Characterization of invasive Group B Streptococcus isolates from Western Australian infants, 2004-2020.

Background. Invasive Group B Streptococcus (GBS; Streptococcus agalactiae) remains a leading cause of infant morbidity and mortality. Intrapartum antibiotic prophylaxis (IAP) has been implemented in many countries with a reduction in early-onset disease, but an effective vaccine may further reduce the disease burden. Candidate vaccines targeting capsular polysaccharides and surface proteins are now in clinical trials.Methods. Using whole-genome sequencing and phenotypic antimicrobial susceptibility testing, we characterized sterile-site GBS isolates recovered from Western Australian infants between 2004 and 2020. Characteristics were compared between three time periods: 2004-2008, 2009-2015 and 2016-2020.Results. A total of 135 isolates were identified. The proportion of serotype III (22.7 % in Period 1 to 47.9 % in Period 3, P=0.04) and clonal complex 17 (13.6-39.6 %, P=0.01) isolates increased over time. Overall coverage of vaccines currently being trialled was >95 %. No isolates were penicillin resistant (MIC>0.25 mg l-1), but 21.5 % of isolates had reduced penicillin susceptibility (MIC>0.12 mg l-1) and penicillin MIC increased significantly over time (P=0.04). Clindamycin resistance increased over time to 45.8 % in the latest period.Conclusions. Based on comprehensive characterization of invasive infant GBS in Western Australia, we found that coverage for leading capsular polysaccharide and surface protein vaccine candidates was high. The demonstrated changes in serotype and molecular type highlight the need for ongoing surveillance, particularly with regard to future GBS vaccination programmes. The reduced susceptibility to IAP agents over time should inform changes to antibiotic guidelines.

Personalized neoantigen vaccine and pembrolizumab in advanced hepatocellular carcinoma: a phase 1/2 trial.

Programmed cell death protein 1 (PD-1) inhibitors have modest efficacy as a monotherapy in hepatocellular carcinoma (HCC). A personalized therapeutic cancer vaccine (PTCV) may enhance responses to PD-1 inhibitors through the induction of tumor-specific immunity. We present results from a single-arm, open-label, phase 1/2 study of a DNA plasmid PTCV (GNOS-PV02) encoding up to 40 neoantigens coadministered with plasmid-encoded interleukin-12 plus pembrolizumab in patients with advanced HCC previously treated with a multityrosine kinase inhibitor. Safety and immunogenicity were assessed as primary endpoints, and treatment efficacy and feasibility were evaluated as secondary endpoints. The most common treatment-related adverse events were injection-site reactions, observed in 15 of 36 (41.6%) patients. No dose-limiting toxicities or treatment-related grade ≥3 events were observed. The objective response rate (modified intention-to-treat) per Response Evaluation Criteria in Solid Tumors 1.1 was 30.6% (11 of 36 patients), with 8.3% (3 of 36) of patients achieving a complete response. Clinical responses were associated with the number of neoantigens encoded in the vaccine. Neoantigen-specific T cell responses were confirmed in 19 of 22 (86.4%) evaluable patients by enzyme-linked immunosorbent spot assays. Multiparametric cellular profiling revealed active, proliferative and cytolytic vaccine-specific CD4+ and CD8+ effector T cells. T cell receptor ß-chain (TCRß) bulk sequencing results demonstrated vaccination-enriched T cell clone expansion and tumor infiltration. Single-cell analysis revealed posttreatment T cell clonal expansion of cytotoxic T cell phenotypes. TCR complementarity-determining region cloning of expanded T cell clones in the tumors following vaccination confirmed reactivity against vaccine-encoded neoantigens. Our results support the PTCV's mechanism of action based on the induction of antitumor T cells and show that a PTCV plus pembrolizumab has clinical activity in advanced HCC. ClinicalTrials.gov identifier: NCT04251117 .

Targeting aging and age-related diseases with vaccines.

Aging is a major risk factor for numerous chronic diseases. Vaccination offers a promising strategy to combat these age-related diseases by targeting specific antigens and inducing immune responses. Here, we provide a comprehensive overview of recent advances in vaccine-based interventions targeting these diseases, including Alzheimer's disease, type II diabetes, hypertension, abdominal aortic aneurysm, atherosclerosis, osteoarthritis, fibrosis and cancer, summarizing current approaches for identifying disease-associated antigens and inducing immune responses against these targets. Further, we reflect on the recent development of vaccines targeting senescent cells, as a strategy for more broadly targeting underlying causes of aging and associated pathologies. In addition to highlighting recent progress in these areas, we discuss important next steps to advance the therapeutic potential of these vaccines, including improving and robustly demonstrating efficacy in human clinical trials, as well as rigorously evaluating the safety and long-term effects of these vaccine strategies.

Burden of antimicrobial prescribing in primary care attributable to sore throat: a retrospective cohort study of patient record data.

BACKGROUND: Reducing antibiotic use in Australia, and the subsequent impact on antimicrobial resistance, requires multiple, sustained approaches with appropriate resources and support. Additional strategies to reduce antibiotic prescribing include effective vaccines, against pathogens such as Streptococcus pyogenes, the most common bacterial cause of sore throat. As part of efforts towards assessing the benefits of introducing new strategies to reduce antimicrobial prescribing, we aimed to determine the burden of antimicrobial prescribing for sore throat in general practice. METHODS: General practice activity data from 2013 - 2017 derived from the first 8 practices participating in the 'Primary Care Audit, Teaching and Research Open Network' (Patron) program were analysed according to reason for visit (upper respiratory tract infection, URTI, or sore throat) and antibiotic prescription. The main outcome measures were percentage of sore throat or URTI presentations with antibiotic prescription by age. RESULTS: A total of 722,339 visits to general practice were made by 65,449 patients; 5.7% of visits were for URTI with 0.8% meeting the more specific criteria for sore throat. 66.1% of sore throat visits and 36.2% of URTI visits resulted in antibiotic prescription. Penicillin, the recommended antibiotic for sore throat when indicated, was the antibiotic of choice in only 52.9% of sore throat cases prescribed antibiotics. Broader spectrum antibiotics were prescribed more frequently in older age groups. CONCLUSIONS: Frequency of antibiotic prescribing for sore throat is high and broad, despite Australian Therapeutic guideline recommendations. Multiple, sustained interventions to reduce prescribing, including availability of effective S. pyogenes vaccines that could reduce the incidence of streptococcal pharyngitis, could obviate the need to prescribe antibiotics and support ongoing efforts to promote antimicrobial stewardship.

Case report: Long-term follow-up of patients who received a FimCH vaccine for prevention of recurrent urinary tract infections caused by antibiotic resistant Enterobacteriaceae: a case report series.

Urinary tract infections (UTI) caused by carbapenem-resistant Enterobacteriaceae (CRE) are considered one of the most urgent health threats to humans according to the Centers for Disease Control (CDC), and the World Health Organization (WHO). A FimCH Vaccine expanded access study is being conducted in patients with a history of antibiotic resistant UTIs who are considered to be at risk for development of CRE UTI. This case series describes the clinical, safety and immunogenicity findings for four participants who received a FimCH four-vaccine series. Participants were followed for 12 months after administration of the fourth vaccine for safety, general health status and UTI occurrence. The study was later amended to allow additional follow-up of up to five years post vaccine administration to assess long-term health status, UTI occurrences and to obtain blood samples for anti-FimH antibody testing. In our population of 4 study participants, the number of symptomatic UTI occurrences caused by gram-negative bacteria in the 12-month period following peak anti-FimH antibody response were approximately 75% lower than the 12-month period preceding study enrollment. These results are consistent with the 30-patient cohort of a Phase 1 study with the same FimCH Vaccine. UTI occurrences increased during the long-term follow-up period for all 4 participants but did not reach the rate observed pre-vaccination. No new safety concerns related to the FimCH Vaccine were identified during long-term follow-up. This case series has clinical importance and public health relevance since it examines and reports on UTI frequency and recurrence following vaccination with the FimCH Vaccine in a high-risk population of patients with recurrent UTI. Additionally, participants described improved well-being following vaccination which was maintained in the long-term follow-up period.

Agency in urgency and uncertainty. Vaccines and vaccination in European media discourses.

Although Covid-19 was not the first pandemic, it was unique in the scale and intensity with which societies responded. Countries reacted differently to the threat posed by the new virus. The public health crisis affected European societies in many ways. It also influenced the way the media portrayed vaccines and discussed factors related to vaccine hesitancy. Europeans differed in their risk perceptions, attitudes towards vaccines and vaccine uptake. In European countries, Covid-19-related discourses were at the centre of media attention for many months. This paper reports on a media analysis which revealed significant differences as well as some similarities in the media debates in different countries. The study focused on seven European countries and considered two dimensions of comparison: between the pre-Covid period and the beginning of the Covid pandemic period, and between countries. The rich methodological approach, including linguistics, semantic field analysis and discourse analysis of mainstream news media, allowed the authors to explore the set of meanings related to vaccination that might influence actors' agency. This approach led the authors to redefine vaccine hesitancy in terms of characteristics of the "society in the situation" rather than the psychological profile of individuals. We argue that vaccine hesitancy can be understood in terms of agency and temporality. This dilemma of choice that transforms the present into an irreversible past and must be taken in relation to an uncertain future, is particularly acute under the pressure of urgency and when someone's health is at stake. As such, it is linked to how vaccine meaning is co-produced within public discourses.

A shared neoantigen vaccine combined with immune checkpoint blockade for advanced metastatic solid tumors: phase 1 trial interim results.

Therapeutic vaccines that elicit cytotoxic T cell responses targeting tumor-specific neoantigens hold promise for providing long-term clinical benefit to patients with cancer. Here we evaluated safety and tolerability of a therapeutic vaccine encoding 20 shared neoantigens derived from selected common oncogenic driver mutations as primary endpoints in an ongoing phase 1/2 study in patients with advanced/metastatic solid tumors. Secondary endpoints included immunogenicity, overall response rate, progression-free survival and overall survival. Eligible patients were selected if their tumors expressed one of the human leukocyte antigen-matched tumor mutations included in the vaccine, with the majority of patients (18/19) harboring a mutation in KRAS. The vaccine regimen, consisting of a chimp adenovirus (ChAd68) and self-amplifying mRNA (samRNA) in combination with the immune checkpoint inhibitors ipilimumab and nivolumab, was shown to be well tolerated, with observed treatment-related adverse events consistent with acute inflammation expected with viral vector-based vaccines and immune checkpoint blockade, the majority grade 1/2. Two patients experienced grade 3/4 serious treatment-related adverse events that were also dose-limiting toxicities. The overall response rate was 0%, and median progression-free survival and overall survival were 1.9 months and 7.9 months, respectively. T cell responses were biased toward human leukocyte antigen-matched TP53 neoantigens encoded in the vaccine relative to KRAS neoantigens expressed by the patients' tumors, indicating a previously unknown hierarchy of neoantigen immunodominance that may impact the therapeutic efficacy of multiepitope shared neoantigen vaccines. These data led to the development of an optimized vaccine exclusively targeting KRAS-derived neoantigens that is being evaluated in a subset of patients in phase 2 of the clinical study. ClinicalTrials.gov registration: NCT03953235 .

Which foreign vaccine should the government purchase in a pandemic? Evidence from a survey experiment in the United States.

BACKGROUND: For many countries confronting a future pandemic, the initial vaccines available will come from abroad. Public hesitancy to receive these foreign vaccines is important, as it may create an incentive for governments to forego procuring them for public use. We investigate the influence of the vaccine's country of origin on public support for government procurement during the early stages of a pandemic and examine whether endorsements from the WHO can mitigate such biases. METHODS: In the summer of 2023, we carried out a survey experiment of 1,110 U.S. residents where we asked respondents to rate their support for vaccine purchasing policies for 20 hypothetical vaccines (13,320 evaluations). We varied the vaccine's country of origin and its endorsement status from the WHO, while also randomizing other vaccine attributes. RESULTS: Compared to foreign vaccines from countries Americans see favorable (e.g., Germany, the United Kingdom), those originating from less favorable countries (e.g., China, Russia), garnered lower support for government procurement. Our causal mediation analysis indicates that this country-of-origin effect is primarily driven by participants' sentiments toward the vaccine. Surprisingly, WHO endorsement does little to mitigate the effect of the vaccine's country of origin. These findings are consistent across various sample subsets and considerations of vaccine quality. CONCLUSION: Our study advances previous work on vaccine country-of-origin effects by assessing its impact on policy preferences for procuring initial vaccines from overseas (as opposed to uptake intentions), identifying a mechanism by which vaccine favoritism occurs, and documenting that neither personal disease susceptibility nor vaccine quality fully mitigates country of origin effects. We conclude by discussing why the study of "vaccine diplomacy" ought to not only include interstate dynamics governing vaccine purchasing and availability but also consider vaccine-producing countries' more general reputations.

Current status of immunological therapies for rheumatoid arthritis with a focus on antigen-specific therapeutic vaccines.

Rheumatoid arthritis (RA) is recognized as an autoimmune joint disease driven by T cell responses to self (or modified self or microbial mimic) antigens that trigger and aggravate the inflammatory condition. Newer treatments of RA employ monoclonal antibodies or recombinant receptors against cytokines or immune cell receptors as well as small-molecule Janus kinase (JAK) inhibitors to systemically ablate the cytokine or cellular responses that fuel inflammation. Unlike these treatments, a therapeutic vaccine, such as CEL-4000, helps balance adaptive immune homeostasis by promoting antigen-specific regulatory rather than inflammatory responses, and hence modulates the immunopathological course of RA. In this review, we discuss the current and proposed therapeutic products for RA, with an emphasis on antigen-specific therapeutic vaccine approaches to the treatment of the disease. As an example, we describe published results of the beneficial effects of CEL-4000 vaccine on animal models of RA. We also make a recommendation for the design of appropriate clinical studies for these newest therapeutic approaches, using the CEL-4000 vaccine as an example. Unlike vaccines that create or boost a new immune response, the clinical success of an immunomodulatory therapeutic vaccine for RA lies in its ability to redirect autoreactive pro-inflammatory memory T cells towards rebalancing the "runaway" immune/inflammatory responses that characterize the disease. Human trials of such a therapy will require alternative approaches in clinical trial design and implementation for determining safety, toxicity, and efficacy. These approaches include adaptive design (such as the Bayesian optimal design (BOIN), currently employed in oncological clinical studies), and the use of disease-related biomarkers as indicators of treatment success.

Recent advances in mRNA-based vaccine for cancer therapy; bench to bedside.

The messenger RNA (mRNA) vaccines have progressed from a theoretical concept to a clinical reality over the last few decades. Compared to conventional vaccination methods, these vaccines have a number of benefits, such as substantial potency, rapid growth, inexpensive production, and safe administration. Nevertheless, their usefulness was restricted up to now due to worries about the erratic and ineffective circulation of mRNA in vivo. Thankfully, these worries have largely been allayed by recent technological developments, which have led to the creation of multiple mRNA vaccination platforms for cancer and viral infections. The mRNA vaccines have been demonstrated as a powerful alternative to traditional conventional vaccines because of their high potency, safety and efficacy, capacity for rapid clinical development, and potential for rapid, low-cost manufacturing. The paper will examine the present status of mRNA vaccine technology and suggest future paths for the advancement and application of this exciting vaccine platform as a common therapeutic choice.

Dendritic cell vaccination in combination with erlotinib in a patient with inoperable lung adenocarcinoma: a case report.

BACKGROUND: Satisfactory treatment for patients with unresectable advanced lung cancer has not yet been established. We report a case of unresectable advanced lung cancer (stage IIIb: T2aN3M0) treated with a total of 15 doses of dendritic cells pulsed with a Wilms' tumor 1 and mucin 1 vaccine in combination with erlotinib, a small molecule epidermal growth factor receptor tyrosine kinase inhibitor, for more than 699 days without recurrence or metastasis. CASE PRESENTATION: A 63-year-old Korean woman was diagnosed with lung adenocarcinoma by pathology and computed tomography. The adenocarcinoma showed an epidermal growth factor receptor (EGFR) mutation, no anaplastic lymphoma kinase expression, and less than 1% expression of programmed death ligand 1. She received erlotinib alone for approximately 1 month. She then received erlotinib and the dendritic cells pulsed with Wilms' tumor 1 and mucin 1 vaccine. The diameter of the erythema at the vaccinated sites was 30 mm at 48 hours after the first vaccination. Moreover, it was maintained at more than 20 mm during the periods of vaccination. These results suggested the induction of antitumor immunity by the vaccine. Remarkably, the tumor size decreased significantly to 12 mm, a 65.7% reduction, after combined therapy with eight doses of the dendritic cells pulsed with Wilms' tumor 1 and mucin 1 vaccine and erlotinib for 237 days based on fluorodeoxyglucose uptake by positron emission tomography/computed tomography and computed tomography. Interestingly, after 321 days of combination therapy, the clinical findings improved, and no tumor was detected based on computed tomography. Validation of the tumor's disappearance persisted for at least 587 days after treatment initiation, without any indication of recurrence or metastasis. CONCLUSION: Standard anticancer therapy combined with the dendritic cells pulsed with Wilms' tumor 1 and mucin 1 vaccine may have therapeutic effects for such patients with unresectable lung adenocarcinoma.

Evolving therapeutic interventions for the management and treatment of Alzheimer's disease.

Alzheimer's Disease (AD) patients experience diverse symptoms, including memory loss, cognitive impairment, behavioral abnormalities, mood changes, and mental issues. The fundamental objective of this review is to discuss novel therapeutic approaches, with special emphasis on recently approved marketed formulations for the treatment of AD, especially Aducanumab, the first FDA approved moiety that surpasses the blood-brain barrier (BBB) and reduces amyloid plaques in the brain, thereby reducing associated cognitive decline. However, it is still in the phase IV trial and is to be completed by 2030. Other drugs such as lecanemab are also under clinical trial and has recently been approved by the FDA and is also discussed here. In this review, we also focus on active and passive immunotherapy for AD as well as several vaccines, such as amyloid-beta epitope-based vaccines, amyloid-beta DNA vaccines, and stem cell therapy for AD, which are in clinical trials. Furthermore, ongoing pre-clinical trials associated with AD and other novel strategies such as curcumin-loaded nanoparticles, Crispr/ cas9, precision medicine, as well as some emerging therapies like anti-sense therapy are also highlighted. Additionally, we discuss some off-labeled drugs like non-steroidal anti-inflammatory drugs (NSAID), anti-diabetic drugs, and lithium, which can manage symptoms of AD and different non-pharmacological approaches are also covered which can help to manage AD. In summary, we have tried to cover all the therapeutic interventions which are available for the treatment and management of AD under sections approved, clinical phase, pre-clinical phase or futuristic interventions, off-labelled drugs, and non-pharmacological interventions for AD, offering positive findings and well as challenges that remain.

Malaria prevention in children: an update.

PURPOSE OF REVIEW: Malaria cases and deaths decreased from 2000 to 2015 but remain increased since 2019. Several new developments and strategies could help reverse this trend. The purpose of this review is to discuss new World Health Organization (WHO) guidelines and recent research on malaria prevention in children. RECENT FINDINGS: Fifteen countries have now rolled out seasonal malaria chemoprophylaxis (SMC) in children at highest risk for severe malaria, and new WHO recommendations provide more flexibility for SMC implementation in terms of target age groups, geographic region, and number of cycles. Recent studies confirm that malaria burden in school aged children, and their contribution to transmission, is high. New guidelines permit expanded chemoprevention options for these children. Two vaccines have been approved for use in malaria endemic countries, RTS,S/AS01 E and R21/Matrix-M. Additionally, pyrethroid-chlorfenapyr bed nets are being deployed to combat resistant mosquitoes. SUMMARY: While challenges remain in malaria control towards elimination, new guidelines and recently approved vaccines offer hope. Monitoring for continued vaccine and chemoprevention effectiveness, and for possible epidemiologic shifts in severe malaria presentation and deaths as additional prevention efforts roll out will be paramount.

COVID -19: On the threshold of the fifth year. The situation in Spain / COVID-19: A las puertas del quinto año

Despite having emerged from pandemic status, the incidence of COVID-19 episodes has recently increased in Spain, including pediatric cases and admissions to Intensive Care Units. Several recombinant variants are circulating among us, particularly XBB arising from two Omicron BA.2 sublineages with mutations in the genes encoding the spicule proteins that could increase binding to the ACE2 receptor and be more prone to immune escape. Faced with these, 3 pharmaceutical companies have developed vaccines adapted to the XBB.1.5 sublineage that are already available for administration in our setting with risks that should not be different from those of previous mRNA vaccines and with clearly favorable benefit/risk ratios. They should be applied to patients with potential for poor COVID-19 evolution and to collectives that have a particular relationship of proximity with them. Their application should be understood not only from a perspective of individual convenience but also from that of collective responsibility. The most convenient seems to be a simultaneous immunization of COVID-19 and influenza in our environment. In the therapeutic aspect, there is little to expect right now from antisera, but the already known antiviral drugs are still available and indicated, although their efficacy will have to be reevaluated due to their impact on populations that are mostly immunized and with a better prognosis than in the past. In our opinion, it is necessary to continue to make a reasonable and timely use of masks and other non-pharmacological means of protection. (AU)

Pese a haber salido de la situación de pandemia, la incidencia de episodios de COVID-19 ha aumentado recientemente en España, incluidos los casos pediátricos y los ingresos en Unidades de Cuidados Intensivos. Circulan entre nosotros diversas variantes recombinantes, particularmente la XBB surgidas de dos sublinajes Omicron BA.2 con mutaciones en los genes que codifican las proteínas de la espícula y que pudieran aumentar la unión al receptor ACE2 y ser más propensas al escape inmune. Frente a ellas, 3 empresas farmacéuticas han elaborado vacunas adaptadas al sublinaje XBB.1.5 que ya se encuentran disponibles para su administración en nuestro medio con riesgos que no deben ser diferentes a los de las vacunas mRNA previas y con relaciones beneficio/riesgos claramente favorables. Deben aplicarse a pacientes con potencial de mala evolución de COVID-19 y a los colectivos que tienen una particular relación de proximidad con ellos. Su aplicación debe ser entendida no sólo desde una perspectiva de conveniencia individual sino desde la de la responsabilidad colectiva. Lo más conveniente parece hacer una inmunización simultánea de COVID-19 y gripe en nuestro medio. En el aspecto terapéutico hay poco que esperar ahora mismo de los antisueros pero siguen estando disponibles e indicados los fármacos antivirales ya conocidos aunque su eficacia tendrá que reevaluarse por su impacto en poblaciones mayoritariamente inmunizadas y con pronóstico mejor que las de tiempos pasados. A nuestro juicio, es necesario seguir haciendo un uso razonable y puntual de mascarillas y otros medios no farmacológicos de protección. (AU)

Photochemical inactivation as an alternative method to produce a whole-cell vaccine for uropathogenic Escherichia coli (UPEC).

Uropathogenic Escherichia coli (UPEC) is the primary causative agent of lower urinary tract infection (UTI). UTI presents a serious health risk and has considerable secondary implications including economic burden, recurring episodes, and overuse of antibiotics. A safe and effective vaccine would address this widespread health problem and emerging antibiotic resistance. Killed, whole-cell vaccines have shown limited efficacy to prevent recurrent UTI in human trials. We explored photochemical inactivation with psoralen drugs and UVA light (PUVA), which crosslinks nucleic acid, as an alternative to protein-damaging methods of inactivation to improve whole-cell UTI vaccines. Exposure of UPEC to the psoralen drug AMT and UVA light resulted in a killed but metabolically active (KBMA) state, as reported previously for other PUVA-inactivated bacteria. The immunogenicity of PUVA-UPEC as compared to formalin-inactivated UPEC was compared in mice. Both generated high UPEC-specific serum IgG titers after intramuscular delivery. However, using functional adherence as a measure of surface protein integrity, we found differences in the properties of PUVA- and formalin-inactivated UPEC. Adhesion mediated by Type-1 and P-fimbriae was severely compromised by formalin but was unaffected by PUVA, indicating that PUVA preserved the functional conformation of fimbrial proteins, which are targets of protective immune responses. In vitro assays indicated that although they retained metabolic activity, PUVA-UPEC lost virulence properties that could negatively impact vaccine safety. Our results imply the potential for PUVA to improve killed, whole-cell UTI vaccines by generating bacteria that more closely resemble their live, infectious counterparts relative to vaccines generated with protein-damaging methods. IMPORTANCE: Lower urinary tract infection (UTI), caused primarily by uropathogenic Escherichia coli, represents a significant health burden, accounting for 7 million primary care and 1 million emergency room visits annually in the United States. Women and the elderly are especially susceptible and recurrent infection (rUTI) is common in those populations. Lower UTI can lead to life-threatening systemic infection. UTI burden is manifested by healthcare dollars spent (1.5 billion annually), quality of life impact, and resistant strains emerging from antibiotic overuse. A safe and effective vaccine to prevent rUTI would address a substantial healthcare issue. Vaccines comprised of inactivated uropathogenic bacteria have yielded encouraging results in clinical trials but improvements that enhance vaccine performance are needed. To that end, we focused on inactivation methodology and provided data to support photochemical inactivation, which targets nucleic acid, as a promising alternative to conventional protein-damaging inactivation methods to improve whole-cell UTI vaccines.

Roles of exosomes in immunotherapy for solid cancers.

Although immunotherapy has made breakthrough progress, its efficacy in solid tumours remains unsatisfactory. Exosomes are the main type of extracellular vesicles that can deliver various intracellular molecules to adjacent or distant cells and organs, mediating various biological functions. Studies have found that exosomes can both activate the immune system and inhibit the immune system. The antigen and major histocompatibility complex (MHC) carried in exosomes make it possible to develop them as anticancer vaccines. Exosomes derived from blood, urine, saliva and cerebrospinal fluid can be used as ideal biomarkers in cancer diagnosis and prognosis. In recent years, exosome-based therapy has made great progress in the fields of drug transportation and immunotherapy. Here, we review the composition and sources of exosomes in the solid cancer immune microenvironment and further elaborate on the potential mechanisms and pathways by which exosomes influence immunotherapy for solid cancers. Moreover, we summarize the potential clinical application prospects of engineered exosomes and exosome vaccines in immunotherapy for solid cancers. Eventually, these findings may open up avenues for determining the potential of exosomes for diagnosis, treatment, and prognosis in solid cancer immunotherapy.

Role of HIV-1 Tat Protein Interactions with Host Receptors in HIV Infection and Pathogenesis.

Each time the virus starts a new round of expression/replication, even under effective antiretroviral therapy (ART), the transactivator of viral transcription Tat is one of the first HIV-1 protein to be produced, as it is strictly required for HIV replication and spreading. At this stage, most of the Tat protein exits infected cells, accumulates in the extracellular matrix and exerts profound effects on both the virus and neighbor cells, mostly of the innate and adaptive immune systems. Through these effects, extracellular Tat contributes to the acquisition of infection, spreading and progression to AIDS in untreated patients, or to non-AIDS co-morbidities in ART-treated individuals, who experience inflammation and immune activation despite virus suppression. Here, we review the role of extracellular Tat in both the virus life cycle and on cells of the innate and adaptive immune system, and we provide epidemiological and experimental evidence of the importance of targeting Tat to block residual HIV expression and replication. Finally, we briefly review vaccine studies showing that a therapeutic Tat vaccine intensifies ART, while its inclusion in a preventative vaccine may blunt escape from neutralizing antibodies and block early events in HIV acquisition.

Vaccines targeting ESR1 activating mutations elicit anti-tumor immune responses and suppress estrogen signaling in therapy resistant ER+ breast cancer.

ER+ breast cancers (BC) are characterized by the elevated expression and signaling of estrogen receptor alpha (ESR1), which renders them sensitive to anti-endocrine therapy. While these therapies are clinically effective, prolonged treatment inevitably results in therapeutic resistance, which can occur through the emergence of gain-of-function mutations in ESR1. The central importance of ESR1 and development of mutated forms of ESR1 suggest that vaccines targeting these proteins could potentially be effective in preventing or treating endocrine resistance. To explore the potential of this approach, we developed several recombinant vaccines encoding different mutant forms of ESR1 (ESR1mut) and validated their ability to elicit ESR1-specific T cell responses. We then developed novel ESR1mut-expressing murine mammary cancer models to test the anti-tumor potential of ESR1mut vaccines. We found that these vaccines could suppress tumor growth, ESR1mut expression and estrogen signaling in vivo. To illustrate the applicability of these findings, we utilize HPLC to demonstrate the presentation of ESR1 and ESR1mut peptides on human ER+ BC cell MHC complexes. We then show the presence of human T cells reactive to ESR1mut epitopes in an ER+ BC patient. These findings support the development of ESR1mut vaccines, which we are testing in a Phase I clinical trial.

Clinical and immunological outcomes of HIV-exposed uninfected and HIV-unexposed uninfected children in the first 24 months of life in Western Kenya.

BACKGROUND: Previous studies show increased morbidity in children who are HIV-exposed but uninfected (HEU) compared to children who are HIV-unexposed uninfected (HUU). We sought to evaluate the effects of prenatal HIV exposure on clinical and immunological outcomes in the first 24 months of life. METHODS: Eighty-five HEU and 168 HUU children from Kenya were followed from birth to 24 months. All mothers living with HIV received combination antiretroviral therapy. Children who were HEU received standard-of-care cotrimoxazole prophylaxis through 18 months. Episodes of acute illness were identified through a combination of active and passive follow up. Trajectories of plasma cytokines, vaccine-specific antibodies, and antimalarial antibodies were examined. RESULTS: Children who were HEU and children who were HUU had similar growth curves. Children who were HEU had lower rates of malaria (rate ratio 0.54, 95% CI 0.38, 0.77) and respiratory illness (rate ratio 0.80, 95% CI 0.68, 0.93). Trajectories of plasma cytokines and vaccine-specific antibodies were similar in children who were HEU and HUU. There were subtle differences in antimalarial antibody dynamics, in which children who were HEU had overall lower antibody levels against five of the 14 malaria antigens tested. CONCLUSIONS: Children who were HEU and born to optimally treated mothers living with HIV had similar growth characteristics and immune profiles compared to children who were HUU. Children who were HEU had reduced risk for malaria and respiratory illness, which may be secondary to cotrimoxazole prophylaxis.