Vaccination against Helicobacter pylori - An approach for cancer prevention?

The gram-negative bacterium Helicobacter pylori is the most common chronic bacterial infection and the main cause of gastric cancer. Due to the increasing antimicrobial resistance of H. pylori, the development of an efficacious vaccine is a valid option to protect from disease or infection and ultimately prevent gastric cancer. However, despite more than 30 years of research, no vaccine has entered the market yet. This review highlights the most relevant previous preclinical and clinical studies to allow conclusions to be drawn on which parameters need special attention in the future to develop an efficacious vaccine against H. pylori and thus prevent gastric cancer.

A field efficacy trial of a trivalent vaccine containing porcine circovirus type 2a and 2b, and Mycoplasma hyopneumoniae in three herds.

BACKGROUND: This field trial was designed to evaluate the efficacy of a new trivalent vaccine containing porcine circovirus type 2a and 2b (PCV2a/b), and Mycoplasma hyopneumoniae at three independent locations. METHODS: Three farms were selected based on their history of PCV2 and M. hyopneumoniae co-infection. Each farm housed a total of 60, 3-day-old pigs that were randomly allocated to one of three treatment groups. Pigs were administered the trivalent vaccine intramuscularly with either a 1.0 ml dose at 3 and 24 days of age or a 2.0 ml dose at 21 days of age in accordance with the manufacturer's recommendations. RESULTS: Clinically, the average daily weight gain of the one-dose and two-dose vaccinated groups within all three farms was significantly higher (p < 0.05) than those of unvaccinated animals during the growing (70-112 days of age), finishing (112-175 days of age) and overall (3-175 days of age) stages of production. One-dose and two-dose vaccinated animals elicited neutralizing antibodies and interferon-γ-secreting cells (IFN-γ-SC), which reduced the amount of PCV2 in terms of blood load and reduced the severity of lymphoid lesions when compared with unvaccinated animals. Similarly, one-dose and two-dose vaccinated animals elicited IFN-γ-SC, which reduced the amount of M. hyopneumoniae in terms of laryngeal load and reduced the severity of lung lesions. CONCLUSIONS: The intramuscular administration of either one or two doses of trivalent vaccine was not significantly different in any of the evaluated parameters. The results of field trial demonstrated that the trivalent vaccine was efficacious in the protection of swine herds where PCV2d and M. hyopneumoniae were in active circulation.

Lives saved with vaccination for 10 pathogens across 112 countries in a pre-COVID-19 world.

Background: Vaccination is one of the most effective public health interventions. We investigate the impact of vaccination activities for Haemophilus influenzae type b, hepatitis B, human papillomavirus, Japanese encephalitis, measles, Neisseria meningitidis serogroup A, rotavirus, rubella, Streptococcus pneumoniae, and yellow fever over the years 2000-2030 across 112 countries. Methods: Twenty-one mathematical models estimated disease burden using standardised demographic and immunisation data. Impact was attributed to the year of vaccination through vaccine-activity-stratified impact ratios. Results: We estimate 97 (95%CrI[80, 120]) million deaths would be averted due to vaccination activities over 2000-2030, with 50 (95%CrI[41, 62]) million deaths averted by activities between 2000 and 2019. For children under-5 born between 2000 and 2030, we estimate 52 (95%CrI[41, 69]) million more deaths would occur over their lifetimes without vaccination against these diseases. Conclusions: This study represents the largest assessment of vaccine impact before COVID-19-related disruptions and provides motivation for sustaining and improving global vaccination coverage in the future. Funding: VIMC is jointly funded by Gavi, the Vaccine Alliance, and the Bill and Melinda Gates Foundation (BMGF) (BMGF grant number: OPP1157270 / INV-009125). Funding from Gavi is channelled via VIMC to the Consortium's modelling groups (VIMC-funded institutions represented in this paper: Imperial College London, London School of Hygiene and Tropical Medicine, Oxford University Clinical Research Unit, Public Health England, Johns Hopkins University, The Pennsylvania State University, Center for Disease Analysis Foundation, Kaiser Permanente Washington, University of Cambridge, University of Notre Dame, Harvard University, Conservatoire National des Arts et Métiers, Emory University, National University of Singapore). Funding from BMGF was used for salaries of the Consortium secretariat (authors represented here: TBH, MJ, XL, SE-L, JT, KW, NMF, KAMG); and channelled via VIMC for travel and subsistence costs of all Consortium members (all authors). We also acknowledge funding from the UK Medical Research Council and Department for International Development, which supported aspects of VIMC's work (MRC grant number: MR/R015600/1).JHH acknowledges funding from National Science Foundation Graduate Research Fellowship; Richard and Peggy Notebaert Premier Fellowship from the University of Notre Dame. BAL acknowledges funding from NIH/NIGMS (grant number R01 GM124280) and NIH/NIAID (grant number R01 AI112970). The Lives Saved Tool (LiST) receives funding support from the Bill and Melinda Gates Foundation.This paper was compiled by all coauthors, including two coauthors from Gavi. Other funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

A Randomized Trial of Mycobacterium w in Severe Presumed Gram-Negative Sepsis.

BACKGROUND: Mycobacterium w (Mw), an immunomodulator, has been shown to resolve early organ failure in severe sepsis. RESEARCH QUESTION: Does Mw improve survival in patients with severe presumed gram-negative sepsis? STUDY DESIGN AND METHODS: This was a randomized, double-blind, placebo-controlled, parallel-group study conducted in ICUs of five tertiary care centers in India. We included consecutive patients (age ≥ 18 years) with presumed gram-negative sepsis in the study within 48 h of the first organ dysfunction. Patients in the treatment arm received 0.3 mL/d of Mw intradermally for 3 consecutive days, whereas the control arm received matching placebo. The primary outcome was 28-day all-cause mortality. The secondary outcomes were ventilator-free days, days receiving vasopressor therapy, ICU and hospital length of stay, nosocomial infection rate, antibiotic use duration, and delta Sequential Organ Failure Assessment (SOFA) score. RESULTS: We included 202 patients with severe sepsis (101 Mw, 101 placebo). The use of Mw significantly reduced the mortality (9/101 vs 20/101; estimate difference, 0.11 [95% CI, 0.01-0.21]; P = .04). We found no difference in ventilator-free days, days receiving vasopressor drugs, ICU length of stay, and the hospital length of stay. The time to mortality (median, 13 days vs 8.5 days) was significantly longer in the Mw than in the placebo arm. The delta SOFA score, rate of nosocomial infections, and antibiotic use duration were similar in the two arms. We found Mw to reduce significantly the odds (OR, 0.37 [95% CI, 0.15-0.9]) of mortality after adjusting for culture-positive sepsis, baseline SOFA score, age, and sex. INTERPRETATION: The use of Mw was associated with a significant reduction in mortality in patients with severe presumed gram-negative sepsis. Further studies are required to confirm our findings. TRIAL REGISTRY: ClinicalTrials.gov; No.: NCT02330432; URL: www.clinicaltrials.gov.

Anti-glycan antibodies: roles in human disease.

Carbohydrate-binding antibodies play diverse and critical roles in human health. Endogenous carbohydrate-binding antibodies that recognize bacterial, fungal, and other microbial carbohydrates prevent systemic infections and help maintain microbiome homeostasis. Anti-glycan antibodies can have both beneficial and detrimental effects. For example, alloantibodies to ABO blood group carbohydrates can help reduce the spread of some infectious diseases, but they also impose limitations for blood transfusions. Antibodies that recognize self-glycans can contribute to autoimmune diseases, such as Guillain-Barre syndrome. In addition to endogenous antibodies that arise through natural processes, a variety of vaccines induce anti-glycan antibodies as a primary mechanism of protection. Some examples of approved carbohydrate-based vaccines that have had a major impact on human health are against pneumococcus, Haemophilus influeanza type b, and Neisseria meningitidis. Monoclonal antibodies specifically targeting pathogen associated or tumor associated carbohydrate antigens (TACAs) are used clinically for both diagnostic and therapeutic purposes. This review aims to highlight some of the well-studied and critically important applications of anti-carbohydrate antibodies.

An Overview of Helicobacter pylori Infection.

Helicobacter pylori (H. pylori) represents one of the most widespread bacterial infections globally. Infection causes chronic gastritis and increases the risk of peptic ulcer disease, gastric adenocarcinoma, and mucosa-associated lymphoid tissue lymphoma. The pioneering discovery of H. pylori by Marshall and Warren in the early 1980s has initiated fervent research into H. pylori as a pathogen ever since. This chapter aims to provide an overview of our understanding of H. pylori infection and its management, with a focus on current options for diagnosis, the challenges associated with H. pylori eradication, and the need for alternative therapeutic strategies based on furthering our understanding of host: H. pylori interactions.

A review on development of MUC1-based cancer vaccine.

Mucin 1 (MUC1) is a transmembrane mucin glycoprotein expressed on the surface of almost all epithelial cells. Aberrantly glycosylated MUC1 is associated with cellular transformation from a normal to malignant phenotype in human cancers. Therefore, MUC1 is the major target for the design and development of cancer vaccines. MUC1-based cancer vaccines are a promising strategy for preventing cancer progression and metastasis. This review summarizes the most significant milestones achieved to date in the development of different MUC-1-based vaccine approaches in clinical trials. Further, it provides perspectives for future research that may promote clinical advances in infection-associated cancers.

The current state of immunization against Gram-negative bacteria in children: a review of the literature.

PURPOSE OF REVIEW: Gram-negative bacteria (GNB) are a major cause of infection worldwide and multidrug resistance in infants and children. The major pathogens include Klebsiella pneumoniae, Escherichia coli, Enterobacter spp., Pseudomonas aeruginosa and Acinetobacter baumannii. With new antibiotic options limited, immunization is likely to play a critical role in prevention. This review discusses their epidemiology, the current state of vaccine research and potential immunization strategies to protect children. A comprehensive review of the literature, conference abstracts along with web searches was performed to identify current and investigational vaccines against the major GNB in children. RECENT FINDINGS: Phase I--III vaccine trials have been undertaken for the major Gram-negative bacteria but not in infants or children. E. coli is a common infection in immune-competent children, including neonatal sepsis. Several vaccines are in late-phase clinical trials, with some already licensed for recurrent urinary tract infections in women. Klebsiella spp. causes community-acquired and hospital-acquired infections, including sepsis in neonates and immunocompromised children although no vaccine trials have extended beyond early phase 2 trials. P. aeruginosa is a common pathogen in patients with cystic fibrosis. Phase 1--3 vaccine and monoclonal antibody trials are in progress, although candidates provide limited coverage against pathogenic strains. Enterobacter spp. and A. baumannii largely cause hospital-acquired infections with experimental vaccines limited to phase 1 research. SUMMARY: The current immunization pipelines for the most prevalent GNB are years away from licensure. Similar to incentives for new antibiotics, global efforts are warranted to expedite the development of effective vaccines.

Single-Cell Immune Competency Signatures Associate with Survival in Phase II GVAX and CRS-207 Randomized Studies in Patients with Metastatic Pancreatic Cancer.

The identification of biomarkers for patient stratification is fundamental to precision medicine efforts in oncology. Here, we identified two baseline, circulating immune cell subsets associated with overall survival in patients with metastatic pancreatic cancer who were enrolled in two phase II randomized studies of GVAX pancreas and CRS-207 immunotherapy. Single-cell mass cytometry was used to simultaneously measure 38 cell surface or intracellular markers in peripheral blood mononuclear cells obtained from a phase IIa patient subcohort (N = 38). CITRUS, an algorithm for identification of stratifying subpopulations in multidimensional cytometry datasets, was used to identify single-cell signatures associated with clinical outcome. Patients with a higher abundance of CD8+CD45RO-CCR7-CD57+ cells and a lower abundance of CD14+CD33+CD85j+ cells had improved overall survival [median overall survival, range (days) 271, 43-1,247] compared with patients with a lower abundance of CD8+CD45RO-CCR7-CD57+ cells and higher abundance of CD14+CD33+CD85j+ cells (77, 24-1,247 days; P = 0.0442). The results from this prospective-retrospective biomarker analysis were validated by flow cytometry in 200 patients with pancreatic cancer enrolled in a phase IIb study (P = 0.0047). The identified immune correlates provide potential prognostic or predictive signatures that could be employed for patient stratification.

Synthetic carbohydrate-based vaccines: challenges and opportunities.

Glycoconjugate vaccines based on bacterial capsular polysaccharides (CPS) have been extremely successful in preventing bacterial infections. The glycan antigens for the preparation of CPS based glycoconjugate vaccines are mainly obtained from bacterial fermentation, the quality and length of glycans are always inconsistent. Such kind of situation make the CMC of glycoconjugate vaccines are difficult to well control. Thanks to the advantage of synthetic methods for carbohydrates syntheses. The well controlled glycan antigens are more easily to obtain, and them are conjugated to carrier protein to from the so-call homogeneous fully synthetic glycoconjugate vaccines. Several fully glycoconjugate vaccines are in different phases of clinical trial for bacteria or cancers. The review will introduce the recent development of fully synthetic glycoconjugate vaccine.

Biomimetic Nanotechnology toward Personalized Vaccines.

While traditional approaches for disease management in the era of modern medicine have saved countless lives and enhanced patient well-being, it is clear that there is significant room to improve upon the current status quo. For infectious diseases, the steady rise of antibiotic resistance has resulted in super pathogens that do not respond to most approved drugs. In the field of cancer treatment, the idea of a cure-all silver bullet has long been abandoned. As a result of the challenges facing current treatment and prevention paradigms in the clinic, there is an increasing push for personalized therapeutics, where plans for medical care are established on a patient-by-patient basis. Along these lines, vaccines, both against bacteria and tumors, are a clinical modality that could benefit significantly from personalization. Effective vaccination strategies could help to address many challenging disease conditions, but current vaccines are limited by factors such as a lack of potency and antigenic breadth. Recently, researchers have turned toward the use of biomimetic nanotechnology as a means of addressing these hurdles. Recent progress in the development of biomimetic nanovaccines for antibacterial and anticancer applications is discussed, with an emphasis on their potential for personalized medicine.

Pathogenesis and clinical management of Helicobacter pylori gastric infection.

Helicobacter pylori (H. pylori) is a gram-negative bacterium that infects approximately 4.4 billion individuals worldwide. However, its prevalence varies among different geographic areas, and is influenced by several factors. The infection can be acquired by means of oral-oral or fecal-oral transmission, and the pathogen possesses various mechanisms that improve its capacity of mobility, adherence and manipulation of the gastric microenvironment, making possible the colonization of an organ with a highly acidic lumen. In addition, H. pylori presents a large variety of virulence factors that improve its pathogenicity, of which we highlight cytotoxin associated antigen A, vacuolating cytotoxin, duodenal ulcer promoting gene A protein, outer inflammatory protein and gamma-glutamyl transpeptidase. The host immune system, mainly by means of a Th1-polarized response, also plays a crucial role in the infection course. Although most H. pylori-positive individuals remain asymptomatic, the infection predisposes the development of various clinical conditions as peptic ulcers, gastric adenocarcinomas and mucosa-associated lymphoid tissue lymphomas. Invasive and non-invasive diagnostic methods, each of them with their related advantages and limitations, have been applied in H. pylori detection. Moreover, bacterial resistance to antimicrobial therapy is a major challenge in the treatment of this infection, and new therapy alternatives are being tested to improve H. pylori eradication. Last but not least, the development of effective vaccines against H. pylori infection have been the aim of several research studies.

Therapeutic Vaccines Against Human Papilloma Viruses: Achievements and Prospects.

Human papillomaviruses of high carcinogenic risk (HR HPVs) are major etiological agents of malignant diseases of the cervix, vulva, penis, anal canal, larynx, head, and neck. Prophylactic vaccination against HPV, which mainly covers girls and women under 25, does not prevent vertical and horizontal HPV transmission in infants and children and does not have a therapeutic effect. As a result, a significant proportion of the population is not protected from the HPV infection and development of HPV-associated neoplastic transformation and cancer, which indicates the need for development and introduction of therapeutic HPV vaccines. Unlike prophylactic vaccines aimed at the formation of virus-neutralizing antibodies, therapeutic vaccines elicit cellular immune response leading to the elimination of infected and malignant cells expressing viral proteins. The ideal targets for vaccine immunotherapy are highly conserved HR HPV oncoproteins E6 and E7 expressed in precancerous and tumor tissues. Here, we describe expression of these proteins during different stages of HPV infection, their antigenic and immunogenic properties, and T-cell epitopes, the response to which correlates with natural regression of HPV-induced neoplastic changes. The review describes patterns of E6 and E7 oncoproteins presentation to the immune system as components of candidate vaccines along with the results of the most promising preclinical trials and animal models used in these trials. Special attention is paid to vaccine candidates which have shown efficacy in clinical trials in patients with HPV-associated neoplastic changes.

Effect of progesterone on the vaccination and immune response against Chlamydia abortus in sheep.

Chlamydia abortus produces ovine enzootic abortion (OEA). Symptoms are not observed until the organism colonises the placenta, eventually causing abortion. Infected animals become carriers and will shed the organism in the following oestruses. This process suggests that sex hormones might play an important role in the physiopathology of OEA, affecting the success of chlamydial clearance and also jeopardising the effectiveness of vaccination. However, the mechanisms through which sex hormones are involved in chlamydial pathogenicity remain unclear. The aim of this study, therefore, was to determine the effect of progesterone on the immune response against C. abortus and on the protection conferred by an experimental inactivated vaccine in sheep. Eighteen sheep were ovariectomised and divided into four groups: vaccinated and progesterone-treated (V-PG), vaccinated and non-treated (V-NT), non-vaccinated and non-treated (NV-NT) and non-vaccinated and progesterone-treated sheep (NV-PG). Animals from both PG groups were treated with commercial medroxyprogesterone acetate impregnated intravaginal sponges before and during the vaccination (V-PG) or just before challenge (NV-PG). The animals from both V groups were subcutaneously immunised with an experimental inactivated vaccine, which was seen to confer high protection in previous studies. All sheep were challenged intratracheally with C. abortus strain AB7 and were sacrificed on day 8 post-infection. Morbidity was measured as the variation in rectal temperature and samples of sera were collected for antibody and cytokine (IFN-γ and IL-10) analysis by commercial ELISA. In addition, lung and lymph node samples were collected for chlamydial detection by qPCR and for histopathological and immunohistochemical analyses. Sheep from the V-PG group showed less severe or no lesions and lower morbidity than the other groups. They also had the highest abundance of regulatory T-cells. The sheep from V-NT also manifested high antibody levels against C. abortus and less severe lesions than those observed in non-vaccinated sheep, which showed high morbidity, low antibody levels and severe lesions, especially in NV-NT. These results confirm the effectiveness of the experimental vaccine employed and suggest that progesterone could enhance the effect.

A peptide-based vaccine for Mycobacterium avium subspecies paratuberculosis.

Recent efforts to develop a live attenuated vaccine against Mycobacterium avium subsp. paratuberculosis (Map), the causative agent of Johne's disease (JD), revealed relA is important in Map virulence. Deletion of the relA gene impairs the ability of Map to establish a persistent infection. Analysis of the basis for this observation revealed infection with a relA deletion mutant (ΔrelA) elicits development of cytotoxic CD8 T cells (CTL) with the ability to kill intracellular bacteria. Further analysis of the recall response elicited by ΔrelA vaccination showed a 35 kDa membrane peptide (MMP) is one of the targets of the immune response, suggesting it might be possible to develop a peptide-based vaccine based on MMP. To explore this possibility, ex vivo vaccination studies were conducted with MMP alone and incorporated into a nanoparticle (NP) vector comprised of poly (D, L-lactide-co-glycolide) and monophosphoryl lipid A (PLGA/MPLA). As reported, ex vivo vaccination studies showed CD8 CTL were elicited with classic and monocyte derived dendritic cells (cDC and MoDC) pulsed with MMP alone and incorporated into a PGLA/MPLA vector. Incorporation of MMP into a NP vector enhanced the ability of CD8 CTL to kill intracellular bacteria. The findings indicate incorporation of MMP into a PGLA/MPLA nanoparticle vector is one of the possible ways to develop a MMP based vaccine for Johne's disease.

Pathogenicity of Helicobacter pylori in cancer development and impacts of vaccination.

Helicobacter pylori affect around 50% of the population worldwide. More importantly, the gastric infection induced by this bacterium is deemed to be associated with the progression of distal gastric carcinoma and gastric mucosal lymphoma in the human. H. pylori infection and its prevalent genotype significantly differ across various geographical regions. Based on numerous virulence factors, H. pylori can target different cellular proteins to modulate the variety of inflammatory responses and initiate numerous "hits" on the gastric mucosa. Such reactions lead to serious complications, including gastritis and peptic ulceration, gastric cancer and gastric mucosa-associated lymphoid structure lymphoma. Therefore, H. pylori have been considered as the type I carcinogen by the Global Firm for Research on Cancer. During the two past decades, different reports revealed that H. pylori possess oncogenic potentials in the gastric mucosa through a complicated interplay between the bacterial factors, various facets, and the environmental factors. Accordingly, numerous signaling pathways could be triggered in the development of gastrointestinal diseases (e.g., gastric cancer). Therefore, the main strategy for the treatment of gastric cancer is controlling the disease far before its onset using preventive/curative vaccination. Increasing the efficiency of vaccines may be achieved by new trials of vaccine modalities, which is used to optimize the cellular immunity. Taken all, H. pylori infection may impose severe complications, for resolving of which extensive researches are essential in terms of immune responses to H. pylori. We envision that H. pylori-mediated diseases can be controlled by advanced vaccines and immunotherapies.

Protection against human papillomavirus type 16-induced tumors in C57BL/6 mice by mucosal vaccination with Lactococcus lactis NZ9000 expressing E6 oncoprotein.

Recombinant strains of Lactococcus lactis NZ9000 that express native and codon-optimized E6 protein (fused to the SPusp45 secretion signal) were successfully constructed by using the nisin-controlled gene expression (NICE) system. Expression of the recombinant strains was evaluated by Western blot analysis. Female mice of strain C57BL/6 were immunized orally with recombinant lactococci expressing inducible E6 oncoprotein and the antigen-specific antibody production (IgA and IgG) and cytokines were measured by ELISA and ELISPOT assay, respectively. Our outcomes indicate that the HPV-16 E6 specific IL-2- and IFN-γ-secreting lymphocytes in the antigen-stimulated intestinal mucosal lymphocytes, splenocytes and vaginal lymphocytes were significantly higher than the control groups. We showed that L. lactis having codon-optimized E6 oncogene had better inhibitory effect on tumor growth, better treatment effects on progression of tumor size, and better survival rate in comparison with L. lactis having native E6 oncogene, (P < 0.0001). In conclusion, the rE6 protein displayed by L. lactis can induce humoral and cellular immunity. Taken together, these preclinical results represent a promising step towards the development of recombinant L. lactis as a live oral vector vaccine to treat the HPV-16 associated with cervical cancer.