Vaccination for healthy aging.

As the world's population grows older, vaccination is becoming a key strategy for promoting healthy aging. Despite scientific progress in adult vaccine development, obstacles such as immunosenescence and vaccine hesitancy remain. To unlock the potential of adult vaccines fully, we must enhance immunization programs, dispel misinformation, and invest in research that deepens our understanding of aging and immunity.

Affinity gaps among B cells in germinal centers drive the selection of MPER precursors.

Current prophylactic human immunodeficiency virus 1 (HIV-1) vaccine research aims to elicit broadly neutralizing antibodies (bnAbs). Membrane-proximal external region (MPER)-targeting bnAbs, such as 10E8, provide exceptionally broad neutralization, but some are autoreactive. Here, we generated humanized B cell antigen receptor knock-in mouse models to test whether a series of germline-targeting immunogens could drive MPER-specific precursors toward bnAbs. We found that recruitment of 10E8 precursors to germinal centers (GCs) required a minimum affinity for germline-targeting immunogens, but the GC residency of MPER precursors was brief due to displacement by higher-affinity endogenous B cell competitors. Higher-affinity germline-targeting immunogens extended the GC residency of MPER precursors, but robust long-term GC residency and maturation were only observed for MPER-HuGL18, an MPER precursor clonotype able to close the affinity gap with endogenous B cell competitors in the GC. Thus, germline-targeting immunogens could induce MPER-targeting antibodies, and B cell residency in the GC may be regulated by a precursor-competitor affinity gap.

Vaccination induces broadly neutralizing antibody precursors to HIV gp41.

A key barrier to the development of vaccines that induce broadly neutralizing antibodies (bnAbs) against human immunodeficiency virus (HIV) and other viruses of high antigenic diversity is the design of priming immunogens that induce rare bnAb-precursor B cells. The high neutralization breadth of the HIV bnAb 10E8 makes elicitation of 10E8-class bnAbs desirable; however, the recessed epitope within gp41 makes envelope trimers poor priming immunogens and requires that 10E8-class bnAbs possess a long heavy chain complementarity determining region 3 (HCDR3) with a specific binding motif. We developed germline-targeting epitope scaffolds with affinity for 10E8-class precursors and engineered nanoparticles for multivalent display. Scaffolds exhibited epitope structural mimicry and bound bnAb-precursor human naive B cells in ex vivo screens, protein nanoparticles induced bnAb-precursor responses in stringent mouse models and rhesus macaques, and mRNA-encoded nanoparticles triggered similar responses in mice. Thus, germline-targeting epitope scaffold nanoparticles can elicit rare bnAb-precursor B cells with predefined binding specificities and HCDR3 features.

The immune evasion roles of Staphylococcus aureus protein A and impact on vaccine development.

While Staphylococcus aureus (S. aureus) bacteria are part of the human commensal flora, opportunistic invasion following breach of the epithelial layers can lead to a wide array of infection syndromes at both local and distant sites. Despite ubiquitous exposure from early infancy, the life-long risk of opportunistic infection is facilitated by a broad repertoire of S. aureus virulence proteins. These proteins play a key role in inhibiting development of a long-term protective immune response by mechanisms ranging from dysregulation of the complement cascade to the disruption of leukocyte migration. In this review we describe the recent progress made in dissecting S. aureus immune evasion, focusing on the role of the superantigen, staphylococcal protein A (SpA). Evasion of the normal human immune response drives the ability of S. aureus to cause infection, often recurrently, and is also thought to be a major hindrance in the development of effective vaccination strategies. Understanding the role of S. aureus virulence protein and determining methods overcoming or subverting these mechanisms could lead to much-needed breakthroughs in vaccine and monoclonal antibody development.

Save the microbes to save the planet. A call to action of the International Union of the Microbiological Societies (IUMS).

Our planet is populated by at least a trillion species of microorganisms. Every life form is sustained by them and they make the planet habitable. Only a minority of them, about 1400 species, cause infectious diseases that are responsible for human morbidity, mortality, pandemics and the resulting huge economic losses. Modern human activities, environmental changes and the attempt to control infectious agents using broad spectrum antibiotics and disinfectants jeopardize the global microbial diversity. The International Union of the Microbiological Societies (IUMS) is launching a call to action to mobilize all microbiological societies globally to promote the development of sustainable solutions to control infectious agents while preserving the global microbial diversity and the healthy life of our planet.

Vaccines for a sustainable planet.

The health of the planet is one objective of the United Nations' Sustainable Development Goals. Vaccines can affect not only human health but also planet health by reducing poverty, preserving microbial diversity, reducing antimicrobial resistance, and preventing an increase in pandemics that is fueled partly by climate change.

Global antibiotic use during the COVID-19 pandemic: analysis of pharmaceutical sales data from 71 countries, 2020-2022.

Background: Despite bacterial coinfection rates of less than 10%, antibiotics are prescribed to an estimated 75% of patients with COVID-19, potentially exacerbating antimicrobial resistance. We estimated the associations of COVID-19 cases and vaccinations with global antibiotic sales during the first two years of the COVID-19 pandemic. Methods: We obtained monthly data on broad-spectrum antibiotic sales volumes (cephalosporins, penicillins, macrolides, and tetracyclines) in 71 countries during March 2020-May 2022 from the IQVIA MIDAS® database. These data were combined with country-month-level COVID-19 case and vaccination data from Our World in Data. We used least squares (pooled) and fixed-effects panel data regression models, accounting for country characteristics, to estimate the associations between antibiotic sales volumes and COVID-19 cases and vaccinations per 1000 people. Findings: Sales of all four antibiotics fell sharply during April and May 2020, followed by a gradual rise to near pre-pandemic levels through May 2022. In fixed-effects regression models, a 10% increase in monthly COVID-19 cases was associated with 0.2%-0.3% higher sales of cephalosporins, 0.2%-0.3% higher sales of penicillins, 0.4%-0.6% higher sales of macrolides, and 0.3% higher sales of all four antibiotics combined per 1000 people. Across continents, a 10% increase in monthly COVID-19 cases was associated with 0.8%, 1.3%, and 1.5% higher macrolides sales in Europe, North America, and Africa respectively. Sales of other antibiotics across continent were also positively associated with COVID-19 cases, although the estimated associations were smaller in magnitude. No consistent associations were observed between antibiotic sales and COVID-19 vaccinations. Results from pooled regression analysis were similar to those from the fixed-effects models. Interpretation: Antibiotic sales were positively associated with COVID-19 cases globally during 2020-2022. Our findings underline that antibiotic stewardship in the context of COVID-19 remains essential. Funding: Bill & Melinda Gates Foundation.

Membrane-bound mRNA immunogens lower the threshold to activate HIV Env V2 apex-directed broadly neutralizing B cell precursors in humanized mice.

Eliciting broadly neutralizing antibodies (bnAbs) is the core of HIV vaccine design. bnAbs specific to the V2-apex region of the HIV envelope acquire breadth and potency with modest somatic hypermutation, making them attractive vaccination targets. To evaluate Apex germline-targeting (ApexGT) vaccine candidates, we engineered knockin (KI) mouse models expressing the germline B cell receptor (BCR) of the bnAb PCT64. We found that high affinity of the ApexGT immunogen for PCT64-germline BCRs was necessary to specifically activate KI B cells at human physiological frequencies, recruit them to germinal centers, and select for mature bnAb mutations. Relative to protein, mRNA-encoded membrane-bound ApexGT immunization significantly increased activation and recruitment of PCT64 precursors to germinal centers and lowered their affinity threshold. We have thus developed additional models for HIV vaccine research, validated ApexGT immunogens for priming V2-apex bnAb precursors, and identified mRNA-LNP as a suitable approach to substantially improve the B cell response.

The trillion dollar vaccine gap.

New technologies and unprecedented public investment have transformed vaccine development and allowed fast delivery of safe and efficacious COVID-19 vaccines, mitigating the impact of the pandemic on health and the economy. A quantum change in public investment for vaccine development and widespread vaccine distribution are necessary to achieve global pandemic preparedness.

Immunology and Technology of Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccines.

We have experienced an enormous cohesive effort of the scientific community to understand how the immune system reacts to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and how to elicit protective immunity via vaccination. This effort resulted in the development of vaccines in record time with high levels of safety, efficacy, and real-life effectiveness. However, the rapid diffusion of viral variants that escape protective antibodies prompted new studies to understand SARS-CoV-2 vulnerabilities and strategies to guide follow-up actions to increase, and maintain, the protection offered by vaccines. In this review, we report the main findings on human immunity to SARS-CoV-2 after natural infection and vaccination; we dissect the immunogenicity and efficacy of the different vaccination strategies that resulted in products widely used in the population; and we describe the impact of viral variants on vaccine-elicited immunity, summarizing the main discoveries and challenges to stay ahead of SARS-CoV-2 evolution. SIGNIFICANCE STATEMENT: This study reviewed findings on human immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), analyzed the immunogenicity and efficacy of the various vaccines currently used in large vaccination campaigns or candidates in advanced clinical development, and discussed the challenging task to ensure high protective efficacy against the rapidly evolving SARS-CoV-2 virus. This manuscript was completed prior to the emergence of the Omicron variant and to global vaccine boosting efforts.

Recent advances and future perspectives on carbohydrate-based cancer vaccines and therapeutics.

Carbohydrates are abundantly expressed on the surface of both eukaryotic and prokaryotic cells, often as post translational modifications of proteins. Glycoproteins are recognized by the immune system and can trigger both innate and humoral responses. This feature has been harnessed to generate vaccines against polysaccharide-encapsulated bacteria such as Streptococcus pneumoniae, Hemophilus influenzae type b and Neisseria meningitidis. In cancer, glycosylation plays a pivotal role in malignancy development and progression. Since glycans are specifically expressed on the surface of tumor cells, they have been targeted for the discovery of anticancer preventive and therapeutic treatments, such as vaccines and monoclonal antibodies. Despite the various efforts made over the last years, resulting in a series of clinical studies, attempts of vaccination with carbohydrate-based candidates have proven unsuccessful, primarily due to the immune tolerance often associated with these glycans. New strategies are thus deployed to enhance carbohydrate-based cancer vaccines. Moreover, lessons learned from glycan immunobiology paved the way to the development of new monoclonal antibodies specifically designed to recognize cancer-bound carbohydrates and induce tumor cell killing. Herein we provide an overview of the immunological principles behind the immune response towards glycans and glycoconjugates and the approaches exploited at both preclinical and clinical level to target cancer-associated glycans for the development of vaccines and therapeutic monoclonal antibodies. We also discuss gaps and opportunities to successfully advance glycan-directed cancer therapies, which could provide patients with innovative and effective treatments.

Vaccines 2020: The era of the digital vaccine is here.

The SARS-CoV-2 pandemic has generated a renaissance in vaccinology, with COVID-19 mRNA vaccines delivering a "digital code" of the viral antigen with no need to purify proteins or inactivate pathogens.

Vaccinology in the post-COVID-19 era.

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.

Mer tyrosine kinase as a possible link between resolution of inflammation and tissue fibrosis in IgG4-related disease.

OBJECTIVES: IgG4-related disease (IgG4-RD) is a systemic fibro-inflammatory disorder characterized by a dysregulated resolution of inflammation and wound healing response that might develop after an apoptotic insult induced by cytotoxic T lymphocytes (CTLs). Mer receptor tyrosine kinase (MerTK) and its ligand, protein S (ProS1), have a pivotal role in the resolution of inflammation, being implicated in the clearance of apoptotic cells, quenching of the immune response and development of tissue fibrosis. In the present work we aimed to investigate a possible involvement of the MerTK signalling pathway in the pathogenesis of IgG4-RD and development of tissue fibrosis. METHODS: MerTK and ProS1 expression patterns in IgG4-RD lesions were evaluated by immunohistochemistry and immunofluorescence studies. Circulating MerTK+ monocytes, soluble Mer and MerTK ligands were measured in the peripheral blood of IgG4-RD patients and healthy controls by flow cytometry and ELISA, respectively. RESULTS: MerTK was highly expressed by macrophages infiltrating IgG4-RD lesions. MerTK+ macrophages were more abundant in IgG4-RD than in Sjögren's syndrome and interacted with apoptotic cells and ProS1-expressing T and B lymphocytes. Moreover, they expressed the pro-fibrotic cytokine TGF-ß and their numbers declined following rituximab-induced disease remission. Circulating MerTK+ monocytes, soluble Mer and MerTK ligands were not increased in the peripheral blood of patients with IgG4-RD. CONCLUSIONS: The MerTK-ProS1 axis is activated in IgG4-RD lesions, possibly leading to persistent stimulation of processes involved in the resolution of inflammation and tissue fibrosis.

Bacteriophages, a multi-tool to fight infectious disease.

The selectivity of bacteriophages and the flexibility of phage-based preventative or curative treatments hold the promise to counteract the emerging antimicrobial resistant bacteria and other pathogens. An increasing understanding of the phage biology and recent scientific advancements in the field suggest that this might be possible.

Quantum leap of monoclonal antibody (mAb) discovery and development in the COVID-19 era.

In recent years the global market for monoclonal antibodies (mAbs) became a multi-billion-dollar business. This success is mainly driven by treatments in the oncology and autoimmune space. Instead, development of effective mAbs against infectious diseases has been lagging behind. For years the high production cost and limited efficacy have blocked broader application of mAbs in the infectious disease space, which instead has been dominated for almost a century by effective and cheap antibiotics and vaccines. Only very few mAbs against RSV, anthrax, Clostridium difficile or rabies have reached the market. This is about to change. The development of urgently needed and highly effective mAbs as preventive and therapeutic treatments against a variety of pathogens is gaining traction. Vast advances in mAb isolation, engineering and production have entirely shifted the cost-efficacy balance. MAbs against devastating diseases like Ebola, HIV and other complex pathogens are now within reach. This trend is further accelerated by ongoing or imminent health crises like COVID-19 and antimicrobial resistance (AMR), where antibodies could be the last resort. In this review we will retrace the history of antibodies from the times of serum therapy to modern mAbs and lay out how the current run for effective treatments against COVID-19 will lead to a quantum leap in scientific, technological and health care system innovation around mAb treatments for infectious diseases.

Transforming vaccine development.

The urgency to develop vaccines against Covid-19 is putting pressure on the long and expensive development timelines that are normally required for development of lifesaving vaccines. There is a unique opportunity to take advantage of new technologies, the smart and flexible design of clinical trials, and evolving regulatory science to speed up vaccine development against Covid-19 and transform vaccine development altogether.

A generalized HIV vaccine design strategy for priming of broadly neutralizing antibody responses.

Vaccine induction of broadly neutralizing antibodies (bnAbs) to HIV remains a major challenge. Germline-targeting immunogens hold promise for initiating the induction of certain bnAb classes; yet for most bnAbs, a strong dependence on antibody heavy chain complementarity-determining region 3 (HCDR3) is a major barrier. Exploiting ultradeep human antibody sequencing data, we identified a diverse set of potential antibody precursors for a bnAb with dominant HCDR3 contacts. We then developed HIV envelope trimer-based immunogens that primed responses from rare bnAb-precursor B cells in a mouse model and bound a range of potential bnAb-precursor human naïve B cells in ex vivo screens. Our repertoire-guided germline-targeting approach provides a framework for priming the induction of many HIV bnAbs and could be applied to most HCDR3-dominant antibodies from other pathogens.