Cost-Effectiveness of a Sublingual Bacterial Vaccine for the Prophylaxis of Recurrent Urinary Tract Infections.

INTRODUCTION: Recurrent urinary tract infections (rUTIs) affect 5-10% of women, resulting in an enormous healthcare and society burden. Uromune® is a polybacterial sublingual vaccine with an excellent clinical benefit in rUTI prophylaxis. This study assesses the impact of sublingual vaccination on healthcare resource use and expenditures associated with this pathology. METHODS: A quasi-experimental, pretest-posttest, single center study including women with rUTI and vaccinated with Uromune® in real-life clinical practice was performed. Variables were the need of healthcare resources, collected prospectively during two follow-up years, and the rUTI-associated expenditure, calculated using the micro-costing methodology; these were compared before and after vaccination. RESULTS: A total of 166 women {mean (standard deviation [SD]) urinary tract infection episodes/year 6.19 (2.15)} were included. After vaccination, annual consultations with a primary care physician (PCP) (43.9%), emergency room visits (71.8%), urinary analysis (90.0%), and ultrasound exams (35.6%) decreased compared to pre-vaccination (all p < 0.001). Per patient consumption in antibiotics, PCP consultations, emergency room visits, and complementary exams significantly decreased (all p < 0.02), resulting in a reduction in healthcare expenditure per patient/year from mean (SD) 1,001.1 (655.0) to 497.1 (444.4) EUR. CONCLUSION: Sublingual bacterial vaccination with Uromune® decreased healthcare resource use and associated expenditure in women with rUTI, representing an optimal strategy to reduce rUTI-associated healthcare and economic burden.

Navigating changes in Clostridioides difficile prevention and treatment.

Clostridioides difficile (C. difficile, previously known as Clostridium difficile) infections are a major health care concern. The Centers for Disease Control and Prevention (CDC) estimates that C. difficile causes almost half a million illnesses in the United States yearly, and approximately 1 in 5 patients with a C. difficile infection (CDI) will experience 1 or more recurrent infections. The incidence of infection has risen dramatically in recent years, and infection severity has increased due to the emergence of hypervirulent strains. There have been noteworthy advances in the development of CDI prevention and treatment, including a growth in the understanding of the role a patient's gut microbiome plays. The 2017 Infectious Diseases Society of America (IDSA) guidelines made a significant change in treatment recommendations for first time CDI episodes by recommending the use of oral vancomycin or fidaxomicin in place of metronidazole as a first-line treatment. The guidelines also included detailed recommendations on the use of fecal microbiota transplant (FMT) in those patients who experience 3 or more recurrent CDI episodes. A number of novel therapies for the treatment of CDI are in various stages of development. Treatments currently in phase 3 trials include the antibiotic ridinilazole, the microbiome products SER-109 and RBX2660, and a vaccine. All of these agents have shown promise in phase 1 and 2 trials. Additionally, several other antibiotic and microbiome candidates are currently in phase 1 or phase 2 trials. A qualitative review and evaluation of the literature on the cost-effectiveness of treatments for CDI in the U.S. setting was conducted, and the summary provided herein. Due to the higher cost of newer agents, cost-effectiveness evaluations will continue to be critical in clinical decision making for CDI. This paper reviews the updated CDI guidelines for prevention and treatment, the role of the microbiome in new and recurrent infections, pipeline medications, and comparative effectiveness research (CER) data on these treatments. DISCLOSURES: Durham and Le have nothing to disclose. Cassano reports consulting fees from Baxter Healthcare. Peer reviewers Drs. Ami Gopalan and Mark Rubin and Ms. Kathleen Jarvis have nothing to disclose. Planners Dr. Christine L. Cooper and Ms. Susan Yarbrough have nothing to disclose.

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.

Toward economic evaluation of the value of vaccines and other health technologies in addressing AMR.

We discuss the need to make economic evaluations of vaccines antimicrobial resistance (AMR)-sensitive and ways to do so. Such AMR-sensitive evaluations can play a role in value-for-money comparisons of different vaccines within a national immunization program, or in comparisons of vaccine-centric and non-vaccine-centric technologies within an anti-AMR program. In general terms, incremental cost-effectiveness ratios and rates of return and their associated decision rules are unaltered by consideration of AMR-related value. The decision metrics need to have their various health, cost, and socioeconomic terms disaggregated into resistance-related subcategories, which in turn have to be measured carefully before they are reaggregated. The fundamental scientific challenges lie primarily in quantifying the causal impact of health technologies on resistance-related health outcomes, and secondarily in ascertaining the economic value of those outcomes. We emphasize the importance of evaluating vaccines in the context of other potentially complementary and substitutable nonvaccine technologies. Complementarity implies that optimal spending on each set of interventions is positive, and substitutability implies that the ratio of spending will depend on relative value for money. We exemplify this general point through a qualitative discussion of the complementarities and (especially the) substitutability between pneumococcal conjugate vaccines and antimicrobial stewardship and between research and development (R&D) of a gonorrhea vaccine versus R&D of a gonorrhea antibiotic. We propose a roadmap for future work, which includes quantifying the causal effects of vaccination and other health technologies on short-term and long-term resistance-related outcomes, measuring the health-sector costs and broader socioeconomic consequences of resistance-related mortality and morbidity, and evaluating vaccines in the context of nonvaccine complements and substitutes.

Cost-Benefit Analysis of a Chlamydia trachomatis Vaccine Program in Adolescent Girls in the United States.

BACKGROUND: With >1.4 million cases in the United States reported to the Centers for Disease Control and Prevention in 2012, Chlamydia trachomatis infection is a major public health concern. We examined the impact of a C trachomatis vaccination program using a decision-analysis model to estimate the effects of vaccination on C trachomatis-associated costs and morbidity. METHODS: We developed a Markov model considering a cohort of 2158117 US females aged 9 to 26 years. Morbidity, death, and healthcare-associated costs associated with chlamydial infection of mothers and fetuses/neonates were calculated over a 17-year time frame. We developed 2 major comparison arms, namely, a C trachomatis vaccination program and no C trachomatis vaccination program. Base-case efficacy and coverage were set to those of human papillomavirus in the United States with all variables, including efficacy and coverage, ranged in sensitivity analyses. RESULTS: On the basis of a base-case analysis, a vaccination program would cost an estimated $710 million for a cohort of 2158117 women over a 17-year period, an increase of $41 million over having no vaccination program. A vaccination program would prevent 34000 cases of C trachomatis infection and 5976 cases of pelvic inflammatory disease. CONCLUSIONS: A C trachomatis vaccination program results in increased cost to the healthcare system but averts significant morbidity and death.

Potential Impact of Food Safety Vaccines on Health Care Costs.

Foodborne pathogens continue to cause several outbreaks every year in many parts of the world. Among the bacterial pathogens involved, Shiga toxin-producing Escherichia coli, Campylobacter jejuni, and nontyphoidal Salmonella species cause a significant number of human infections worldwide, resulting in a huge annual economic burden that amounts to millions of dollars in health care costs. Human infections are primarily caused by the consumption of contaminated food. Vaccination of food-producing animals is an attractive, cost-effective strategy to lower the levels of these pathogens that will ultimately result in a safer food supply and fewer human infections. However, producers are often reluctant to routinely vaccinate animals against these pathogens since they do not cause any detectable clinical symptoms. This review highlights recent approaches used to develop effective food safety vaccines and the potential impact these vaccines might have on health care costs.

Historical review of clinical vaccine studies at Oswaldo Cruz Institute and Oswaldo Cruz Foundation--technological development issues.

This paper presents, from the perspective of technological development and production, the results of an investigation examining 61 clinical studies with vaccines conducted in Brazil between 1938-2013, with the participation of the Oswaldo Cruz Institute (IOC) and the Oswaldo Cruz Foundation (Fiocruz). These studies have been identified and reviewed according to criteria, such as the kind of vaccine (viral, bacterial, parasitic), their rationale, design and methodological strategies. The results indicate that IOC and Fiocruz have accumulated along this time significant knowledge and experience for the performance of studies in all clinical phases and are prepared for the development of new vaccines products and processes. We recommend national policy strategies to overcome existing regulatory and financing constraints.

Economic analysis of vaccination to control bovine brucellosis in the States of Sao Paulo and Mato Grosso, Brazil.

Brucellosis is a zoonotic disease that causes important economic losses in Brazil, and the country has therefore established a national program for its control and eradication. Using data generated in the last national brucellosis survey, we conducted an economic analysis in two Brazilian States with different brucellosis status, Mato Grosso (with high prevalence) and Sao Paulo (with low prevalence). The economic analysis was based on the calculation of the additional benefits and costs of controlling bovine brucellosis through the vaccination of heifers aged between 3 and 8 months with S19 vaccine, considering maximal and minimal impacts of the disease. The analysis showed that vaccinating 90% of the replacement heifers aged 3-8 months of age offers the best economic performance in a vaccination program against bovine brucellosis if compared to vaccination rates of 70% and 80%. Moreover, regions with higher prevalences of bovine brucellosis would experience significant economic advantages when implementing a vaccination strategy to control the disease. This economic analysis will allow decision makers to plan more economically effective vaccination programs.

Relative cost-effectiveness of a norovirus vaccine in the deployed military setting compared to a vaccine against Campylobacter sp., ETEC, and Shigella sp.

Norovirus (NoV) has been identified as a significant cause of acute gastrointestinal illness among deployed military troops. We conducted a cost-effectiveness analysis for the use of a NoV vaccine in the military using a previously developed model that evaluated vaccines for ETEC, Campylobacter, and Shigella for prevention of non-outbreak associated travelers' diarrhea. Under conservative assumptions, acquisition of a NoV vaccine by the Department of Defense is estimated to result in a cost-effectiveness ratio per duty day lost to illness (CERDDL) of $1344 compared to a CERDDL of $776, $800, and $1275 for ETEC, Campylobacter sp., and Shigella sp., respectively compared to current management strategies. The absolute value of avoiding a duty day lost is likely to vary under different scenarios, and further study is needed to evaluate how improved diagnostics and prevention of outbreaks may impact the relative value of this vaccine. Overall, this study demonstrates the utility of a previously established evidence-based decision tool for prioritization of vaccine acquisition in an important target population.

Modelling of control options for an outbreak of Mycoplasma gallisepticum in egg production: a decision support tool.

Mycoplasma gallisepticum (MG) is a bacterium that causes respiratory disease in chickens, leading to reduced egg production. A dynamic simulation model was developed that can be used to assess the costs and benefits of control using antimicrobials or vaccination in caged or free range systems. The intended users are veterinarians and egg producers. A user interface is provided for input of flock specific parameters. The economic consequence of an MG outbreak is expressed as a reduction in expected egg output. The model predicts that either vaccination or microbial treatment can approximately halve potential losses from MG in some circumstances. Sensitivity analysis is used to test assumptions about infection rate and timing of an outbreak. Feedback from veterinarians points to the value of the model as a discussion tool with producers.

Systematic review of economic evaluation analyses of available vaccines in Spain from 1990 to 2012.

OBJECTIVE: The objective of this survey was to describe the evolution of economic evaluation studies on vaccines available in Spain. METHODS: We conducted a systematic review of the economic evaluations published by Spanish researchers in major bibliographic databases available online from 1990 to 2012. For all references identified, we limited them to full economic evaluation carried out in Spanish vaccine programs. The following variables were analyzed: type of study, year of publication, vaccine evaluated, the herd immunity and the main methodological aspects proposed by international guidelines. The type of vaccines studied were Hepatitis A and B, Rotavirus, Influenza, Varicella, Tetanus, Measles, Human papillomavirus, Streptococcus pneumoniae infection and Neisseria meningitides serogroup C infection. RESULTS: A total of 34 references was included in the study. The number of economic evaluations has been increasing over the years by 86%. For many of the vaccines there were no economic evaluations, while others such as the vaccine against S. pneumoniae infection took up most of the studies. The non-vaccinated comparison was the most used strategy. The cost-effectiveness model was selected in 60% of cases. The most common health outcome was "cost per case prevented" and in 82% of the studies did not consider herd immunity. The results showed a cost-effectiveness ratio which was below breakeven. CONCLUSIONS: It is clear that the existence of a huge gap in this kind of work compared to other countries. Although the quality of the work discussed here was significant, we found many areas which could be improved. The reviewed literature exposed the great benefit of vaccination for society by analysing the health outcomes achieved for decades since its implementation. However, the evidence on the efficiency and effectiveness vaccination is not very high, and there are few studies about economic evaluation.

Acute bacterial meningitis in infants and children: epidemiology and management.

Acute bacterial meningitis (ABM) continues to be associated with high mortality and morbidity, despite advances in antimicrobial therapy. The causative organism varies with age, immune function, immunization status, and geographic region, and empiric therapy for meningitis is based on these factors. Haemophilus influenzae type b (Hib), Streptococcus pneumoniae, and Neisseria meningitidis cause the majority of cases of ABM. Disease epidemiology is changing rapidly due to immunization practices and changing bacterial resistance patterns. Hib was the leading cause of meningitis in children prior to the introduction of an effective vaccination. In those countries where Hib vaccine is a part of the routine infant immunization schedule, Hib has now been virtually eradicated as a cause of childhood meningitis. Vaccines have also been introduced for pneumococcal and meningococcal diseases, which have significantly changed the disease profile. Where routine pneumococcal immunization has been introduced there has been a reported increase in invasive pneumococcal disease due to non-vaccine serotypes. In those parts of the world that have introduced conjugate meningococcal vaccines, there has been a significant change in the epidemiology of meningococcal meningitis. As a part of the United Nations Millennium Development Goal 4, the WHO has introduced a new vaccine policy to improve vaccine availability in resource poor countries. In addition, antibiotic resistance is an increasing problem, especially with pneumococcal infection. Effective treatment focuses on early recognition and use of effective antibiotics. This review will attempt to focus on the changing epidemiology of ABM in pediatric patients due to vaccination, the changing patterns of infecting bacterial serotypes due to vaccination, and on antibiotic resistance and its impact on current management strategies.

Vaccine production, distribution, access, and uptake.

For human vaccines to be available on a global scale, complex production methods, meticulous quality control, and reliable distribution channels are needed to ensure that the products are potent and effective at the point of use. The technologies used to manufacture different types of vaccines can strongly affect vaccine cost, ease of industrial scale-up, stability, and, ultimately, worldwide availability. The complexity of manufacturing is compounded by the need for different formulations in different countries and age-groups. Reliable vaccine production in appropriate quantities and at affordable prices is the cornerstone of developing global vaccination policies. However, to ensure optimum access and uptake, strong partnerships are needed between private manufacturers, regulatory authorities, and national and international public health services. For vaccines whose supply is insufficient to meet demand, prioritisation of target groups can increase the effect of these vaccines. In this report, we draw from our experience of vaccine development and focus on influenza vaccines as an example to consider production, distribution, access, and other factors that affect vaccine uptake and population-level effectiveness.

Vaccinating against Helicobacter pylori infection.

Helicobacter pylori infection of the gastric mucosa remains a cause of significant morbidity and mortality almost 30 years after its discovery. H. pylori infection can lead to several gastric maladies, including gastric cancer, and although antimicrobial therapies for the infection exist, the cost of treatment for gastric cancer and the prognosis of individuals who present with this disease make vaccine development a cost effective alternative to bacterial eradication. Experimental mucosal and systemic H. pylori vaccines in mice significantly reduce bacterial load and sometimes provide sterilizing immunity. Clinical trials of oral vaccines consisting of H. pylori proteins with bacterial exotoxin adjuvants or live attenuated bacterial vectors expressing H. pylori proteins induce adaptive immune mechanisms but fail to consistently reduce bacterial load. Clinical trials and murine studies demonstrate that where H. pylori is killed, either spontaneously or following vaccination, the host demonstrated cellular immunity. Improved efficacy of vaccines may be achieved in new trials of vaccine formulations that include multiple antigens and use methods to optimize cellular immunity. Unfortunately, the industrial sponsors that served as the primary engine for much of the previous animal and human research have withdrawn their support. A renewed or expanded commitment from the biotechnology or pharmaceutical industry that could exploit recent advances in our understanding of the host immune response to H. pylori is necessary for the advancement of an H. pylori vaccine.

Diagnostic sampling strategies for virulent ovine footrot: simulating detection of Dichelobacter nodosus serogroups for bivalent vaccine formulation.

Dichelobacter nodosus is a slow-growing anaerobic bacterium that is the causative agent of virulent ovine footrot. Vaccination targeted at up to two specific serogroups can eliminate those serogroups from infected flocks, but requires identification of serogroups present in infected flocks. Serogroups can be identified using slide agglutination or polymerase chain reaction (PCR) methods. The objectives of this project were to use stochastic simulation modeling to estimate the efficacy of sampling strategies encompassing 5-40 sheep per flock and 2-4 colonies per sheep, and to compare efficacies based on slide agglutination or multiplex PCR test results. Foot swabs collected from sheep in 12 flocks were used as the basis for a sampling strategy simulation model. None of the evaluated sampling strategies identified the two most common serogroups in the flock, or all serogroups present in the flock, in 95% of iterations. However, a simulated sample of 22 sheep/flock and 2 colonies/sheep resulted in a simulated vaccine that protected 95% of the sheep that could be protected by a single bivalent vaccine, while a sample of 24 sheep/flock and 2 colonies/sheep resulted in a series of simulated bivalent vaccines that protected 95% of diseased infected sheep. The difference in outcome was due to the distribution and frequency of serogroups within certain flocks where some serogroups were uncommon and others dominant. A sampling strategy (>40 sheep/flock, 4 colonies/sheep) that will identify the two most common serogroups in a flock 95% of the time may not be cost effective. Evaluating efficacy based on the expected effect on the flock may be more useful than one which seeks to determine the most common serogroups. These findings are broadly applicable to diseases where more than one strain or type of pathogen may be present and must be represented in a vaccine.