— August 19, 2026 · Daily Zinc Lowered the Infection Rate in Young Ugandan Children With Sickle Cell Anemia in the ZIPS-2 Trial

Table of Contents

1. ZIPS-2 at a Glance
2. What Was Done
3. What Was Found, Number by Number
4. How Zinc Works in the Immune System
5. Sickle Cell Anemia and Infection
6. How It Fits With Earlier Research
7. What It Cannot Show
8. What the Authors and Reports Said
9. What Remains Unknown
10. Sources and Primary Documents
11. Key Research Papers
12. Connections

ZIPS-2 at a Glance

• Paper — Namazzi R, Mellencamp KA, Bagala I, et al. “Daily Zinc Supplementation for Infection Prevention in Children With Sickle Cell Anemia: The ZIPS-2 Randomized Clinical Trial.” JAMA, published online August 19, 2026 (PMID 42616536).
• Who — 100 children aged 1.00 to 4.99 years with sickle cell anemia (the HbSS form), treated at the paediatric sickle cell clinic of Jinja Regional Referral Hospital, Jinja, Uganda. Mean age 36.0 months; 45 girls (45%).
• Design — randomised, double-blind, placebo-controlled; 50 children per group. Registered before it began (ClinicalTrials.gov NCT06561061, first posted August 19, 2024).
• Dose (a trial fact) — zinc sulfate 20 mg as a dispersible tablet, or an identical placebo tablet, once a day for six months.
• Background treatment — 45 children (45%) were already taking hydroxyurea at enrolment; all children started or continued hydroxyurea after enrolment.
• Main result — 80 infections on zinc vs 124 on placebo; 305.7 vs 480.7 infections per 100 person-years; adjusted incidence rate ratio 0.62 (95% CI 0.45 to 0.86).
• Safety — no adverse events requiring the tablets to be stopped in either group; no child lost to follow-up.
• Funding — grants from a university paediatric research centre and a medical research charity, plus support from a university student fundraising endowment; the paper states the funders had no role in the design, analysis or decision to publish.

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What Was Done

The study team screened 118 children at the Jinja sickle cell clinic between February 10 and April 30, 2025, and enrolled 100. To take part, a child had to be between 1.00 and 4.99 years old, weigh at least 5.0 kg, and have sickle cell anemia of the HbSS type confirmed by hemoglobin electrophoresis, the laboratory test that separates the different forms of inherited hemoglobin. The trial registry lists the exclusions: a known chronic illness such as HIV, cancer or active tuberculosis; severe malnutrition by World Health Organization growth standards; and a very low neutrophil count (below 500 cells per microlitre), neutrophils being the white blood cells that attack bacteria.

Each child was assigned at random to one of two arms of 50. One arm received a 20 mg dispersible tablet (one that dissolves in water) of zinc sulfate once a day, the other an identical-looking placebo tablet. Treatment lasted six months, and follow-up ended on November 7, 2025.

The primary outcome, the one question the trial was built and sized to answer, was the number of all-cause infections per 100 person-years. “All-cause” means every infection was counted, whatever the germ or body site, provided it met the trial’s “standardized clinical criteria.” A person-year is one child followed for one year; using it lets researchers compare infection rates fairly when follow-up times differ slightly. The main comparison was adjusted for each child’s age, sex and hydroxyurea use at the start.

The registry also names secondary outcomes: infections requiring a hospital stay, side effects serious enough to stop the study tablet, and stroke or death, plus an exploratory measure, the change in blood-flow speed in the brain’s arteries on a transcranial Doppler scan (a screening test for stroke risk in sickle cell disease). Of these, only the side-effect result appears in the abstract. The registry’s one-line summary describes the aim as reducing “severe or invasive infections,” while its detailed description and its listed primary outcome name all-cause infection, which is the outcome the paper reports.

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What Was Found, Number by Number

• Enrolment and follow-up — 118 children screened, 100 randomised (50 zinc, 50 placebo). The paper reports “complete ascertainment for all participants and no loss to follow-up” over the six months.
• Infections counted — 80 in the zinc group and 124 in the placebo group.
• Infection rate, zinc — 305.7 infections per 100 person-years (95% CI 242.4 to 380.4).
• Infection rate, placebo — 480.7 infections per 100 person-years (95% CI 399.8 to 573.1).
• Rate difference — −176.0 infections per 100 person-years (95% CI −300.8 to −51.3).
• Incidence rate ratio, adjusted for baseline age, sex and hydroxyurea use — 0.62 (95% CI 0.45 to 0.86).
• Side effects — “No adverse events requiring discontinuation of the study intervention were observed in either group.”

An incidence rate ratio compares two rates. A value of 1 would mean the same rate in both groups; 0.62 means the zinc group’s infection rate was 0.62 times the placebo group’s. The 95% confidence interval, 0.45 to 0.86, is the range of values the data fit reasonably well. Because the whole range sits below 1, the result is statistically significant, but the range is wide, which is typical of a trial of 100 children: the data fit a modest reduction as well as a large one.

The count includes every infection that met the trial’s criteria, not only severe ones. For comparison, the earlier ZIPS trial at the same hospital, which counted only severe or invasive infections, recorded 282 and 270 per 100 person-years in its two arms. The ZIPS-2 abstract does not break the 80 and 124 infections down by type (for example malaria, pneumonia, diarrhoea or upper-respiratory infections), and it does not report hospital admissions, blood zinc levels, growth, blood counts or copper status.

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How Zinc Works in the Immune System

Zinc is a trace mineral that many of the body’s enzymes, such as carbonic anhydrase, need in order to work. Several lines of research link it to the immune system, especially to T cells, the white blood cells that coordinate the body’s defences.

• Thymulin — a hormone made by the thymus, the gland where T cells mature. In a 1988 study in the Journal of Clinical Investigation, Ananda Prasad’s team showed that thymulin’s activity depends on zinc held in the molecule. Thymulin activity fell during mild zinc deficiency, including in six adults with sickle cell anemia, and returned when zinc was given. In volunteers whose zinc was depleted by diet, the same study recorded a lower ratio of CD4 (helper) to CD8 T cells and lower activity of interleukin-2, a T-cell growth signal, both corrected by zinc; similar correctable T-cell changes were seen in the zinc-deficient adults with sickle cell anemia.
• Interleukin-2 and infection — in a 1999 study of 32 adults with sickle cell disease, long-term zinc raised zinc inside white blood cells and raised interleukin-2 production, alongside fewer documented bacterial infections.
• Inflammation and oxidative stress — in a 2008 randomised trial in 36 people with sickle cell disease, three months of zinc lowered markers of oxidative damage, and white blood cells produced less of the inflammatory signals tumour necrosis factor-alpha and interleukin-1 beta, compared with placebo.

People with sickle cell disease are thought to be at particular risk of running low. Prasad’s 1975 study in Clinical Chemistry found lower zinc in the plasma, red blood cells and hair of patients than of healthy controls, and higher zinc loss in the urine; the more zinc a patient lost in urine, the less was found in their red cells. His 1999 paper names two probable causes: heavy zinc loss through the kidneys (hyperzincuria) and a higher need for zinc caused by the constant breakdown of red blood cells. The site’s zinc deficiency and immunity page covers the general picture.

ZIPS-2 itself tested whether zinc lowers infections, not how. Its abstract reports no measurement of thymulin, T cells or inflammation, so these mechanisms are the background the trial was built on rather than something it showed.

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Sickle Cell Anemia and Infection

Sickle cell anemia is an inherited disorder of hemoglobin, the oxygen-carrying protein in red blood cells. A 2022 review in JAMA describes how the hemoglobin forms long chains when it gives up its oxygen, so the red cells sickle and break apart; this blocks small blood vessels and causes hemolytic anemia, repeated episodes of severe pain and progressive damage to organs. The review estimates that about 300,000 babies are born with sickle cell disease worldwide each year, and that most people with the disease live in sub-Saharan Africa, India, the Mediterranean and the Middle East. The ZIPS-2 paper opens with the problem it addresses: “Despite existing prevention strategies, infections remain a major cause of morbidity and mortality in children in Africa with sickle cell anemia.”

Two long-standing measures form the base of sickle-cell care for young children:

• Penicillin prophylaxis — children with sickle cell anemia are especially prone to bacterial infection, above all by Streptococcus pneumoniae. In a 1986 US trial in children under three, 105 given twice-daily oral penicillin and 110 given placebo, penicillin cut pneumococcal bloodstream infections by 84% (2 of 105 children vs 13 of 110), and the trial was stopped early. Three children on placebo died of the infection; none on penicillin did. The authors concluded that newborns be screened for sickle cell disease and that affected children receive penicillin by four months of age.
• Hydroxyurea — a daily drug that, in the review’s words, “increases fetal hemoglobin and reduces red blood cell sickling” and “remains first-line therapy” for most people with the disease. The NOHARM trial, run in Uganda with some of the same investigators as ZIPS and published in 2017, randomised 104 children to hydroxyurea and 103 to placebo for a year. It found no increase in malaria (rate ratio 0.7, 95% CI 0.2 to 2.7) and fewer sickle-cell complications (45% vs 69%), with serious adverse events and sepsis similar between groups. In ZIPS-2, every child was on hydroxyurea after enrolment.

The ZIPS-2 abstract does not list the rest of the routine care given. In the earlier ZIPS trial at the same hospital, all children received daily folic acid, penicillin prophylaxis, monthly sulphadoxine-pyrimethamine to prevent malaria and an insecticide-treated bed net.

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How It Fits With Earlier Research

Prasad and sickle cell disease. Ananda Prasad, the physician whose 1961 work first raised the possibility of human zinc deficiency (told on the site’s zinc history page), spent decades studying zinc in sickle cell disease. In his 1975 study, nine patients with sickle cell anemia (seven men and two women) took 660 mg of zinc sulfate a day; two 17-year-old males grew 5 cm and 7 cm taller over 49 and 42 weeks, all but one patient gained weight (0.5 to 4.1 kg), and one leg ulcer healed in six weeks. In his 1999 study of 32 adults, the zinc-deficient patients (groups of 11 and 10) were observed for a year and then given 50 to 75 mg of elemental zinc a day, one group for three years and the other for two years after a year on placebo; infections confirmed by laboratory culture fell (P = 0.0026), as did hospital admissions and pain crises (P = 0.0001). The 2008 randomised trial from the same group, in 36 patients given 25 mg of zinc three times a day or placebo for three months, also recorded fewer infections on zinc, along with higher plasma zinc and hemoglobin. The ZIPS team describes the earlier trials of zinc for preventing infection as small studies in adolescents and adults in the United States and India.

ZIPS, the first Ugandan trial. The 2023 ZIPS trial in Blood Advances enrolled 252 children aged 1.00 to 4.99 at the same hospital and assigned 124 to 10 mg of zinc and 126 to placebo for 12 months. Its primary outcome was narrower than ZIPS-2’s: severe or invasive infections only. These did not differ (282 vs 270 per 100 person-years; rate ratio 1.04, 95% CI 0.81 to 1.32). Serum zinc in the zinc group rose from a mean of 61.4 to 72.2 µg/dL, but 41.3% of those children were still below the deficiency cut-off of 65 µg/dL at the end, compared with 54.7% in the placebo group. Height-for-age did not differ between groups. In an analysis not planned in advance, stroke or death was less common on zinc (hazard ratio 0.22, 95% CI 0.05 to 1.00, P = 0.05). The authors named the single dose as a key limitation and called for testing whether higher doses work. ZIPS-2 doubled the dose and counted all infections, so the two trials differ in dose, length and outcome and cannot be compared directly.

Zinc and childhood infection in general. A 1999 pooled analysis of randomised trials in children in low-income countries found that continuous zinc supplements were linked to less diarrhoea (odds ratio for new episodes 0.82, 95% CI 0.72 to 0.93) and less pneumonia (odds ratio 0.59, 95% CI 0.41 to 0.83). The 2023 Cochrane review of preventive zinc in children aged 6 months to 12 years, covering 96 trials and 219,584 children, found that zinc likely reduces diarrhoea (risk ratio 0.91, 95% CI 0.90 to 0.93) but makes little to no difference to lower-respiratory infections such as pneumonia (risk ratio 1.01, 95% CI 0.95 to 1.08) or to overall deaths (risk ratio 0.93, 95% CI 0.84 to 1.03), with a slight gain in height. It also found more vomiting with zinc (risk ratio 1.29, 95% CI 1.14 to 1.46). That review left out children with chronic diseases, so children with sickle cell anemia fall outside it; ZIPS-2 tests zinc in exactly that group.

Same issue, different nutrient. The same day, JAMA published the STArT trial of intravenous arginine for sickle-cell pain episodes in 10 US children’s hospitals. That trial was halted early for futility: arginine did not shorten the time to crisis resolution compared with placebo (median 60.8 vs 65.8 hours; difference 7.2 hours, 95% CI −21.6 to 35.9).

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What It Cannot Show

• Small and single-site. 100 children at one hospital. The confidence interval is wide, and a result from one clinic may not repeat elsewhere. The authors and the news coverage both name this.
• Short. Six months of treatment says nothing about benefits or harms over years.
• Young children only. All participants were under five; the authors write that effectiveness in older children still has to be assessed.
• One setting. The trial took place in a malaria-endemic region of Uganda, where zinc deficiency was common in the earlier ZIPS trial (64.5% and 60.7% of children in its two arms at enrolment). Results may differ where children start with better zinc status or face different infections.
• All-cause infections. The primary outcome counted every infection that met the clinical criteria. The abstract does not say whether zinc reduced severe infections, hospital stays, strokes or deaths, which the earlier 10 mg trial and the registry treat as important outcomes.
• Hydroxyurea started during the trial. 45% of the children were on hydroxyurea at the start and all were on it afterwards. Randomisation is designed to spread this evenly between the groups, and the analysis adjusted for baseline use, but the background treatment was changing during follow-up.
• Full results not read here. Zinc levels, growth, copper status, blood counts and the breakdown of infections are in the full paper, which was not available for this report.

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What the Authors and Reports Said

The authors. The paper’s conclusion reads: “Zinc supplementation at 20 mg per day reduced all-cause infection in children with sickle cell anemia younger than 5 years in Uganda. Multisite clinical trials are needed to validate these findings and to assess effectiveness in older children.” The key points put the meaning more cautiously: zinc at 20 mg daily “may be a strategy to reduce infections” in this age group.

JAMA. The journal issued a media release on August 19, 2026 and published a short research summary of the trial alongside it.

Later coverage. On September 1, 2026, the medical news site EMJ reported the trial, describing the rate ratio of 0.62 as “an approximately 38% lower rate of infection.” That percentage is the outlet’s reading of the ratio; the paper’s abstract reports the ratio itself. The report also wrote that the researchers “cautioned that further investigation is required before the findings can be applied more broadly,” because the study “was conducted at a single centre in Uganda, included only 100 participants, and was restricted to children younger than 5 years.”

Health agencies. No statement from a health agency or guideline body about the trial was found in the research for this report.

Disclosures. One author reported nonfinancial support from the hospital outside the submitted work; no other conflicts were reported. The acknowledgments credit the funding of the earlier 10 mg trial with building the systems at the Jinja site that allowed this trial to start quickly.

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What Remains Unknown

• Whether it holds up elsewhere. The authors call for multisite trials; until then, ZIPS-2 is one positive trial at one site, following one negative trial (at a lower dose and with a stricter outcome) at the same site.
• The right dose and duration. 10 mg for a year did not reduce severe infections and left many children zinc-deficient; 20 mg for six months reduced all-cause infections. Whether more, less or longer treatment changes the result has not been tested.
• Severe outcomes. Effects on hospital admissions, stroke and death are registered secondary outcomes whose results do not appear in the abstract. The earlier trial’s lower rate of stroke or death on zinc came from an unplanned analysis and has not been confirmed.
• Zinc and copper balance. Long-term zinc therapy can lower copper. In 1978, Prasad’s team described an adult with sickle cell anemia who developed low copper, small red cells and a low white-cell count after two years of zinc therapy, corrected with copper, and low levels of the copper protein ceruloplasmin in several other patients on oral zinc (see zinc and copper deficiency). The ZIPS-2 abstract does not report copper status.
• Who benefits most. Whether the effect depends on a child’s zinc level at the start, on hydroxyurea, or on the local mix of infections is not reported in the abstract. Serum zinc, the usual zinc test, is an imperfect marker: the earlier trial’s authors note that it shifts with inflammation, meals and the time of day.
• Older children and adults. The adult studies were small and older; ZIPS-2 did not include anyone over five.

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Sources and Primary Documents

Every ZIPS-2 figure above was taken from the paper’s abstract and key points, its declarations, or the trial registry, not from news coverage. The full text is paywalled and its PubMed Central copy is embargoed.

1. Namazzi R, Mellencamp KA, Bagala I, Conroy AL, Kato C, Birungi I, Kasembo P, Kyarisiima G, Tenywa E, Ren J, Goings MJ, Cusick SE, John CC (2026). Daily Zinc Supplementation for Infection Prevention in Children With Sickle Cell Anemia: The ZIPS-2 Randomized Clinical Trial. JAMA, published online August 19, 2026:e2614190. — doi:10.1001/jama.2026.14190 · PubMed PMID: 42616536
2. JAMA (2026). Daily Zinc Supplementation for Infection Prevention in Children With Sickle Cell Anemia: Research Summary. JAMA, published online August 19, 2026:e2615889. — doi:10.1001/jama.2026.15889 · PubMed PMID: 42616550
3. ClinicalTrials.gov (first posted August 19, 2024; completed November 7, 2025). Zinc for Infection Prevention in Sickle Cell Anemia-2 (ZIPS-2). Lead sponsor Indiana University. — NCT06561061
4. JAMA Network (August 19, 2026). Media release: daily zinc supplementation for infection prevention in children with sickle cell anemia. — JAMA Network media release
5. Morris CR, Hatabah D, Korman R, et al.; Pediatric Emergency Care Applied Research Network (PECARN) (2026). Arginine Therapy for Sickle Cell Disease Acute Pain Episodes: The STArT Randomized Clinical Trial. JAMA, published online August 19, 2026:e2613310. — doi:10.1001/jama.2026.13310 · PubMed PMID: 42616542

News coverage: EMJ, September 1, 2026 (Daily Zinc Cuts Infections in Sickle Cell Anaemia).

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Key Research Papers

Background papers on zinc and immunity, zinc in sickle cell disease, standard sickle-cell care and zinc trials in children, in the order they appear above. Each was checked against PubMed and, where a DOI exists, Crossref before it was written down.

1. Prasad AS, Meftah S, Abdallah J, Kaplan J, Brewer GJ, Bach JF, Dardenne M (1988). Serum thymulin in human zinc deficiency. Journal of Clinical Investigation 82(4):1202-1210. — PubMed PMID: 3262625
2. Prasad AS, Beck FW, Kaplan J, Chandrasekar PH, Ortega J, Fitzgerald JT, Swerdlow P (1999). Effect of zinc supplementation on incidence of infections and hospital admissions in sickle cell disease (SCD). American Journal of Hematology 61(3):194-202. — PubMed PMID: 10398312
3. Bao B, Prasad AS, Beck FW, Snell D, Suneja A, Sarkar FH, Doshi N, Fitzgerald JT, Swerdlow P (2008). Zinc supplementation decreases oxidative stress, incidence of infection, and generation of inflammatory cytokines in sickle cell disease patients. Translational Research 152(2):67-80. — PubMed PMID: 18674741
4. Prasad AS, Schoomaker EB, Ortega J, Brewer GJ, Oberleas D, Oelshlegel FJ Jr (1975). Zinc deficiency in sickle cell disease. Clinical Chemistry 21(4):582-587. — PubMed PMID: 1116294
5. Kavanagh PL, Fasipe TA, Wun T (2022). Sickle Cell Disease: A Review. JAMA 328(1):57-68. — PubMed PMID: 35788790
6. Gaston MH, Verter JI, Woods G, Pegelow C, Kelleher J, Presbury G, et al. (1986). Prophylaxis with oral penicillin in children with sickle cell anemia. A randomized trial. New England Journal of Medicine 314(25):1593-1599. — PubMed PMID: 3086721
7. Opoka RO, Ndugwa CM, Latham TS, Lane A, Hume HA, Kasirye P, Hodges JS, Ware RE, John CC (2017). Novel use Of Hydroxyurea in an African Region with Malaria (NOHARM): a trial for children with sickle cell anemia. Blood 130(24):2585-2593. — PubMed PMID: 29051184
8. Namazzi R, Opoka R, Conroy AL, Datta D, Tagoola A, Bond C, et al. (2023). Zinc for infection prevention in children with sickle cell anemia: a randomized double-blind placebo-controlled trial. Blood Advances 7(13):3023-3031. — PubMed PMID: 36735400
9. Bhutta ZA, Black RE, Brown KH, Gardner JM, Gore S, Hidayat A, et al. (1999). Prevention of diarrhea and pneumonia by zinc supplementation in children in developing countries: pooled analysis of randomized controlled trials. Journal of Pediatrics 135(6):689-697. — PubMed PMID: 10586170
10. Imdad A, Rogner J, Sherwani RN, Sidhu J, Regan A, Haykal MR, et al. (2023). Zinc supplementation for preventing mortality, morbidity, and growth failure in children aged 6 months to 12 years. Cochrane Database of Systematic Reviews 3(3):CD009384. — PubMed PMID: 36994923
11. Prasad AS, Brewer GJ, Schoomaker EB, Rabbani P (1978). Hypocupremia induced by zinc therapy in adults. JAMA 240(20):2166-2168. — PubMed PMID: 359844

PubMed Topic Searches

1. PubMed: Zinc supplementation and infection in sickle cell disease
2. PubMed: Zinc, thymulin and T cells
3. PubMed: Zinc supplementation, pneumonia and diarrhoea in children
4. PubMed: Zinc-induced copper deficiency
5. PubMed: Hydroxyurea for children with sickle cell anemia in Africa

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Connections

• News Archive
• Sickle Cell Disease — the inherited hemoglobin disorder and its care
• Sickle Cell Disease: History — how the disease and its treatments were discovered
• Zinc — the essential trace mineral
• Zinc: History and Discovery — Ananda Prasad and the discovery of human zinc deficiency
• Zinc for Immune Function — the research on zinc and the immune system
• Zinc Deficiency — symptoms, causes and recovery
• Zinc Deficiency: Weakened Immunity — how low zinc affects defences against infection
• Excess Zinc and Copper Deficiency — the zinc–copper balance
• Zinc Test (Serum Zinc) — how zinc status is measured and its limits
• Copper Test — serum copper and ceruloplasmin
• Copper — the trace mineral that long-term zinc therapy can lower
• Anemia — low red-cell and hemoglobin states and their causes
• Streptococcus pneumoniae — the germ penicillin prophylaxis targets
• Pneumonia — infection of the lungs
• Malaria — the parasite common where the trial took place
• Arginine — the amino acid tested for sickle-cell pain in the same journal issue

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