Includes abstract.Includes bibliographical references.Immunization against vaccine-preventable infections is essential to reducing childhood morbidity and mortality. The immaturity and tolerogenicity of the immune system of infants renders them susceptible to infectious diseases and makes induction of protective immunity via vaccines a challenge. HIV-exposed infants are HIV uninfected and born to HIV-infected mothers and have increased morbidity and mortality of unknown aetiology. We hypothesise that T cells of HIV-exposed uninfected (HEU) infants have impaired proliferative ability and cytokine production in response to vaccine antigens than HIV unexposed (HU) infants

In this thesis we investigated maintenance requirements of Salmonella during chronic infections, and determined the relevant antigen properties that might facilitate the development of Salmonella vaccines. Overall, we wanted to achieve two goals: a)To identify suitable targets to eradicate persisting Salmonella. b)Identify antigen properties for developing enteric fever vaccine. To achieve the first goal we established a practical Salmonella mouse infection model for identifying bacterial maintenance functions essential for persistency.Using this model, we evaluated twelve Salmonella defects. Our data revealed extremely relaxed environment of Salmonella during persistency compared to the acute infection. On the other hand, we identified that unsatuarated/ cyclopropane fatty acid synthesis pathway might contain suitable targets for antimicrobial chemotherapy of chronic infections. To achieve the second goal, we tested thirty seven in vivo expressed antigens for immunogenicity and protectivity in a mouse typhoid fever model. We identified novel Salmonella antigens that conferred partial protection against virulent Salmonella in a typhoid fever model. The identified antigens had high sequence conservation among several Salmonella serovars suggesting that these antigens might be suitable as vaccine candidates against systemic Salmonella infection caused by diverse serovars. Using model antigens expressed in Salmonella and autologous antigens, our data also revealed that surface associated antigens might be promising for inducing both humoral and cellular immunity to Salmonella, as recognition of such antigens might enable uniquely detection and destruction of live Salmonella. This may provide a strategy to discover additional protective antigens for Salmonella and other intracellular pathogens

Feiyang Xiong,1,2,* Xiayi Fang,1,* Yanping Lu,3 Wenliang Lv2 1Hunan University of Chinese Medicine, Changsha, Hunan, People’s Republic of China; 2Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China; 3Department of Hepatology, Shenzhen Bao’an District Traditional Chinese Medicine Hospital, Shenzhen, People’s Republic of China*These authors contributed equally to this workCorrespondence: Yanping Lu, Department of Hepatology, Shenzhen Bao’an District Traditional Chinese Medicine Hospital, Shenzhen, People’s Republic of China, Tel +8613973195144, Email 1171932654@qq.com Wenliang Lv, Department of Infection, Guang’anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, People’s Republic of China, Tel +8619267490697, Email 754774067@qq.comAbstract: Antimicrobial resistance (AMR) is one of the major threats to global health, with a complex and diverse underlying mechanism. Vaccines reduce the dependence on antimicrobial agents by preventing and treating bacterial and viral infections, as well as secondary infections caused by both, thereby lowering the risk of AMR. Unlike traditional antibiotics, bacterial vaccines trigger a long-lasting immune response that not only prevents bacterial infections but also inhibits the spread of resistant strains. They show significant advantages in reducing antibiotic use and lowering resistance risks. However, the development of bacterial vaccines faces several challenges, including the diversity of bacterial antigens, rapid evolution, and the difficulty of achieving broad-spectrum immune protection. Despite these challenges, advancements in vaccine technology and the optimization of delivery systems are making the application prospects of bacterial vaccines in combating resistant strains increasingly promising. We sequentially discuss resistance mechanisms, existing and emerging vaccine platforms, enabling technologies, and future perspectives.Keywords: antimicrobial resistance, bacterial vaccines, bacterial infections, challenges, technolog

Sexually transmitted infections (STIs) caused by bacterial pathogens Chlamydia trachomatis, Neisseria gonorrhoeae, and Treponema pallidum present significant public health challenges. These infections profoundly impact reproductive health, leading to pelvic inflammatory disease, infertility, and increased susceptibility to other infections. Prevention measures, including antibiotic treatments, are limited by the often-asymptomatic nature of these infections, the need for repetitive and continual screening of sexually active persons, antibiotic resistance for gonorrhea, and shortages of penicillin for syphilis. While vaccines exist for viral STIs like human papillomavirus (HPV) and hepatitis B virus (HBV), there are no vaccines available for bacterial STIs. This review examines the immune responses in the female genital tract to these bacterial pathogens and the implications for developing effective vaccines against bacterial STIs

DNA vaccines are an exciting development in vaccine technology which may have a special role in preventing viral infections and as 'theracines' for cancer. Their use in preventing bacterial infections has, by comparison, been less well documented. While it is unlikely that traditional, highly successful and cheap vaccines for diseases such as diphtheria will be replaced by DNA vaccines, naked DNA may be particularly appropriate for preventing bacterial infections where cytotoxic T cells confer protection, or where a Th1 type T cell response mediates resistance. For example, DNA vaccines containing different mycobacterial antigens have been shown to inhibit overt infections by Mycobacterium tuberculosis in rodent models. The use of DNA vaccines in bacterial infections may be complicated by fundamental differences between prokaryotic and eukaryotic genes and gene products, including mRNA stability, codon bias, secondary structures surrounding native start sequences and glycosylation. These problems can be solved by re-synthesis of bacterial genes to produce 'new' sequences which are more highly expressed by eukaryotic cells

Tuberculosis remains the most common cause of death due to a single infective organism. Despite the availability of a vaccine and chemotherapeutic options, the global disease burden remains relatively unaffected. The ability of the mycobacterial etiological agents to adopt a semidormant, phenotypically drug-resistant state requires that chemotherapy is both complex and lengthy. The emergence of drug resistance has raised the possibility of virtually untreatable tuberculosis. Furthermore, the currently used bacillus Calmette–Guerin vaccine has had mixed success in protecting susceptible populations. Given this backdrop, the need for novel anti-infectives and more effective vaccines is clearly evident. Recent progress, described herein, has seen the development and entry into clinical trials of several new drugs and vaccine candidate

Background: Rotaviruses (RVs) are the most important cause of acute gastroenteritis in humans and animals. These viruses cause diarrheal disease primarily in the young, but infection and disease in older children and adults can occur, resulting in more than 600 000 deaths per annum, mainly in developing countries. RV particle is nonenveloped, with the viral genome of 11 segments of double-stranded RNA surrounded by three concentric protein layers: the outer layer is composed of VP (Viral Protein) 7 and VP4, the intermediate layer is formed by VP6, and the innermost layer is composed by VP2. Studies of natural infection in children indicated that primary infections can protect against severe disease upon secondary infection. For these reasons the most frequent approach to Rotavirus vaccine design was based on the use of attenuated animal or human Rotavirus strains, orally delivered to mimic natural infection. However, several major drawbacks have affected the development and application of these live Rotavirus-based oral vaccines, including the withdrawal from market of one of these vaccines because of adverse effects (gut intussusception). Moreover Rotaviruses are constantly and rapidly evolving, due both to their segmented genomes and to the fact that their genes can reassort between strains coinfecting a same host, and this fact is an important threat to the rational of using live attenuated Rotavirus strains as vaccines, both because these strains can revert to more virulent phenotypes and because these vaccine strains are being released to the nature in the faeces of the inoculated person, raising a considerable ecological concern. It is therefore critical to develop alternatives to this classical approach, both to generate a deeper understanding and to explore the potential of novel vaccination strategies. Aim: the goal of this project is the production of a collection of plasmids and HSV-1-based vectors expressing Rotavirus antigens as tool for research on Rotaviruses and the development of innovative genetic vaccines to fight against Rotavirus, based on the use of replication-defective HSV-1 vectors. Methods: the Rotavirus genes (vp7, vp4, vp6 and vp2) were subcloned first in basic plasmids (pcDNA Hygro 3.1+ or 3.1-, or in pBSSK) then in plasmids that have HSV specific loci sequences (pB41, pB5, pgJHE), where the Rotavirus cassettes were inserted between these Herpes sequences in order to recombine them into the viral genomes. Homologous recombinations have been carried out using standard calcium phosphate transfection. The recombinant backbones used (T0ZGFP, THZ and S0ZgJGFP) are replication-defective HSV-1 viral vectors that has low toxicity due to the deletion of one or more immediate early genes essential for viral replication; in addition they contain marker genes (gfp gene or lacZ gene) useful for the identification of the recombinant backbone which has integrated the transgene in its genome. Transfection and isolation of the recombinant viruses were performed in modified Vero cells (7b or E5), capable of providing the essential immediate early gene products in trans. The recombinant viruses containing the Rotavirus transgenes were identified by isolation of a clear plaque phenotype for GFP under the fluorescent microscope or after X-gal staining. All the recombinant viruses have been purified by three rounds of limiting dilution and the presence of the transgenes was verified by Southern blot analysis. The protein expression was evaluated by immunofluorescence and Western blot techniques with specific mono/polyclonal antibodies. Main results: a lot of plasmids containing Rotavirus genes of human, mice or simian origin and a large set of HSV-1-based vectors expressing Rotavirus proteins were constructed. The expression of VP6, VP2 and VP7 Rotavirus proteins (of murine or simian origin, under ICP0 promoter or HCMV promoter control, and in different loci of HSV genome) was visible in Western blot analysis. Moreover, nanotubes formed by VP6 protein were detected after immunofluorescence assays. Conclusions: plasmids and recombinant HSV-vectors carrying Rotavirus genes represent a tool to improve the research on Rotavirus and to elucidate the features of individual Rotavirus antigens. HSV-1-based vectors expressing Rotavirus antigens could represent an attractive alternative strategy to current vaccines. In addition, the possibility to cross recombinant HSV-vectors carrying Rotavirus genes in different loci of HSV could enhance the immune response by the construction of virus-like particles (VLPs); VLPs are a highly effective type of subunit vaccines that mimic the overall structure of virus particles without any requirement that they contain infectious genetic material

A crisis in bacterial infections looms as ageing populations, increasing rates of bacteraemia and healthcare-associated infections converge with increasing antimicrobial resistance and a paucity of new antimicrobial classes. New initiatives are needed to develop bacterial vaccines for older adults in whom immune senescence plays a critical role. Novel vaccines require an expanded repertoire to prevent mucosal diseases such as pneumonia, skin and soft tissue infections and urinary tract infections that are major causes of morbidity and mortality in the elderly, and key drivers of antimicrobial resistance. This review considers the challenges inherent to the prevention of bacterial diseases, particularly mucosal infections caused by major priority bacterial pathogens against which current vaccines are sub-optimal. It has become clear that prevention of many lung, urinary tract and skin infections requires more than circulating antibodies. Induction of Th1/Th17 cellular responses with tissue-resident memory (Trm) cells homing to mucosal tissues may be a pre-requisite for success.

Global coverage of infant Haemophilus influenzae type b (Hib) vaccination has increased considerably during the past decade, partly due to GAVI Alliance donations of the vaccine to low-income countries. In settings where large numbers of children receive only one or two vaccine doses rather than the recommended three doses, dose-specific efficacy estimates are needed to predict impact. The objective of this meta-analysis is to determine Hib vaccine efficacy against different clinical outcomes after receiving one, two or three doses of vaccine. Studies were eligible for inclusion if a prospective, controlled design had been used to evaluate commercially available Hib conjugate vaccines. Eight studies were included. Pooled vaccine efficacies against invasive Hib disease after one, two or three doses of vaccine were 59%, 92% and 93%, respectively. The meta-analysis provides robust estimates for use in decision-analytical models designed to predict the impact of Hib vaccine

Every person over the course of their lifetime is repeatedly infected by a variety of respiratory viruses that represent risk factors for the development of bacterial complications. The most dangerous among the etiological factors of acute respiratory viral diseases is the influenza A virus. This virus is capable of causing catastrophic pandemics with high mortality mainly due to secondary bacterial pneumonia. As has been shown in numerous recent studies, the main mechanism of provoking bacterial infections irrespective of the type of respiratory virus is the imbalanced response of the antiviral innate immunity – excessive interferon response and uncontrolled inflammation. The probability of severe bacterial complications in the course of acute respiratory viral infections is determined by both the virulence of the virus itself and by the composition of the respiratory microbiota at the time of the viral infection as well as by the genetic characteristics of the organism. The occurrence of severe bacterial complications is also affected by the chronic diseases that have an impact on the regulation of the innate immune response. This review summarizes the current concept of the mechanisms of the development of post viral bacterial complications as well as the potential prevention strategies for these complications.Every person over the course of their lifetime is repeatedly infected by a variety of respiratory viruses that represent risk factors for the development of bacterial complications. The most dangerous among the etiological factors of acute respiratory viral diseases is the influenza A virus. This virus is capable of causing catastrophic pandemics with high mortality mainly due to secondary bacterial pneumonia. As has been shown in numerous recent studies, the main mechanism of provoking bacterial infections irrespective of the type of respiratory virus is the imbalanced response of the antiviral innate immunity – excessive interferon response and uncontrolled inflammation. The probability of severe bacterial complications in the course of acute respiratory viral infections is determined by both the virulence of the virus itself and by the composition of the respiratory microbiota at the time of the viral infection as well as by the genetic characteristics of the organism. The occurrence of severe bacterial complications is also affected by the chronic diseases that have an impact on the regulation of the innate immune response. This review summarizes the current concept of the mechanisms of the development of post viral bacterial complications as well as the potential prevention strategies for these complications