1790GAHB dose induced a significant booster response in previously-primed adults, regardless of priming dose, and strong immune response in vaccine-naïve individuals. Vaccination was well tolerated.
Approximately 164,000 deaths yearly are due to shigellosis, primarily in developing countries. Thus, a safe and affordable Shigella vaccine is an important public health priority. The GSK Vaccines ...Institute for Global Health (GVGH) developed a candidate Shigella sonnei vaccine (1790GAHB) using the Generalized Modules for Membrane Antigens (GMMA) technology. The paper reports results of 1790GAHB Phase 1 studies in healthy European adults.
To evaluate the safety and immunogenicity profiles of 1790GAHB, we performed two parallel, phase 1, observer-blind, randomized, placebo-controlled, dose escalation studies in France (“study 1”) and the United Kingdom (“study 2”) between February 2014 and April 2015 (ClinicalTrials.gov, number NCT02017899 and NCT02034500, respectively) in 18–45years old subjects (50 in study 1, 52 in study 2). Increasing doses of Alhydrogel adsorbed 1790, expressed by both O Antigen (OAg) and protein quantity, or placebo were given either by intramuscular route (0.059/1, 0.29/5, 1.5/25, 2.9/50, 5.9/100μg of OAg/μg of protein; study 1) or by intradermal (ID), intranasal (IN) or intramuscular (IM) route of immunization (0.0059/0.1, 0.059/1, 0.59/10μg ID, 0.29/5, 1.2/20, 4.8/80μg IN and 0.29/5μg IM, respectively; study 2). In absence of serologic correlates of protection for Shigella sonnei, vaccine induced immunogenicity was compared to anti-LPS antibody in a population naturally exposed to S. sonnei.
Vaccines were well tolerated in both studies and no death or vaccine related serious adverse events were reported. In study 1, doses ≥1.5/25μg elicited serum IgG median antibody greater than median level in convalescent subjects after the first dose. No vaccine group in study 2 achieved median antibody greater than the median convalescent antibody.
Intramuscularly administered Shigella sonnei GMMA vaccine is well tolerated, up to and including 5.9/100μg and induces antibody to the OAg of at least the same magnitude of those observed following natural exposure to the pathogen. Vaccine administered by ID or IN, although well tolerated, is poorly immunogenic at the doses delivered. The data support the use of the GMMA technology for the development of intramuscular multivalent Shigella vaccines.
•GVGH GMMA vaccine against S. sonnei was well tolerated by IM, IN and ID routes of immunization in young European adults.•Doses ≥1.5/25μg elicited serum IgG median antibody greater than median level in convalescent subjects after the first dose.•Clinical data support the use of the GMMA technology for the development of intramuscular Shigella multivalent vaccines.
Shigellosis is an important cause of diarrhoea especially in children of developing countries. No vaccine is available. Based on the 2015 Global Burden of Disease, Shigella caused approximately 164,000 deaths due to diarrhoea in 2015, supporting the public health relevance of the disease and the need for a vaccine. The GMMA (Generalized Modules for Membrane Antigens) technology was used for the development of a vaccine against Shigella sonnei which, tested in these trials for the first time, was shown to be well tolerated in young adults and induced specific antibody titres at least as high as after natural infection.
Summary Background Typhoid vaccination is a public health priority in developing countries where young children are greatly affected by typhoid fever. Because present vaccines are not recommended for ...children younger than 2 years, the Novartis Vaccines Institute for Global Health developed a conjugate vaccine (Vi-CRM197 ) for infant immunisation. We aimed to assess the immunogenicity and safety of Vi-CRM197 in participants of various ages in endemic countries in south and southeast Asia. Methods We did two randomised, observer-blind, age de-escalation, phase 2 trials at two sites in Pakistan and India (study A), and at one site in the Philippines (study B), between March 2, 2011, and Aug 9, 2012. Adults aged 18–45 years, children aged 24–59 months, older infants aged 9–12 months, and infants aged 6–8 weeks were randomly assigned (1:1) with a computer-generated randomisation list (block size of four) to receive either 5 μg Vi-CRM197 or 25 μg Vi-polysaccharide vaccine (or 13-valent pneumococcal conjugate vaccine in children younger than 2 years). Both infant populations received Vi-CRM197 concomitantly with vaccines of the Expanded Programme on Immunization (EPI), according to WHO schedule. With the exception of designated study site personnel responsible for vaccine preparation, study investigators, those assessing outcomes, and data analysts were masked to treatment allocation. We specified no a-priori null hypothesis for the immunogenicity or safety objectives and all analyses were descriptive. Analyses were by modified intention-to-treat. These studies are registered with ClinicalTrials.gov , numbers NCT01229176 and NCT01437267. Findings 320 participants were enrolled and vaccinated in the two trials: 200 in study A (all age groups) and 120 in study B (children and infants only), of whom 317 (99%) were included in the modified intention-to-treat analysis. One dose of Vi-CRM197 significantly increased concentrations of anti-Vi antibody in adults (from 113 U/mL 95% CI 67–190 to 208 U/mL 117–369), children (201 U/mL 138–294 to 368 U/mL 234–580), and older infants (179 U/mL 129–250 to 249 U/mL 130–477). However, in children and older infants, a second dose of conjugate vaccine had no incremental effect on antibody titres and, at all ages, concentrations of antibodies increased substantially 6 months after vaccination (from 55 U/mL 33–94 to 63 U/mL 35–114 in adults, from 23 U/mL 15–34 to 51 U/mL 34–76 in children, and from 21 U/mL 14–31 to 22 U/mL 14–33 in older infants). Immune response in infants aged 6–8 weeks was lower than that in older participants and, 6 months after third vaccination, antibody concentrations were significantly higher than pre-vaccination concentrations in Filipino (21 U/mL 16–28 vs 2·88 U/mL 1·95–4·25), but not Pakistani (3·76 U/mL 2·77–5·08 vs 2·77 U/mL 2·1–3·66), infants. Vi-CRM197 was safe and well tolerated and did not induce any significant interference with EPI vaccines. No deaths or vaccine-related serious adverse events were reported throughout the studies. Interpretation Vi-CRM197 is safe and immunogenic in endemic populations of all ages. Given at 9 months of age, concomitantly with measles vaccine, Vi-CRM197 shows a promise for potential inclusion in EPI schedules of countries endemic for typhoid. An apparent absence of booster response and a reduction in antibody titres 6 months after immunisation should be further investigated, but data show that an immunogenic typhoid vaccine can be safely delivered to infants during EPI visits recommended by WHO. Funding Sclavo Vaccines Association and Regione Toscana.
Shigellosis accounts for substantial morbidity and mortality worldwide and is the second most common cause of moderate and severe diarrhoea in children.
This phase 2b study (NCT03527173), conducted ...between August 2018 and November 2019, evaluated vaccine efficacy (VE), safety, and immunogenicity of a Shigella sonnei GMMA candidate vaccine (1790GAHB) in adults, using a S. sonnei 53 G controlled human infection model. Participants (randomized 1:1) received two doses of 1790GAHB or placebo (GAHB-Placebo), at day (D) 1 and D29, and an oral challenge of S. sonnei 53 G at D57. VE was evaluated using several endpoints, reflecting different case definitions of shigellosis. For the primary endpoint, the success criterion was a lower limit of the 90% confidence interval >0.
Thirty-six and 35 participants received 1790GAHB or placebo, respectively; 33 and 29 were challenged, 15 and 12 developed shigellosis. VE was not demonstrated for any endpoint. Adverse events were more frequent in 1790GAHB versus placebo recipients post-vaccination. Anti-S. sonnei lipopolysaccharide (LPS) IgG responses increased at D29 and remained stable through D57 in group 1790GAHB; no increase was shown in placebo recipients.
1790GAHB had an acceptable safety profile and induced anti-LPS IgG responses but did not demonstrate clinical efficacy against shigellosis. Baseline/pre-challenge antibody levels were higher in participants who did not develop shigellosis post-challenge, suggesting a role of anti-LPS IgG antibodies in clinical protection, although not fully elucidated in this study. For further vaccine development an increased S. sonnei O-antigen content is likely needed to enhance anti-LPS immune responses.
GlaxoSmithKline Biologicals SA, Bill and Melinda Gates Foundation
Typhoid fever causes more than 21 million cases of disease and 200,000 deaths yearly worldwide, with more than 90% of the disease burden being reported from Asia. Epidemiological data show high ...disease incidence in young children and suggest that immunization programs should target children below two years of age: this is not possible with available vaccines. The Novartis Vaccines Institute for Global Health developed a conjugate vaccine (Vi-CRM₁₉₇) for infant vaccination concomitantly with EPI vaccines, either starting at 6 weeks with DTP or at 9 months with measles vaccine. We report the results from a Phase 1 and a Phase 2 dose ranging trial with Vi-CRM₁₉₇ in European adults.
Following randomized blinded comparison of single vaccination with either Vi-CRM₁₉₇ or licensed polysaccharide vaccines (both containing 25·0 µg of Vi antigen), a randomised observer blinded dose ranging trial was performed in the same center to compare three concentrations of Vi-CRM₁₉₇ (1·25 µg, 5·0 µg and 12·5 µg of Vi antigen) with the polysaccharide vaccine.
All vaccines were well tolerated. Compared to the polysaccharide vaccine, Vi-CRM₁₉₇ induced a higher incidence of mild to moderate short lasting local pain. All Vi-CRM₁₉₇ formulations induced higher Vi antibody levels compared to licensed control, with clear dose response relationship.
Vi-CRM₁₉₇ did not elicit safety concerns, was highly immunogenic and is therefore suitable for further clinical testing in endemic populations of South Asia.
ClinicalTrials.gov NCT01123941 NCT01193907.
Shigella spp. are a leading bacterial cause of diarrhea. No widely licensed vaccines are available and there is no generally accepted correlate of protection. We tested a S. sonnei Generalized ...Modules for Membrane Antigen (GMMA)-based vaccine (1790GAHB) in a phase 2b, placebo-controlled, randomized, controlled human infection model study (NCT03527173) enrolling healthy United States adults aged 18-50 years. We report analyses evaluating immune responses to vaccination, with the aim to identify correlates of risk for shigellosis among assessed immunomarkers. We found that 1790GAHB elicited S. sonnei lipopolysaccharide specific α4β7+ immunoglobulin (Ig) G and IgA secreting B cells which are likely homing to the gut, indicating the ability to induce a mucosal in addition to a systemic response, despite parenteral delivery. We were unable to establish or confirm threshold levels that predict vaccine efficacy facilitating the evaluation of vaccine candidates. However, serum anti-lipopolysaccharide IgG and bactericidal activity were identified as potential correlates of risk for shigellosis.
(Pallas) has been introduced either intentionally or accidentally in different areas outside its native range, where it is often regarded as invasive.
(Schrank) has been recorded to parasitize
in the ...field, both in the native and introduced areas, Italy included. The percent of parasitism found in our field investigation was low (four percent). The effect of exposure time of
to
and the impact of parasitization on host longevity, oviposition capacity and egg fertility were evaluated in the laboratory. The acceptance and suitability of
as host for
were then studied, in comparison with the native coccinellid
(L.), which shares the same ecological niche. The effects of parasitization on female longevity and reproduction capacity in the exotic vs. the indigenous lady beetle were also investigated. The overall results showed that
negatively affected the fitness of
, more than that of
. The parasitoid may thus play a marginal role in controlling the populations of the Asian lady beetle, without representing a threat to
.
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