The Circadian Biology of Heart Failure.

Driven by autonomous molecular clocks that are synchronized by a master pacemaker in the suprachiasmatic nucleus, cardiac physiology fluctuates in diurnal rhythms that can be partly or entirely circadian. Cardiac contractility, metabolism, and electrophysiology, all have diurnal rhythms, as does the neurohumoral control of cardiac and kidney function. In this review, we discuss the evidence that circadian biology regulates cardiac function, how molecular clocks may relate to the pathogenesis of heart failure, and how chronotherapeutics might be applied in heart failure. Disrupting molecular clocks can lead to heart failure in animal models, and the myocardial response to injury seems to be conditioned by the time of day. Human studies are consistent with these findings, and they implicate the clock and circadian rhythms in the pathogenesis of heart failure. Certain circadian rhythms are maintained in patients with heart failure, a factor that can guide optimal timing of therapy. Pharmacologic and nonpharmacologic manipulation of circadian rhythms and molecular clocks show promise in the prevention and treatment of heart failure.

Differential Impact In Vivo of Pf4-ΔCre-Mediated and Gp1ba-ΔCre-Mediated Depletion of Cyclooxygenase-1 in Platelets in Mice.

BACKGROUND: Low-dose aspirin is widely used for the secondary prevention of cardiovascular disease. The beneficial effects of low-dose aspirin are attributable to its inhibition of platelet Cox (cyclooxygenase)-1-derived thromboxane A2. Until recently, the use of the Pf4 (platelet factor 4) Cre has been the only genetic approach to generating megakaryocyte/platelet ablation of Cox-1 in mice. However, Pf4-ΔCre displays ectopic expression outside the megakaryocyte/platelet lineage, especially during inflammation. The use of the Gp1ba (glycoprotein 1bα) Cre promises a more specific, targeted approach. METHODS: To evaluate the role of Cox-1 in platelets, we crossed Pf4-ΔCre or Gp1ba-ΔCre mice with Cox-1flox/flox mice to generate platelet Cox-1-/- mice on normolipidemic and hyperlipidemic (Ldlr-/-; low-density lipoprotein receptor) backgrounds. RESULTS: Ex vivo platelet aggregation induced by arachidonic acid or adenosine diphosphate in platelet-rich plasma was inhibited to a similar extent in Pf4-ΔCre Cox-1-/-/Ldlr-/- and Gp1ba-ΔCre Cox-1-/-/Ldlr-/- mice. In a mouse model of tail injury, Pf4-ΔCre-mediated and Gp1ba-ΔCre-mediated deletions of Cox-1 were similarly efficient in suppressing platelet prostanoid biosynthesis. Experimental thrombogenesis and attendant blood loss were similar in both models. However, the impact on atherogenesis was divergent, being accelerated in the Pf4-ΔCre mice while restrained in the Gp1ba-ΔCres. In the former, accelerated atherogenesis was associated with greater suppression of PGI2 biosynthesis, a reduction in the lipopolysaccharide-evoked capacity to produce PGE2 (prostaglandin E) and PGD2 (prostanglandin D), activation of the inflammasome, elevated plasma levels of IL-1ß (interleukin), reduced plasma levels of HDL-C (high-density lipoprotein receptor-cholesterol), and a reduction in the capacity for reverse cholesterol transport. By contrast, in the latter, plasma HDL-C and α-tocopherol were elevated, and MIP-1α (macrophage inflammatory protein-1α) and MCP-1 (monocyte chemoattractant protein 1) were reduced. CONCLUSIONS: Both approaches to Cox-1 deletion similarly restrain thrombogenesis, but a differential impact on Cox-1-dependent prostanoid formation by the vasculature may contribute to an inflammatory phenotype and accelerated atherogenesis in Pf4-ΔCre mice.

Circadian disruption in lung fibroblasts enhances NF-κB activity to exacerbate neutrophil recruitment.

Fibroblasts are stromal cells abundant throughout tissues, including the lungs. Fibroblasts are integral coordinators of immune cell recruitment through chemokine secretion. Circadian rhythms direct the recruitment of immune cells to the lung, which in turn impacts response to infection and survival. Although fibroblasts display robust circadian rhythms, the contribution of the fibroblast molecular clock to lung-specific migration of immune cells and recruitment remains to be established. Mice challenged intranasally with lipopolysaccharide (LPS) at dusk showed increased expression of the pro-inflammatory cytokine IL-1ß and chemokine CXCL5 in the lung, which was accompanied by increased neutrophil recruitment. Primary lung fibroblasts with knockdown of the core clock gene Bmal1 and immortalized Bmal1-/- lung fibroblasts also displayed increased Cxcl5 expression under IL-1ß stimulation. Conditioned media obtained from IL-1ß-stimulated Bmal1-/- immortalized fibroblasts-induced greater neutrophil migration compared with Bmal1+/+ lung fibroblast controls. Phosphorylation of the NF-κB subunit, p65, was enhanced in IL-1ß-stimulated Bmal1-/- lung fibroblasts, and pharmacological inhibition of NF-κB attenuated the enhanced CXCL5 production and neutrophil recruitment observed in these cells. Collectively, these results demonstrate that Bmal1 represses NF-κB activity in lung fibroblasts to control chemokine expression and immune cell recruitment during an inflammatory response.

Polar lipids modify Alzheimer's Disease pathology by reducing astrocyte pro-inflammatory signaling through platelet-activating factor receptor (PTAFR) modulation.

BACKGROUND: Pro-inflammatory processes triggered by the accumulation of extracellular amyloid beta (Aß) peptides are a well-described pathology in Alzheimer's disease (AD). Activated astrocytes surrounding Aß plaques contribute to inflammation by secreting proinflammatory factors. While astrocytes may phagocytize Aß and contribute to Aß clearance, reactive astrocytes may also increase Aß production. Therefore, identifying factors that can attenuate astrocyte activation and neuroinflammation and how these factors influence pro-inflammatory pathways is important for developing therapeutic and preventive strategies in AD. Here, we identify the platelet-activating factor receptor (PTAFR) pathway as a key mediator of astrocyte activation. Intriguingly, several polar lipids (PLs) have exhibited anti-inflammatory protective properties outside the central nervous system through their inhibitory effect on the PTAFR pathway. Thus, we additionally investigated whether different PLs also exert inhibitory effects on the PAF pathway in astrocytes and whether their presence influences astrocytic pro-inflammatory signaling and known AD pathologies in vitro. METHODS: PLs from salmon and yogurt were extracted using novel food-grade techniques and their fatty acid profile was determined using LC/MS. The effect of PLs on parameters such as astrocyte activation and generation of oxygen species (ROS) was assessed. Additionally, effects of the secretome of astrocytes treated with these polar lipids on aged neurons was measured. RESULTS: We show that PLs obtained from salmon and yogurt lower astrocyte activation, the generation of reactive oxygen species (ROS), and extracellular Aß accumulation. Cell health of neurons exposed to the secretome of astrocytes treated with salmon-derived PLs and Aß was less affected than those treated with astrocytes exposed to Aß only. CONCLUSION: Our results highlight a novel underlying mechanism, why consuming PL-rich foods such as fish and dairy may reduce the risk of developing dementia and associated disorders.

Modulation of the Immune Response to Severe Acute Respiratory Syndrome Coronavirus 2 Vaccination by Nonsteroidal Anti-Inflammatory Drugs.

Evidence is scarce to guide the use of nonsteroidal anti-inflammatory drugs (NSAIDs) to mitigate severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) vaccine-related adverse effects, given the possibility of blunting the desired immune response. In this pilot study, we deeply phenotyped a small number of volunteers who did or did not take NSAIDs concomitant with SARS-CoV-2 immunizations to seek initial information on the immune response. A SARS-CoV-2 vaccine-specific receptor binding domain (RBD) IgG antibody response and efficacy in the evoked neutralization titers were evident irrespective of concomitant NSAID consumption. Given the sample size, only a large and consistent signal of immunomodulation would have been detectable, and this was not apparent. However, the information gathered may inform the design of a definitive clinical trial. Here we report a series of divergent omics signals that invites additional hypotheses testing. SIGNIFICANCE STATEMENT: The impact of nonsteroidal anti-inflammatory drugs (NSAIDs) on the immune response elicited by repeat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immunizations was profiled by immunophenotypic, proteomic, and metabolomic approaches in a clinical pilot study of small sample size. A SARS-CoV-2 vaccine-specific immune response was evident irrespective of concomitant NSAID consumption. The information gathered may inform the design of a definitive clinical trial.

Cardiovascular Diseases and Marine Oils: A Focus on Omega-3 Polyunsaturated Fatty Acids and Polar Lipids.

Cardiovascular diseases (CVD) remain the leading cause of death across the globe, hence, establishing strategies to counteract CVD are imperative to reduce mortality and the burden on health systems. Dietary modification is an effective primary prevention strategy against CVD. Research regarding dietary supplementation has become increasingly popular. This review focuses on the current in vivo, in vitro, and epidemiological studies associated with that of omega-3 polyunsaturated fatty acids (n-3 PUFAs) and polar lipids (PLs) and how they play a role against CVD. Furthermore, this review focuses on the results of several major clinical trials examining n-3 PUFAs regarding both primary and secondary prevention of CVD. Notably, we place a lens on the REDUCE-IT and STRENGTH trials. Finally, supplementation of PLs has recently been suggested as a potential alternative avenue for the reduction of CVD incidence versus neutral forms of n-3 PUFAs. However, the clinical evidence for this argument is currently rather limited. Therefore, we draw on the current literature to suggest future clinical trials for PL supplementation. We conclude that despite conflicting evidence, future human trials must be completed to confirm whether PL supplementation may be more effective than n-3 PUFA supplementation to reduce cardiovascular risk.

The current use and evolving landscape of nutraceuticals.

The nutraceutical market is currently a high-impact multi-billion-dollar industry, and it is anticipated to grow rapidly over the next decade. Nutraceuticals comprise diverse food-derived product categories that have become widespread due to increased consumer awareness of potential health benefits and the need for improved wellness. This targeted review is designed to identify the current global trends, market opportunities, and regulations that drive the nutraceutical industry. Safety and efficacy concerns are also explored with a view to highlighting areas that necessitate further research and oversight. Key drivers of the nutraceutical market include aging populations, consumer awareness, consumer lifestyle, increasing cost of healthcare, and marketing channels. Although some nutraceuticals hold promising preventive and therapeutic opportunities, there is a lack of a universal definition and regulatory framework among countries. Moreover, there is a lack of adequate evidence for their efficacy, safety, and effectiveness, which was even further highlighted during the ongoing coronavirus pandemic. Future prospective epidemiological studies can delineate the health impact of nutraceuticals and help set the scientific basis and rationale foundation for clinical trials, reducing the time and cost of trials themselves. Together, an understanding of the key drivers of the nutraceutical market alongside a consistent and well-defined regulatory framework will provide further opportunities for growth, expansion, and segmentation of nutraceuticals applications.

Bioactive Lipids of Marine Microalga Chlorococcum sp. SABC 012504 with Anti-Inflammatory and Anti-Thrombotic Activities.

Microalgae are at the start of the food chain, and many are known producers of a significant amount of lipids with essential fatty acids. However, the bioactivity of microalgal lipids for anti-inflammatory and antithrombotic activities have rarely been investigated. Therefore, for a sustainable source of the above bioactive lipids, the present study was undertaken. The total lipids of microalga Chlorococcum sp., isolated from the Irish coast, were fractionated into neutral-, glyco-, and phospho-lipids, and were tested in vitro for their anti-inflammatory and antithrombotic activities. All tested lipid fractions showed strong anti-platelet-activating factor (PAF) and antithrombin activities in human platelets (half maximal inhibitory concentration (IC50) values ranging ~25-200 µg of lipid) with the highest activities in glyco- and phospho-lipid fractions. The structural analysis of the bioactive lipid fraction-2 revealed the presence of specific sulfoquinovosyl diacylglycerols (SQDG) bioactive molecules and the HexCer-t36:2 (t18:1/18:1 and 18:2/18:0) cerebrosides with a phytosphingosine (4-hydrosphinganine) base, while fraction-3 contained bioactive phosphatidylcholine (PC) and phosphatidylethanolamine (PE) molecules. These novel bioactive lipids of Chlorococcum sp. with putative health benefits may indicate that marine microalgae can be a sustainable alternative source for bioactive lipids production for food supplements and nutraceutical applications. However, further studies are required towards the commercial technology pathways development and biosafety analysis for the use of the microalga.

In Vitro Antithrombotic Properties of Salmon (Salmo salar) Phospholipids in a Novel Food-Grade Extract.

Marine and salmon polar lipids (PLs) extracted by conventional extractions with non-food-grade solvents (CE-salmon-PLs) possess antithrombotic bioactivities against platelet-activating factor (PAF) and thrombin. Similar effects of food-grade-extracted (FGE) marine PLs have not yet been reported. In this study, food-grade solvents were used to extract PLs from Irish organic farmed salmon (Salmo salar) fillets (FGE-salmon-PLs), while their antithrombotic bioactivities were assessed in human platelets induced by platelet aggregation agonists (PAF/thrombin). FGE-salmon-PLs were further separated by thin layer chromatography (TLC) into lipid subclasses, and the antithrombotic bioactivities of each subclass were also assessed. LC-MS was utilized to elucidate the structure-activity relationships. FGE-salmon-PLs strongly inhibited PAF-induced platelet aggregation, while their relevant anti-thrombin effects were at least three times more potent than the previously reported activities of CE-salmon-PLs. TLC-derived lipid fractions corresponding to phosphatidylcholines (PC) and phosphatidylethanolamines (PE) were the most bioactive lipid subclasses obtained, especially against thrombin. Their LC-MS analysis elucidated that they are diacyl- or alkyl-acyl- PC and PE moieties baring ω3 polyunsaturated fatty acids (PUFA) at their sn-2 position, such as eicosapentaenoic acid (EPA) or docosahexaenoic acid (DHA). Our results concerning the potent antithrombotic effects of FGE-salmon-PLs against both PAF and thrombin pathways strongly suggest that such food-grade extracts are putative candidates for the development of novel cardioprotective supplements and nutraceuticals.

Forty Years Since the Structural Elucidation of Platelet-Activating Factor (PAF): Historical, Current, and Future Research Perspectives.

In the late 1960s, Barbaro and Zvaifler described a substance that caused antigen induced histamine release from rabbit platelets producing antibodies in passive cutaneous anaphylaxis. Henson described a 'soluble factor' released from leukocytes that induced vasoactive amine release in platelets. Later observations by Siraganuan and Osler observed the existence of a diluted substance that had the capacity to cause platelet activation. In 1972, the term platelet-activating factor (PAF) was coined by Benveniste, Henson, and Cochrane. The structure of PAF was later elucidated by Demopoulos, Pinckard, and Hanahan in 1979. These studies introduced the research world to PAF, which is now recognised as a potent phospholipid mediator. Since its introduction to the literature, research on PAF has grown due to interest in its vital cell signalling functions and more sinisterly its role as a pro-inflammatory molecule in several chronic diseases including cardiovascular disease and cancer. As it is forty years since the structural elucidation of PAF, the aim of this review is to provide a historical account of the discovery of PAF and to provide a general overview of current and future perspectives on PAF research in physiology and pathophysiology.

Structural Elucidation of Irish Organic Farmed Salmon (Salmo salar) Polar Lipids with Antithrombotic Activities.

While several marine polar lipids (PL) have exhibited cardioprotective properties through their effects on the platelet-activating factor (PAF) pathways, salmon PL have not been tested so far. In this study, the antithrombotic activities of salmon PL were assessed in human platelets and the structural characterisation of bioactive salmon PL was performed by GC-MS and LC-MS analyses. PL from fillets of Irish organic farmed salmon (Salmo salar) were extracted and separated into several lipid subclasses by thin-layer chromatography (TLC), while their fatty acid profile was fully characterised by GC-MS. Salmon total lipids (TL), total neutral lipids (TNL), total polar lipids (TPL), and each PL subclass obtained by TLC were further assessed for their in vitro effects towards PAF-induced and thrombin-induced platelet aggregation in human platelets. Salmon PL exhibited antithrombotic effects on human platelet aggregation, mostly through their strong inhibitory effects against the PAF pathway with IC50 values comparable to other marine PL, but with lower effects towards the thrombin pathway. PL fractions corresponding to phosphatidylcholine and phosphatidylethanolamine derivatives exhibited the most potent anti-PAF effects, while LC-MS analysis putatively elucidated their structure/function relationship. Several diacyl-PC/PE and alkyl-acyl-PC/PE species containing mostly docosahexaenoic acid at their sn-2 glycerol-backbone may be responsible for the bioactivity. The data presented suggests that salmon contains PL with strong antithrombotic bioactivities.

Phospholipids of Animal and Marine Origin: Structure, Function, and Anti-Inflammatory Properties.

In this review paper, the latest literature on the functional properties of phospholipids in relation to inflammation and inflammation-related disorders has been critically appraised and evaluated. The paper is divided into three sections: Section 1 presents an overview of the relationship between structures and biological activities (pro-inflammatory or anti-inflammatory) of several phospholipids with respect to inflammation. Section 2 and Section 3 are dedicated to the structures, functions, compositions and anti-inflammatory properties of dietary phospholipids from animal and marine sources. Most of the dietary phospholipids of animal origin come from meat, egg and dairy products. To date, there is very limited work published on meat phospholipids, undoubtedly due to the negative perception that meat consumption is an unhealthy option because of its putative associations with several chronic diseases. These assumptions are addressed with respect to the phospholipid composition of meat products. Recent research trends indicate that dairy phospholipids possess anti-inflammatory properties, which has led to an increased interest into their molecular structures and reputed health benefits. Finally, the structural composition of phospholipids of marine origin is discussed. Extensive research has been published in relation to ω-3 polyunsaturated fatty acids (PUFAs) and inflammation, however this research has recently come under scrutiny and has proved to be unreliable and controversial in terms of the therapeutic effects of ω-3 PUFA, which are generally in the form of triglycerides and esters. Therefore, this review focuses on recent publications concerning marine phospholipids and their structural composition and related health benefits. Finally, the strong nutritional value of dietary phospholipids are highlighted with respect to marine and animal origin and avenues for future research are discussed.

A new era for food in health? The FDA announces a qualified health claim for yogurt intake and type 2 diabetes mellitus risk reduction.

INTRODUCTION: Over the last two decades research has grown regarding dairy intake and health. It has been reported by many that yogurt intake may be associated with reduced risk of type 2 diabetes mellitus (T2D). In this report, the United States Food and Drug Administration (FDA) decision to announce a qualified health claim for yogurt products regarding reduced risk of T2D in response to a Danone North America petition is discussed. METHODS: Relevant literature cited in the petition along with supporting evidence from PubMed and Google Scholar databases until April 1st, 2024 were used. Literature was found using relevant keywords. RESULTS: On March 1st, 2024, the United States Food and Drug Administration (FDA) announced the first ever qualified health claim, stating that eating yogurt regularly may reduce the risk of T2D according to limited scientific evidence. The enforcement discretion letter was critically reviewed and discussed regarding its future implications for people with T2M and public health. CONCLUSIONS: It is unclear how this FDA decision will affect public health and nutrition in the long-term. Limited scientific evidence suggests that at least 3 servings of yogurt per week may reduce the risk of T2D incidence for the general population. Yogurt will not cure or treat people with T2D.

Disruption of the PGE2 synthesis / response pathway restrains atherogenesis in programmed cell death-1 (Pd-1) deficient hyperlipidemic mice.

Immune checkpoint inhibitors (ICIs) that target programmed cell death 1 (PD-1) have revolutionized cancer treatment by enabling the restoration of suppressed T-cell cytotoxic responses. However, resistance to single-agent ICIs limits their clinical utility. Combinatorial strategies enhance their antitumor effects, but may also enhance the risk of immune related adverse effects of ICIs. Prostaglandin (PG) E2, formed by the sequential action of the cyclooxygenase (COX) and microsomal PGE synthase (mPGES-1) enzymes, acting via its E prostanoid (EP) receptors, EPr2 and EPr4, promotes lymphocyte exhaustion, revealing an additional target for ICIs. Thus, COX inhibitors and EPr4 antagonists are currently being combined with ICIs potentially to enhance antitumor efficacy in clinical trials. However, given the cardiovascular (CV) toxicity of COX inhibitors, such combinations may increase the risk particularly of CV AEs. Here, we compared the impact of distinct approaches to disruption of the PGE2 synthesis /response pathway - global or myeloid cell specific depletion of mPges-1 or global depletion of Epr4 - on the accelerated atherogenesis in Pd-1 deficient hyperlipidemic (Ldlr-/-) mice. All strategies restrained the atherogenesis. While depletion of mPGES-1 suppresses PGE2 biosynthesis, reflected by its major urinary metabolite, PGE2 biosynthesis was increased in mice lacking EPr4, consistent with enhanced expression of aortic Cox-1 and mPges-1. Deletions of mPges-1 and Epr4 differed in their effects on immune cell populations in atherosclerotic plaques; the former reduced neutrophil infiltration, while the latter restrained macrophages and increased the infiltration of T-cells. Consistent with these findings, chemotaxis by bone-marrow derived macrophages from Epr4-/- mice was impaired. Epr4 depletion also resulted in extramedullary lymphoid hematopoiesis and inhibition of lipoprotein lipase activity (LPL) with coincident spelenomegaly, leukocytosis and dyslipidemia. Targeting either mPGES-1 or EPr4 may restrain lymphocyte exhaustion while mitigating CV irAEs consequent to PD-1 blockade.

Dietary Patterns, Physical Activity, and Lifestyle in the Onset, Prevention, and Management of Noncommunicable Diseases.

Noncommunicable diseases (NCDs) are on the rise due to population growth and aging, which will cause a significant burden on global health systems [...].

The Coming of Age of Nucleic Acid Vaccines during COVID-19.

In the 21st century, several emergent viruses have posed a global threat. Each pathogen has emphasized the value of rapid and scalable vaccine development programs. The ongoing severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic has made the importance of such efforts especially clear. New biotechnological advances in vaccinology allow for recent advances that provide only the nucleic acid building blocks of an antigen, eliminating many safety concerns. During the COVID-19 pandemic, these DNA and RNA vaccines have facilitated the development and deployment of vaccines at an unprecedented pace. This success was attributable at least in part to broader shifts in scientific research relative to prior epidemics: the genome of SARS-CoV-2 was available as early as January 2020, facilitating global efforts in the development of DNA and RNA vaccines within 2 weeks of the international community becoming aware of the new viral threat. Additionally, these technologies that were previously only theoretical are not only safe but also highly efficacious. Although historically a slow process, the rapid development of vaccines during the COVID-19 crisis reveals a major shift in vaccine technologies. Here, we provide historical context for the emergence of these paradigm-shifting vaccines. We describe several DNA and RNA vaccines in terms of their efficacy, safety, and approval status. We also discuss patterns in worldwide distribution. The advances made since early 2020 provide an exceptional illustration of how rapidly vaccine development technology has advanced in the last 2 decades in particular and suggest a new era in vaccines against emerging pathogens. IMPORTANCE The SARS-CoV-2 pandemic has caused untold damage globally, presenting unusual demands on but also unique opportunities for vaccine development. The development, production, and distribution of vaccines are imperative to saving lives, preventing severe illness, and reducing the economic and social burdens caused by the COVID-19 pandemic. Although vaccine technologies that provide the DNA or RNA sequence of an antigen had never previously been approved for use in humans, they have played a major role in the management of SARS-CoV-2. In this review, we discuss the history of these vaccines and how they have been applied to SARS-CoV-2. Additionally, given that the evolution of new SARS-CoV-2 variants continues to present a significant challenge in 2022, these vaccines remain an important and evolving tool in the biomedical response to the pandemic.

Application of Traditional Vaccine Development Strategies to SARS-CoV-2.

Over the past 150 years, vaccines have revolutionized the relationship between people and disease. During the COVID-19 pandemic, technologies such as mRNA vaccines have received attention due to their novelty and successes. However, more traditional vaccine development platforms have also yielded important tools in the worldwide fight against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). A variety of approaches have been used to develop COVID-19 vaccines that are now authorized for use in countries around the world. In this review, we highlight strategies that focus on the viral capsid and outwards, rather than on the nucleic acids inside. These approaches fall into two broad categories: whole-virus vaccines and subunit vaccines. Whole-virus vaccines use the virus itself, in either an inactivated or an attenuated state. Subunit vaccines contain instead an isolated, immunogenic component of the virus. Here, we highlight vaccine candidates that apply these approaches against SARS-CoV-2 in different ways. In a companion article (H. M. Rando, R. Lordan, L. Kolla, E. Sell, et al., mSystems 8:e00928-22, 2023, https://doi.org/10.1128/mSystems.00928-22), we review the more recent and novel development of nucleic acid-based vaccine technologies. We further consider the role that these COVID-19 vaccine development programs have played in prophylaxis at the global scale. Well-established vaccine technologies have proved especially important to making vaccines accessible in low- and middle-income countries. Vaccine development programs that use established platforms have been undertaken in a much wider range of countries than those using nucleic acid-based technologies, which have been led by wealthy Western countries. Therefore, these vaccine platforms, though less novel from a biotechnological standpoint, have proven to be extremely important to the management of SARS-CoV-2. IMPORTANCE The development, production, and distribution of vaccines is imperative to saving lives, preventing illness, and reducing the economic and social burdens caused by the COVID-19 pandemic. Vaccines that use cutting-edge biotechnology have played an important role in mitigating the effects of SARS-CoV-2. However, more traditional methods of vaccine development that were refined throughout the 20th century have been especially critical to increasing vaccine access worldwide. Effective deployment is necessary to reducing the susceptibility of the world's population, which is especially important in light of emerging variants. In this review, we discuss the safety, immunogenicity, and distribution of vaccines developed using established technologies. In a separate review, we describe the vaccines developed using nucleic acid-based vaccine platforms. From the current literature, it is clear that the well-established vaccine technologies are also highly effective against SARS-CoV-2 and are being used to address the challenges of COVID-19 globally, including in low- and middle-income countries. This worldwide approach is critical for reducing the devastating impact of SARS-CoV-2.

The Coming of Age of Nucleic Acid Vaccines during COVID-19.

In the 21st century, several emergent viruses have posed a global threat. Each pathogen has emphasized the value of rapid and scalable vaccine development programs. The ongoing SARS-CoV-2 pandemic has made the importance of such efforts especially clear. New biotechnological advances in vaccinology allow for recent advances that provide only the nucleic acid building blocks of an antigen, eliminating many safety concerns. During the COVID-19 pandemic, these DNA and RNA vaccines have facilitated the development and deployment of vaccines at an unprecedented pace. This success was attributable at least in part to broader shifts in scientific research relative to prior epidemics; the genome of SARS-CoV-2 was available as early as January 2020, facilitating global efforts in the development of DNA and RNA vaccines within two weeks of the international community becoming aware of the new viral threat. Additionally, these technologies that were previously only theoretical are not only safe but also highly efficacious. Although historically a slow process, the rapid development of vaccines during the COVID-19 crisis reveals a major shift in vaccine technologies. Here, we provide historical context for the emergence of these paradigm-shifting vaccines. We describe several DNA and RNA vaccines and in terms of their efficacy, safety, and approval status. We also discuss patterns in worldwide distribution. The advances made since early 2020 provide an exceptional illustration of how rapidly vaccine development technology has advanced in the last two decades in particular and suggest a new era in vaccines against emerging pathogens.

Application of Traditional Vaccine Development Strategies to SARS-CoV-2.

Over the past 150 years, vaccines have revolutionized the relationship between people and disease. During the COVID-19 pandemic, technologies such as mRNA vaccines have received attention due to their novelty and successes. However, more traditional vaccine development platforms have also yielded important tools in the worldwide fight against the SARS-CoV-2 virus. A variety of approaches have been used to develop COVID-19 vaccines that are now authorized for use in countries around the world. In this review, we highlight strategies that focus on the viral capsid and outwards, rather than on the nucleic acids inside. These approaches fall into two broad categories: whole-virus vaccines and subunit vaccines. Whole-virus vaccines use the virus itself, either in an inactivated or attenuated state. Subunit vaccines contain instead an isolated, immunogenic component of the virus. Here, we highlight vaccine candidates that apply these approaches against SARS-CoV-2 in different ways. In a companion manuscript, we review the more recent and novel development of nucleic-acid based vaccine technologies. We further consider the role that these COVID-19 vaccine development programs have played in prophylaxis at the global scale. Well-established vaccine technologies have proved especially important to making vaccines accessible in low- and middle-income countries. Vaccine development programs that use established platforms have been undertaken in a much wider range of countries than those using nucleic-acid-based technologies, which have been led by wealthy Western countries. Therefore, these vaccine platforms, though less novel from a biotechnological standpoint, have proven to be extremely important to the management of SARS-CoV-2.