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Tekeoğlu İ, Şahin MZ, Kamanlı A, Nas K. The influence of zinc levels on osteoarthritis: A comprehensive review. Nutr Res Rev 2025; 38:282-293. [PMID: 39311401 DOI: 10.1017/s0954422424000234] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 04/29/2025]
Abstract
Osteoarthritis (OA), a disease with a multifactorial aetiology and an enigmatic root cause, affects the quality of life of many elderly patients. Even though there are certain medications utilised to reduce the symptomatic effects, a reliable treatment method to reverse the disease is yet to be discovered. Zinc is a cofactor of over 3000 proteins and is the only metal found in all six classes of enzymes. We explored zinc’s effect on the immune system and the bones as OA affects both. We also discussed zinc-dependent enzymes, highlighting their significant role in the disease’s pathogenesis. It is important to note that both excessive and deficient zinc levels can negatively affect bone health and immune function, thereby exacerbating OA. The purpose of this review is to offer a better understanding of zinc’s impact on OA pathogenesis and to provide clarity regarding its beneficial and detrimental outcomes. We searched thoroughly systematic reviews, meta-analysis, review articles, research articles and randomised controlled trials to ensure a comprehensive review. In brief, using zinc supplementation in the treatment of OA may act as a doubled-edged sword, offering potential benefits but also posing risks.
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Affiliation(s)
- İbrahim Tekeoğlu
- Sakarya University Faculty of Medicine, Department of Rheumatology, Sakarya University Training and Research Hospital, Sakarya, Türkiye
| | - Muhammed Zahid Şahin
- Sakarya University Faculty of Medicine, Department of Physical Medicine and Rehabilitation, Sakarya University Training and Research Hospital, Sakarya, Türkiye
| | - Ayhan Kamanlı
- Sakarya University Faculty of Medicine, Department of Rheumatology, Sakarya University Training and Research Hospital, Sakarya, Türkiye
| | - Kemal Nas
- Sakarya University Faculty of Medicine, Department of Rheumatology, Sakarya University Training and Research Hospital, Sakarya, Türkiye
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Schulz MT, Rink L. Zinc deficiency as possible link between immunosenescence and age-related diseases. Immun Ageing 2025; 22:19. [PMID: 40390089 PMCID: PMC12087153 DOI: 10.1186/s12979-025-00511-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2024] [Accepted: 04/23/2025] [Indexed: 05/21/2025]
Abstract
As global life expectancy increases, research reveals a critical challenge in aging: the progressive deterioration of immune function, termed immunosenescence. This age-related immune decline is characterized by a complex dysregulation of immune responses, which leaves older adults increasingly vulnerable to infections, chronic inflammatory states, and various degenerative diseases. Without intervention, immunosenescence significantly contributes to morbidity and mortality among the elderly, intensifying healthcare burdens and diminishing quality of life on both individual and societal levels. This review explores the essential role of zinc, a trace element critical for immune health, in mitigating the impact of immunosenescence and slowing the cascade of immunological dysfunctions associated with aging. By modulating the activity of key immune cells and pathways, zinc supplementation emerges as a promising approach to strengthen immunity, reduce oxidative stress, and counteract "inflammaging," a state of chronic, low-grade inflammation that accelerates tissue damage and drives disease progression. Zinc's involvement in cellular defense and repair mechanisms across the immune system highlights its ability to enhance immune cell functionality, resilience, and adaptability, strengthening the body's resistance to infection and its ability to manage stressors that contribute to diseases of aging. Indeed, zinc has demonstrated potential to improve immune responses, decrease inflammation, and mitigate the risk of age-related conditions including diabetes, depression, cardiovascular disease, and vision loss. Given the prevalent barriers to adequate zinc intake among older adults, including dietary limitations, decreased absorption, and interactions with medications, this review underscores the urgent need to address zinc deficiency in aging populations. Recent findings on zinc's cellular and molecular effects on immune health present zinc supplementation as a practical, accessible intervention for supporting healthier aging and improving quality of life. By integrating zinc into targeted strategies, public health efforts may not only sustain immunity in the elderly but also extend healthy longevity, reduce healthcare costs, and potentially mitigate the incidence and impact of chronic diseases that strain healthcare systems worldwide.
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Affiliation(s)
- Michael Tobias Schulz
- Institute of Immunology, Faculty of Medicine, RWTH Aachen University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany
| | - Lothar Rink
- Institute of Immunology, Faculty of Medicine, RWTH Aachen University Hospital, Pauwelsstraße 30, 52074, Aachen, Germany.
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Burke RM, Ramani S, Lynch J, Cooper LV, Cho H, Bandyopadhyay AS, Kirkwood CD, Steele AD, Kang G. Geographic disparities impacting oral vaccine performance: Observations and future directions. Clin Exp Immunol 2025; 219:uxae124. [PMID: 39774633 PMCID: PMC11773816 DOI: 10.1093/cei/uxae124] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 11/01/2024] [Accepted: 01/06/2025] [Indexed: 01/11/2025] Open
Abstract
Oral vaccines have several advantages compared with parenteral administration: they can be relatively cheap to produce in high quantities, easier to administer, and induce intestinal mucosal immunity that can protect against infection. These characteristics have led to successful use of oral vaccines against rotavirus, polio, and cholera. Unfortunately, oral vaccines for all three diseases have demonstrated lower performance in the highest-burden settings where they are most needed. Rotavirus vaccines are estimated to have >85% effectiveness against hospitalization in children <12 months in countries with low child mortality, but only ~65% effectiveness in countries with high child mortality. Similarly, oral polio vaccines have lower immunogenicity in developing country settings compared with high-resource settings. Data are more limited for oral cholera vaccines, but suggest lower titers among children compared with adults, and, for some vaccines, lower efficacy in endemic settings compared with non-endemic settings. These disparities are likely multifactorial, and available evidence suggests a role for maternal factors (e.g. transplacental antibodies, breastmilk), host factors (e.g. genetic polymorphisms-with the best evidence for rotavirus-or previous infection), and environmental factors (e.g. gut microbiome, co-infections). Overall, these data highlight the rather ambiguous and often contradictory nature of evidence on factors affecting oral vaccine response, cautioning against broad extrapolation of outcomes based on one population or one vaccine type. Meaningful impact on performance of oral vaccines will likely only be possible with a suite of interventions, given the complex and multifactorial nature of the problem, and the degree to which contributing factors are intertwined.
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Affiliation(s)
- Rachel M Burke
- Global Development Division, Bill & Melinda Gates Foundation, Seattle, WA, USA
| | - Sasirekha Ramani
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX, USA
| | - Julia Lynch
- Office of the Director General, International Vaccine Institute, Seoul, Republic of Korea
| | - Laura V Cooper
- School of Public Health, Imperial College London, London, UK
| | - Haeun Cho
- Department of Data Science and Innovation, International Vaccine Institute, Seoul, Republic of Korea
| | | | - Carl D Kirkwood
- Global Health Division, Bill & Melinda Gates Foundation, Seattle, WA, USA
| | - A Duncan Steele
- Global Health Division, Bill & Melinda Gates Foundation, Seattle, WA, USA
| | - Gagandeep Kang
- Global Health Division, Bill & Melinda Gates Foundation, Seattle, WA, USA
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Chowdhury MR, Islam A, Yurina V, Shimosato T. Water pollution, cholera, and the role of probiotics: a comprehensive review in relation to public health in Bangladesh. Front Microbiol 2025; 15:1523397. [PMID: 39877756 PMCID: PMC11772269 DOI: 10.3389/fmicb.2024.1523397] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2024] [Accepted: 12/27/2024] [Indexed: 01/31/2025] Open
Abstract
Cholera, a disease caused by Vibrio cholerae, remains a pervasive public health threat, particularly in regions with inadequate water sanitation and hygiene infrastructure, such as Bangladesh. This review explores the complex interplay between water pollution and cholera transmission in Bangladesh, highlighting how contaminated water bodies serve as reservoirs for V. cholerae. A key focus is the potential role of probiotics as a novel intervention approach for cholera prevention and management. Probiotics are promising as an adjunctive approach to existing therapies as they can enhance gut barrier function, induce competitive exclusion of pathogens, and modulate host immune responses. Recent probiotic advancements include engineering strains that disrupt V. cholerae biofilms and inhibit their virulence. Integrating probiotics with traditional cholera control measures could significantly enhance their effectiveness and provide a multifaceted approach to combating this persistent disease. This review aims to shed light on the potential of probiotics in revolutionizing cholera management and to offer insights into their application as both preventive and therapeutic tools in the fight against this enduring public health challenge.
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Affiliation(s)
- Md. Rayhan Chowdhury
- Graduate School of Medicine, Science and Technology, Shinshu University, Nagano, Japan
| | - Ariful Islam
- Department of Genetic Engineering and Biotechnology, University of Rajshahi, Rajshahi, Bangladesh
| | - Valentina Yurina
- Department of Pharmacy, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia
| | - Takeshi Shimosato
- Graduate School of Medicine, Science and Technology, Shinshu University, Nagano, Japan
- Department of Pharmacy, Faculty of Medicine, Universitas Brawijaya, Malang, Indonesia
- Institute for Aqua Regeneration, Shinshu University, Nagano, Japan
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Bjelakovic G, Nikolova D, Bjelakovic M, Pavlov CS, Sethi NJ, Korang SK, Gluud C. Effects of primary or secondary prevention with vitamin A supplementation on clinically important outcomes: a systematic review of randomised clinical trials with meta-analysis and trial sequential analysis. BMJ Open 2024; 14:e078053. [PMID: 38816049 PMCID: PMC11141198 DOI: 10.1136/bmjopen-2023-078053] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/25/2023] [Accepted: 05/20/2024] [Indexed: 06/01/2024] Open
Abstract
OBJECTIVES This systematic review with meta-analyses of randomised trials evaluated the preventive effects of vitamin A supplements versus placebo or no intervention on clinically important outcomes, in people of any age. METHODS We searched different electronic databases and other resources for randomised clinical trials that had compared vitamin A supplements versus placebo or no intervention (last search 16 April 2024). We used Cochrane methodology. We used the random-effects model to calculate risk ratios (RRs), with 95% CIs. We analysed individually and cluster randomised trials separately. Our primary outcomes were mortality, adverse events and quality of life. We assessed risks of bias in the trials and used Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) to assess the certainty of the evidence. RESULTS We included 120 randomised trials (1 671 672 participants); 105 trials allocated individuals and 15 allocated clusters. 92 trials included children (78 individually; 14 cluster randomised) and 28 adults (27 individually; 1 cluster randomised). 14/105 individually randomised trials (13%) and none of the cluster randomised trials were at overall low risk of bias. Vitamin A did not reduce mortality in individually randomised trials (RR 0.99, 95% CI 0.93 to 1.05; I²=32%; p=0.19; 105 trials; moderate certainty), and this effect was not affected by the risk of bias. In individually randomised trials, vitamin A had no effect on mortality in children (RR 0.96, 95% CI 0.88 to 1.04; I²=24%; p=0.28; 78 trials, 178 094 participants) nor in adults (RR 1.04, 95% CI 0.97 to 1.13; I²=24%; p=0.27; 27 trials, 61 880 participants). Vitamin A reduced mortality in the cluster randomised trials (0.84, 95% CI 0.76 to 0.93; I²=66%; p=0.0008; 15 trials, 14 in children and 1 in adults; 364 343 participants; very low certainty). No trial reported serious adverse events or quality of life. Vitamin A slightly increased bulging fontanelle of neonates and infants. We are uncertain whether vitamin A influences blindness under the conditions examined. CONCLUSIONS Based on moderate certainty of evidence, vitamin A had no effect on mortality in the individually randomised trials. Very low certainty evidence obtained from cluster randomised trials suggested a beneficial effect of vitamin A on mortality. If preventive vitamin A programmes are to be continued, supporting evidence should come from randomised trials allocating individuals and assessing patient-meaningful outcomes. PROSPERO REGISTRATION NUMBER CRD42018104347.
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Affiliation(s)
- Goran Bjelakovic
- Department of Internal Medicine, Medical Faculty, University of Nis, Nis, Serbia
- Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- Clinic of Gastroenterohepatology, University Clinical Centre, Nis, Serbia
| | - Dimitrinka Nikolova
- Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Milica Bjelakovic
- Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- Clinic of Gastroenterohepatology, University Clinical Centre, Nis, Serbia
| | - Chavdar S Pavlov
- Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- Department of Gastroenterology, Botkin Hospital, Moscow, Russian Federation
- Department of Therapy, I.M. Sechenov, First Moscow State Medical University, Moscow, Russian Federation
| | - Naqash J Sethi
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Steven Kwasi Korang
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Christian Gluud
- Cochrane Hepato-Biliary Group, Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- Copenhagen Trial Unit, Centre for Clinical Intervention Research, The Capital Region, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
- Department of Regional Health Research, The Faculty of Heath Sciences, University of Southern Denmark, Odense, Denmark
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Stefanache A, Lungu II, Butnariu IA, Calin G, Gutu C, Marcu C, Grierosu C, Bogdan Goroftei ER, Duceac LD, Dabija MG, Popa F, Damir D. Understanding How Minerals Contribute to Optimal Immune Function. J Immunol Res 2023; 2023:3355733. [PMID: 37946846 PMCID: PMC10632063 DOI: 10.1155/2023/3355733] [Citation(s) in RCA: 14] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Revised: 08/16/2023] [Accepted: 09/09/2023] [Indexed: 11/12/2023] Open
Abstract
Sufficient mineral supply is vital not only for the innate immune system but also for the components of the adaptive immune defense, which encompass defense mechanisms against pathogens and the delicate balance of pro- and anti-inflammatory regulation in the long term. Generally, a well-balanced diet is capable of providing the necessary minerals to support the immune system. Nevertheless, specific vulnerable populations should be cautious about obtaining adequate amounts of minerals such as magnesium, zinc, copper, iron, and selenium. Inadequate levels of these minerals can temporarily impair immune competence and disrupt the long-term regulation of systemic inflammation. Therefore, comprehending the mechanisms and sources of these minerals is crucial. In exceptional circumstances, mineral deficiencies may necessitate supplementation; however, excessive intake of supplements can have adverse effects on the immune system and should be avoided. Consequently, any supplementation should be approved by medical professionals and administered in recommended doses. This review emphasizes the crucial significance of minerals in promoting optimal functioning of the immune system. It investigates the indispensable minerals required for immune system function and the regulation of inflammation. Moreover, it delves into the significance of maintaining an optimized intake of minerals from a nutritional standpoint.
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Affiliation(s)
- Alina Stefanache
- “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | - Ionut-Iulian Lungu
- “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
| | | | - Gabriela Calin
- Faculty of Dental Medicine, “Apollonia” University of Iasi, 11 Pacurari Street, Iasi 700511, Romania
| | - Cristian Gutu
- Faculty of Medicine and Pharmacy, University Dunarea de Jos, 47 Domneasca Street, Galati 800008, Romania
| | - Constantin Marcu
- Faculty of Medicine and Pharmacy, University Dunarea de Jos, 47 Domneasca Street, Galati 800008, Romania
| | - Carmen Grierosu
- Faculty of Dental Medicine, “Apollonia” University of Iasi, 11 Pacurari Street, Iasi 700511, Romania
| | | | - Letitia-Doina Duceac
- Faculty of Medicine and Pharmacy, University Dunarea de Jos, 47 Domneasca Street, Galati 800008, Romania
| | | | - Florina Popa
- Faculty of Medicine and Pharmacy, University Dunarea de Jos, 47 Domneasca Street, Galati 800008, Romania
| | - Daniela Damir
- “Grigore T. Popa” University of Medicine and Pharmacy, Iasi 700115, Romania
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Sampath V, Cho S, Lee BR, Kim NH, Kim IH. Enhancement of protective vaccine-induced antibody titer to swine diseases and growth performance by Amino-Zn, yucca extract, and β-mannanase feed additive in wean-finishing pigs. Front Vet Sci 2023; 10:1095877. [PMID: 37662989 PMCID: PMC10470888 DOI: 10.3389/fvets.2023.1095877] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 07/26/2023] [Indexed: 09/05/2023] Open
Abstract
The primary purpose of this research is to determine the effect of Amino-Zn (AZn), Yucca schidigera extract (YE), and β-mannanase enzyme supplementation on growth performance, nutrient digestibility, fecal gas emission, and immune response in pigs. A total of 180 crossbred pigs (6.57 ± 1 kg) were randomly assigned to one of three dietary treatments: CON-corn soybean meal (basal diet); TRT1-CON +1,000 ppm AZn + 0.07% yucca extract (YE) + 0.05% β-mannanase; and TRT2-CON +2,000 ppm AZn + 0.07% YE+ 0.05% β-mannanase for 22 weeks. Each treatment had 12 replicates with 5 pigs per pen. Pigs fed a diet supplemented with AZn, YE, and β-mannanase linearly increased (p < 0.05) BW and average daily gain at weeks 6, 12, 17, and 18. In contrast, the gain-to-feed ratio showed a linear increase (p < 0.05) from weeks 6 to 17 and the overall trial period. Moreover, the inclusion of experimental diets linearly decreased (p > 0.05) noxious gas emissions such as ammonia, hydrogen sulfide, acetic acid, carbon dioxide, and methyl mercaptans. The dietary inclusion of AZn, YE, and β-mannanase significantly increased the serological immune responses to Mycoplasma hyopneumoniae (MH) and foot-and-mouth disease virus (FMDV-O type) at the end of week 6 and porcine circovirus-2 (PCV-2) at week 19. Based on this result, we infer that the combination of AZn, YE, and β-mannanase supplement would serve as a novel in-feed additive to enhance growth performance and act as a boosting agent and immune stimulatory to increase the efficacy of swine vaccinations.
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Affiliation(s)
- Vetriselvi Sampath
- Department of Animal Resources, Dankook University, Cheonan, Republic of Korea
| | - Sungbo Cho
- Department of Animal Resources, Dankook University, Cheonan, Republic of Korea
| | | | - Nam-Hun Kim
- ZinexBio Corporation, Asan, Republic of Korea
| | - In Ho Kim
- Department of Animal Resources, Dankook University, Cheonan, Republic of Korea
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Imdad A, Rogner J, Sherwani RN, Sidhu J, Regan A, Haykal MR, Tsistinas O, Smith A, Chan XHS, Mayo-Wilson E, Bhutta ZA. Zinc supplementation for preventing mortality, morbidity, and growth failure in children aged 6 months to 12 years. Cochrane Database Syst Rev 2023; 3:CD009384. [PMID: 36994923 PMCID: PMC10061962 DOI: 10.1002/14651858.cd009384.pub3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/31/2023]
Abstract
BACKGROUND Zinc deficiency is prevalent in low- and middle-income countries, and is considered a significant risk factor for morbidity, mortality, and linear growth failure. The effectiveness of preventive zinc supplementation in reducing prevalence of zinc deficiency needs to be assessed. OBJECTIVES To assess the effects of zinc supplementation for preventing mortality and morbidity, and for promoting growth, in children aged 6 months to 12 years. SEARCH METHODS A previous version of this review was published in 2014. In this update, we searched CENTRAL, MEDLINE, Embase, five other databases, and one trials register up to February 2022, together with reference checking and contact with study authors to identify additional studies. SELECTION CRITERIA Randomized controlled trials (RCTs) of preventive zinc supplementation in children aged 6 months to 12 years compared with no intervention, a placebo, or a waiting list control. We excluded hospitalized children and children with chronic diseases or conditions. We excluded food fortification or intake, sprinkles, and therapeutic interventions. DATA COLLECTION AND ANALYSIS Two review authors screened studies, extracted data, and assessed the risk of bias. We contacted study authors for missing information and used GRADE to assess the certainty of evidence. The primary outcomes of this review were all-cause mortality; and cause-specific mortality, due to all-cause diarrhea, lower respiratory tract infection (LRTI, including pneumonia), and malaria. We also collected information on a number of secondary outcomes, such as those related to diarrhea and LRTI morbidity, growth outcomes and serum levels of micronutrients, and adverse events. MAIN RESULTS We included 16 new studies in this review, resulting in a total of 96 RCTs with 219,584 eligible participants. The included studies were conducted in 34 countries; 87 of them in low- or middle-income countries. Most of the children included in this review were under five years of age. The intervention was delivered most commonly in the form of syrup as zinc sulfate, and the most common dose was between 10 mg and 15 mg daily. The median duration of follow-up was 26 weeks. We did not consider that the evidence for the key analyses of morbidity and mortality outcomes was affected by risk of bias. High-certainty evidence showed little to no difference in all-cause mortality with preventive zinc supplementation compared to no zinc (risk ratio (RR) 0.93, 95% confidence interval (CI) 0.84 to 1.03; 16 studies, 17 comparisons, 143,474 participants). Moderate-certainty evidence showed that preventive zinc supplementation compared to no zinc likely results in little to no difference in mortality due to all-cause diarrhea (RR 0.95, 95% CI 0.69 to 1.31; 4 studies, 132,321 participants); but probably reduces mortality due to LRTI (RR 0.86, 95% CI 0.64 to 1.15; 3 studies, 132,063 participants) and mortality due to malaria (RR 0.90, 95% CI 0.77 to 1.06; 2 studies, 42,818 participants); however, the confidence intervals around the summary estimates for these outcomes were wide, and we could not rule out a possibility of increased risk of mortality. Preventive zinc supplementation likely reduces the incidence of all-cause diarrhea (RR 0.91, 95% CI 0.90 to 0.93; 39 studies, 19,468 participants; moderate-certainty evidence) but results in little to no difference in morbidity due to LRTI (RR 1.01, 95% CI 0.95 to 1.08; 19 studies, 10,555 participants; high-certainty evidence) compared to no zinc. There was moderate-certainty evidence that preventive zinc supplementation likely leads to a slight increase in height (standardized mean difference (SMD) 0.12, 95% CI 0.09 to 0.14; 74 studies, 20,720 participants). Zinc supplementation was associated with an increase in the number of participants with at least one vomiting episode (RR 1.29, 95% CI 1.14 to 1.46; 5 studies, 35,192 participants; high-certainty evidence). We report a number of other outcomes, including the effect of zinc supplementation on weight and serum markers such as zinc, hemoglobin, iron, copper, etc. We also performed a number of subgroup analyses and there was a consistent finding for a number of outcomes that co-supplementation of zinc with iron decreased the beneficial effect of zinc. AUTHORS' CONCLUSIONS Even though we included 16 new studies in this update, the overall conclusions of the review remain unchanged. Zinc supplementation might help prevent episodes of diarrhea and improve growth slightly, particularly in children aged 6 months to 12 years of age. The benefits of preventive zinc supplementation may outweigh the harms in regions where the risk of zinc deficiency is relatively high.
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Affiliation(s)
- Aamer Imdad
- Department of Pediatrics, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Jaimie Rogner
- Departments of Medicine and Pediatrics, University of Rochester Medical Center, Rochester, NY, USA
| | - Rida N Sherwani
- Department of Pediatrics, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Jasleen Sidhu
- Norton College of Medicine, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Allison Regan
- Norton College of Medicine, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Maya R Haykal
- Norton College of Medicine, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Olivia Tsistinas
- Health Sciences Library, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Abigail Smith
- Health Sciences Library, SUNY Upstate Medical University, Syracuse, NY, USA
| | - Xin Hui S Chan
- Pandemic Sciences Institute, University of Oxford, Oxford, UK
| | - Evan Mayo-Wilson
- Department of Epidemiology, UNC Gillings School of Global Public HealthMcGavran-Greenberg Hall, Chapel Hill, NC, USA
| | - Zulfiqar A Bhutta
- Centre for Global Child Health, The Hospital for SickKids, Toronto, Canada
- Center of Excellence for Women and Child Health, Aga Khan University, Karachi, Pakistan
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Chisenga CC, Bosomprah S, Chilyabanyama ON, Alabi P, Simuyandi M, Mwaba J, Ng'ombe H, Laban NM, Luchen CC, Chilengi R. Assessment of the influence of ABO blood groups on oral cholera vaccine immunogenicity in a cholera endemic area in Zambia. BMC Public Health 2023; 23:152. [PMID: 36690955 PMCID: PMC9869508 DOI: 10.1186/s12889-023-15051-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2022] [Accepted: 01/13/2023] [Indexed: 01/25/2023] Open
Abstract
BACKGROUND Histo-blood group antigens (HBGAs) which include the ABO and Lewis antigen systems have been known for determining predisposition to infections. For instance, blood group O individuals have a higher risk of severe illness due to V. cholerae compared to those with non-blood group O antigens. We set out to determine the influence that these HBGAs have on oral cholera vaccine immunogenicity and seroconversion in individuals residing within a cholera endemic area in Zambia. METHODOLOGY We conducted a longitudinal study nested under a clinical trial in which samples from a cohort of 223 adults who were vaccinated with two doses of Shanchol™ and followed up over 4 years were used. We measured serum vibriocidal geometric mean titers (GMTs) at Baseline, Day 28, Months 6, 12, 24, 30, 36 and 48 in response to the vaccine. Saliva obtained at 1 year post vaccination was tested for HBGA phenotypes and secretor status using an enzyme-linked immunosorbent assay (ELISA). RESULTS Of the 133/223 participants included in the final analysis, the majority were above 34 years old (58%) and of these, 90% were males. Seroconversion rates to V. cholerae O1 Inaba with non-O (23%) and O (30%) blood types were comparable. The same pattern was observed against O1 Ogawa serotype between non-O (25%) and O (35%). This trend continued over the four-year follow-up period. Similarly, no significant differences were observed in seroconversion rates between the non-secretors (26%) and secretors (36%) against V. cholerae O1 Inaba. The same was observed for O1 Ogawa in non-secretors (22%) and the secretors (36%). CONCLUSION Our results do not support the idea that ABO blood grouping influence vaccine uptake and responses against cholera.
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Affiliation(s)
| | - Samuel Bosomprah
- Centre for Infectious Disease Research in Zambia, Lusaka, Zambia
- Department of Biostatistics, School of Public Health, University of Ghana, Accra, Ghana
| | | | - Peter Alabi
- Centre for Infectious Disease Research in Zambia, Lusaka, Zambia
| | | | - John Mwaba
- Centre for Infectious Disease Research in Zambia, Lusaka, Zambia
- Department of Biomedical Sciences, School of Health Sciences, University of Zambia, Lusaka, Zambia
| | - Harriet Ng'ombe
- Centre for Infectious Disease Research in Zambia, Lusaka, Zambia
- Department of Biomedical Sciences, School of Health Sciences, University of Zambia, Lusaka, Zambia
| | - Natasha M Laban
- Centre for Infectious Disease Research in Zambia, Lusaka, Zambia
| | - Charlie C Luchen
- Centre for Infectious Disease Research in Zambia, Lusaka, Zambia
| | - Roma Chilengi
- Centre for Infectious Disease Research in Zambia, Lusaka, Zambia
- School of Medicine, University of Lusaka, Lusaka, Zambia
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10
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Kewcharoenwong C, Sein MM, Nithichanon A, Khongmee A, Wessells KR, Hinnouho GM, Barffour MA, Kounnavong S, Hess SY, Stephensen CB, Lertmemongkolchai G. Daily preventive zinc supplementation increases the antibody response against pathogenic Escherichia coli in children with zinc insufficiency: a randomised controlled trial. Sci Rep 2022; 12:16084. [PMID: 36167891 PMCID: PMC9515173 DOI: 10.1038/s41598-022-20445-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2022] [Accepted: 09/13/2022] [Indexed: 12/03/2022] Open
Abstract
Zinc deficiency impairs the antibody-mediated immune response and is common in children from lower-income countries. This study aimed to investigate the impact of different zinc supplementation regimens (7, 10 or 20 mg/day elemental zinc)—therapeutic dispersible zinc tablets (TZ), daily multiple micronutrient powder (MNP), daily preventive zinc tablets (PZ) and placebo powder (control)—and compare between baseline and endline antibody production against pathogenic Escherichia coli in Laotian children (aged 6–23 months). Fifty representative plasma samples of each treatment group were randomly selected from 512 children to determine anti-E. coli IgG antibody levels and avidity. Of the 200 children, 78.5% had zinc deficiency (plasma zinc concentration < 65 µg/dL) and 40% had anaemia before receiving zinc supplementation. aAfter receiving the TZ, MNP or PZ regimen, the plasma anti-E. coli IgG levels were significantly increased compared with baseline; the effect on the antibody level was more pronounced in children with zinc deficiency. Interestingly, there was increased anti-E. coli IgG avidity in the control and PZ groups. This study suggests that PZ might be the optimal zinc supplementation regimen to increase both the quantity and quality of antibody responses in children with zinc deficiency. Clinical trial registration: https://clinicaltrials.gov/ct2/show/NCT02428647 (NCT02428647, 29/04/2015).
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Affiliation(s)
| | - Myint Myint Sein
- The Centre for Research & Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
| | - Arnone Nithichanon
- Department of Microbiology, Faculty of Medicine, Research and Diagnostic Center for Emerging Infectious Diseases (RCEID), Khon Kaen University, Khon Kaen, Thailand
| | - Aranya Khongmee
- The Centre for Research & Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand
| | - K Ryan Wessells
- Department of Nutrition, Institute for Global Nutrition, University of California, Davis, CA, USA
| | - Guy-Marino Hinnouho
- Department of Nutrition, Institute for Global Nutrition, University of California, Davis, CA, USA.,Helen Keller International, Washington, DC, USA
| | - Maxwell A Barffour
- Department of Nutrition, Institute for Global Nutrition, University of California, Davis, CA, USA.,Public Health Program, College of Health and Human Services, Missouri State University, Springfield, MO, USA
| | - Sengchanh Kounnavong
- Lao Tropical and Public Health Institute, Vientiane, Lao People's Democratic Republic
| | - Sonja Y Hess
- Department of Nutrition, Institute for Global Nutrition, University of California, Davis, CA, USA
| | - Charles B Stephensen
- Department of Nutrition, Institute for Global Nutrition, University of California, Davis, CA, USA.,Agricultural Research Service, Western Human Nutrition Research Center, USDA, Davis, CA, USA
| | - Ganjana Lertmemongkolchai
- Faculty of Associated Medical Sciences, Chiang Mai University, Chiang Mai, 50200, Thailand. .,The Centre for Research & Development of Medical Diagnostic Laboratories, Faculty of Associated Medical Sciences, Khon Kaen University, Khon Kaen, Thailand.
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11
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Imdad A, Mayo-Wilson E, Haykal MR, Regan A, Sidhu J, Smith A, Bhutta ZA. Vitamin A supplementation for preventing morbidity and mortality in children from six months to five years of age. Cochrane Database Syst Rev 2022; 3:CD008524. [PMID: 35294044 PMCID: PMC8925277 DOI: 10.1002/14651858.cd008524.pub4] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
BACKGROUND Vitamin A deficiency (VAD) is a major public health problem in low- and middle-income countries, affecting 190 million children under five years of age and leading to many adverse health consequences, including death. Based on prior evidence and a previous version of this review, the World Health Organization has continued to recommend vitamin A supplementation (VAS) for children aged 6 to 59 months. The last version of this review was published in 2017, and this is an updated version of that review. OBJECTIVES To assess the effects of vitamin A supplementation (VAS) for preventing morbidity and mortality in children aged six months to five years. SEARCH METHODS We searched CENTRAL, MEDLINE, Embase, six other databases, and two trials registers up to March 2021. We also checked reference lists and contacted relevant organisations and researchers to identify additional studies. SELECTION CRITERIA Randomised controlled trials (RCTs) and cluster-RCTs evaluating the effect of synthetic VAS in children aged six months to five years living in the community. We excluded studies involving children in hospital and children with disease or infection. We also excluded studies evaluating the effects of food fortification, consumption of vitamin A rich foods, or beta-carotene supplementation. DATA COLLECTION AND ANALYSIS For this update, two review authors independently assessed studies for inclusion resolving discrepancies by discussion. We performed meta-analyses for outcomes, including all-cause and cause-specific mortality, disease, vision, and side effects. We used the GRADE approach to assess the quality of the evidence. MAIN RESULTS The updated search identified no new RCTs. We identified 47 studies, involving approximately 1,223,856 children. Studies were set in 19 countries: 30 (63%) in Asia, 16 of these in India; 8 (17%) in Africa; 7 (15%) in Latin America, and 2 (4%) in Australia. About one-third of the studies were in urban/periurban settings, and half were in rural settings; the remaining studies did not clearly report settings. Most studies included equal numbers of girls and boys and lasted about one year. The mean age of the children was about 33 months. The included studies were at variable overall risk of bias; however, evidence for the primary outcome was at low risk of bias. A meta-analysis for all-cause mortality included 19 trials (1,202,382 children). At longest follow-up, there was a 12% observed reduction in the risk of all-cause mortality for VAS compared with control using a fixed-effect model (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.83 to 0.93; high-certainty evidence). Nine trials reported mortality due to diarrhoea and showed a 12% overall reduction for VAS (RR 0.88, 95% CI 0.79 to 0.98; 1,098,538 children; high-certainty evidence). There was no evidence of a difference for VAS on mortality due to measles (RR 0.88, 95% CI 0.69 to 1.11; 6 studies, 1,088,261 children; low-certainty evidence), respiratory disease (RR 0.98, 95% CI 0.86 to 1.12; 9 studies, 1,098,538 children; low-certainty evidence), and meningitis. VAS reduced the incidence of diarrhoea (RR 0.85, 95% CI 0.82 to 0.87; 15 studies, 77,946 children; low-certainty evidence), measles (RR 0.45, 95% CI 0.30 to 0.69; 2 studies, 1,982 children; low-certainty evidence), Bitot's spots (RR 0.42, 95% CI 0.33 to 0.53; 5 studies, 1,063,278 children; moderate-certainty evidence), night blindness (RR 0.32, 95% CI 0.21 to 0.50; 2 studies, 22,972 children; moderate-certainty evidence), and VAD (RR 0.71, 95% CI 0.65 to 0.78; 4 studies, 2262 children, moderate-certainty evidence). However, there was no evidence of a difference on incidence of respiratory disease (RR 0.99, 95% CI 0.92 to 1.06; 11 studies, 27,540 children; low-certainty evidence) or hospitalisations due to diarrhoea or pneumonia. There was an increased risk of vomiting within the first 48 hours of VAS (RR 1.97, 95% CI 1.44 to 2.69; 4 studies, 10,541 children; moderate-certainty evidence). AUTHORS' CONCLUSIONS This update identified no new eligible studies and the conclusions remain the same. VAS is associated with a clinically meaningful reduction in morbidity and mortality in children. Further placebo-controlled trials of VAS in children between six months and five years of age would not change the conclusions of this review, although studies that compare different doses and delivery mechanisms are needed. In populations with documented VAD, it would be unethical to conduct placebo-controlled trials.
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Affiliation(s)
- Aamer Imdad
- Department of Pediatrics, Division of Pediatric Gastroenterology, Hepatology and Nutrition, SUNY Upstate Medical University, Syracuse, New York, USA
| | - Evan Mayo-Wilson
- Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, Baltimore, Maryland, USA
| | - Maya R Haykal
- College of Medicine, SUNY Upstate Medical University, Syracuse, New York, USA
| | - Allison Regan
- College of Medicine, SUNY Upstate Medical University, Syracuse, New York, USA
| | - Jasleen Sidhu
- College of Medicine, SUNY Upstate Medical University, Syracuse, New York, USA
| | - Abigail Smith
- Health Sciences Library, SUNY Upstate Medical University, Syracuse, New York, USA
| | - Zulfiqar A Bhutta
- Centre for Global Child Health, The Hospital for Sick Children, Toronto, Canada
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12
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Xu W, Liu Y, Zou X, Luo H, Wu W, Xia J, Chan MTV, Fang S, Shu Y, Wu WKK, Zhang L. Hypozincemia in COVID-19 Patients Correlates With Stronger Antibody Response. Front Immunol 2022; 12:785599. [PMID: 35058926 PMCID: PMC8763690 DOI: 10.3389/fimmu.2021.785599] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2021] [Accepted: 12/09/2021] [Indexed: 12/14/2022] Open
Abstract
Zinc ion as an enzyme cofactor exhibits antiviral and anti-inflammatory activity during infection, but circulating zinc ion level during Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection is unclear. This study aimed to evaluate serum zinc ion level in Coronavirus Disease 2019 (COVID-19) patients and healthy subjects, as well as its correlation with antibodies against SARS-CoV-2. 114 COVID-19 patients and 48 healthy subjects (38 healthy volunteers and 10 close contacts of patients with COVID-19) were included. Zinc ion concentration and levels of antibodies against SARS-CoV-2 Spike 1 + Spike 2 proteins, nucleocapsid protein, and receptor-binding domain in serum were measured. Results showed that the concentration of zinc ion in serum from COVID-19 patients [median: 6.4 nmol/mL (IQR 1.5 – 12.0 nmol/mL)] were significantly lower than that from the healthy subjects [median: 15.0 nmol/mL (IQR 11.9 – 18.8 nmol/mL)] (p < 0.001) and the difference remained significant after age stratification (p < 0.001) or when the patients were at the recovery stage (p < 0.001). Furthermore, COVID-19 patients with more severe hypozincemia showed higher levels of IgG against the receptor-binding domain of SARS-CoV-2 spike protein. Further studies to confirm the effect of zinc supplementation on improving the outcomes of COVID-19, including antibody response against SARS-CoV-2, are warranted.
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Affiliation(s)
- Wenye Xu
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Yingzhi Liu
- Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Xuan Zou
- Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Huanle Luo
- School of Public Health (Shenzhen), Sun Yet-Sen University, Shenzhen, China
| | - Weihua Wu
- Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Junjie Xia
- Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Matthew T V Chan
- Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Shisong Fang
- Shenzhen Center for Disease Control and Prevention, Shenzhen, China
| | - Yuelong Shu
- Key Laboratory of Tropical Disease Control, Ministry of Education, Sun Yat-sen University, Guangzhou, China
| | - William K K Wu
- Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China.,State Key Laboratory of Digestive Diseases, Li Ka Shing Institute of Health Sciences, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
| | - Lin Zhang
- Department of Medicine and Therapeutics, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China.,Department of Anaesthesia and Intensive Care and Peter Hung Pain Research Institute, The Chinese University of Hong Kong, Hong Kong, Hong Kong SAR, China
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13
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Luchen CC, Mwaba J, Ng’ombe H, Alabi PIO, Simuyandi M, Chilyabanyama ON, Hatyoka LM, Mubanga C, Bosomprah S, Chilengi R, Chisenga CC. Effect of HIV status and retinol on immunogenicity to oral cholera vaccine in adult population living in an endemic area of Lukanga Swamps, Zambia. PLoS One 2021; 16:e0260552. [PMID: 34855835 PMCID: PMC8639067 DOI: 10.1371/journal.pone.0260552] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2021] [Accepted: 10/20/2021] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND We set out to assess the impact of human immunodeficiency virus (HIV) and micronutrient deficiency as indicated by serum retinol levels on the immune responses to Oral Cholera Vaccine (Shanchol™) in a cohort of participants in Lukanga Swamps, Zambia. Cholera remains endemic in Zambia with vaccines being the only effective preventive measures. However, the effect of these vaccines on populations living with HIV has not been widely documented. METHODS HIV testing and confirmation was done using the Alere Determine™ HIV-1/2 and Uni-Gold™ kits while vibriocidal antibody assay was applied for vaccine immunogenicity. Serum retinol analysis was assessed by Shimadzu Prominence HCT-2010 High Performance Liquid Chromatography (HPLC). The primary outcome was log transformed geometric mean titre. RESULTS From 47 participants screened for HIV, 51% (24) tested positive. There was a statistically significant reduction in Ogawa geometric mean ratio (GMR) by 67% (GMR = 0.33; 95% CI: -0.15, 0.76; p-value = 0.009) attributable to HIV positivity with a non-significant reduction in Inaba GMR by about 50% due to HIV positivity. When doubling of retinol levels modelled, GMR reduction against Ogawa were non-significant but that against Inaba resulted in a significant reduction in geometric mean titer (GMT) (GMT-0.33, C.I 0.16-0.66, p-value 0.002). At 1000copies/ml viral load cut off and 350 cells/μl CD4 counts, Ogawa GMT was two times higher 11.16 (95%CI: 8.20-15.19) versus 6.06 (95%CI: 4.04-9.10) in low viremia participants, and three times higher in above threshold CD4 count participants; 24.81 (95%CI: 18.94-32.50) versus 7.07 (95%CI: 5.22-9.58). CONCLUSION Our results show that while Shanchol™ is immunogenic in both HIV+/- individuals, HIV + participants responded poorly. Viral load and CD4 count affected vaccine immunogenicity. More research is required for detailed understanding of this in order to appropriately inform policy and practice.
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Affiliation(s)
- Charlie Chaluma Luchen
- Enteric Diseases and Vaccine Research Unit, Centre for Infectious Disease Research in Zambia (CIDRZ), Lusaka, Zambia
- Amsterdam UMC, University of Amsterdam, Institute for Infection and Immunity, Amsterdam, the Netherlands
| | - John Mwaba
- Enteric Diseases and Vaccine Research Unit, Centre for Infectious Disease Research in Zambia (CIDRZ), Lusaka, Zambia
- University of Zambia, School of Health Sciences, Lusaka, Zambia
| | - Harriet Ng’ombe
- Enteric Diseases and Vaccine Research Unit, Centre for Infectious Disease Research in Zambia (CIDRZ), Lusaka, Zambia
- University of Zambia, School of Health Sciences, Lusaka, Zambia
| | - Peter Ibukun Oluwa Alabi
- Enteric Diseases and Vaccine Research Unit, Centre for Infectious Disease Research in Zambia (CIDRZ), Lusaka, Zambia
| | - Michelo Simuyandi
- Enteric Diseases and Vaccine Research Unit, Centre for Infectious Disease Research in Zambia (CIDRZ), Lusaka, Zambia
| | - Obvious N. Chilyabanyama
- Enteric Diseases and Vaccine Research Unit, Centre for Infectious Disease Research in Zambia (CIDRZ), Lusaka, Zambia
| | - Luiza Miyanda Hatyoka
- Enteric Diseases and Vaccine Research Unit, Centre for Infectious Disease Research in Zambia (CIDRZ), Lusaka, Zambia
| | - Cynthia Mubanga
- Enteric Diseases and Vaccine Research Unit, Centre for Infectious Disease Research in Zambia (CIDRZ), Lusaka, Zambia
| | - Samuel Bosomprah
- Enteric Diseases and Vaccine Research Unit, Centre for Infectious Disease Research in Zambia (CIDRZ), Lusaka, Zambia
- Department of Biostatistics, School of Public Health, University of Ghana, Accra, Ghana
| | - Roma Chilengi
- Enteric Diseases and Vaccine Research Unit, Centre for Infectious Disease Research in Zambia (CIDRZ), Lusaka, Zambia
| | - Cleopatra Caroline Chisenga
- Enteric Diseases and Vaccine Research Unit, Centre for Infectious Disease Research in Zambia (CIDRZ), Lusaka, Zambia
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14
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Bahroudi M, Bakhshi B, Soudi S, Najar-Peerayeh S. Immunomodulatory effects of mesenchymal stem cell-conditioned media on lipopolysaccharide of Vibrio cholerae as a vaccine candidate. Stem Cell Res Ther 2021; 12:564. [PMID: 34732259 PMCID: PMC8567566 DOI: 10.1186/s13287-021-02622-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2021] [Accepted: 10/11/2021] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Vibrio cholerae is the causative agent of cholera, which is commonly associated with high morbidity and mortality, and presents a major challenge to healthcare systems throughout the world. Lipopolysaccharide (LPS) is required for full protection against V. cholerae but can induce inflammation and septic shock. Mesenchymal stem cells (MSCs) are currently used to treat infectious and inflammatory diseases. Therefore, this study aimed to evaluate the immune-modulating effects of the LPS-MSC-conditioned medium (CM) on V. cholerae LPS immunization in a murine model. METHODS After preconditioning MSCs with LPS, mice were immunized intraperitoneally on days 0 and 14 with the following combinations: LPS + LPS-MSC-CM; detoxified LPS (DLPS) + MSC-CM; LPS + MSC sup; LPS; LPS-MSC-CM; MSC supernatant (MSC sup); and PBS. The mouse serum and saliva samples were collected to evaluate antibody (serum IgG and saliva IgA) and cytokine responses (TNF-α, IL-10, IL-6, TGF-β, IL-4, IL-5, and B-cell activating factor (BAFF)). RESULTS The LPS + LPS-MSC-CM significantly increased total IgG and IgA compared to other combinations (P < 0.001). TNF-α levels, in contrast to IL-10 and TGF-β, were reduced significantly in mice receiving the LPS + LPS-MSC-CM compared to mice receiving only LPS. IL-4, IL-5, and BAFF levels significantly increased in mice receiving increased doses of LPS + LPS-MSC-CM compared to those who received only LPS. The highest vibriocidal antibody titer (1:64) was observed in LPS + LPS-MSC-CM-immunized mice and resulted in a significant improvement in survival in infant mice infected by V. cholerae O1. CONCLUSIONS The LPS-MSC-CM modulates the immune response to V. cholerae LPS by regulating inflammatory and anti-inflammatory responses and inducing vibriocidal antibodies, which protect neonate mice against V. cholerae infection.
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Affiliation(s)
- Mahboube Bahroudi
- Department of Bacteriology, Faculty of Medical Sciences, Tarbiat Modares University, Jalal-Ale-Ahmad Ave., 14117-13116, Tehran, Iran
| | - Bita Bakhshi
- Department of Bacteriology, Faculty of Medical Sciences, Tarbiat Modares University, Jalal-Ale-Ahmad Ave., 14117-13116, Tehran, Iran.
| | - Sara Soudi
- Department of Immunology, Faculty of Medical Sciences, Tarbiat Modares University, Jalal-Ale-Ahmad Ave., 14117-13116, Tehran, Iran
| | - Shahin Najar-Peerayeh
- Department of Bacteriology, Faculty of Medical Sciences, Tarbiat Modares University, Jalal-Ale-Ahmad Ave., 14117-13116, Tehran, Iran
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15
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Isanaka S, Garba S, Plikaytis B, Malone McNeal M, Guindo O, Langendorf C, Adehossi E, Ciglenecki I, Grais RF. Immunogenicity of an oral rotavirus vaccine administered with prenatal nutritional support in Niger: A cluster randomized clinical trial. PLoS Med 2021; 18:e1003720. [PMID: 34375336 PMCID: PMC8354620 DOI: 10.1371/journal.pmed.1003720] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Accepted: 07/06/2021] [Indexed: 11/18/2022] Open
Abstract
BACKGROUND Nutritional status may play a role in infant immune development. To identify potential boosters of immunogenicity in low-income countries where oral vaccine efficacy is low, we tested the effect of prenatal nutritional supplementation on immune response to 3 doses of a live oral rotavirus vaccine. METHODS AND FINDINGS We nested a cluster randomized trial within a double-blind, placebo-controlled randomized efficacy trial to assess the effect of 3 prenatal nutritional supplements (lipid-based nutrient supplement [LNS], multiple micronutrient supplement [MMS], or iron-folic acid [IFA]) on infant immune response (n = 53 villages and 1,525 infants with valid serology results: 794 in the vaccine group and 731 in the placebo group). From September 2015 to February 2017, participating women received prenatal nutrient supplement during pregnancy. Eligible infants were then randomized to receive 3 doses of an oral rotavirus vaccine or placebo at 6-8 weeks of age (mean age: 6.3 weeks, 50% female). Infant sera (pre-Dose 1 and 28 days post-Dose 3) were analyzed for anti-rotavirus immunoglobulin A (IgA) using enzyme-linked immunosorbent assay (ELISA). The primary immunogenicity end point, seroconversion defined as ≥3-fold increase in IgA, was compared in vaccinated infants among the 3 supplement groups and between vaccine/placebo groups using mixed model analysis of variance procedures. Seroconversion did not differ by supplementation group (41.1% (94/229) with LNS vs. 39.1% (102/261) with multiple micronutrients (MMN) vs. 38.8% (118/304) with IFA, p = 0.91). Overall, 39.6% (n = 314/794) of infants who received vaccine seroconverted, compared to 29.0% (n = 212/731) of infants who received placebo (relative risk [RR]: 1.36; 95% confidence interval [CI]: 1.18, 1.57, p < 0.001). This study was conducted in a high rotavirus transmission setting. Study limitations include the absence of an immune correlate of protection for rotavirus vaccines, with the implications of using serum anti-rotavirus IgA for the assessment of immunogenicity and efficacy in low-income countries unclear. CONCLUSIONS This study showed no effect of the type of prenatal nutrient supplementation on immune response in this setting. Immune response varied depending on previous exposure to rotavirus, suggesting that alternative delivery modalities and schedules may be considered to improve vaccine performance in high transmission settings. TRIAL REGISTRATION ClinicalTrials.gov NCT02145000.
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Affiliation(s)
- Sheila Isanaka
- Department of Research, Epicentre, Paris, France
- Departments of Nutrition and Global Health and Population, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America
- * E-mail:
| | | | - Brian Plikaytis
- BioStat Consulting, LLC, Worthington, Ohio, United States of America
| | - Monica Malone McNeal
- Department of Pediatrics, University of Cincinnati, Division of Infectious Diseases, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio, United States of America
| | | | | | | | - Iza Ciglenecki
- Médecins Sans Frontières—Operational Center Geneva, Geneva, Switzerland
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16
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Vedhara K, Royal S, Sunger K, Caldwell DM, Halliday V, Taylor CM, Fairclough L, Avery A, Welton NJ. Effects of non-pharmacological interventions as vaccine adjuvants in humans: a systematic review and network meta-analysis. Health Psychol Rev 2020; 15:245-271. [PMID: 33222621 DOI: 10.1080/17437199.2020.1854050] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
INTRODUCTION Psychological and behavioural may enhance vaccine effectiveness. We conducted a systematic review and network meta-analysis (NMA) to examine the effects of non-pharmacological adjuvants on vaccine effectiveness, as measured by antibody responses to vaccination. AREAS COVERED Electronic databases (EMBASE, Medline, PsychINFO, CINAHL) were searched from inception to 6th February 2018. This yielded 100 eligible papers, reporting 106 trials: 79 interventions associated with diet and/or nutrition; 12 physical activity interventions and 9 psychological interventions.Over half (58/106) of trials reported evidence of an enhanced antibody response to vaccination across one or more outcomes. The NMA considered the comparative effects between all intervention types, control and placebo for antibody titres (48 studies), seroconversion (25 studies) and seroprotection (23 studies) separately. The NMA provided weak evidence in support of nutritional formulae and probiotics in increasing antibody titres. EXPERT OPINION This review offers a comprehensive summary of the literature on non-pharmacological interventions as vaccine adjuvants. The evidence is characterised by considerable heterogeneity but provides early evidence in support of nutritional formulae and probiotic interventions. Psychological and exercise-based interventions were characterised by limited and unreliable evidence. Large, well-designed studies including consistent core outcomes and measures of intervention adherence and fidelity are required.
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Affiliation(s)
- Kavita Vedhara
- Division of Primary Care, University of Nottingham, Nottingham, UK
| | - Simon Royal
- University of Nottingham Health Service, Cripps Health Centre, Nottingham, UK
| | - Kanchan Sunger
- Division of Primary Care, University of Nottingham, Nottingham, UK
| | - Deborah M Caldwell
- School of Social & Community Medicine, University of Bristol, Bristol, UK.,NIHR Health Protection Research Unit in Behavioural Science and Evaluation, University of Bristol, Bristol, UK
| | - Vanessa Halliday
- School of Health & Related Research, University of Sheffield, Sheffield, UK
| | - Caroline M Taylor
- Centre for Academic Child Health, Bristol Medical School, University of Bristol, Bristol, UK
| | - Lucy Fairclough
- School of Life Sciences, University of Nottingham, Nottingham, UK
| | - Anthony Avery
- Division of Primary Care, University of Nottingham, Nottingham, UK
| | - Nicky J Welton
- School of Social & Community Medicine, University of Bristol, Bristol, UK.,NIHR Health Protection Research Unit in Behavioural Science and Evaluation, University of Bristol, Bristol, UK
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17
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Evaluating association of vaccine response to low serum zinc and vitamin D levels in children of a birth cohort study in Dhaka. Vaccine 2020; 39:59-67. [PMID: 33121844 PMCID: PMC7735373 DOI: 10.1016/j.vaccine.2020.10.048] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2020] [Revised: 10/07/2020] [Accepted: 10/12/2020] [Indexed: 02/03/2023]
Abstract
MAL-ED Bangladesh birth cohort data used in the analysis. Relationship between vaccine titers and micronutrient data explored. Positive association found between serum zinc level and tetanus vaccine titer. The finding implicates the importance of improving zinc nutrition status of the children. Background Vaccine-preventable infectious diseases are often responsible for childhood morbidity and high rates of mortality. Immune response to the vaccine is associated with multiple factors in early childhood and measured by antibody titers. Among them, micronutrient deficiencies such as vitamin D and zinc deficiencies are the most important in resource-limited settings like Bangladesh. Objective We aimed to evaluate the association of vaccine response to low serum zinc and vitamin D levels in children. Methods We evaluated vaccine response for measles and poliovirus, tetanus and pertussis toxoid, and Ig A antibody levels to rotavirus by ELISA and serum vitamin D and zinc at 7 and 15 months in the MAL-ED birth cohort of the Bangladesh site. By using population-specific generalized estimating equations (GEE), the association between each explanatory variable and the binary outcome variable was examined longitudinally where the dependent variable was vaccine titers and the independent variables were low serum vitamin D and zinc levels. Results The GEE multivariable model identified a positive association between serum zinc level and tetanus vaccine titer (OR: 1.84; 95% CI: 1.07–3.17 and p value = 0.028) after adjusting for age, gender, birth weight, WAMI score, diarrhea, ALRI, exclusive breastfeeding, serum ferritin, serum retinol and undernutrition (stunting, wasting, underweight). No association was found between the rest of the vaccine titers with serum vitamin D and zinc level (p > 0.05). Conclusion In the MAL-ED birth cohort, where children were followed for five years, serum zinc level had a positive impact on tetanus vaccine titers.
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18
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Hallowell BD, Tate J, Parashar U. An overview of rotavirus vaccination programs in developing countries. Expert Rev Vaccines 2020; 19:529-537. [PMID: 32543239 DOI: 10.1080/14760584.2020.1775079] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
INTRODUCTION Rotavirus is the leading cause of acute diarrhea among children <5 years worldwide. As all children are equally susceptible to infection and disease development, rotavirus vaccination programs are the best upstream approach to preventing rotavirus disease, and the subsequent risk of hospitalization or death. AREAS COVERED We provide an overview of global rotavirus vaccine policy, summarize the burden of rotavirus disease in developing countries, review data on the effectiveness, impact, safety, and the cost-effectiveness of rotavirus vaccination programs, and identify areas for further research and improvement. EXPERT OPINION Rotavirus vaccines continue to be an effective, safe, and cost-effective solution to preventing rotavirus disease. As two new rotavirus vaccines enter the market (Rotasiil and Rotavac) and Asian countries continue to introduce rotavirus vaccines into their national immunization programs, documenting vaccine safety, effectiveness, and impact in these settings will be paramount.
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Affiliation(s)
- Benjamin D Hallowell
- Division of Viral Diseases, Centers for Disease Control and Prevention , Atlanta, GA, USA.,Epidemic Intelligence Service, CDC , Atlanta, GA, USA
| | - Jacqueline Tate
- Division of Viral Diseases, Centers for Disease Control and Prevention , Atlanta, GA, USA
| | - Umesh Parashar
- Division of Viral Diseases, Centers for Disease Control and Prevention , Atlanta, GA, USA
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Ray A, Sarkar K, Haldar P, Ghosh R. Oral cholera vaccine delivery strategy in India: Routine or campaign?-A scoping review. Vaccine 2020; 38 Suppl 1:A184-A193. [PMID: 31377080 DOI: 10.1016/j.vaccine.2019.07.082] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2019] [Revised: 07/13/2019] [Accepted: 07/24/2019] [Indexed: 11/28/2022]
Abstract
Oral Cholera Vaccine (OCV) has been recognized as an adjunct tool for prevention and control of cholera. However, policy directions are currently unavailable in India to guide the vaccine delivery. We conducted a scoping review to inform the policy about the scopes and challenges of different strategic choices of OCV delivery in India in light of current evidences, highlighting the scope of new research. METHODS Adopting the Arksey and O'Malley Framework for review, we searched for literatures on "efficacy", "effectiveness", and "cost" of oral cholera vaccine delivery through different strategies in Pubmed and Scopus. RESULTS We found that the protective efficacy of OCV depends on its coverage. Evidence on effectiveness of OCV are available for both reactive and pre-vaccination campaigns. Reactive high-risk vaccination is more effective than reactive ring and mass vaccination. Pre-vaccination campaigns are more effective than reactive vaccination when vaccine availability is adequate. Pre-vaccination through school campaigns in 1-14 years age group have been cost effective in India. Vaccination campaigns in under-5 children are also cost effective in spite of low efficacy due to the scope of averting a higher number of cases. However, no evidence is available regarding efficacy and effectiveness of OCV in children <1 year as well as the effectiveness of delivering OCV through routine immunization. CONCLUSION Little evidence exist to depict mass-campaign as more economic and effective than routine expanded programme on immunization (EPI) session for delivery of OCV. Considering operational feasibility, it needs to be explored whether OCV delivery strategy is compatible with India's current EPI, if it can be introduced in routine immunization at measles containing vaccine age-schedule, optionally preceded by a campaign in targeted hot-spots in the 1-14 year age-group. Safety and efficacy data of OCV during infancy as well as hot-spot surveillance are pre-requisites for formulation of such EPI policy.
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Chowdhury F, Bhuiyan TR, Akter A, Bhuiyan MS, Khan AI, Tauheed I, Ahmed T, Ferdous J, Dash P, Basher SR, Hakim A, Lynch J, Kim JH, Excler JL, Kim DR, Clemens JD, Qadri F. Augmented immune responses to a booster dose of oral cholera vaccine in Bangladeshi children less than 5 years of age: Revaccination after an interval of over three years of primary vaccination with a single dose of vaccine. Vaccine 2020; 38:1753-1761. [PMID: 31879124 PMCID: PMC7014297 DOI: 10.1016/j.vaccine.2019.12.034] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2019] [Revised: 10/31/2019] [Accepted: 12/13/2019] [Indexed: 12/12/2022]
Abstract
We have earlier reported that a single dose of oral cholera vaccine (OCV) is protective in adults and children ≥5 years of age and sustained for 2 years. We enrolled participants (n = 240) from this study, between March-September 2017, over 3 years after receiving a primary single dose. Immune responses were measured in placebo group (Primary Immunization group: PI) and compared with those who received a single dose (Booster Immunization group: BI). The children were 4 to <5 years, 5 to <18 years and adults >18 years. Blood was collected at day 0 (before vaccination) and after receiving 1st and 2nd doses of OCV. Overall, the BI and PI groups showed vibriocidal antibody response after 1st and 2nd dose of vaccination in all age groups to V. cholerae O1 and O139. Young children in the BI group showed significantly higher vibriocidal antibody response two weeks after receiving the first dose as compared to PI group to LPS. Elevated plasma IgA responses to LPS after the first dose were observed among the BI group compared to the PI group among the young children. Mucosal antibody responses measured in fecal extracts showed similar increases as that of vibriocidal and LPS responses in the BI group. These results suggest a single boosting dose of OCV generated immune response in primed population >5 years of age who had earlier received OCV. However, young children who had received OCV earlier, boosting after a single dose, resulted in increased immune responses compared to the PI group. Further studies are needed to assess protection obtained from different strategies, especially for young children and to determine the numbers of primary and booster doses needed. In addition, more information is needed regarding the optimum interval between primary and booster doses to plan future interventions for cholera control. ClinicalTrials.gov Identifier: NCT02027207.
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Affiliation(s)
- Fahima Chowdhury
- International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh
| | - Taufiqur Rahman Bhuiyan
- International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh
| | - Afroza Akter
- International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh
| | - Md Saruar Bhuiyan
- International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh
| | - Ashraful Islam Khan
- International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh
| | - Imam Tauheed
- International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh
| | - Tasnuva Ahmed
- International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh
| | - Jannatul Ferdous
- International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh
| | - Pinki Dash
- International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh
| | - Salima Raiyan Basher
- International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh
| | - Al Hakim
- International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh
| | - Julia Lynch
- International Vaccine Institute (IVI), Seoul, Republic of Korea
| | - Jerome H Kim
- International Vaccine Institute (IVI), Seoul, Republic of Korea
| | | | - Deok Ryun Kim
- International Vaccine Institute (IVI), Seoul, Republic of Korea
| | - John D Clemens
- International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh; UCLA Fielding School of Public Health, Los Angeles, CA, USA; Korea University School of Medicine, Seoul, Republic of Korea
| | - Firdausi Qadri
- International Centre for Diarrhoeal Disease Research Bangladesh (icddr,b), Dhaka, Bangladesh.
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Shaikh H, Lynch J, Kim J, Excler JL. Current and future cholera vaccines. Vaccine 2019; 38 Suppl 1:A118-A126. [PMID: 31879125 DOI: 10.1016/j.vaccine.2019.12.011] [Citation(s) in RCA: 42] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2019] [Revised: 11/08/2019] [Accepted: 12/06/2019] [Indexed: 01/21/2023]
Abstract
Cholera remains a major global public health problem that is primarily linked to insufficient access to safe water and proper sanitation. Oral Cholera Vaccine (OCV) has been recommended as an additional public health tool along with WASH in cholera endemic countries and in areas at risk for outbreaks. The new generation OCV is safe and offers good protection in older children and adults while limited protection in younger children less than five years of age has been observed. The combination of direct vaccine protection and vaccine herd immunity effects makes OCV highly cost-effective and, therefore, attractive for use in developing countries. Additionally, in recent studies OCV was safe in pregnant women, supporting its use in pregnant women in cholera endemic countries. However, knowledge need to be developed for current vaccines for their prolonged duration of protection and vaccines need improvements for better immune response in younger children. A single dose vaccination regimen would be more cost-effective and easier to deliver. Recent approaches have focused on designing genetically attenuated cholera strains for use in single-dose cholera vaccines. The global demand for OCV has been boosted by the WHO recommendation to use OCV and is driven largely by epidemics and outbreaks and has been increasing due to the availability of cheaper easy-to-use vaccines, feasibility of mass OCV vaccination campaigns, demonstration of protection to underserved population in precarious situations, and vaccine costs being borne by Gavi (Vaccine Alliance). For rapid access in emergency and equitable distribution of OCV in cholera-endemic low-income countries, a global OCV stockpile was established in 2013 with support from the Global Alliance for Vaccines and Immunization. The three WHO-prequalified vaccines are Dukoral®, Shanchol™, Euvichol® (and Euvichol® Plus presentation), the latter two being included in the stockpile.
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Affiliation(s)
- Hanif Shaikh
- International Vaccine Institute, Seoul, Republic of Korea; K.E.M. Hospital Research Centre, Pune, Maharashtra, India.
| | - Julia Lynch
- International Vaccine Institute, Seoul, Republic of Korea
| | - Jerome Kim
- International Vaccine Institute, Seoul, Republic of Korea
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Read SA, Obeid S, Ahlenstiel C, Ahlenstiel G. The Role of Zinc in Antiviral Immunity. Adv Nutr 2019; 10:696-710. [PMID: 31305906 PMCID: PMC6628855 DOI: 10.1093/advances/nmz013] [Citation(s) in RCA: 415] [Impact Index Per Article: 69.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2018] [Revised: 01/17/2019] [Accepted: 01/22/2019] [Indexed: 12/16/2022] Open
Abstract
Zinc is an essential trace element that is crucial for growth, development, and the maintenance of immune function. Its influence reaches all organs and cell types, representing an integral component of approximately 10% of the human proteome, and encompassing hundreds of key enzymes and transcription factors. Zinc deficiency is strikingly common, affecting up to a quarter of the population in developing countries, but also affecting distinct populations in the developed world as a result of lifestyle, age, and disease-mediated factors. Consequently, zinc status is a critical factor that can influence antiviral immunity, particularly as zinc-deficient populations are often most at risk of acquiring viral infections such as HIV or hepatitis C virus. This review summarizes current basic science and clinical evidence examining zinc as a direct antiviral, as well as a stimulant of antiviral immunity. An abundance of evidence has accumulated over the past 50 y to demonstrate the antiviral activity of zinc against a variety of viruses, and via numerous mechanisms. The therapeutic use of zinc for viral infections such as herpes simplex virus and the common cold has stemmed from these findings; however, there remains much to be learned regarding the antiviral mechanisms and clinical benefit of zinc supplementation as a preventative and therapeutic treatment for viral infections.
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Affiliation(s)
- Scott A Read
- Blacktown Medical School, Western Sydney University, Blacktown, New South Wales, Australia
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, New South Wales, Australia
| | - Stephanie Obeid
- The Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia
| | - Chantelle Ahlenstiel
- The Kirby Institute, University of New South Wales, Sydney, New South Wales, Australia
| | - Golo Ahlenstiel
- Blacktown Medical School, Western Sydney University, Blacktown, New South Wales, Australia
- Storr Liver Centre, The Westmead Institute for Medical Research, The University of Sydney and Westmead Hospital, Westmead, New South Wales, Australia
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Steele A, Victor J, Carey M, Tate J, Atherly D, Pecenka C, Diaz Z, Parashar U, Kirkwood C. Experiences with rotavirus vaccines: can we improve rotavirus vaccine impact in developing countries? Hum Vaccin Immunother 2019; 15:1215-1227. [PMID: 30735087 PMCID: PMC6663148 DOI: 10.1080/21645515.2018.1553593] [Citation(s) in RCA: 49] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2018] [Revised: 11/06/2018] [Accepted: 11/22/2018] [Indexed: 12/16/2022] Open
Abstract
Rotavirus vaccines have been introduced into over 95 countries globally and demonstrate substantial impact in reducing diarrheal mortality and diarrheal hospitalizations in young children. The vaccines are also considered by WHO as "very cost effective" interventions for young children, particularly in countries with high diarrheal disease burden. Yet the full potential impact of rotavirus immunization is yet to be realized. Large countries with big birth cohorts and where disease burden is high in Africa and Asia have not yet implemented rotavirus vaccines at all or at scale. Significant advances have been made demonstrating the impact of the vaccines in low- and lower-middle income countries, yet the modest effectiveness of the vaccines in these settings is challenging. Current research highlights these challenges and considers alternative strategies to overcome them, including alternative immunization schedules and host factors that may inform us of new opportunities.
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Affiliation(s)
- A.D. Steele
- Enteric and Diarrheal Diseases, Bill & Melinda Gates Foundation, Seattle, WA, USA
| | - J.C. Victor
- Policy, Access and Innovation, Center for Vaccine Innovation and Access, Seattle, WA, USA
| | - M.E. Carey
- Enteric and Diarrheal Diseases, Bill & Melinda Gates Foundation, Seattle, WA, USA
| | - J.E. Tate
- Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - D.E. Atherly
- Policy, Access and Innovation, Center for Vaccine Innovation and Access, Seattle, WA, USA
| | - C. Pecenka
- Policy, Access and Innovation, Center for Vaccine Innovation and Access, Seattle, WA, USA
| | - Z. Diaz
- Enteric and Diarrheal Diseases, Bill & Melinda Gates Foundation, Seattle, WA, USA
| | - U.D. Parashar
- Division of Viral Diseases, Centers for Disease Control and Prevention, Atlanta, GA, USA
| | - C.D. Kirkwood
- Enteric and Diarrheal Diseases, Bill & Melinda Gates Foundation, Seattle, WA, USA
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Church JA, Parker EP, Kirkpatrick BD, Grassly NC, Prendergast AJ. Interventions to improve oral vaccine performance: a systematic review and meta-analysis. THE LANCET. INFECTIOUS DISEASES 2019; 19:203-214. [PMID: 30712836 PMCID: PMC6353819 DOI: 10.1016/s1473-3099(18)30602-9] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/18/2018] [Revised: 08/06/2018] [Accepted: 09/21/2018] [Indexed: 12/20/2022]
Abstract
BACKGROUND Oral vaccines underperform in low-income and middle-income countries compared with in high-income countries. Whether interventions can improve oral vaccine performance is uncertain. METHODS We did a systematic review and meta-analysis of interventions designed to increase oral vaccine efficacy or immunogenicity. We searched Ovid-MEDLINE and Embase for trials published until Oct 23, 2017. Inclusion criteria for meta-analysis were two or more studies per intervention category and available seroconversion data. We did random-effects meta-analyses to produce summary relative risk (RR) estimates. This study is registered with PROSPERO (CRD42017060608). FINDINGS Of 2843 studies identified, 87 were eligible for qualitative synthesis and 66 for meta-analysis. 22 different interventions were assessed for oral poliovirus vaccine (OPV), oral rotavirus vaccine (RVV), oral cholera vaccine (OCV), and oral typhoid vaccines. There was generally high heterogeneity. Seroconversion to RVV was significantly increased by delaying the first RVV dose by 4 weeks (RR 1·37, 95% CI 1·16-1·62) and OPV seroconversion was increased with monovalent or bivalent OPV compared with trivalent OPV (RR 1·51, 95% CI 1·20-1·91). There was some evidence that separating RVV and OPV increased RVV seroconversion (RR 1·21, 95% CI 1·00-1·47) and that higher vaccine inoculum improved OCV seroconversion (RR 1·12, 95% CI 1·00-1·26). There was no evidence of effect for anthelmintics, antibiotics, probiotics, zinc, vitamin A, withholding breastfeeding, extra doses, or vaccine buffering. INTERPRETATION Most strategies did not improve oral vaccine performance. Delaying RVV and reducing OPV valence should be considered within immunisation programmes to reduce global enteric disease. New strategies to address the gap in oral vaccine efficacy are urgently required. FUNDING Wellcome Trust, Bill & Melinda Gates Foundation, UK Medical Research Council, and WHO Polio Research Committee.
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Affiliation(s)
- James A Church
- Centre for Genomics & Child Health, Blizard Institute, Queen Mary University of London, London, UK; Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe.
| | - Edward P Parker
- Department of Infectious Disease Epidemiology, St Mary's Campus, Imperial College London, London, UK
| | - Beth D Kirkpatrick
- Department of Microbiology and Molecular Genetics, Vaccine Testing Center, University of Vermont College of Medicine, Burlington, VT, USA
| | - Nicholas C Grassly
- Department of Infectious Disease Epidemiology, St Mary's Campus, Imperial College London, London, UK
| | - Andrew J Prendergast
- Centre for Genomics & Child Health, Blizard Institute, Queen Mary University of London, London, UK; Zvitambo Institute for Maternal and Child Health Research, Harare, Zimbabwe
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Bom APDA, Corrêa IBS, Argondizzo APC, Medeiros MA, Santos RBD, Souza TLFD, Silva Junior JGD. Conformational analysis of Pneumococcal Surface Antigen A (PsaA) upon zinc binding by fluorescence spectroscopy. AN ACAD BRAS CIENC 2018; 90:2299-2310. [PMID: 29947666 DOI: 10.1590/0001-3765201820170151] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2017] [Accepted: 06/28/2017] [Indexed: 11/22/2022] Open
Abstract
PsaA (pneumococcal surface antigen A) is a S. pneumoniae virulence factor that belongs to the metal transport system. The Manganese PsaA binding has been associated with oxidative stress resistance becoming a pivotal element in the bacteria virulence. It has been shown that Zinc inhibits the Manganese acquisition and promotes bacteria toxicity. We have performed a PsaA conformational analysis both in the presence (Zn-rPsaA) and in the absence of Zinc (free-rPsaA). We performed experiments in the presence of different Zinc concentrations to determine the metal minimum concentration which induced a conformational change. The protein in free and Zn-binding condition was also studied in pH ranging 2.6-8.0 and in temperature ranging 25oC-85oC. pH experiments showed a decrease of fluorescence intensity only in acidic medium. Analysis of the heat-induced denaturation demonstrated that Zinc-binding promoted an increase in melting temperature from 55oC (free-rPsaA) to 78.8oC (Zn-rPsaA) according to fluorescence measurements. In addition, the rPsaA stabilization by Zinc was verified through analysis of urea and guanidine hydrochloride denaturation. Data showed that Zinc promoted an increase in the rPsaA stability and its removal by EDTA can lead to a PsaA intermediate conformation. These findings can be considered in the development of vaccines containing PsaA as antigen.
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Affiliation(s)
- Ana Paula D Ano Bom
- Lab. of Macromolecules, Bio-Manguinhos, Fiocruz, Av. Brasil, 4365, Room 205, Manguinhos, 21040-900 Rio de Janeiro, RJ, Brazil
| | - Izabella B S Corrêa
- Lab. of Macromolecules, Bio-Manguinhos, Fiocruz, Av. Brasil, 4365, Room 205, Manguinhos, 21040-900 Rio de Janeiro, RJ, Brazil
| | - Ana Paula C Argondizzo
- Lab. of Recombinant Technologies, Bio-Manguinhos, Fiocruz, Av. Brasil, 4365, Room 209, Manguinhos, 21040-900 Rio de Janeiro, RJ, Brazil
| | - Marco Alberto Medeiros
- Lab. of Recombinant Technologies, Bio-Manguinhos, Fiocruz, Av. Brasil, 4365, Room 209, Manguinhos, 21040-900 Rio de Janeiro, RJ, Brazil
| | - Roger B Dos Santos
- Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Av Carlos Chagas Filho, 373, Room 21, Ilha do Fundão, 21941-901 Rio de Janeiro, RJ, Brazil
| | - Theo Luiz F de Souza
- Faculdade de Farmácia, Universidade Federal do Rio de Janeiro, Av Carlos Chagas Filho, 373, Room 21, Ilha do Fundão, 21941-901 Rio de Janeiro, RJ, Brazil
| | - José G da Silva Junior
- Lab. of Macromolecules, Bio-Manguinhos, Fiocruz, Av. Brasil, 4365, Room 205, Manguinhos, 21040-900 Rio de Janeiro, RJ, Brazil
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Lazarus RP, John J, Shanmugasundaram E, Rajan AK, Thiagarajan S, Giri S, Babji S, Sarkar R, Kaliappan PS, Venugopal S, Praharaj I, Raman U, Paranjpe M, Grassly NC, Parker EPK, Parashar UD, Tate JE, Fleming JA, Steele AD, Muliyil J, Abraham AM, Kang G. The effect of probiotics and zinc supplementation on the immune response to oral rotavirus vaccine: A randomized, factorial design, placebo-controlled study among Indian infants. Vaccine 2018; 36:273-279. [PMID: 28874323 PMCID: PMC12001858 DOI: 10.1016/j.vaccine.2017.07.116] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2017] [Revised: 07/20/2017] [Accepted: 07/28/2017] [Indexed: 01/25/2023]
Abstract
BACKGROUND Strategies are needed to improve oral rotavirus vaccine (RV), which provides suboptimal protection in developing countries. Probiotics and zinc supplementation could improve RV immunogenicity by altering the intestinal microbiota and immune function. METHODS Infants 5weeks old living in urban Vellore, India were enrolled in a randomized, double-blind, placebo-controlled trial with a 4-arm factorial design to assess the effects of daily zinc (5mg), probiotic (1010Lactobacillus rhamnosus GG) or placebo on the immunogenicity of two doses of RV (Rotarix®, GlaxoSmithKline Biologicals) given at 6 and 10weeks of age. Infants were eligible for participation if healthy, available for the study duration and without prior receipt of RV or oral poliovirus vaccine other than the birth dose. The primary outcome was seroconversion to rotavirus at 14weeks of age based on detection of VP6-specific IgA at ≥20U/ml in previously seronegative infants or a fourfold rise in concentration. RESULTS The study took place during July 2012 to February 2013. 620 infants were randomized equally between study arms and 551 (88.9%) completed per protocol. Seroconversion was recorded in 54/137 (39.4%), 42/136 (30.9%), 40/143 (28.0%), and 37/135 (27.4%) infants receiving (1) probiotic and zinc, (2) probiotic and placebo, (3) placebo and zinc, (4) two placebos. Seroconversion showed a modest improvement among infants receiving probiotic (difference between groups 1, 2 and 3, 4 was 7.5% (97.5% Confidence Interval (CI): -1.4%, 16.2%), p=0.066) but not zinc (difference between groups 1, 3 and 2, 4 was 4.4% (97.5% CI: -4.4%, 13.2%), p=0.272). 16 serious adverse events were recorded, none related to study interventions. CONCLUSIONS Zinc or probiotic supplementation did not significantly improve the low immunogenicity of rotavirus vaccine given to infants in a poor urban community in India. A modest effect of combined supplementation deserves further investigation. TRIAL REGISTRATION The trial was registered in India (CTRI/2012/05/002677).
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Affiliation(s)
- Robin P Lazarus
- Division of Gastrointestinal Sciences, Christian Medical College, Vellore, India
| | - Jacob John
- Department of Community Health, Christian Medical College, Vellore, India
| | - E Shanmugasundaram
- Division of Gastrointestinal Sciences, Christian Medical College, Vellore, India
| | - Anand K Rajan
- Department of Clinical Virology, Christian Medical College, Vellore, India
| | - S Thiagarajan
- Department of Clinical Virology, Christian Medical College, Vellore, India
| | - Sidhartha Giri
- Division of Gastrointestinal Sciences, Christian Medical College, Vellore, India
| | - Sudhir Babji
- Division of Gastrointestinal Sciences, Christian Medical College, Vellore, India
| | - Rajiv Sarkar
- Division of Gastrointestinal Sciences, Christian Medical College, Vellore, India
| | | | - Srinivasan Venugopal
- Division of Gastrointestinal Sciences, Christian Medical College, Vellore, India
| | - Ira Praharaj
- Division of Gastrointestinal Sciences, Christian Medical College, Vellore, India
| | - Uma Raman
- Division of Gastrointestinal Sciences, Christian Medical College, Vellore, India
| | - Meghana Paranjpe
- Division of Gastrointestinal Sciences, Christian Medical College, Vellore, India
| | - Nicholas C Grassly
- Department of Infectious Disease Epidemiology, Imperial College London, London, UK
| | - Edward P K Parker
- Department of Infectious Disease Epidemiology, Imperial College London, London, UK
| | | | | | | | | | - Jayaprakash Muliyil
- Division of Gastrointestinal Sciences, Christian Medical College, Vellore, India
| | - Asha M Abraham
- Department of Clinical Virology, Christian Medical College, Vellore, India
| | - Gagandeep Kang
- Division of Gastrointestinal Sciences, Christian Medical College, Vellore, India.
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Parker EPK, Ramani S, Lopman BA, Church JA, Iturriza-Gómara M, Prendergast AJ, Grassly NC. Causes of impaired oral vaccine efficacy in developing countries. Future Microbiol 2018; 13:97-118. [PMID: 29218997 PMCID: PMC7026772 DOI: 10.2217/fmb-2017-0128] [Citation(s) in RCA: 154] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2017] [Accepted: 09/13/2017] [Indexed: 12/12/2022] Open
Abstract
Oral vaccines are less immunogenic when given to infants in low-income compared with high-income countries, limiting their potential public health impact. Here, we review factors that might contribute to this phenomenon, including transplacental antibodies, breastfeeding, histo blood group antigens, enteric pathogens, malnutrition, microbiota dysbiosis and environmental enteropathy. We highlight several clear risk factors for vaccine failure, such as the inhibitory effect of enteroviruses on oral poliovirus vaccine. We also highlight the ambiguous and at times contradictory nature of the available evidence, which undoubtedly reflects the complex and interconnected nature of the factors involved. Mechanisms responsible for diminished immunogenicity may be specific to each oral vaccine. Interventions aiming to improve vaccine performance may need to reflect the diversity of these mechanisms.
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Affiliation(s)
- Edward PK Parker
- Department of Infectious Disease Epidemiology, St Mary's Campus, Imperial College London, London, W2 1PG, UK
| | | | - Benjamin A Lopman
- Department of Epidemiology, Rollins School of Public Health, Emory University, Atlanta, GA 30322, USA
| | - James A Church
- Centre for Paediatrics, Blizard Institute, Queen Mary University of London, London, E1 2AT, UK
| | - Miren Iturriza-Gómara
- Centre for Global Vaccine Research, Institute of Infection & Global Health, University of Liverpool, Liverpool, L69 7BE, UK
| | - Andrew J Prendergast
- Centre for Paediatrics, Blizard Institute, Queen Mary University of London, London, E1 2AT, UK
| | - Nicholas C Grassly
- Department of Infectious Disease Epidemiology, St Mary's Campus, Imperial College London, London, W2 1PG, UK
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Velasquez DE, Parashar U, Jiang B. Decreased performance of live attenuated, oral rotavirus vaccines in low-income settings: causes and contributing factors. Expert Rev Vaccines 2017; 17:145-161. [PMID: 29252042 DOI: 10.1080/14760584.2018.1418665] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
INTRODUCTION Numerous studies have shown that the oral rotavirus vaccines are less effective in infants born in low income countries compared to those born in developed countries. Identifying the specific factors in developing countries that decrease and/or compromise the protection that rotavirus vaccines offer, could lead to a path for designing new strategies for the vaccines' improvement. AREAS COVERED We accessed PubMed to identify rotavirus vaccine performance studies (i.e., efficacy, effectiveness and immunogenicity) and correlated performance with several risk factors. Here, we review the factors that might contribute to the low vaccine efficacy, including passive transfer of maternal rotavirus antibodies, rotavirus seasonality, oral polio vaccine (OPV) administered concurrently, microbiome composition and concomitant enteric pathogens, malnutrition, environmental enteropathy, HIV, and histo blood group antigens. EXPERT COMMENTARY We highlight two major factors that compromise rotavirus vaccines' efficacy: the passive transfer of rotavirus IgG antibodies to infants and the co-administration of rotavirus vaccines with OPV. We also identify other potential risk factors that require further research because the data about their interference with the efficacy of rotavirus vaccines are inconclusive and at times conflicting.
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Affiliation(s)
- Daniel E Velasquez
- a Division of Viral Diseases , Centers for Disease Control and Prevention , Atlanta , GA , USA
| | - Umesh Parashar
- a Division of Viral Diseases , Centers for Disease Control and Prevention , Atlanta , GA , USA
| | - Baoming Jiang
- a Division of Viral Diseases , Centers for Disease Control and Prevention , Atlanta , GA , USA
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Pneumococcal vaccination for splenectomized patients with thalassemia major in Indonesia. Vaccine 2017; 35:4583-4586. [PMID: 28712490 DOI: 10.1016/j.vaccine.2017.07.011] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2017] [Revised: 06/25/2017] [Accepted: 07/03/2017] [Indexed: 11/21/2022]
Abstract
INTRODUCTION Streptococcus pneumoniae is a capsulated bacterium that can cause severe infection in patients with thalassemia major, particularly those who have undergone splenectomy. The absence of the spleen as well as zinc deficiency in splenectomized patients with thalassemia major increases the possibility of developing invasive pneumococcal infection. The aims of this study are to evaluate pneumococcal IgG levels following PCV and PPV immunizations and the effect of zinc supplementation on qualitative specific immune responses in splenectomized patients with thalassemia. METHODS Splenectomized patients with thalassemia major were administered a PCV pneumococcal vaccine (Prevenar 13®) at the start of the trial, after which they were randomly assigned to 2 groups (zinc and placebo group). After 8weeks, the patients received a PPV pneumococcal vaccine (Pneumovax®). Zinc syrup was provided to the zinc group at a dose of 1.5mg/kg/day (maximum of 50mg/day). Pneumococcal IgG examinations were conducted at the start of the trial and after 12weeks. RESULTS In the group without PPV, the median initial pneumococcal IgG value was 315 (ranging from 65 to 1419) mU/mL for the zinc group and 338.5 (ranging from 82 to 1648) mU/mL for the placebo group. The median final pneumococcal IgG value was 1812.5 (ranging from 834 to 2444) mU/mL for the zinc group and 2857.5 (ranging from 834 to 2624) for the placebo group. The increase in the pneumococcal IgG value between the two groups was comparable (p=0.642). In the group with previous PPV, the median initial pneumococcal IgG value was 1333 (ranging from 793 to 2031) mU/mL for the zinc group and 880 (ranging from 74 to 1686) mU/mL for the placebo group. The median final pneumococcal IgG value was 1487 (ranging from 635 to 1757) mU/mL for the zinc group and 1012 (ranging from 292 to 1732) mU/mL for the placebo group. The increase in the pneumococcal IgG value between the two groups was comparable (p=0.528). CONCLUSION There is no difference in the increase in pneumococcal IgG level in splenectomized patients with thalassemia major prior to and after receiving PPV. There were no differences observed in the development of pneumococcal IgG following zinc supplementation.
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Imdad A, Mayo‐Wilson E, Herzer K, Bhutta ZA, Cochrane Developmental, Psychosocial and Learning Problems Group. Vitamin A supplementation for preventing morbidity and mortality in children from six months to five years of age. Cochrane Database Syst Rev 2017; 3:CD008524. [PMID: 28282701 PMCID: PMC6464706 DOI: 10.1002/14651858.cd008524.pub3] [Citation(s) in RCA: 133] [Impact Index Per Article: 16.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/28/2022]
Abstract
BACKGROUND Vitamin A deficiency (VAD) is a major public health problem in low- and middle-income countries, affecting 190 million children under five years of age and leading to many adverse health consequences, including death. Based on prior evidence and a previous version of this review, the World Health Organization has continued to recommend vitamin A supplementation for children aged 6 to 59 months. There are new data available from recently published randomised trials since the previous publication of this review in 2010, and this update incorporates this information and reviews the evidence. OBJECTIVES To assess the effects of vitamin A supplementation (VAS) for preventing morbidity and mortality in children aged six months to five years. SEARCH METHODS In March 2016 we searched CENTRAL, Ovid MEDLINE, Embase, six other databases, and two trials registers. We also checked reference lists and contacted relevant organisations and researchers to identify additional studies. SELECTION CRITERIA Randomised controlled trials (RCTs) and cluster-RCTs evaluating the effect of synthetic VAS in children aged six months to five years living in the community. We excluded studies involving children in hospital and children with disease or infection. We also excluded studies evaluating the effects of food fortification, consumption of vitamin A rich foods, or beta-carotene supplementation. DATA COLLECTION AND ANALYSIS For this update, two reviewers independently assessed studies for inclusion and abstracted data, resolving discrepancies by discussion. We performed meta-analyses for outcomes, including all-cause and cause-specific mortality, disease, vision, and side effects. We used the GRADE approach to assess the quality of the evidence. MAIN RESULTS We identified 47 studies (4 of which are new to this review), involving approximately 1,223,856 children. Studies took place in 19 countries: 30 (63%) in Asia, 16 of these in India; 8 (17%) in Africa; 7 (15%) in Latin America, and 2 (4%) in Australia. About one-third of the studies were in urban/periurban settings, and half were in rural settings; the remaining studies did not clearly report settings. Most of the studies included equal numbers of girls and boys and lasted about a year. The included studies were at variable overall risk of bias; however, evidence for the primary outcome was at low risk of bias. A meta-analysis for all-cause mortality included 19 trials (1,202,382 children). At longest follow-up, there was a 12% observed reduction in the risk of all-cause mortality for vitamin A compared with control using a fixed-effect model (risk ratio (RR) 0.88, 95% confidence interval (CI) 0.83 to 0.93; high-quality evidence). This result was sensitive to choice of model, and a random-effects meta-analysis showed a different summary estimate (24% reduction: RR 0.76, 95% CI 0.66 to 0.88); however, the confidence intervals overlapped with that of the fixed-effect model. Nine trials reported mortality due to diarrhoea and showed a 12% overall reduction for VAS (RR 0.88, 95% CI 0.79 to 0.98; 1,098,538 participants; high-quality evidence). There was no significant effect for VAS on mortality due to measles, respiratory disease, and meningitis. VAS reduced incidence of diarrhoea (RR 0.85, 95% CI 0.82 to 0.87; 15 studies; 77,946 participants; low-quality evidence) and measles (RR 0.50, 95% CI 0.37 to 0.67; 6 studies; 19,566 participants; moderate-quality evidence). However, there was no significant effect on incidence of respiratory disease or hospitalisations due to diarrhoea or pneumonia. There was an increased risk of vomiting within the first 48 hours of VAS (RR 1.97, 95% CI 1.44 to 2.69; 4 studies; 10,541 participants; moderate-quality evidence). AUTHORS' CONCLUSIONS Vitamin A supplementation is associated with a clinically meaningful reduction in morbidity and mortality in children. Therefore, we suggest maintaining the policy of universal supplementation for children under five years of age in populations at risk of VAD. Further placebo-controlled trials of VAS in children between six months and five years of age would not change the conclusions of this review, although studies that compare different doses and delivery mechanisms are needed. In populations with documented vitamin A deficiency, it would be unethical to conduct placebo-controlled trials.
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Affiliation(s)
- Aamer Imdad
- Vanderbilt University School of MedicineDepartment of Pediatrics, D. Brent Polk Division of Gastroenterology, Hepatology and NutritionNashvilleTNUSA37212
| | - Evan Mayo‐Wilson
- Johns Hopkins University Bloomberg School of Public HealthDepartment of Epidemiology615 North Wolfe StreetBaltimoreMarylandUSA21205
| | - Kurt Herzer
- Johns Hopkins School of MedicineTower 711600 North Wolfe St.BaltimoreMDUSA21287
| | - Zulfiqar A Bhutta
- Hospital for Sick ChildrenCentre for Global Child HealthTorontoONCanadaM5G A04
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Abstract
BACKGROUND In developing countries, diarrhoea causes around 500,000 child deaths annually. Zinc supplementation during acute diarrhoea is currently recommended by the World Health Organization (WHO) and the United Nations Children's Fund (UNICEF). OBJECTIVES To evaluate oral zinc supplementation for treating children with acute or persistent diarrhoea. SEARCH METHODS We searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (the Cochrane Library 2016, Issue 5), MEDLINE, Embase, LILACS, CINAHL, mRCT, and reference lists up to 30 September 2016. We also contacted researchers. SELECTION CRITERIA Randomized controlled trials (RCTs) that compared oral zinc supplementation with placebo in children aged one month to five years with acute or persistent diarrhoea, including dysentery. DATA COLLECTION AND ANALYSIS Both review authors assessed trial eligibility and risk of bias, extracted and analysed data, and drafted the review. The primary outcomes were diarrhoea duration and severity. We summarized dichotomous outcomes using risk ratios (RR) and continuous outcomes using mean differences (MD) with 95% confidence intervals (CI). Where appropriate, we combined data in meta-analyses (using either a fixed-effect or random-effects model) and assessed heterogeneity.We assessed the certainty of the evidence using the GRADE approach. MAIN RESULTS Thirty-three trials that included 10,841 children met our inclusion criteria. Most included trials were conducted in Asian countries that were at high risk of zinc deficiency. Acute diarrhoeaThere is currently not enough evidence from well-conducted RCTs to be able to say whether zinc supplementation during acute diarrhoea reduces death or number of children hospitalized (very low certainty evidence).In children older than six months of age, zinc supplementation may shorten the average duration of diarrhoea by around half a day (MD -11.46 hours, 95% CI -19.72 to -3.19; 2581 children, 9 trials, low certainty evidence), and probably reduces the number of children whose diarrhoea persists until day seven (RR 0.73, 95% CI 0.61 to 0.88; 3865 children, 6 trials, moderate certainty evidence). In children with signs of malnutrition the effect appears greater, reducing the duration of diarrhoea by around a day (MD -26.39 hours, 95% CI -36.54 to -16.23; 419 children, 5 trials, high certainty evidence).Conversely, in children younger than six months of age, the available evidence suggests zinc supplementation may have no effect on the mean duration of diarrhoea (MD 5.23 hours, 95% CI -4.00 to 14.45; 1334 children, 2 trials, moderate certainty evidence), or the number of children who still have diarrhoea on day seven (RR 1.24, 95% CI 0.99 to 1.54; 1074 children, 1 trial, moderate certainty evidence).None of the included trials reported serious adverse events. However, zinc supplementation increased the risk of vomiting in both age groups (children greater than six months of age: RR 1.57, 95% CI 1.32 to 1.86; 2605 children, 6 trials, moderate certainty evidence; children less than six months of age: RR 1.54, 95% CI 1.05 to 2.24; 1334 children, 2 trials, moderate certainty evidence). Persistent diarrhoeaIn children with persistent diarrhoea, zinc supplementation probably shortens the average duration of diarrhoea by around 16 hours (MD -15.84 hours, 95% CI -25.43 to -6.24; 529 children, 5 trials, moderate certainty evidence). AUTHORS' CONCLUSIONS In areas where the prevalence of zinc deficiency or the prevalence of malnutrition is high, zinc may be of benefit in children aged six months or more. The current evidence does not support the use of zinc supplementation in children less six months of age, in well-nourished children, and in settings where children are at low risk of zinc deficiency.
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Affiliation(s)
- Marzia Lazzerini
- Institute for Maternal and Child Health IRCCS Burlo GarofoloWHO Collaborating Centre for Maternal and Child HealthVia dell'Istria 65/1, 34137TriesteItaly
| | - Humphrey Wanzira
- Institute for Maternal and Child Health IRCCS Burlo GarofoloWHO Collaborating Centre for Maternal and Child HealthVia dell'Istria 65/1, 34137TriesteItaly
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Saha A, Rosewell A, Hayen A, MacIntyre CR, Qadri F. Improving immunization approaches to cholera. Expert Rev Vaccines 2016; 16:235-248. [PMID: 27805467 DOI: 10.1080/14760584.2017.1249470] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
Abstract
INTRODUCTION Cholera's impact is greatest in resource-limited countries. In the last decade several large epidemics have led to a global push to improve and implement the tools for cholera prevention and control. Areas covered: PubMed, Google Scholar and the WHO website were searched to review the literature and summarize the current status of cholera vaccines to make recommendations on improving immunization approaches to cholera. Oral cholera vaccines (OCVs) have demonstrated their effectiveness in endemic, outbreak response and emergency settings, highlighting their potential for wider adoption. While two doses of the currently available OCVs are recommended by manufacturers, a single dose would be easier to implement. Encouragingly, recent studies have shown that cold chain requirements may no longer be essential. The establishment of the global OCV stockpile in 2013 has been a major advance in cholera preparedness. New killed and live-attenuated vaccines are being actively explored as candidate vaccines for endemic settings and/or as a traveller's vaccine. The recent advances in cholera vaccination approaches should be considered in the global cholera control strategy. Expert commentary: The development of affordable cholera vaccines is a major success to improve cholera control. New vaccines and country specific interventions will further reduce the burden of this disease globally.
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Affiliation(s)
- Amit Saha
- a School of public Health and Community medicine , University of New South Wales , Sydney , NSW , Australia.,b Infectious Diseases Division , International Centre for Diarrhoeal Disease Research Bangladesh (icddr, b) , Dhaka , Bangladesh
| | - Alexander Rosewell
- a School of public Health and Community medicine , University of New South Wales , Sydney , NSW , Australia
| | - Andrew Hayen
- a School of public Health and Community medicine , University of New South Wales , Sydney , NSW , Australia.,c Faculty of Health , University of Technology Sydney , Sydney , NSW , Australia
| | - C Raina MacIntyre
- a School of public Health and Community medicine , University of New South Wales , Sydney , NSW , Australia
| | - Firdausi Qadri
- b Infectious Diseases Division , International Centre for Diarrhoeal Disease Research Bangladesh (icddr, b) , Dhaka , Bangladesh
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Maares M, Haase H. Zinc and immunity: An essential interrelation. Arch Biochem Biophys 2016; 611:58-65. [PMID: 27021581 DOI: 10.1016/j.abb.2016.03.022] [Citation(s) in RCA: 204] [Impact Index Per Article: 22.7] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2016] [Revised: 03/16/2016] [Accepted: 03/23/2016] [Indexed: 12/27/2022]
Abstract
The significance of the essential trace element zinc for immune function has been known for several decades. Zinc deficiency affects immune cells, resulting in altered host defense, increased risk of inflammation, and even death. The micronutrient zinc is important for maintenance and development of immune cells of both the innate and adaptive immune system. A disrupted zinc homeostasis affects these cells, leading to impaired formation, activation, and maturation of lymphocytes, disturbed intercellular communication via cytokines, and weakened innate host defense via phagocytosis and oxidative burst. This review outlines the connection between zinc and immunity by giving a survey on the major roles of zinc in immune cell function, and their potential consequences in vivo.
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Affiliation(s)
- Maria Maares
- Department of Food Chemistry and Toxicology, Berlin Institute of Technology, Gustav-Meyer-Allee 25, D-13355 Berlin, Germany
| | - Hajo Haase
- Department of Food Chemistry and Toxicology, Berlin Institute of Technology, Gustav-Meyer-Allee 25, D-13355 Berlin, Germany.
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Azman AS, Luquero FJ, Ciglenecki I, Grais RF, Sack DA, Lessler J. The Impact of a One-Dose versus Two-Dose Oral Cholera Vaccine Regimen in Outbreak Settings: A Modeling Study. PLoS Med 2015; 12:e1001867. [PMID: 26305226 PMCID: PMC4549326 DOI: 10.1371/journal.pmed.1001867] [Citation(s) in RCA: 75] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2014] [Accepted: 07/15/2015] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND In 2013, a stockpile of oral cholera vaccine (OCV) was created for use in outbreak response, but vaccine availability remains severely limited. Innovative strategies are needed to maximize the health impact and minimize the logistical barriers to using available vaccine. Here we ask under what conditions the use of one dose rather than the internationally licensed two-dose protocol may do both. METHODS AND FINDINGS Using mathematical models we determined the minimum relative single-dose efficacy (MRSE) at which single-dose reactive campaigns are expected to be as or more effective than two-dose campaigns with the same amount of vaccine. Average one- and two-dose OCV effectiveness was estimated from published literature and compared to the MRSE. Results were applied to recent outbreaks in Haiti, Zimbabwe, and Guinea using stochastic simulations to illustrate the potential impact of one- and two-dose campaigns. At the start of an epidemic, a single dose must be 35%-56% as efficacious as two doses to avert the same number of cases with a fixed amount of vaccine (i.e., MRSE between 35% and 56%). This threshold decreases as vaccination is delayed. Short-term OCV effectiveness is estimated to be 77% (95% CI 57%-88%) for two doses and 44% (95% CI -27% to 76%) for one dose. This results in a one-dose relative efficacy estimate of 57% (interquartile range 13%-88%), which is above conservative MRSE estimates. Using our best estimates of one- and two-dose efficacy, we projected that a single-dose reactive campaign could have prevented 70,584 (95% prediction interval [PI] 55,943-86,205) cases in Zimbabwe, 78,317 (95% PI 57,435-100,150) in Port-au-Prince, Haiti, and 2,826 (95% PI 2,490-3,170) cases in Conakry, Guinea: 1.1 to 1.2 times as many as a two-dose campaign. While extensive sensitivity analyses were performed, our projections of cases averted in past epidemics are based on severely limited single-dose efficacy data and may not fully capture uncertainty due to imperfect surveillance data and uncertainty about the transmission dynamics of cholera in each setting. CONCLUSIONS Reactive vaccination campaigns using a single dose of OCV may avert more cases and deaths than a standard two-dose campaign when vaccine supplies are limited, while at the same time reducing logistical complexity. These findings should motivate consideration of the trade-offs between one- and two-dose campaigns in resource-constrained settings, though further field efficacy data are needed and should be a priority in any one-dose campaign.
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Affiliation(s)
- Andrew S. Azman
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
| | | | | | | | - David A. Sack
- Department of International Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
| | - Justin Lessler
- Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
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Ahmad SM, Hossain MB, Monirujjaman M, Islam S, Huda MN, Kabir Y, Raqib R, Lönnerdal BL. Maternal zinc supplementation improves hepatitis B antibody responses in infants but decreases plasma zinc level. Eur J Nutr 2015. [PMID: 26208687 DOI: 10.1007/s00394-015-0999-6] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
Abstract
PURPOSE The World Health Report identifies zinc deficiency as one of the major causes of disease in developing countries, and infants are at particular risk. We aimed to investigate the effect of maternal zinc supplementation on the infant's immune function in a population at risk of deficiency. METHODS In a randomized, double-blind placebo-controlled trial, mothers were supplemented either with 20 mg/day of elemental zinc (n = 20) or placebo (n = 19) at the beginning of second trimester, which continued until 6 months postpartum. Indicators of the infants' immune function measured included interleukin (IL)-7, thymic size and response to hepatitis B vaccination. RESULTS Infants born from mothers receiving zinc supplements during pregnancy and postpartum had significantly lower plasma zinc (p < 0.05) but marginally higher IL-7 and antibody responses to hepatitis B vaccination (p < 0.10) than infants born from mothers not receiving zinc. Maternal zinc supplementation showed no negative impact on copper status of mothers or their infants. Maternal zinc supplementation did not influence infant thymic size, but cord blood IL-7 was found positively associated with thymus size at 1 month of age (r = 0.392) and with hepatitis B vaccine response at 6 months of age (r = 0.386). CONCLUSION Prenatal and postnatal zinc supplementation marginally improved T cell-dependent antibody responses in infants along with IL-7, a cytokine involved in human T cell development and maintaining homeostasis.
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Affiliation(s)
| | | | - Md Monirujjaman
- Nutritional Biochemistry, Center for Vaccine Sciences, icddr,b, Mohakhali, Dhaka, 1212, Bangladesh
| | - Sharmin Islam
- Nutritional Biochemistry, Center for Vaccine Sciences, icddr,b, Mohakhali, Dhaka, 1212, Bangladesh
| | - Md Nazmul Huda
- Nutritional Biochemistry, Center for Vaccine Sciences, icddr,b, Mohakhali, Dhaka, 1212, Bangladesh.,Department of Nutrition, University of California, Davis, Davis, CA, 95616, USA
| | - Yearul Kabir
- Department of Biochemistry and Molecular Biology, University of Dhaka, Dhaka, Bangladesh
| | - Rubhana Raqib
- Nutritional Biochemistry, Center for Vaccine Sciences, icddr,b, Mohakhali, Dhaka, 1212, Bangladesh
| | - Bo L Lönnerdal
- Department of Nutrition, University of California, Davis, Davis, CA, 95616, USA
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Braga CBM, Ferreira de Miranda Santos IK, Palmeira P, Peria FM, de Figueiredo Ribeiro SM, Martinez EZ, da Rocha JJR, Carvalho da Cunha SFD. Effect of Zinc Supplementation on Serological Response to Vaccination AgainstStreptococcus Pneumoniaein Patients Undergoing Chemotherapy for Colorectal Cancer. Nutr Cancer 2015; 67:926-32. [DOI: 10.1080/01635581.2015.1053497] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/23/2022]
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Raiten DJ, Sakr Ashour FA, Ross AC, Meydani SN, Dawson HD, Stephensen CB, Brabin BJ, Suchdev PS, van Ommen B. Inflammation and Nutritional Science for Programs/Policies and Interpretation of Research Evidence (INSPIRE). J Nutr 2015; 145:1039S-1108S. [PMID: 25833893 PMCID: PMC4448820 DOI: 10.3945/jn.114.194571] [Citation(s) in RCA: 150] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2014] [Revised: 06/08/2014] [Accepted: 10/29/2014] [Indexed: 02/06/2023] Open
Abstract
An increasing recognition has emerged of the complexities of the global health agenda—specifically, the collision of infections and noncommunicable diseases and the dual burden of over- and undernutrition. Of particular practical concern are both 1) the need for a better understanding of the bidirectional relations between nutritional status and the development and function of the immune and inflammatory response and 2) the specific impact of the inflammatory response on the selection, use, and interpretation of nutrient biomarkers. The goal of the Inflammation and Nutritional Science for Programs/Policies and Interpretation of Research Evidence (INSPIRE) is to provide guidance for those users represented by the global food and nutrition enterprise. These include researchers (bench and clinical), clinicians providing care/treatment, those developing and evaluating programs/interventions at scale, and those responsible for generating evidence-based policy. The INSPIRE process included convening 5 thematic working groups (WGs) charged with developing summary reports around the following issues: 1) basic overview of the interactions between nutrition, immune function, and the inflammatory response; 2) examination of the evidence regarding the impact of nutrition on immune function and inflammation; 3) evaluation of the impact of inflammation and clinical conditions (acute and chronic) on nutrition; 4) examination of existing and potential new approaches to account for the impact of inflammation on biomarker interpretation and use; and 5) the presentation of new approaches to the study of these relations. Each WG was tasked with synthesizing a summary of the evidence for each of these topics and delineating the remaining gaps in our knowledge. This review consists of a summary of the INSPIRE workshop and the WG deliberations.
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Affiliation(s)
- Daniel J Raiten
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD;
| | - Fayrouz A Sakr Ashour
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, NIH, Bethesda, MD
| | - A Catharine Ross
- Departments of Nutritional Sciences and Veterinary and Biomedical Science and Center for Molecular Immunology and Infectious Disease, Pennsylvania State University, University Park, PA
| | - Simin N Meydani
- Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA
| | - Harry D Dawson
- USDA-Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet, Genomics, and Immunology Laboratory, Beltsville, MD
| | - Charles B Stephensen
- Agricultural Research Service, Western Human Nutrition Research Center, USDA, Davis, CA
| | - Bernard J Brabin
- Child and Reproductive Health Group, Liverpool School of Tropical Medicine, Liverpool, United Kingdom; Global Child Health Group, Academic Medical Centre, University of Amsterdam, Amsterdam, The Netherlands
| | - Parminder S Suchdev
- Department of Pediatrics and Global Health, Emory University, Atlanta, GA; and
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Bonaventura P, Benedetti G, Albarède F, Miossec P. Zinc and its role in immunity and inflammation. Autoimmun Rev 2014; 14:277-85. [PMID: 25462582 DOI: 10.1016/j.autrev.2014.11.008] [Citation(s) in RCA: 465] [Impact Index Per Article: 42.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2014] [Accepted: 11/15/2014] [Indexed: 12/12/2022]
Abstract
Zinc (Zn) nutritional importance has been known for a long time, but in the last decades its importance in immune modulation has arisen. This review aims at describing the mechanisms involved in the regulation of Zn homeostasis and their effects on the immune response focusing on those which are implicated in the physiopathology of rheumatoid arthritis. Zn functions as a modulator of the immune response through its availability, which is tightly regulated by several transporters and regulators. When this mechanism is disturbed, Zn availability is reduced, altering survival, proliferation and differentiation of the cells of different organs and systems and, in particular, cells of the immune system. Zn deficiency affects cells involved in both innate and adaptive immunity at the survival, proliferation and maturation levels. These cells include monocytes, polymorphonuclear-, natural killer-, T-, and B-cells. T cell functions and the balance between the different T helper cell subsets are particularly susceptible to changes in Zn status. While acute Zn deficiency causes a decrease in innate and adaptive immunity, chronic deficiency increases inflammation. During chronic deficiency, the production of pro-inflammatory cytokines increases, influencing the outcome of a large number of inflammatory diseases, including rheumatoid arthritis.
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Affiliation(s)
- Paola Bonaventura
- Immunogenomics and Inflammation Unit and the Department of Clinical Immunology and Rheumatology, Hospices Civils de Lyon, EA 4130 University of Lyon 1, Hôpital Edouard Herriot, Lyon, France
| | - Giulia Benedetti
- Immunogenomics and Inflammation Unit and the Department of Clinical Immunology and Rheumatology, Hospices Civils de Lyon, EA 4130 University of Lyon 1, Hôpital Edouard Herriot, Lyon, France
| | - Francis Albarède
- CNRS UMR 5276 "Laboratoire de Géologie de Lyon", Ecole Normale Supérieure, 46 Allée d'Italie, 69634 Lyon, France
| | - Pierre Miossec
- Immunogenomics and Inflammation Unit and the Department of Clinical Immunology and Rheumatology, Hospices Civils de Lyon, EA 4130 University of Lyon 1, Hôpital Edouard Herriot, Lyon, France.
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Lopez AL, Gonzales MLA, Aldaba JG, Nair GB. Killed oral cholera vaccines: history, development and implementation challenges. THERAPEUTIC ADVANCES IN VACCINES 2014; 2:123-36. [PMID: 25177492 DOI: 10.1177/2051013614537819] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Cholera is still a major global health problem, affecting mainly people living in unsanitary conditions and who are at risk for outbreaks of cholera. During the past decade, outbreaks are increasingly reported from more countries. From the early killed oral cholera vaccine, rapid improvements in vaccine development occurred as a result of a better understanding of the epidemiology of the disease, pathogenesis of cholera infection and immunity. The newer-generation oral killed cholera vaccines have been shown to be safe and effective in field trials conducted in cholera endemic areas. Likewise, they have been shown to be protective when used during outbreak settings. Aside from providing direct protection to vaccinated individuals, recent studies have demonstrated that these killed oral vaccines also confer indirect protection through herd immunity. Although new-generation oral cholera vaccines should not be considered in isolation from other preventive approaches in countries where they are most needed, especially improved water quality and sanitation, these vaccines serve as immediately available public health tools for preventing further morbidity and mortality from cholera. However, despite its availability for more than two decades, use of these vaccines has not been optimized. Although there are limitations of the currently available oral cholera vaccines, recent data show that the vaccines are safe, feasible to use even in difficult circumstances and able to provide protection in various settings. Clear identification of the areas and target population groups who will benefit from the use of the cholera vaccines will be required and strategies to facilitate accessibility and usage of these vaccines in these areas and population groups will need to be developed.
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Affiliation(s)
- Anna Lena Lopez
- Institute of Child Health and Human Development, University of the Philippines Manila-National Institutes of Health, 623 P. Gil St., Manila 1000, Philippines
| | | | - Josephine G Aldaba
- Institute of Child Health and Human Development, National Institutes of Health, University of the Philippines Manila, Manila, Philippines
| | - G Balakrish Nair
- Translational Health Science and Technology Institute, Haryana, India
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Mayo-Wilson E, Junior JA, Imdad A, Dean S, Chan XHS, Chan ES, Jaswal A, Bhutta ZA. Zinc supplementation for preventing mortality, morbidity, and growth failure in children aged 6 months to 12 years of age. Cochrane Database Syst Rev 2014:CD009384. [PMID: 24826920 DOI: 10.1002/14651858.cd009384.pub2] [Citation(s) in RCA: 88] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/17/2023]
Abstract
BACKGROUND Zinc deficiency is prevalent in low- and middle-income countries, and contributes to significant diarrhoea-, pneumonia-, and malaria-related morbidity and mortality among young children. Zinc deficiency also impairs growth. OBJECTIVES To assess the effects of zinc supplementation for preventing mortality and morbidity, and for promoting growth, in children aged six months to 12 years of age. SEARCH METHODS Between December 2012 and January 2013, we searched CENTRAL, MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, Embase, African Index Medicus, Conference Proceedings Citation Index, Dissertation Abstracts, Global Health, IndMED, LILACS, WHOLIS, metaRegister of Controlled Trials, and WHO ICTRP. SELECTION CRITERIA Randomised controlled trials of preventive zinc supplementation in children aged six months to 12 years compared with no intervention, a placebo, or a waiting list control. We excluded hospitalised children and children with chronic diseases or conditions. We excluded food fortification or intake, sprinkles, and therapeutic interventions. DATA COLLECTION AND ANALYSIS Two authors screened studies, extracted data, and assessed risk of bias. We contacted trial authors for missing information. MAIN RESULTS We included 80 randomised controlled trials with 205,401 eligible participants. We did not consider that the evidence for the key analyses of morbidity and mortality outcomes were affected by risk of bias. The risk ratio (RR) for all-cause mortality was compatible with a reduction and a small increased risk of death with zinc supplementation (RR 0.95, 95% confidence interval (CI) 0.86 to 1.05, 14 studies, high-quality evidence), and also for cause-specific mortality due to diarrhoea (RR 0.95, 95% CI 0.69 to 1.31, four studies, moderate-quality evidence), lower respiratory tract infection (LRTI) (RR 0.86, 95% CI 0.64 to 1.15, three studies, moderate-quality evidence), or malaria (RR 0.90, 95% CI 0.77 to 1.06, two studies, moderate-quality evidence).Supplementation reduced diarrhoea morbidity, including the incidence of all-cause diarrhoea (RR 0.87, 95% CI 0.85 to 0.89, 26 studies, moderate-quality evidence), but the results for LRTI and malaria were imprecise: LRTI (RR 1, 95% CI 0.94 to 1.07, 12 studies, moderate-quality evidence); malaria (RR 1.05, 95% 0.95 to 1.15, four studies, moderate-quality evidence).There was moderate-quality evidence of a very small improvement in height with supplementation (standardised mean difference (SMD) -0.09, 95% CI -0.13 to -0.06; 50 studies), but the size of this effect might not be clinically important. There was a medium to large positive effect on zinc status.Supplementation was associated with an increase in the number of participants with at least one vomiting episode (RR 1.29, 95% CI 1.14 to 1.46, five studies, high-quality evidence). We found no clear evidence of benefit or harm of supplementation with regard to haemoglobin or iron status. Supplementation had a negative effect on copper status. AUTHORS' CONCLUSIONS In our opinion, the benefits of preventive zinc supplementation outweigh the harms in areas where the risk of zinc deficiency is relatively high. Further research should determine optimal intervention characteristics such as supplement dose.
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Affiliation(s)
- Evan Mayo-Wilson
- Department of Epidemiology, Johns Hopkins University Bloomberg School of Public Health, 615 North Wolfe Street, Baltimore MD, MD, USA, 21205
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Chowdhury MI, Sheikh A, Qadri F. Development of Peru-15 (CholeraGarde®), a live-attenuated oral cholera vaccine: 1991–2009. Expert Rev Vaccines 2014; 8:1643-52. [DOI: 10.1586/erv.09.137] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
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43
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LaRocque RC, Harris JB, Ryan ET, Qadri F, Calderwood SB. Postgenomic approaches to cholera vaccine development. Expert Rev Vaccines 2014; 5:337-46. [PMID: 16827618 DOI: 10.1586/14760584.5.3.337] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/08/2022]
Abstract
Cholera remains an important public health threat. A cholera vaccine that provides durable protection at the mucosal surface, especially among children in endemic settings, is urgently needed. The availability of the complete genome sequence of a clinical isolate of Vibrio cholerae O1 El Tor has allowed for comparative and functional genomic approaches in the study of cholera. This work holds promise for the identification of bacterial targets of protective human immune responses and may contribute to the development of a new generation of cholera vaccines.
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Affiliation(s)
- Regina C LaRocque
- Division of Infectious Diseases, Massachusetts General Hospital, GRJ 504, 55 Fruit Street, Boston, MA 02114, USA.
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44
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Haase H, Rink L. Zinc signals and immune function. Biofactors 2014; 40:27-40. [PMID: 23804522 DOI: 10.1002/biof.1114] [Citation(s) in RCA: 175] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/28/2013] [Revised: 04/23/2013] [Accepted: 04/25/2013] [Indexed: 12/21/2022]
Abstract
For more than 50 years, it has been known that zinc deficiency compromises immune function. During this time, knowledge about the biochemistry of zinc has continued to grow, but only recent years have provided in-depth molecular insights into the multiple aspects of zinc as a regulator of immunity. A network based on ZnT and ZIP proteins for transport and metallothionein for storage tightly regulates zinc availability, and virtually all aspects of innate and adaptive immunity are affected by zinc. In vivo, zinc deficiency alters the number and function of neutrophil granulocytes, monocytes, natural killer (NK)-, T-, and B-cells. T cell functions and balance between the different subsets are particularly susceptible to changes in zinc status. This article focuses in particular on the main mechanisms by which zinc ions exert essential functions in the immune system. On the one hand, this includes tightly protein bound zinc ions serving catalytic or structural functions in a multitude of different proteins, in particular enzymes and transcription factors. On the other hand, increasing evidence arises for a regulatory role of free zinc ions in signal transduction, especially in cells of the immune system. Identification of several molecular targets, including phosphatases, phosphodiesterases, caspases, and kinases suggest that zinc ions are a second messenger regulating signal transduction in various kinds of immune cells.
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Affiliation(s)
- Hajo Haase
- Institute of Immunology, Medical Faculty, RWTH Aachen University, Pauwelsstrasse 30, Aachen, Germany
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45
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Provenzano D, Kovác P, Wade WF. The ABCs (Antibody, B Cells, and Carbohydrate Epitopes) of Cholera Immunity: Considerations for an Improved Vaccine. Microbiol Immunol 2013; 50:899-927. [PMID: 17179659 DOI: 10.1111/j.1348-0421.2006.tb03866.x] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Cholera, a diarrheal disease, is known for explosive epidemics that can quickly kill thousands. Endemic cholera is a seasonal torment that also has a significant mortality. Not all nations with extensive rural communities can achieve the required infrastructure or behavioral changes to prevent epidemic or endemic cholera. For some communities, a single-dose cholera vaccine that protects those at risk is the most efficacious means to reduce morbidity and mortality. It is clear that our understanding of what a protective cholera immune response is has not progressed at the rate our understanding of the pathogenesis and molecular biology of cholera infection has. This review addresses V. cholerae lipopolysaccharide (LPS)-based immunogens because LPS is the only immunogen proven to induce protective antibody in humans. We discuss the role of anti-LPS antibodies in protection from cholera, the importance and the potential role of B cell subsets in protection that is based on their anatomical location and the intrinsic antigen-receptor specificity of various subsets is introduced.
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Affiliation(s)
- Daniele Provenzano
- Department of Biological Sciences, University of Texas-Brownsville, Brownsville, TX 78520, USA
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46
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Gestational zinc deficiency impairs humoral and cellular immune responses to hepatitis B vaccination in offspring mice. PLoS One 2013; 8:e73461. [PMID: 24069198 PMCID: PMC3775768 DOI: 10.1371/journal.pone.0073461] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2013] [Accepted: 07/19/2013] [Indexed: 01/31/2023] Open
Abstract
Background Gestational zinc deficiency has been confirmed to impair the infant immune function. However, knowledge about effects of maternal mild zinc deficiency during pregnancy on hepatitis B vaccine responsiveness in offspring is limited. In this report, we aimed to examine how maternal zinc deficiency during pregnancy influences humoral and cellular immune responses to hepatitis B vaccination in offspring of BALB/c mice. Methodology/Principal Findings From day 1 of pregnancy upon delivery, maternal mice were given a standard diet (30 mg/kg/day zinc), zinc deficient diet (8 mg/kg/day zinc), or combination of zinc deficient diet (8 mg/kg/day zinc in the first 2 weeks of gestation) and zinc supplement diet (150 mg/kg/day zinc for the last week of pregnancy), respectively. Newborn pups of these maternal mice were immunized with hepatitis B vaccine at postnatal weeks 0, 2 and 4. Then, splenocytes and blood samples from the offspring mice were harvested for detection of serum zinc concentrations, humoral and cell-mediated immune responses, expression of cytokines using ELISA, CCK-8 and flow cytometric analysis. Results from the present study demonstrated that gestational zinc deficiency inhibited antibody responses, and decreased the proliferative capacity of T cells in offsprings immunized with hepatitis B vaccine. Additionally, HBsAg-specific cytokines analysis revealed that gestational zinc deficiency could inhibit secretion of IFN-γ from splenocytes, and decrease IFN-γ expression of CD4+ and CD8+ T cells. Conclusions/Significance Gestational zinc deficiency can weaken the humoral and cell-mediated immune responses to hepatitis B vaccine via decreasing B cell counts and hepatitis B virus-specific immunoglobulin G production, as well as reducing T cell proliferation, CD4+/CD8+ T cell ratio, and Th1-type immune responses.
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Qadir MI, Arshad A, Ahmad B. Zinc: Role in the management of diarrhea and cholera. World J Clin Cases 2013; 1:140-142. [PMID: 24303485 PMCID: PMC3845954 DOI: 10.12998/wjcc.v1.i4.140] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/23/2013] [Revised: 05/30/2013] [Accepted: 06/08/2013] [Indexed: 02/05/2023] Open
Abstract
Diarrhea and cholera are major health problems. Vibrio cholera, the causative agent of cholera, infects the small intestine, resulting in vomiting, massive watery diarrhea and dehydration. Reduced water and electrolyte absorption is also due to zinc deficiency. Zinc has an important role in recovery from the disease. The combination of zinc with cholera vaccine and oral rehydration solutions has a positive impact on cholera and diarrhea. It has led to a decrease in the mortality and morbidity associated with diarrhea.
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Camacho AI, Irache JM, Gamazo C. Recent progress towards development of a Shigella vaccine. Expert Rev Vaccines 2013; 12:43-55. [PMID: 23256738 DOI: 10.1586/erv.12.135] [Citation(s) in RCA: 38] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
The burden of dysentery due to shigellosis among children in the developing world is still a major concern. A safe and efficacious vaccine against this disease is a priority, since no licensed vaccine is available. This review provides an update of vaccine achievements focusing on subunit vaccine strategies and the forthcoming strategies surrounding this approach. In particular, this review explores several aspects of the pathogenesis of shigellosis and the elicited immune response as being the basis of vaccine requirements. The use of appropriate Shigella antigens, together with the right adjuvants, may offer safety, efficacy and more convenient delivery methods for massive worldwide vaccination campaigns.
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Abstract
BACKGROUND In developing countries, diarrhoea causes around two million child deaths annually. Zinc supplementation during acute diarrhoea is currently recommended by the World Health Organization and UNICEF. OBJECTIVES To evaluate oral zinc supplementation for treating children with acute or persistent diarrhoea. SEARCH METHODS In February 2012, we searched the Cochrane Infectious Diseases Group Specialized Register, CENTRAL (The Cochrane Library 2011, Issue 11), MEDLINE, EMBASE, LILACS, CINAHL, mRCT, and reference lists. We also contacted researchers. SELECTION CRITERIA Randomized controlled trials comparing oral zinc supplementation with placebo in children aged one month to five years with acute or persistent diarrhoea, including dysentery. DATA COLLECTION AND ANALYSIS Both authors assessed trial eligibility and risk of bias, extracted and analysed data, and drafted the review. Diarrhoea duration and severity were the primary outcomes. We summarized dichotomous outcomes using risk ratios (RR) and continuous outcomes using mean differences (MD) with 95% confidence intervals (CI). Where appropriate, we combined data in meta-analyses (using the fixed- or random-effects model) and assessed heterogeneity.The quality of evidence has been assessed using the GRADE methods MAIN RESULTS Twenty-four trials, enrolling 9128 children, met our inclusion criteria. The majority of the data is from Asia, from countries at high risk of zinc deficiency, and may not be applicable elsewhere. Acute diarrhoea. There is currently not enough evidence from well conducted randomized controlled trials to be able to say whether zinc supplementation during acute diarrhoea reduces death or hospitalization (very low quality evidence).In children aged greater than six months with acute diarrhoea, zinc supplementation may shorten the duration of diarrhoea by around 10 hours (MD -10.44 hours, 95% CI -21.13 to 0.25; 2175 children, six trials, low quality evidence), and probably reduces the number of children whose diarrhoea persists until day seven (RR 0.73, 95% CI 0.61 to 0.88; 3865 children, six trials, moderate quality evidence). In children with signs of moderate malnutrition the effect appears greater, reducing the duration of diarrhoea by around 27 hours (MD -26.98 hours, 95% CI -14.62 to -39.34; 336 children, three trials, high quality evidence).Conversely, In children aged less than six months, the available evidence suggests zinc supplementation may have no effect on mean diarrhoea duration (MD 5.23 hours, 95% CI -4.00 to 14.45; 1334 children, two trials, low quality evidence), and may even increase the proportion of children whose diarrhoea persists until day seven (RR 1.24, 95% CI 0.99 to 1.54; 1074 children, one trial, moderate quality evidence).No trials reported serious adverse events, but zinc supplementation during acute diarrhoea causes vomiting in both age groups (RR 1.59, 95% 1.27 to 1.99; 5189 children, 10 trials, high quality evidence). Persistent diarrhoea. In children with persistent diarrhoea, zinc supplementation probably shortens the duration of diarrhoea by around 16 hours (MD -15.84 hours, 95% CI -25.43 to -6.24; 529 children, five trials, moderate quality evidence). AUTHORS' CONCLUSIONS In areas where the prevalence of zinc deficiency or the prevalence of moderate malnutrition is high, zinc may be of benefit in children aged six months or more.The current evidence does not support the use of zinc supplementation in children below six months of age.
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Affiliation(s)
- Marzia Lazzerini
- Unit for Health Services Research and International Health,WHO Collaborating Centre forMaternal and ChildHealth, Institute forMaternal and Child Health, Trieste, Italy.
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Saha A, Chowdhury MI, Nazim M, Alam MM, Ahmed T, Hossain MB, Hore SK, Sultana GNN, Svennerholm AM, Qadri F. Vaccine specific immune response to an inactivated oral cholera vaccine and EPI vaccines in a high and low arsenic area in Bangladeshi children. Vaccine 2012. [PMID: 23200936 DOI: 10.1016/j.vaccine.2012.11.049] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
BACKGROUND Immune responses to the inactivated oral whole cell cholera toxin B (CTB) subunit cholera vaccine, Dukoral(®), as well as three childhood vaccines in the national immunization system were compared in children living in high and low arsenic contaminated areas in Bangladesh. In addition, serum complement factors C3 and C4 levels were evaluated among children in the two areas. VACCINATIONS: Toddlers (2-5 years) were orally immunized with two doses of Dukoral 14 days apart. Study participants had also received diphtheria, tetanus and measles vaccines according to the Expanded Program on Immunization (EPI) in Bangladesh. RESULTS The mean level of arsenic in the urine specimens in the children of the high arsenic area (HAA, Shahrasti, Chandpur) was 291.8μg/L while the level was 6.60μg/L in the low arsenic area (LAA, Mirpur, Dhaka). Cholera specific vibriocidal antibody responses were significantly increased in the HAA (87%, P<0.001) and the LAA (75%, P<0.001) children after vaccination with Dukoral, but no differences were found between the two groups. Levels of CTB specific IgA and IgG antibodies were comparable between the two groups, whereas LPS specific IgA and IgG were higher in the LAA group, although response rates were comparable. Diphtheria and tetanus vaccine specific IgG responses were significantly higher in the HAA compared to the LAA group (P<0.001, P=0.048 respectively), whereas there were no differences in the measles specific IgG responses between the groups. Complement C3 and C4 levels in sera were higher in participants from the HAA than the LAA groups (P<0.001, P=0.049 respectively). CONCLUSIONS The study demonstrates that the oral cholera vaccine as well as the EPI vaccines studied are immunogenic in children in high and low arsenic areas in Bangladesh. The results are encouraging for the potential use of cholera vaccines as well as the EPI vaccines in arsenic endemic areas.
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Affiliation(s)
- Amit Saha
- Centre for Vaccine Sciences, International Centre for Diarrheal Disease Research, Bangladesh (icddr,b), Dhaka, Bangladesh
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