Whole-cell Vaccine Research Articles

Irradiated whole cell Chlamydia vaccine confers significant protection in a murine genital tract challenge model.

Chlamydia trachomatis infections are the most common bacterial STIs globally and can lead to serious morbidity if untreated. Development of a killed, whole-cell vaccine has been stymied by coincident epitope destruction during inactivation. Here, we present a prototype Chlamydia vaccine composed of elementary bodies (EBs) from the related mouse pathogen, Chlamydia muridarum (Cm). EBs inactivated by gamma rays (Ir-Cm) in the presence of the antioxidant Mn2+-Decapeptide (DEHGTAVMLK) Phosphate (MDP) are protected from epitope damage but not DNA damage. Cm EBs gamma-inactivated with MDP retain their structure and provide significant protection in a murine genital tract infection model. Mice vaccinated with Ir-Cm (+MDP) exhibited elevated levels of Cm-specific IgG and IgA antibodies, reduced bacterial burdens, accelerated clearance, and distinctive cytokine responses compared to unvaccinated controls and animals vaccinated with EBs irradiated without MDP. Preserving EB epitopes with MDP during gamma inactivation offers the potential for a polyvalent, whole-cell vaccine against C. trachomatis.

Exogenous or in situ vaccination to trigger clinical responses in pancreatic cancer.

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease for which remarkable therapeutic resistance is the norm. Conventional immunotherapies, like immune checkpoint inhibitors, show limited efficacy in PDA due to a remarkably immunosuppressive tumor microenvironment (TME) and systemic inflammation. This review discusses the potential of both exogenous and in situ vaccination strategies to overcome these barriers and enhance anti-tumor immunity in PDA. Exogenous vaccines, including whole-cell, dendritic cell, peptide, and nucleic acid-based vaccines, have shown varying degrees of promise but face challenges related to antigen selection, production complexities, and patient-specific factors. In contrast, in situ vaccination strategies leverage conventional cytotoxic therapies, such as chemotherapy and radiation therapy, to induce immunogenic cell death and modulate the TME with the aim to stimulate anti-tumor immunity. While preclinical studies support the use of in situ vaccination, balancing the stimulatory and inhibitory effects is likely fundamental to eliciting productive anti-tumor responses in patients. Ongoing research seeks to identify new innovative strategies that can harness the endogenous immune response and trigger in situ vaccination. Overall, while both vaccination approaches offer significant potential, further research and clinical trials will be needed to optimize these strategies for improving patient outcomes in PDA.

Effect of the MONTANIDE™ IMS 1312 adjuvant on the innate and adaptive immune responses of Nile tilapia (Oreochromis niloticus) against Streptococcusagalactiae through immersion vaccination

Streptococcus agalactiae is a common pathogenic bacterium caused of streptococcosis, which has a negative impact on Nile tilapia aquaculture. Numerous vaccines have been developed recently to combat this disease, which are key components of global health efforts to prevent disease outbreaks. MONTANIDE™ IMS 1312 is a micro-emulsion recommended for immersion of fish. However, the data on the effectiveness of those immersion vaccines containing this aqueous adjuvant in fish are limited. The objective of this research was to explore the potential of MONTANIDE™ IMS 1312, an adjuvant for immersion vaccination, administered with an S. agalactiae inactivated whole-cell vaccine (SAIV) in Nile tilapia. Fish were separated into three groups: 1) fish were vaccinated by immersion vaccination with PBS (CTRL), 2) fish were vaccinated by immersion vaccination with SAIV vaccine alone (SAIV), and 3) fish were vaccinated by immersion vaccination with SAIV containing MONTANIDE™ IMS 1312. We found that the activity of several innate immunity parameters was increased significantly (P < 0.05) following the immunization. As expected, the levels of specific IgM antibody were significantly increased post-vaccination, and the highest IgM antibody levels were found in the fish vaccinated with SAIV containing MONTANIDE™ IMS 1312. Analysis of the transcriptional expression of major pro-inflammatory cytokines, as well as the presence of IgM+ B cells, revealed significant increases, suggesting that Nile tilapia were able to initiate cellular immune responses following vaccination. Taken together, our results indicate that using MONTANIDE™ IMS 1312 in combination with a SAIV can induce strong protection post S. agalactiae infection. Importantly, administration of an adjuvanted immersion vaccine is safe, no side effects were observed, and it does not negatively impact fish growth. In conclusion, MONTANIDE™ IMS 1312 has the potential to be used as adjuvants for immersion vaccines against streptococcosis in Nile tilapia.

A whole-cell pertussis vaccine engineered to elicit reduced reactogenicity protects baboons against pertussis challenge.

Whole-cell pertussis (wP) vaccines introduced in the 1940s led to a dramatic reduction of pertussis incidence and are still widely used in low- and middle-income countries (LMICs) worldwide. The reactogenicity of wP vaccines resulted in reduced public acceptance, which drove the development and introduction of acellular pertussis (aP) vaccines in high-income countries in the 1990s. Increased incidence of pertussis disease has been observed in high-income countries following the introduction of aP vaccines despite near universal rates of pediatric vaccination. These increases are attributed to the reduced protection against colonization, carriage, and transmission as well as reduced duration of immunity conferred by aP vaccines relative to the wP vaccines they replaced. A reduced reactogenicity whole-cell pertussis (RRwP) vaccine was recently developed with the goal of achieving the same protection as conferred by wP vaccination but with an improved safety profile, which may benefit countries in which wP vaccines are still in routine use. In this study, we tested the RRwP vaccine in a baboon model of pertussis infection. We found that the RRwP vaccine induced comparable cellular and humoral immune responses and comparable protection following challenge relative to the wP vaccine, while significantly reducing injection-site reactogenicity.IMPORTANCEThe World Health Organization (WHO) recommended in 2015 that countries administering wP vaccines in their national vaccine programs should continue to do so, and that switching to aP vaccines for primary infant immunization should only be considered if periodic booster vaccinations and/or maternal immunization could be assured and sustained in their national immunization schedules (WHO, Vaccine 34:1423-1425, 2016, https://doi.org/10.1016/j.vaccine.2015.10.136). Due to the considerably higher cost of aP vaccines and the larger number of doses required, most LMICs continue to use wP vaccines. The development and introduction of a wP vaccine that induces fewer adverse events without sacrificing protection would significantly benefit countries in which wP vaccines are still in routine use. The results of this study indicate this desirable goal may be achievable.

Mechanotransduction-Piloted Whole-Cell Vaccines for Spatiotemporal Modulation of Postoperative Antitumor Immunity.

Whole tumor cell vaccines hold promise by presenting a broader spectrum of autologous-origin tumor antigens to combat postoperative recurrence and metastasis. However, challenges such as intractable adjuvant modification and obscure interactions with antigen-presenting cells in the postoperative microenvironment impede their translation into effective personalized immunotherapies. In this study, we propose cancer vaccines derived from manganese oxide-immobilized resected tumor cells, featuring whole tumor antigens and adjustable stiffness to modulate interactions with antigen-presenting cells in the postoperative microenvironment. These vaccines effectively stimulate dendritic cell phagocytosis and function through sequential stiffness-mediated mechanotransduction and interferon signaling. We evaluated their efficacy using an orthotopic triple-negative breast cancer mouse model and found that combining the vaccines with radiotherapy effectively inhibits postoperative tumor recurrence and metastasis. Our study underscores the potential of utilizing mechanotransduced adjuvants alongside directly inactivated whole-cell vaccines as a universal solution for preventing postoperative tumor recurrence.

Molecular mechanisms of Coxiella burnetii formalin-fixed cellular vaccine reactogenicity.

Local and systemic reactogenic responses to Q-VAX have prevented licensing of this vaccine outside of Australia. These reactogenic responses occur in previously sensitized individuals and have not been well defined at the cellular level, in part because many studies have been done in guinea pigs that have limited molecular tools. We previously characterized a mouse model of reactogenicity where local reaction sites showed an influx of CD8+ and IFNγ-expressing IL17a+ CD4+ T cells consistent with a Th1 delayed-type hypersensitivity. In this study, we determined, using depletion and adoptive transfer experiments, that both anti-Coxiella antibodies and CD4+ T cells were essential for localized reactions at the site of vaccination. Furthermore, IFNγ depletion showed significant histological changes at the local reaction sites demonstrating the essential nature of this cytokine to reactogenicity. In addition to the cells and cytokines required for this response, we determined that whole cell vaccine (WCV) material remained at the site of vaccination for at least 26 weeks post-injection. Transmission electron microscopy (TEM) of these sites demonstrated intact rod-shaped bacteria at 2 weeks post-injection and partially degraded bacteria within macrophages at 26 weeks post-injection. Finally, because small cell variants (SCVs) are an environmentally stable form, we determined that local reactions were more severe when the WCV material was prepared with higher levels of SCVs compared to typical WCV or with higher levels of large cell variant (LCV). These studies support the hypothesis that antigen persistence at the site of injection contributes to this reactogenicity and that anti-Coxiella antibodies, CD4+ T cells, and IFNγ each contribute to this process.

Enhancement of clinical signs in C3H/HeJ mice vaccinated with a highly immunogenic Leptospira methyl-accepting chemotaxis protein following challenge.

Leptospirosis is the most widespread zoonosis and a life-threatening disease in humans and animals. Licensed killed whole-cell vaccines are available for animals; however, they do not offer heterologous protection, do not induce long-term protection, or prevent renal colonization. In this study, we characterized an immunogenic Leptospira methyl-accepting chemotaxis protein (MCP) identified through a reverse vaccinology approach, predicted its structure, and tested the protective efficacy of a recombinant MCP fragment in the C3H/HeJ mice model. The predicted structure of the full-length MCP revealed an architecture typical for topology class I MCPs. A single dose of MCP vaccine elicited a significant IgG antibody response in immunized mice compared to controls (P < 0.0001), especially the IgG1 and IgG2a subclasses. The vaccination with MCP, despite eliciting a robust immune response, did not protect mice from disease and renal colonization. However, survival curves significantly differed between groups, and the MCP-vaccinated group developed clinical signs faster than the control group. There were differences in gross and histopathological changes between the MCP-vaccinated and control groups. The factors leading to enhanced disease process in vaccinated animals need further investigation. We speculate that anti-MCP antibodies may block the MCP signaling cascade and may limit chemotaxis, preventing Leptospira from reaching its destination, but facilitating its maintenance and replication in the blood stream. Such a phenomenon may exist in endemic areas where humans are highly exposed to Leptospira antigens, and the presence of antibodies might lead to disease enhancement. The role of this protein in Leptospira pathogenesis should be further evaluated to comprehend the lack of protection and potential exacerbation of the disease process. The absence of immune correlates of protection from Leptospira infection is still a major limitation of this field and efforts to gather this knowledge are needed.

Immunotherapeutic advances in glioma management: The rise of vaccine-based approaches.

Gliomas, particularly glioblastoma multiforme (GBM), are highly aggressive brain tumors that present significant challenges in oncology due to their rapid progression and resistance to conventional therapies. Despite advancements in treatment, the prognosis for patients with GBM remains poor, necessitating the exploration of novel therapeutic approaches. One such emerging strategy is the development of glioma vaccines, which aim to stimulate the immune system to target and destroy tumor cells. This review aims to provide a comprehensive evaluation of the current landscape of glioma vaccine development, analyzing the types of vaccines under investigation, the outcomes of clinical trials, and the challenges and opportunities associated with their implementation. The goal is to highlight the potential of glioma vaccines in advancing more effective and personalized treatments for glioma patients. This narrative review systematically assessed the role of glioma vaccines by including full-text articles published between 2000 and 2024 in English. Databases such as PubMed/MEDLINE, EMBASE, the Cochrane Library, and Scopus were searched using key terms like "glioma," "brain tumor," "glioblastoma," "vaccine," and "immunotherapy." The review incorporated both pre-clinical and clinical studies, including descriptive studies, animal-model studies, cohort studies, and observational studies. Exclusion criteria were applied to omit abstracts, case reports, posters, and non-peer-reviewed studies, ensuring the inclusion of high-quality evidence. Clinical trials investigating various glioma vaccines, including peptide-based, DNA/RNA-based, whole-cell, and dendritic-cell vaccines, have shown promising results. These vaccines demonstrated potential in extending survival rates and managing adverse events in glioma patients. However, significant challenges remain, such as therapeutic resistance due to tumor heterogeneity and immune evasion mechanisms. Moreover, the lack of standardized guidelines for evaluating vaccine responses and issues related to ethical considerations, regulatory hurdles, and vaccine acceptance among patients further complicate the implementation of glioma vaccines. Addressing the challenges associated with glioma vaccines involves exploring combination therapies, targeted approaches, and personalized medicine. Combining vaccines with traditional therapies like radiotherapy or chemotherapy may enhance efficacy by boosting the immune system's ability to fight tumor cells. Personalized vaccines tailored to individual patient profiles present an opportunity for improved outcomes. Furthermore, global collaboration and equitable distribution are critical for ensuring access to glioma vaccines, especially in low- and middle-income countries with limited healthcare resources CONCLUSION: Glioma vaccines represent a promising avenue in the fight against gliomas, offering hope for improving patient outcomes in a disease that is notoriously difficult to treat. Despite the challenges, continued research and the development of innovative strategies, including combination therapies and personalized approaches, are essential for overcoming current barriers and transforming the treatment landscape for glioma patients.

The impact of acellular pertussis vaccination in pregnancy on the immunogenicity of acellular versus whole-cell pertussis vaccines in infancy: A protocol for a phase IV randomised, controlled mother-infant pertussis vaccine trial (The Gambian Pertussis Study, GaPs)

Background Worldwide we have yet to achieve optimal control of pertussis, an important vaccine-preventable respiratory disease that has a particularly high burden of morbidity and mortality in infants under 1 year. Pertussis immunisation in pregnancy is an effective tool to protect infants in early life. However, there are concerns regarding the impact of maternal antibodies on the infant’s subsequent vaccine responses. The exact nature, duration, and clinical significance of this interaction is poorly understood. Methods We will conduct a phase IV randomised-controlled double-blinded (pregnant women) open-label (infants) trial, GaPs, in a cohort of 600 mother-infant pairs in The Gambia. Healthy pregnant women aged between 18 and 40 years will be recruited from two government antenatal healthcare centres in the Gambian peri-urban western region. They will be randomised to receive either a pertussis booster (TdaP-IPV) or Tetanus-Toxoid (TT, control) at 28-34 weeks’ gestation. Their infants will be further randomised to receive either acellular (aP) or whole-cell pertussis (wP) vaccines as part of the primary immunisation series at 8, 12 and 16 weeks of age and then followed up for 9-months postnatally. Clinical and safety data will be collected from each maternal-infant pair alongside blood samples and mucosal lining fluid, at baseline and multiple time points post-vaccination. Outcomes The trial aims to evaluate the quantity, quality, and persistence of immune responses, at both systemic and mucosal levels, to aP versus wP-containing priming schedules in Gambian infants up to 9-months of age, as well as the impact of pertussis immunisation in pregnancy on these responses. The primary endpoint measured will be the difference in the geometric mean concentration of anti-pertussis-toxin (PT) antibody in aP compared to wP-vaccinated infants at 16-weeks and 9-months postnatally. A further in-depth systems vaccinology approach will be embedded within the trial’s secondary and exploratory endpoints.

Immunogenicity and Protective Efficacy of an Acellular Pertussis Vaccine Candidate in a Mice Model.

Acellular pertussis vaccines (aPVs) have been developed as an alternative to whole-cell pertussis vaccines (wPVs) due to their similar efficacy but reduced reactogenicity. The aPV contains three or more immunogenic components of BP. We aimed to evaluate the immunogenicity and protective potency of an aPV vaccine produced in our laboratory consisting of pertussis toxin (PT), filamentous hemagglutinin (FHA), and pertactin (PRN) in mice. The aPV components were produced and purified from the supernatant and pellet of the bacterial culture. Two doses of formulated vaccine in parallel with two commercial vaccines, were administered intraperitoneally (IP) in mice at 3-week intervals. Antibody titers against aPV antigens were measured by ELISA after primary and booster vaccinations. To assess the protective efficacy, an intranasal challenge with a live pathogenic BP strain was conducted two weeks after the booster vaccination, and bacterial count (colony-forming unit, CFU) in the lungs was conducted two hours and ten days after the challenge. The results demonstrated a significant increase in antibody titers against all pertussis antigens in the serum of vaccinated groups compared to the negative control group, following both the primary and booster doses. No significant differences were observed between our formulation and the commercial vaccines. Furthermore, the CFU results showed complete eradication of infection 10 days after the challenge in all immunized groups, in contrast to the control group. Our aPV formulation, the first aPV candidate developed in Iran, exhibits immunogenicity and protective efficacy comparable to commercial vaccines. Further investigation in human subjects is warranted.

Exploring the journey: A comprehensive review of vaccine development against Klebsiella pneumoniae

Klebsiella pneumoniae, a prominent nosocomial pathogen, poses a critical global health threat due to its multidrug-resistant (MDR) and hypervirulent strains. This comprehensive review focuses into the complex approaches undertaken in the development of vaccines against K. pneumoniae. Traditional methods, such as whole-cell and ribosomal-based vaccines, are compared with modern strategies, including DNA and mRNA vaccines, and extracellular vesicles (EVs), among others. Each method presents unique advantages and challenges, emphasising the complexity of developing an effective vaccine against this pathogen. Significant advancements in computational tools and artificial intelligence (AI) have revolutionised antigen identification and vaccine design, enhancing the precision and efficiency of developing multiepitope-based vaccines. The review also highlights the potential of glycomics and immunoinformatics in identifying key antigenic components and elucidating immune evasion mechanisms employed by K. pneumoniae. Despite progress, challenges remain in ensuring the safety, efficacy, and manufacturability of these vaccines. Notably, EVs demonstrate promise due to their intrinsic adjuvant properties and ability to elicit robust immune responses, although concerns regarding inflammation and antigen variability persist. This review provides a critical overview of the current landscape of K. pneumoniae vaccine development, stressing the need for continued innovation and interdisciplinary collaboration to address this pressing public health issue. The integration of advanced computational methods and AI holds the potential to accelerate the development of effective immunotherapies, paving the way for novel vaccines against MDR K. pneumoniae.

Transient reemergence of Bordetella parapertussis in France in 2022.

Between March and October 2022, a peak of detection of Bordetella parapertussis by qPCR, real-time PCR was observed in France.Hypothesis/Gap Statement. Whether this peak was due to resurgence from previous circulating lineages or reintroduction into the country was unknown.Objective. The objective of this study is to understand B. parapertussis-transient increase observed in France in 2022 whereas it had virtually stopped being reported since the start of the COVID-19 pandemic in 2020.Methods. We analysed real-time PCR (qPCR) data from the two largest French outpatient laboratories performing whooping cough diagnosis and characterized all B. parapertussis isolates collected in the 2016-2022 period by the French National Reference Centre for Whooping Cough.Results. Microbiological analyses reveal that 13 of 18 bacterial isolates collected in 2022 produce the vaccine antigen pertactin, whereas none of the 22 isolates collected in the 2016-2021 period did.Conclusion. We hypothesize a re-introduction of B. parapertussis from regions of the world where whole-cell vaccines are still in use.

Complete genome of the Listeria monocytogenes strain AUF, used as a live listeriosis veterinary vaccine

Listeria monocytogenes (Lm) is a highly pathogenic bacterium that can cause listeriosis, a relatively rare food-borne infectious disease that affects farm, domestic, wild animals and humans as well. The infected livestock is the frequent sources of Lm. Vaccination is one of the methods of controlling listeriosis in target farm animals to prevent Lm-associated food contamination. Here we report the complete sequence of the Lm strain AUF attenuated from a fully-virulent Lm strain by ultraviolet irradiation, successfully used since the 1960s as a live whole-cell veterinary vaccine. The de novo assembled genome consists of a circular chromosome of 2,942,932 bp length, including more than 2,800 CDSs, 17 pseudogenes, 5 antibiotic resistance genes, and 56/92 virulence genes. Two wild Lm strains, the EGD and the 10403S that is also used in cancer Immunotherapy, were the closest homologs for the Lm strain AUF. Although all three strains belonged to different sequence types (ST), namely ST12, ST85, and ST1538, they were placed in the same genetic lineage II, CC7.

Genomic tailoring of autogenous poultry vaccines to reduce Campylobacter from farm to fork

Campylobacter is a leading cause of food-borne gastroenteritis worldwide, linked to the consumption of contaminated poultry meat. Targeting this pathogen at source, vaccines for poultry can provide short-term caecal reductions in Campylobacter numbers in the chicken intestine. However, this approach is unlikely to reduce Campylobacter in the food chain or human incidence. This is likely as vaccines typically target only a subset of the high genomic strain diversity circulating among chicken flocks, and rapid evolution diminishes vaccine efficacy over time. To address this, we used a genomic approach to develop a whole-cell autogenous vaccine targeting isolates harbouring genes linked to survival outside of the host. We hyper-immunised a whole major UK breeder farm to passively target offspring colonisation using maternally-derived antibody. Monitoring progeny, broiler flocks revealed a near-complete shift in the post-vaccination Campylobacter population with an ~50% reduction in isolates harbouring extra-intestinal survival genes and a significant reduction of Campylobacter cells surviving on the surface of meat. Based on these findings, we developed a logistic regression model that predicted that vaccine efficacy could be extended to target 65% of a population of clinically relevant strains. Immuno-manipulation of poultry microbiomes towards less harmful commensal isolates by competitive exclusion, has major potential for reducing pathogens in the food production chain.

Immunogenicity, reactogenicity, and IgE-mediated immune responses of a mixed whole-cell and acellular pertussis vaccine schedule in Australian infants: A randomised, double-blind, noninferiority trial.

In many countries, infant vaccination with acellular pertussis (aP) vaccines has replaced use of more reactogenic whole-cell pertussis (wP) vaccines. Based on immunological and epidemiological evidence, we hypothesised that substituting the first aP dose in the routine vaccination schedule with wP vaccine might protect against IgE-mediated food allergy. We aimed to compare reactogenicity, immunogenicity, and IgE-mediated responses of a mixed wP/aP primary schedule versus the standard aP-only schedule. OPTIMUM is a Bayesian, 2-stage, double-blind, randomised trial. In stage one, infants were assigned (1:1) to either a first dose of a pentavalent wP combination vaccine (DTwP-Hib-HepB, Pentabio PT Bio Farma, Indonesia) or a hexavalent aP vaccine (DTaP-Hib-HepB-IPV, Infanrix hexa, GlaxoSmithKline, Australia) at approximately 6 weeks old. Subsequently, all infants received the hexavalent aP vaccine at 4 and 6 months old as well as an aP vaccine at 18 months old (DTaP-IPV, Infanrix-IPV, GlaxoSmithKline, Australia). Stage two is ongoing and follows the above randomisation strategy and vaccination schedule. Ahead of ascertainment of the primary clinical outcome of allergist-confirmed IgE-mediated food allergy by 12 months old, here we present the results of secondary immunogenicity, reactogenicity, tetanus toxoid IgE-mediated immune responses, and parental acceptability endpoints. Serum IgG responses to diphtheria, tetanus, and pertussis antigens were measured using a multiplex fluorescent bead-based immunoassay; total and specific IgE were measured in plasma by means of the ImmunoCAP assay (Thermo Fisher Scientific). The immunogenicity of the mixed schedule was defined as being noninferior to that of the aP-only schedule using a noninferiority margin of 2/3 on the ratio of the geometric mean concentrations (GMR) of pertussis toxin (PT)-IgG 1 month after the 6-month aP. Solicited adverse reactions were summarised by study arm and included all children who received the first dose of either wP or aP. Parental acceptance was assessed using a 5-point Likert scale. The primary analyses were based on intention-to-treat (ITT); secondary per-protocol (PP) analyses were also performed. The trial is registered with ANZCTR (ACTRN12617000065392p). Between March 7, 2018 and January 13, 2020, 150 infants were randomised (75 per arm). PT-IgG responses of the mixed schedule were noninferior to the aP-only schedule at approximately 1 month after the 6-month aP dose [GMR = 0·98, 95% credible interval (0·77 to 1·26); probability (GMR > 2/3) > 0·99; ITT analysis]. At 7 months old, the posterior median probability of quantitation for tetanus toxoid IgE was 0·22 (95% credible interval 0·12 to 0·34) in both the mixed schedule group and in the aP-only group. Despite exclusions, the results were consistent in the PP analysis. At 6 weeks old, irritability was the most common systemic solicited reaction reported in wP (65 [88%] of 74) versus aP (59 [82%] of 72) vaccinees. At the same age, severe systemic reactions were reported among 14 (19%) of 74 infants after wP and 8 (11%) of 72 infants after aP. There were 7 SAEs among 5 participants within the first 6 months of follow-up; on blinded assessment, none were deemed to be related to the study vaccines. Parental acceptance of mixed and aP-only schedules was high (71 [97%] of 73 versus 69 [96%] of 72 would agree to have the same schedule again). Compared to the aP-only schedule, the mixed schedule evoked noninferior PT-IgG responses, was associated with more severe reactions, but was well accepted by parents. Tetanus toxoid IgE responses did not differ across the study groups. Trial registered at the Australian and New Zealand Clinical 207 Trial Registry (ACTRN12617000065392p).

Immunogenicity and efficacy of CNA25 as a potential whole-cell vaccine against systemic candidiasis

Disseminated fungal infections account for ~1.5 million deaths per year worldwide, and mortality may increase further due to a rise in the number of immunocompromised individuals and drug-resistance fungal species. Since an approved antifungal vaccine is yet to be available, this study explored the immunogenicity and vaccine efficacy of a DNA polymerase mutant strain of Candida albicans. CNA25 is a pol32ΔΔ strain that exhibits growth defects and does not cause systemic candidiasis in mice. Immunized mice with live CNA25 were fully protected against C. albicans and C. parapsilosis but partially against C. tropicalis and C. glabrata infections. CNA25 induced steady expression of TLR2 and Dectin-1 receptors leading to a faster recognition and clearance by the immune system associated with the activation of protective immune responses mostly mediated by neutrophils, macrophages, NK cells, B cells, and CD4+ and CD8+ T cells. Molecular blockade of Dectin-1, IL-17, IFNγ, and TNFα abolished resistance to reinfection. Altogether, this study suggested that CNA25 collectively activates innate, adaptive, and trained immunity to be a promising live whole-cell vaccine against systemic candidiasis.

Antibody persistence to diphtheria toxoid, tetanus toxoid, Bordetella pertussis antigens, and Haemophilus influenzae type b following primary and first booster with pentavalent versus hexavalent vaccines

ABSTRACT Thailand has incorporated the whole-cell (wP) pertussis vaccine into the expanded program on immunization since 1977 and has offered the acellular pertussis (aP) vaccine as an optional vaccine for infants since 2001. We followed healthy children from a clinical trial (ClinicalTrials.gov NCT02408926) in which children were randomly assigned to receive either pentavalent (DTwP-HB-Hib) or hexavalent (DTaP-IPV-HB-Hib) vaccines for their primary series (administered at 2, 4, and 6 months) and first booster vaccination (18 months). Both groups received Tdap-IPV as a second booster at the age of 4 y. Blood samples were collected for evaluation of antibody persistence to diphtheria toxoid (DT), tetanus toxoid (TT), and Bordetella pertussis (B. pertussis) between 2 and 6 y of age annually, and for the immunogenicity study of Tdap-IPV at 1 month after the second booster. Antibody persistence to Haemophilus influenzae type b (Hib) was followed until 3 y of age. A total of 105 hexavalent-vaccinated children and 91 pentavalent-vaccinated children completed this study. Both pentavalent and hexavalent groups demonstrated increased antibody levels against DT, TT, and B. pertussis antigens following the second booster with Tdap-IPV. All children achieved a seroprotective concentration for anti-DT and anti-TT IgG at 1 month post booster. The hexavalent group possessed significantly higher anti-pertactin IgG (adjusted p = .023), whereas the pentavalent group possessed significantly higher anti-pertussis toxin IgG (adjusted p < .001) after the second booster. Despite declining levels post-second booster, a greater number of children sustained protective levels of anti-DT and anti-TT IgG compared to those after the first booster.

MV140 Mucosal Vaccine Induces Targeted Immune Response for Enhanced Clearance of Uropathogenic E. coli in Experimental Urinary Tract Infection.

MV140 is an inactivated whole-cell bacterial mucosal vaccine with proven clinical efficacy against recurrent urinary tract infections (UTIs). These infections are primarily caused by uropathogenic E. coli (UPEC) strains, which are unique in their virulence factors and remarkably diverse. MV140 contains a non-UPEC strain, suggesting that it may induce an immune response against different UPEC-induced UTIs in patients. To verify this, we experimentally evaluated the cellular and humoral responses to UTI89, a prototypical UPEC strain, in mice vaccinated with MV140, as well as the degree of protection achieved in a UPEC UTI89 model of acute cystitis. The results show that both cellular (Th1/Th17) and antibody (IgG/IgA) responses to UTI89 were induced in MV140-immunized mice. MV140 vaccination resulted in an early increased clearance of UTI89 viable bacteria in the bladder and urine following transurethral infection. This was accompanied by a highly significant increase in CD4+ T cells in the bladder and an increase in urinary neutrophils. Collectively, our results support that MV140 induces cross-reactive humoral and cellular immune responses and cross-protection against UPEC strains.

Yersinia pestis NLP subunit vaccine platform: Protective efficacy and immunological profile

Abstract Yersinia pestis (Yp) is the etiological agent of plague, a disease that remains a concern as demonstrated by recent outbreaks in Madagascar. Infection with Yp results in a rapidly progressing illness that can only be treated with antibiotics. Live attenuated or whole-cell inactivated vaccines confer short-lived protection against bubonic but not pneumonic plague. Subunit vaccine formulations may circumvent some of these shortfalls. Here we compare the immunogenicity generated by the most advanced subunit vaccine (rF1V) against a nanolipoprotein particle (NLP)-based vaccine. BALB/c mice were immunized twice, four weeks apart. Four weeks later, splenocytes and sera were collected for immune profiling and mice were aerosol challenged with Yp CO92. Both formulations induced a strong IgG response against F1 and V proteins, along with a robust memory B cell response and cell-mediated response with Th1- and Th2-related cytokines. NLP-based vaccine induced a stronger cytokine response against F1, V, and F1V proteins relative to the rF1V vaccine. As with rF1V, the inclusion of Alhydrogel in NLP vaccine formulations was critical for enhanced immunogenicity and protective efficacy. Addition of Francisella tularensis antigens to the Yp NLP vaccine platform did not impair vaccine efficacy, based on protection and antibody response. The modularity and lipid bilayer structure of NLPs allows for incorporation of many protective antigens with variable ratios against multiple pathogens.

Single-Cell Oral Delivery Platform for Enhanced Acid Resistance and Intestinal Adhesion.

Oral delivery of cells, such as probiotics and vaccines, has proved to be inefficient since cells are generally damaged in an acidic stomach prior to arrival at the intestine to exert their health benefits. In addition, short retention in the intestine is another obstacle which affects inefficiency. To overcome these obstacles, a cell-in-shell structure was designed with pH-responsive and mucoadhesive properties. The pH-responsive shell consisting of three cationic layers of chitosan and three anionic layers of trans-cinnamic acid (t-CA) was made via layer-by-layer (LbL) assembly. t-CA layers are hydrophobic and impermeable to protons in acid, thus enhancing cell gastric resistance in the stomach, while chitosan layers endow strong interaction between the cell surface and the mucosal wall which facilitates cell mucoadhesion in the intestine. Two model cells, probiotic L. rhamnosus GG and dead Streptococcus iniae, which serve as inactivated whole-cell vaccine were chosen to test the design. Increased survival and retention during oral administration were observed for coated cells as compared with naked cells. Partial removal of the coating (20-60% removal) after acid treatment indicates that the coated vaccine can expose its surface immunogenic protein after passage through the stomach, thus facilitating vaccine immune stimulation in the intestine. As a smart oral delivery platform, this design can be extended to various macromolecules, thus providing a promising strategy to formulate oral macromolecules in the prevention and treatment of diseases at a cellular level.