In the last century, life expectancy has increased considerably, thanks to the introduction of antibiotics, hygiene and vaccines that have contributed to the cure and prevention of many infectious ...diseases. The era of antimicrobial therapy started in the nineteenth century with the identification of chemical compounds with antimicrobial properties. However, immediately after the introduction of these novel drugs, microorganisms started to become resistant through different strategies. Although resistance mechanisms were already present before antibiotic introduction, their large-scale use and mis-use have increased the number of resistant microorganisms. Rapid spreading of mobile elements by horizontal gene transfer such as plasmids and integrative conjugative elements (ICE) carrying multiple resistance genes has dramatically increased the worldwide prevalence of relevant multi drug-resistant human pathogens such as
, and
. Today, antimicrobial resistance (AMR) remains one of the major global concerns to be addressed and only global efforts could help in finding a solution. In terms of magnitude the economic impact of AMR is estimated to be comparable to that of climate global change in 2030. Although antibiotics continue to be essential to treat such infections, non-antibiotic therapies will play an important role in limiting the increase of antibiotic resistant microorganisms. Among non-antibiotic strategies, vaccines and therapeutic monoclonal antibodies (mAbs) play a strategic role. In this review, we will summarize the evolution and the mechanisms of antibiotic resistance, and the impact of AMR on life expectancy and economics.
The discovery of vaccine antigens through whole genome sequencing (WGS) contrasts with the classical hypothesis-driven laboratory-based analysis of microbes to identify components to elicit ...protective immunity. This radical change in scientific direction and action in vaccine research is captured in the term
. The complete genome sequence of an isolate of
serogroup B (MenB) was systematically analyzed to identify proteins predicted to be secreted or exported to the outer membrane. This identified hundreds of genes coding for potential surface-exposed antigens. These were amplified, cloned in expression vectors and used to immunize mice. Antisera against 350 recombinant antigens were obtained and analyzed in a panel of immunological assays from which 28 were selected as potentially protective based on the -antibody dependent, complement mediated- serum bactericidal activity assay. Testing of these candidate vaccine antigens, using a large globally representative strain collection of Neisseria species isolated from cases of disease and carriage, indicated that no single component would be sufficient to induce broad coverage and that a "universal" vaccine should contain multiple antigens. The final choice of antigens to be included was based on cross-protective ability, assayed by serum bactericidal activity and maximum coverage of the extensive antigenic variability of MenB strains. The resulting multivalent vaccine formulation selected consisted of three recombinant antigens (Neisserial Heparin Binding Antigen or NHBA, Factor H binding protein or fHbp and Neisseria Adhesin A or NadA). To improve immunogenicity and potential strain coverage, an outer membrane vesicle component obtained from the epidemic New Zealand strain (OMVNz) was added to the formulation to create a four component vaccine, called 4CMenB. A series of phase 2 and 3 clinical trials were conducted to evaluate safety and tolerability and to estimate the vaccine effectiveness of human immune responses at different ages and how these were affected by various factors including concomitant vaccine use and lot-to-lot consistency. 4CMenB was approved in Europe in 2013 and introduced in the National Immunization Program in the UK starting from September 2015 when the vaccine was offered to all newborns using a 2, 4, and 12 months schedule., The effectiveness against invasive MenB disease measured at 11 months after the study start and 5 months after the second vaccination was 83% and there have been no safety concerns.
Introduction: Neisseria meningitidis serogroup B (MenB) is the most common cause of bacterial meningitis in many industrialized countries and occurs at any age. The highest incidence is in infants ...aged <1 year, followed by children and adolescents. Four-component MenB vaccine (4CMenB, Bexsero) is the only MenB vaccine authorized for use in all age-groups. Experience with 4CMenB is growing as it is implemented in different countries/age-groups encompassing university students, children, adolescents, and infant mass vaccination programs.
Areas covered: An update of recently available data describing the mechanism of immunogenicity of 4CMenB and real-world evidence of vaccine effectiveness and disease impact. We discuss the appropriate age for vaccination to maximize population impacts.
Expert commentary: Invasive meningococcal disease is uncommon and sufficiently powered efficacy studies were not feasible during 4CMenB development. Additionally, several thousand genetically diverse invasive MenB strains circulate globally, varying widely in surface protein expression. This posed significant challenges in predicting clinical protection with MenB vaccines. Five years of 4CMenB use post-licensure confirm the clinical benefit of vaccination as predicted during development. Preliminary evidence suggests an extended impact on other meningococcal serogroups and Neisseria gonorrhoeae.
Vaccines, new opportunities for a new society Rappuoli, Rino; Pizza, Mariagrazia; Del Giudice, Giuseppe ...
Proceedings of the National Academy of Sciences,
08/2014, Letnik:
111, Številka:
34
Journal Article
Recenzirano
Odprti dostop
Vaccination is the most effective medical intervention ever introduced and, together with clean water and sanitation, it has eliminated a large part of the infectious diseases that once killed ...millions of people. A recent study concluded that since 1924 in the United States alone, vaccines have prevented 40 million cases of diphtheria, 35 million cases of measles, and a total of 103 million cases of childhood diseases. A report from the World Health Organization states that today vaccines prevent 2.5 million deaths per year: Every minute five lives are saved by vaccines worldwide. Overall, vaccines have done and continue to do an excellent job in eliminating or reducing the impact of childhood diseases. Furthermore, thanks to new technologies, vaccines now have the potential to make an enormous contribution to the health of modern society by preventing and treating not only communicable diseases in all ages, but also noncommunicable diseases such as cancer and neurodegenerative disorders. The achievement of these results requires the development of novel technologies and health economic models able to capture not only the mere cost–benefit of vaccination, but also the value of health per se.
Neisseria meningitidis is the main cause of meningitis and sepsis, potentially life-threatening conditions. Thanks to advancements in vaccine development, vaccines are now available for five out of ...six meningococcal disease-causing serogroups (A, B, C, W, and Y). Vaccination programs with monovalent meningococcal serogroup C (MenC) conjugate vaccines in Europe have successfully decreased MenC disease and carriage. The use of a monovalent MenA conjugate vaccine in the African meningitis belt has led to a near elimination of MenA disease. Due to the emergence of non-vaccine serogroups, recommendations have gradually shifted, in many countries, from monovalent conjugate vaccines to quadrivalent MenACWY conjugate vaccines to provide broader protection. Recent real-world effectiveness of broad-coverage, protein-based MenB vaccines has been reassuring. Vaccines are also used to control meningococcal outbreaks. Despite major improvements, meningococcal disease remains a global public health concern. Further research into changing epidemiology is needed. Ongoing efforts are being made to develop next-generation, pentavalent vaccines including a MenACWYX conjugate vaccine and a MenACWY conjugate vaccine combined with MenB, which are expected to contribute to the global control of meningitis.
Vaccinology in the post-COVID-19 era Rappuoli, Rino; De Gregorio, Ennio; Del Giudice, Giuseppe ...
Proceedings of the National Academy of Sciences - PNAS,
01/2021, Letnik:
118, Številka:
3
Journal Article
Recenzirano
Odprti dostop
The COVID-19 pandemic is a shocking reminder of how our world would look in the absence of vaccination. Fortunately, new technologies, the pace of understanding new and existing pathogens, and the ...increased knowledge of the immune system allow us today to develop vaccines at an unprecedented speed. Some of the vaccine technologies that are fast-tracked by the urgency of COVID-19 may also be the answer for other health priorities, such as antimicrobial resistance, chronic infections, and cancer, that the post-COVID-19 world will urgently need to face. This perspective analyzes the way COVID-19 is transforming vaccinology and the opportunities for vaccines to have an increasingly important role in health and well-being.
Introduction: The successful development of two broadly protective vaccines targeting Neisseria meningitidis serogroup B (MenB); 4CMenB and rLP2086, is the most significant recent advance in ...meningococcal disease prevention.
Areas covered: Here we review the principles underlying the development of each vaccine and the novel methods used to estimate vaccine coverage. We update clinical and post-licensure experience with 4CMenB and rLP2086.
Expert commentary: The immunogenicity and acceptable safety profile of 4CMenB and rLP2086 has been demonstrated in clinical trials. Continuing uncertainties exist around the appropriate age groups to be immunized, the degree and duration of efficacy, and the impact on nasopharyngeal carriage which has implications for strategies to interrupt transmission and maximize herd protection effects. Universal vaccination programs such as those undertaken in Quebec and the United Kingdom are providing important information on these issues. The potential for MenB vaccines to prevent infection by other serogroups appears promising, and the impact of MenB vaccines on other pathogenic neisserial species with similar surface proteins warrants further investigation.
Diarrheal diseases are one of the major causes of mortality among children under five years old and intestinal pathogenic
(InPEC) plays a role as one of the large causative groups of these infections ...worldwide. InPECs contribute significantly to the burden of intestinal diseases, which are a critical issue in low- and middle-income countries (Asia, Africa and Latin America). Intestinal pathotypes such as enteropathogenic
(EPEC) and enterotoxigenic
(ETEC) are mainly endemic in developing countries, while ETEC strains are the major cause of diarrhea in travelers to these countries. On the other hand, enterohemorrhagic
(EHEC) are the cause of large outbreaks around the world, mainly affecting developed countries and responsible for not only diarrheal disease but also severe clinical complications like hemorrhagic colitis and hemolytic uremic syndrome (HUS). Overall, the emergence of antibiotic resistant strains, the annual cost increase in the health care system, the high incidence of traveler diarrhea and the increased number of HUS episodes have raised the need for effective preventive treatments. Although the use of antibiotics is still important in treating such infections, non-antibiotic strategies are either a crucial option to limit the increase in antibiotic resistant strains or absolutely necessary for diseases such as those caused by EHEC infections, for which antibiotic therapies are not recommended. Among non-antibiotic therapies, vaccine development is a strategy of choice but, to date, there is no effective licensed vaccine against InPEC infections. For several years, there has been a sustained effort to identify efficacious vaccine candidates able to reduce the burden of diarrheal disease. The aim of this review is to summarize recent milestones and insights in vaccine development against InPECs.
Aluminum hydroxide (alum) and the oil-in-water emulsion MF59 are widely used, safe and effective adjuvants, yet their mechanism of action is poorly understood. We assessed the effects of alum and ...MF59 on human immune cells and found that both induce secretion of chemokines, such as CCL2 (MCP-1), CCL3 (MIP-1alpha), CCL4 (MIP-1beta), and CXCL8 (IL-8), all involved in cell recruitment from blood into peripheral tissue. Alum appears to act mainly on macrophages and monocytes, whereas MF59 additionally targets granulocytes. Accordingly, monocytes and granulocytes migrate toward MF59-conditioned culture supernatants. In monocytes, both adjuvants lead to increased endocytosis, enhanced surface expression of MHC class II and CD86, and down-regulation of the monocyte marker CD14, which are all phenotypic changes consistent with a differentiation toward dendritic cells (DCs). When monocyte differentiation into DCs is induced by addition of cytokines, these adjuvants enhanced the acquisition of a mature DC phenotype and lead to an earlier and higher expression of MHC class II and CD86. In addition, MF59 induces further up-regulation of the maturation marker CD83 and the lymph node-homing receptor CCR7 on differentiating monocytes. Alum induces a similar but not identical pattern that clearly differs from the response to LPS. This model suggests a common adjuvant mechanism that is distinct from that mediated by danger signals. We conclude that during vaccination, adjuvants such as MF59 may increase recruitment of immune cells into the injection site, accelerate and enhance monocyte differentiation into DCs, augment Ag uptake, and facilitate migration of DCs into tissue-draining lymph nodes to prime adaptive immune responses.
Generalized Modules for Membrane Antigens (GMMA) are outer membrane vesicles derived from Gram-negative bacteria engineered to provide an over-vesiculating phenotype, which represent an attractive ...platform for the design of affordable vaccines. GMMA can be further genetically manipulated to modulate the risk of systemic reactogenicity and to act as delivery system for heterologous polysaccharide or protein antigens. GMMA are able to induce strong immunogenicity and protection in animal challenge models, and to be well-tolerated and immunogenic in clinical studies. The high immunogenicity could be ascribed to their particulate size, to their ability to present to the immune system multiple antigens in a natural conformation which mimics the bacterial environment, as well as to their intrinsic self-adjuvanticity. However, GMMA mechanism of action and the role in adjuvanticity are still unclear and need further investigation. In this review, we discuss progresses in the development of the GMMA vaccine platform, highlighting successful applications and identifying knowledge gaps and potential challenges.
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