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Vaccine Tech – Best Supporting Actors

April 24, 2024 - Kristin DeBellis, PharmD

The World Health Organization (WHO) will celebrate the 50th year of its Essential/Expanded Programme on Immunization (EPI), a coordinated mission to provide universal access to life-saving vaccines during this year’s World Immunization Week.1 While vaccine history can be traced back over 500 years, these past 50 years have witnessed important advances. Eradication of smallpox around 1980 marked a key programmatic success that spurred public-private partnerships, and innovations geared toward improving safety, efficacy, and the supply-chain followed, including the groundbreaking production and distribution of messenger RNA (mRNA) vaccines.1,2

 

Rather than using whole pathogens, some vaccines now include only partial components (antigens), known as antigen subunit vaccines, designed to stimulate the immune system. However, these may need an added agent to induce an adequate and longer response – adjuvants.3 Adjuvants are now found in diverse immune-based therapies for allergies, cancer, and autoimmune diseases.3-5 Additionally, they can be credited with improving vaccine stability, reducing the required dose and frequency of administrations, providing response in patient population with immune challenges, and aiding development on a scalable level.4,5

The most common adjuvants are aluminum salts, still used today after nearly a century. They were initially devised as a purification and delivery system but were also found to improve immune response.5 Interest in finding adjuvants to help provide longer-lasting, disease-specific, and population-specific immune response (e.g., neonates, pregnant women, older adults, immune-suppressed individuals) led to the creation of the US National Institute of Allergy and Infectious Diseases (NIAID) within the National Institutes of Health. Launched to support adjuvant research and development programs in 2004, NIAID established its first strategic plan in 2010. Between 2009 and 2018, 5 new adjuvant compounds were employed in US Food and Drug Administration (FDA)-approved vaccines.4,6 NIAID established an online Vaccine Adjuvant Compendium in 2020 as a searchable repository for adjuvant developers and vaccine researchers to readily share their findings; more than 80 formulations are currently listed, with their corresponding immune profile, administration route(s), and investigational uses.4,7

Aside from the most prevalent, aluminum salts, 4 adjuvants are currently used in FDA-approved, commercially available vaccines, and others are in vaccines maintained in the Strategic National Stockpile.8,9 In 2015, the FDA approved the FLUAD® influenza vaccine for people ≥65 years of age containing MF-59®, a water-in-oil emulsion adjuvant made from squalene, an oil occurring naturally in plant cells. It has been found to provoke a improved response in infants, older adults, and other at-risk persons.5,6,9 A similar enhanced response in targeted populations was found with the adjuvant system AS01, liposomal formulations composed of a lipid plus a natural extract from a soapbark tree, called saponin, currently used in the Shingrix® shingles vaccine, and is being tested in investigational malaria and HIV vaccines.8-10 CpG systems, various synthetic forms of DNA are available in several motifs, with CpG 1018 used in the FDA-approved Heplisav-B® hepatitis B virus vaccine.8,9

Some vaccines, including the commonly used measles/mumps/rubella, and recently deployed mRNA vaccines for COVID-19 are considered self-adjuvanted, meaning they provoke a robust immune response without the need for an adjuvant.8,11 However, mRNA technology still presents large-scale production challenges and ultra-cold storage limit worldwide access.10 The Novavax Covid-19 vaccine candidate, an antigen subunit type, uses their proprietary Matrix-M™ adjuvant made of saponins, cholesterol, and phospholipids, received FDA Emergency Use Authorization in 2022.8,11 Data so far indicate this formulation provokes a good immune response across different strains of the SARS-CoV-2 virus, including in those patients who are immunosuppressed.11,12 Novavax COVID-19 can be refrigerated prior to use, thus helping to solve a key storage issue.10,13

 

Aside from the saponin-based adjuvants discussed, momentum is building behind plant products for a variety of reasons. Their mucosal absorption capabilities make them unique candidates for oral vaccinations, and they are considered environmentally nontoxic. Inulin has been found by the FDA to be safe, renewable, and biodegradable. A delta particulate form developed under the NIAID program and is currently being studied across a wide range of disease targets.14

Data so far indicate this formulation provokes a good immune response across different strains of the SARS-CoV-2 virus, including in those patients who are immunosuppressed.

As these products begin to reshape the landscape of available vaccines, it is clear that COVID-19 will not be the only disease for which multiple options will be available from which to choose. The day is coming when the need to understand the qualities adjuvants impart will be as important as knowing the mechanism of the active agent. Start now by reading any of the following resources:

 

The WHO’s EPI has come a long way in the last 50 years, but the award for Best Performance by a Supporting Actor goes to adjuvants for their shining performance in new vaccine technology over the past decade.

 

References

 

 

1. 50th anniversary of the Expanded Programme on Immunization (EPI) (who.int). Accessed February 14, 2024. https://www.who.int/news-room/events/detail/2024/01/01/default-calendar/50th-anniversary-of-the-expanded-programme-on-immunization-(epi)

 

 

2. College of Physicians of Philadelphia. History of vaccines. Vaccine timeline: before Jenner to after COVID-19. Accessed February 14, 2024. https://historyofvaccines.org/history/vaccine-timeline/overview

 

 

3. NIH-NIAID. Vaccine types. Accessed February 22, 2024. https://www.niaid.nih.gov/research/vaccine-types

 

 

4. NIH-NIAID. Vaccine adjuvants. Accessed February 22, 2024. https://www.niaid.nih.gov/research/vaccine-adjuvants

 

 

5. Facciola A, Visalli G, Laguna A, et al. An overview of vaccine adjuvants: current evidence and future perspectives. Vaccines (Basel). 2022;10(5):819. doi:10.3390/vaccines10050819

 

 

6. NIH-NIAID. 2018 NIAID Strategic Plan for Research on Vaccine Adjuvants. NIAID. Accessed March 27, 2024. https://www.niaid.nih.gov/sites/default/files/NIAIDStrategicPlanVaccineAdjuvants2018.pdf

 

 

7. NIH-NIAID. Vaccine Adjuvant Compendium (VAC). Accessed March 12, 2024. https://www.niaid.nih.gov/research/vaccine-adjuvant-compendium-vac

 

 

8. Vaccine safety. Adjuvants and vaccines. Accessed February 22, 2024. https://www.cdc.gov/vaccinesafety/concerns/adjuvants.html

 

 

9. Common ingredients in FDA-approved vaccines. Accessed March 12, 2024. https://www.fda.gov/vaccines-blood-biologics/safety-availability-biologics/common-ingredients-fda-approved-vaccines

 

 

10. Nanishi E, Angelidou A, Rotman C, et al. Precision vaccine adjuvants for older adults: a scoping review. Clin Infect Dis. 2022;75(suppl 1):S72-S80. doi:10.1093/cid/ciac302

 

 

11. Stertman L, Palm AE, Zarnegar B, et al. The Matrix-M™ adjuvant: a critical component of vaccines for the 21st century. Hum Vaccin Immunother. 2023;19(1):2189885. doi:10.1080/21645515.2023.2189885

 

 

12. Mueller-Enz M, Woopen C, Katoul Al Rahbani G, et al. NVX-CoV2373-induced T- and B-cellular immunity in immunosuppressed people with multiple sclerosis that failed to respond to mRNA and viral vector SARS-CoV-2 vaccines. Front Immunol. 2023;14:1081933. doi:10.3389/fimmu.2023.1081933

 

 

13. Novavax COVID-19 Vaccine, Adjuvanted. Package insert. Novavax Inc; 2023. Accessed March 27, 2024. https://www.fda.gov/media/159897/download?attachment

 

 

14. Kumar A, Sharma A, Tirpude NV, et al. Plant‑derived immuno‑adjuvants in vaccines formulation: a promising avenue for improving vaccines efficacy against SARS‑CoV‑2 virus. Pharmacol Rep. 2022;74(6):1238-1254. doi:10.1007/s43440-022-00418-4

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The Silent Killer: Stress, Hypertension, and the Quest for Calm

April 11, 2024 - Omar Chaker, PharmD

The Silent Killer: Stress, Hypertension, and the Quest for Calm
The Silent Killer: Stress, Hypertension, and the Quest for Calm
Photo Credit: Elliot Manches via Centre for Ageing Better

Introduction 

 

Hypertension, commonly known as high blood pressure, poses a significant health risk when left uncontrolled, potentially leading to heart disease, stroke, and kidney disease. It is often termed the “silent killer” due to its subtle symptoms.1 Nearly half of American adults have hypertension, defined as a systolic blood pressure greater than 130 mm Hg or a diastolic blood pressure greater than 80 mm Hg, or are taking medication for hypertension.2 April, recognized as Stress Awareness Month, serves as a time to spotlight the intricate link between chronic stress and hypertension. Managing stress can improve mental and physical well-being and minimize exacerbation of health-related issues.3 In this post, we delve into the connection between stress and hypertension, discuss the role of stress management techniques and antihypertensive medications, and explore the newest advancements in stress and hypertension management. 

The Silent Killer: Stress, Hypertension, and the Quest for Calm
Photo Credit: In-Press Photography via Centre for Ageing Better

The Physiology of Stress and Hypertension

 

Chronic stress triggers hormonal surges that temporarily elevate blood pressure. When such conditions become routine, they pave the way for sustained high blood pressure, or hypertension. When faced with a stressor, the body initiates a complex, coordinated response known as the fight or flight reaction. This response is mediated by the sympathetic nervous system (SNS) and the hypothalamic-pituitary-adrenal (HPA) axis, two key components of the body’s stress response system.4  

 

The SNS responds to stress by releasing catecholamines, primarily adrenaline (also called epinephrine) and noradrenaline (also called norepinephrine), into the bloodstream. These hormones increase heart rate and the force of heart contraction and constrict blood vessels, leading to an immediate rise in blood pressure. This acute response is designed to prepare the body to face or escape from perceived threats.4 

 

The HPA axis is also activated by stress. The hypothalamus stimulates the pituitary gland to secrete adrenocorticotropic hormone, which stimulates the adrenal glands to release cortisol, a stress hormone that is widely understood to play a role in maintaining homeostasis during stress. Under stressful circumstances, cortisol promotes endoplasmic glucose production to provide our bodies energy; however, chronically elevated cortisol levels can lead to several negative effects, including increased blood pressure, sodium and water retention, and is even suggested to affect endothelial function in blood vessels, all factors contributing to sustained hypertension.4 

 

Another crucial system involved in blood pressure regulation is the renin-angiotensin-aldosterone system (RAAS), which is a target for many antihypertensive medications used today. Stress can indirectly influence RAAS activity, leading to increased production of angiotensin II, a potent vasoconstrictor, and secretion of aldosterone, promoting sodium and water retention. These effects collectively contribute to the development and maintenance of hypertension.5  

Antihypertensive Medications  

 

The management of hypertension has evolved signi cantly, with antihypertensive medications playing a pivotal role. These medications work by lowering blood pressure to reduce the risk of heart disease and stroke.

CLASS DESCRIPTION

Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers (ARBs) 

Reduce blood pressure by relaxing blood vessels 

Beta-blockers 

Decrease heart rate and the heart’s output of blood

Diuretics 

Commonly known as water pills, work by helping the kidneys to remove excess salt (sodium) and water from the body by reducing blood volume, leading to a decrease in blood pressure

Renin inhibitors 

Directly target renin, an enzyme produced by the kidneys that initiates RAAS

New Therapies in Hypertension Treatment 

 

Recent advancements in hypertension treatment focus on more targeted mechanisms of action and improved patient compliance. For instance9: 

 

  • Angiotensin receptor-neprilysin inhibitors (ARNIs) are a novel class of drugs that combine an ARB with a neprilysin inhibitor. Neprilysin is an enzyme that breaks down natriuretic peptides, which help to reduce blood volume and pressure. By inhibiting neprilysin, ARNIs enhance the effects of natriuretic peptides, offering a powerful new approach to blood pressure management. 

 

Innovative therapies and devices are also under development, aiming to provide long-term solutions for resistant hypertension, such as renal denervation, which uses radiofrequency or ultrasound ablation to reduce sympathetic nerve activity between the kidneys and the brain, showing promising results in lowering blood pressure in patients who do not respond well to conventional medication.10 

The Silent Killer: Stress, Hypertension, and the Quest for Calm
Photo Credit: Peter Kindersley via Centre for Ageing Better

Managing Stress to Control Hypertension 

Effective stress management involves a multifaceted approach, incorporating lifestyle changes, relaxation techniques, and psychological strategies. Here’s how to build a comprehensive stress reduction plan: 

 

Lifestyle modifications8: 

  • Regular physical activity: exercise serves as a natural stress reliever, promoting the release of endorphins, the body’s natural painkillers and mood elevators. Aim for at least 150 minutes of moderate-intensity aerobic exercise, such as brisk walking or cycling, or 75 minutes of vigorous-intensity activity, like running or swimming, per week. 
  • Balanced diet (Dietary Approaches to Stop Hypertension diet): eating a healthy diet can have a profound effect on stress levels. A balanced intake of fruits, vegetables, whole grains, lean protein, and healthy fats is essential. Limit caffeine, sugar, and sodium intake, which can increase stress, anxiety, and blood pressure levels. 

Relaxation techniques4 

  • Deep breathing exercises: deep breathing activates the body’s relaxation response, helping to reduce stress. Techniques such as diaphragmatic breathing, abdominal breathing, and paced respiration can help calm the mind and reduce blood pressure. 

Psychological strategies4: 

  • Cognitive-behavioral therapy (CBT): CBT is a structured, time-limited psychotherapy that helps individuals recognize and alter negative thought patterns and behaviors that contribute to stress. It’s particularly effective in managing stress-related disorders. 

Conclusion 

 

April is recognized as National Stress Awareness Month to bring attention to the negative impact of stress. It is critical to recognize what stress and anxiety look like, take steps to build resilience, and know where to go for help. With advancements in antihypertensive medications and therapies, along with effective stress management strategies, there is hope for those affected. Awareness, education, and proactive management are key to controlling stress and hypertension while leading a healthier life.  

 

Please see the additional resources available to effectively cope with stress: 

References  

 

1. American Heart Association. High blood pressure. Accessed March 11, 2024. https://www.heart.org/en/health-topics/high-blood-pressure.    

 

2. Ostchega Y, Fryar CD, Nwankwo T, Nguyen DT. Hypertension Prevalence Among Adults Aged 18 and Over: United States, 2017-2018. NCHS Data Brief. 2020;(364):1-8.   

 

3. National Institutes of Health. National stress awareness month. Accessed March 11, 2024. https://hr.nih.gov/working-nih/civil/national-stress-awareness-month. 

   

4. American Psychological Association. Stress effects on the body. Accessed March 11, 2024. https://www.apa.org/topics/stress/body#:~:text=Chronic%20stress%2C%20or%20a%20constant,a%20toll%20on%20the%20body.    

 

5. Navar LG. Physiology: hemodynamics, endothelial function, renin-angiotensin-aldosterone system, sympathetic nervous system. J Am Soc Hypertens. 2014;8(7):519-524.   

 

6. National Heart, Lung, and Blood Institute. High blood pressure – causes and risk factors. Accessed March 11, 2024. https://www.nhlbi.nih.gov/health/high-blood-pressure/causes.    

 

7. National Institute on Aging. High blood pressure and older adults. Accessed March 11, 2024. https://www.nia.nih.gov/health/high-blood-pressure/high-blood-pressure-and-older-adults#:~:text=The%20chance%20of%20having%20high,high%20blood%20pressure%20after%20menopause. 

   

8. Whelton PK, Carey RM, Aronow WS, et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. Hypertension. 2018;71(6):e13-e115.   

 

9. Ali A, Ortega-Legaspi JM. Is it time to adopt angiotensin receptor-neprilysin inhibitors (ARNI) therapy as standard of care for the management of hypertension? Ann Palliat Med. 2022;11(10):3040-3042.    

 

10. Fengler K. Renal denervation for resistant hypertension: a concise update on treatment options and the latest clinical evidence. Cardiol Ther. 2022;11(3):385-392.