Hybrid immunity and SARS-CoV-2 antibodies: results of the HEROES-RECOVER prospective cohort study.

BACKGROUND: There are limited data on whether hybrid immunity differs by count and order of immunity-conferring events (SARS-CoV-2 infection or COVID-19 vaccination). From a cohort of health care personnel, first responders, and other frontline workers in six US states, we examined heterogeneity of the effect of hybrid immunity on SARS-CoV-2 antibody levels. METHODS: Exposures included event-count (sum of infections and vaccine doses) and event-order, categorized into seven permutations of vaccination and/or infection. Outcome was level of serum binding antibodies against receptor binding domain (RBD) of the ancestral SARS-CoV-2 spike protein (total RBD-binding Ig), measured by enzyme-linked immunosorbent assay. Mean antibody levels were examined up to 365 days after each of the 1st-7th events. RESULTS: Analysis included 5,793 participants measured from August 7, 2020 to April 15, 2023. Hybrid immunity from infection before one or two vaccine doses elicited modestly superior antibody responses after the 2nd and 3rd events (compared to infections or vaccine-doses alone). This superiority was not evident after the 4th and 5th events (additional doses). Among adults infected before vaccination, adjusted geometric mean ratios (95% CI) of anti-RBD early response (versus vaccinated-only) were 1.23 (1.14-1.33), 1.09 (1.03-1.14), 0.87 (0.81-0.94), and 0.99 (0.85-1.15) after the 2nd-5th events, respectively. Post-vaccination infections elicited superior responses: adjusted geometric mean ratios (95% CI) of anti-RBD early response (versus vaccinated-only) were: 0.93 (0.75-1.17), 1.11 (1.06-1.16), 1.17 (1.11-1.24), and 1.20 (1.07-1.34) after the 2nd-5th events, respectively. CONCLUSIONS AND RELEVANCE: Findings reflecting heterogeneity in antibody levels by permutations of infection and vaccination history could inform COVID-19 vaccination policy.

Longitudinal parental perception of COVID-19 vaccines for children in a multi-site, cohort study.

OBJECTIVES: Pediatric COVID-19 vaccine hesitancy and uptake is not well understood. Among parents of a prospective cohort of children aged 6 months-17 years, we assessed COVID-19 vaccine knowledge, attitudes, and practices (KAP), and uptake over 15 months. METHODS: The PROTECT study collected sociodemographic characteristics of children at enrollment and COVID-19 vaccination data and parental KAPs quarterly. Univariable and multivariable logistic regression models were used to test the effect of KAPs on vaccine uptake; McNemar's test for paired samples was used to evaluate KAP change over time. RESULTS: A total of 2,837 children were enrolled, with more than half (61 %) vaccinated by October 2022. Positive parental beliefs about vaccine safety and effectiveness strongly predicted vaccine uptake among children aged 5-11 years (aOR 13.1, 95 % CI 8.5-20.4 and aOR 6.4, 95 % CI 4.3-9.6, respectively) and children aged 12+ years (aOR 7.0, 95 % CI 3.8-13.0 and aOR 8.9, 95 % CI 4.4-18.0). Compared to enrollment, at follow-up parents (of vaccinated and unvaccinated children) reported higher self-assessed vaccine knowledge, but more negative beliefs towards vaccine safety, effectiveness, and trust in government. Parents unlikely to vaccinate their children at enrollment reported more positive beliefs on vaccine knowledge, safety, and effectiveness at follow-up. CONCLUSION: The PROTECT cohort allows for an examination of factors driving vaccine uptake and how beliefs about COVID-19 and the COVID-19 vaccines change over time. Findings of the current analysis suggest that these beliefs change over time and policies aiming to increase vaccine uptake should focus on vaccine safety and effectiveness.

Humoral Immune Response to Messenger RNA Coronavirus Disease 2019 Vaccination Among Children Aged 5-11 Years in a Multisite Prospective Cohort Study, September 2021-September 2022.

Background: The PROTECT study is a longitudinal cohort study initiated in July 2021 with weekly testing for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in 4 states: Arizona, Florida, exas, and Utah. This study aims to examine vaccine-elicited antibody response against postvaccination SARS-CoV-2 infections. Methods: Children aged 5-11 years had serum collected 14-59 days after their second dose of monovalent Pfizer-BioNTech coronavirus disease 2019 messenger RNA vaccine. Vaccine-elicited antibodies were measured using the area under the curve (AUC) and end-point titer using enzyme-linked immunosorbent assay (receptor-binding domain [RBD] and S2) and surrogate neutralization assays against ancestral (WA1) and Omicron (BA.2). Results: 79 vaccinated participants (33 [41.7%] female; median age, 8.8 years [standard deviation, 1.9 years]), 48 (60.8%) were from Tucson, Arizona; 64 (81.0%) were non-Hispanic white; 63 (80.8%) attended school in person; 68 (86.1%) did not have any chronic conditions; and 47 (59.5%) were infected after vaccination. Uninfected children had higher AUCs against WA1 (P = .009) and Omicron (P = .02). The geometric mean and surrogate neutralization titer above the limit of detection was 346.0 for WA1 and 39.7 for Omicron, an 8.7-fold decrease (P < .001). After adjustment of covariates in the WA1-specific model, we observed a 47% reduction in the odds of postvaccination infection for every standard deviation increase in RBD AUC (aOR, 0.53 [95% confidence interval, .29-.97) and a 69% reduction in the odds of infection for every 3-fold increase in RBD end titer (0.31 [.06-1.57]). Conclusions: Children with higher antibody levels experienced a lower incidence of postvaccination SARS-CoV-2 infection.

Risk Factors for Reinfection with SARS-CoV-2 Omicron Variant among Previously Infected Frontline Workers.

In a cohort of essential workers in the United States previously infected with SARS-CoV-2, risk factors for reinfection included being unvaccinated, infrequent mask use, time since first infection, and being non-Hispanic Black. Protecting workers from reinfection requires a multipronged approach including up-to-date vaccination, mask use as recommended, and reduction in underlying health disparities.

Genetics in the X-Men film franchise: mutants as allegories of difference.

This article analyzes the complete corpus of live-action X-Men movies for their depictions of genetics and otherness. The researchers watched and qualitatively coded all thirteen movies produced by 20th Century Fox that take place in the same shared cinematic universe, beginning with X-Men (2000) and ending with The New Mutants (2020). The X-Men movies are unusual summer blockbusters since they explore genetic topics through their central characters, mutants, who are genetically different from their non-mutant peers. Mutants in the films evoke a plurality of analogies, such as mutant-as-Black and mutant-as-queer. These intersecting metaphors build upon a core of genetic difference to create a versatile but limited picture of prejudice, solidarity, and otherness.

Interim Estimate of Vaccine Effectiveness of BNT162b2 (Pfizer-BioNTech) Vaccine in Preventing SARS-CoV-2 Infection Among Adolescents Aged 12-17 Years - Arizona, July-December 2021.

The BNT162b2 (Pfizer-BioNTech) mRNA COVID-19 vaccine has demonstrated high efficacy in preventing infection with SARS-CoV-2 (the virus that causes COVID-19) in randomized placebo-controlled Phase III trials in persons aged 12-17 years (referred to as adolescents in this report) (1); however, data on real-word vaccine effectiveness (VE) among adolescents are limited (1-3). As of December 2021, the Pfizer-BioNTech vaccine is approved by the Food and Drug Administration (FDA) for adolescents aged 16-17 years and under FDA emergency use authorization for those aged 12-15 years. In a prospective cohort in Arizona, 243 adolescents aged 12-17 years were tested for SARS-CoV-2 by reverse transcription-polymerase chain reaction (RT-PCR) each week, irrespective of symptoms, and upon onset of COVID-19-like illness during July 25-December 4, 2021; the SARS-CoV-2 B.1.617.2 (Delta) variant was the predominant strain during this study period. During the study, 190 adolescents contributed fully vaccinated person-time (≥14 days after receiving 2 doses of Pfizer-BioNTech vaccine), 30 contributed partially vaccinated person-time (receipt of 1 dose or receipt of 2 doses but with the second dose completed <14 days earlier), and 66 contributed unvaccinated person-time. Using the Cox proportional-hazards model, the estimated VE of full Pfizer-BioNTech vaccination for preventing SARS-CoV-2 infection was 92% (95% CI = 79%-97%), adjusted for sociodemographic characteristics, health information, frequency of social contact, mask use, location, and local virus circulation. These findings from a real-world setting indicate that 2 doses of Pfizer-BioNTech vaccine are highly effective in preventing SARS-CoV-2 infection among Arizona adolescents. CDC recommends COVID-19 vaccination for all eligible persons in the United States, including persons aged 12-17 years.

Real-world screening for diabetes in early pregnancy: Improved screening uptake using universal glycated haemoglobin.

AIMS: To improve perinatal outcomes, screening for hyperglycaemia using 75 g oral glucose tolerance test (OGTT) is recommended for all pregnant women at 24-28 weeks gestation (routine), and earlier if high-risk. Screening coverage for remote and Aboriginal Australian women is less than ideal. This study examined OGTT completion (early and routine) by women from rural and remote Western Australia compared with early glycated haemoglobin (HbA1c). METHODS: In 2015-2018, 27 primary health care sites recruited 600 (233 Aboriginal) women aged ≥16-years, without pre-existing diabetes, who delivered >30-weeks gestation. All women presenting <20-weeks gestation (541) were offered an early study HbA1c. Early OGTTs were requested at the discretion of the local clinician, with routine OGTT offered at 24-28 weeks. RESULTS: HbA1c uptake was high (85.7% Aboriginal, 86.4% non-Aboriginal); OGTT completion in Aboriginal women was low (early OGTT: 38.6% v 69.6% non-Aboriginal, P < 0.001; routine OGTT: 44.5% v 84.7% non-Aboriginal, P < 0.001). Aboriginal women with both early tests had HbA1c completed 3-weeks prior to OGTT (9.6 ± 3.5 v 12.5 ± 3.5 weeks gestation, P < 0.001). CONCLUSIONS: Universal early pregnancy HbA1c appears feasible as an early screening test for women at risk of hyperglycaemia in pregnancy and would expedite and increase screening in Aboriginal women compared to an early OGTT.

Prediabetes and pregnancy: Early pregnancy HbA1c identifies Australian Aboriginal women with high-risk of gestational diabetes mellitus and adverse perinatal outcomes.

AIMS: To assess whether early pregnancy HbA1c can predict gestational diabetes mellitus (GDM) and adverse birth outcomes in Australian women. METHODS: Prospective study of 466 women without diabetes, aged ≥16-years at first antenatal presentation. Recruitment was from 27 primary healthcare sites in rural and remote Australia from 9-January 2015 to 31-May 2018. HbA1c was measured with first antenatal investigations (<20-weeks gestation). Primary outcome measure was predictive value of HbA1c for GDM, by routine 75 g oral glucose tolerance test (OGTT; ≥24-weeks gestation), and for large-for-gestational-age (LGA) newborn. RESULTS: Of 396 (129 Aboriginal) women with routine OGTT, 28.8% had GDM (24.0% Aboriginal). HbA1c ≥5.6% (≥38 mmol/mol) was highly predictive (71.4%, 95% CI; 47.8-88.7%) for GDM in Aboriginal women, and in the total cohort increased risk for LGA newborn (RR 2.04, 95% CI; 1.03-4.01, P = 0.040). There were clear differences between Aboriginal and non-Aboriginal women: 16.3% v 5.2% (P < 0.001) had elevated HbA1c whereas 12.4% v 29.6% (P < 0.001) developed hyperglycemia during pregnancy. CONCLUSIONS: Early pregnancy HbA1c ≥5.6% (≥38 mmol/mol) identifies Aboriginal women with apparent prediabetes and elevated risk of having an LGA newborn. Universal HbA1c at first antenatal presentation could facilitate earlier management of hyperglycemia and improved perinatal outcome in this high-risk population.

Women with type 1 diabetes and women with type 2 diabetes differ in knowledge and beliefs about contraception and pregnancy.

AIMS: To assess differences in knowledge and beliefs about pregnancy in women with diabetes. METHODS: Questions were from the Australian 'Contraception, Pregnancy & Women's Health' survey. Women (18-50 years) were eligible if pregnant or planning pregnancy. Knowledge and beliefs items were adapted from the Reproductive Health and Behaviours Questionnaire. RESULTS: Compared to women with type 2 diabetes (n = 103), women with type 1 diabetes (n = 526) had higher scores for knowledge about pregnancy in diabetes (type 1 diabetes 9.8 ± 2.4 vs. type 2 diabetes 7.7 ± 3.1), beliefs about benefits (type 1 diabetes 18.4 ± 2.2 vs. type 2 diabetes 17.2 ± 3.3), cues-to-action (type 1 diabetes 2.7 ± 1.4 vs. type 2 diabetes 1.5 ± 1.3) and self-efficacy (type 1 diabetes 22.6 ± 5.5 vs. type 2 diabetes 20.2 ± 6.1 (all p < 0.001) regarding preparing for pregnancy. Major knowledge gaps were the need for higher dose folate compared to women without diabetes and uncertainty about breastfeeding recommendations. Women with type 1 diabetes believed more strongly in the benefits of 'close to target' glucose levels prior to pregnancy and using contraception to prevent unplanned pregnancy; they also felt more confident to access pre-pregnancy care and to wait for optimal glycaemia before pregnancy. Women with type 2 diabetes were less aware of contraceptive choices, and risks associated with hyperglycaemia before or early in pregnancy. CONCLUSIONS: The findings highlighted main gaps in knowledge and beliefs about planning for pregnancy. Especially in type 2 diabetes, there is a need for evidence-based messaging and strategies addressing these gaps, to raise understanding to prepare for future pregnancies.

ADIPS 2020 guideline for pre-existing diabetes and pregnancy.

This is the full version of the Australasian Diabetes in Pregnancy Society (ADIPS) 2020 guideline for pre-existing diabetes and pregnancy. The guideline encompasses the management of women with pre-existing type 1 diabetes and type 2 diabetes in relation to pregnancy, including preconception, antepartum, intrapartum and postpartum care. The management of women with monogenic diabetes or cystic fibrosis-related diabetes in relation to pregnancy is also discussed.

Infection control professionals' information-seeking preferences.

OBJECTIVES: The aims of this study were to: 1) establish whether infection control professionals (ICPs) who had access to and utilised medical librarian services for evidence-based medicine (EBM) research perceived this assistance to be useful and 2) to establish whether ICPs who used electronic or hard copy resources for EBM research perceived that those resources had a significant impact on their work. METHODS: Convenience sampling was used to collect quantitative data via a questionnaire. Study participants were members of South-west and Western chapters of the Association for Professionals in Infection Control and Epidemiology. There were 264 questionnaires distributed in this study; 179 participants completed the questionnaire. The response rate for eligible respondents was 59.5% (157). RESULTS: Results indicated 56.7% (51) of the ICPs with librarian access reported requesting assistance from their work facility librarian. In reference to locating infection control information, 77.9% (95), 87.3% (124) and 93.3% (138) of ICPs found textbooks, journals and the Internet 'very useful' or 'useful', respectively. CONCLUSION: Study results indicated ICPs who used the assistance of medical librarians and/or hard copy or electronic resources for EBM research perceived such sources to be valuable for obtaining infection control information.

The current state of Indigenous and Aboriginal women with diabetes in pregnancy: a systematic review.

UNLABELLED: To undertake a systematic review of diabetes in pregnancy (DIP), determining prevalence and impact on maternal and child health outcomes for Indigenous and Aboriginal women. METHOD: Electronic searches of MEDLINE, Embase, CINAHL, ERIC, DARE, CDSR, PsycINFO, Austhealth and HealthInfoNet were undertaken. Changes in diagnostic criteria for DIP and variability in methodology meant a qualitative synthesis of the data was undertaken. RESULTS: From the 142 potential studies, 42 peer reviewed journal articles met the inclusion criteria. GDM prevalence in 65% of studies was greater for Indigenous and Aboriginal women than the comparison groups; Pacific Islander 8.1%, Canadian Aboriginal 11.5%, American Indian 7.9%, Australian Aboriginal 8.4% compared with 2-5% worldwide. Of studies reporting high birth weight (>4000 g) and DIP, 75% had a higher than expected prevalence, 86% had higher macrosomia prevalence and 63% had higher stillbirth rates. Studies with Alaskan, Australian Aboriginal and Pacific Islander women had GDM prevalence both greater and less than comparison groups. CONCLUSION: Correcting the health disparity for Indigenous and Aboriginal women with DIP is a health priority. DIP prevalence is not the same for all Indigenous and Aboriginal women. Inconsistent study design without robust data is interfering with accurate prevalence of DIP. New international consensus guidelines provide opportunities for high quality studies of DIP for Indigenous and Aboriginal women.

It's not just about the HbA1c, Doc! Understanding the psychosocial is also important in managing diabetes?

OBJECTIVE: Despite significant efforts at a primary care level, at least 35% of people with diabetes fail to meet health targets. It is assumed that these poor results are a consequence of the patient not understanding their disease or not caring. This study seeks to understand what really lies behind poor control. DESIGN SETTING AND PARTICIPANTS: A qualitative study using semistructured interviews was conducted in a primary care setting in rural Western Australia. People living with diabetes for at least two years were specifically selected on the basis of whether they had either 'good' (HbA1c < 7%) or 'poor' (HbA1c > 8%) control. RESULTS: Interviews revealed that people understood only too well their disease and their responsibilities. Frequently, either they did not choose to make diabetes a priority in their lives or were unable to make appropriate lifestyle changes which were demanded for good blood sugar control. Their life/social stresses often influenced their glucose control. CONCLUSION: Poor control in our study was not related to lack of knowledge but more to how diabetes was prioritised in their lives. Attention to the patients' priorities is required to accomplish improved glycaemic control.

Characterization of baboon NK cells and their xenogeneic activity.

BACKGROUND: Baboons are commonly used as models for transplantation and preclinical testing of various types of therapeutic agents. For proper assessment of information gathered from these models, differences between the baboon and human immune systems need to be characterized. Natural killer (NK) cells are the first line of defense against many infectious agents and cancer and are important mediators of transplantation rejection reactions, particularly during xenotransplantation. In this study, we examined baboon NK cell function and developed methods for purifying and expanding these cells. METHODS: Baboon NK cells were analyzed using a combination of extracellular and intracellular cell staining, cell sorting, interleukin (IL)-2 mediated stimulation and expansion, and 4 h cytotoxicity assays with human and pig target cell lines. RESULTS: Baboon peripheral blood mononuclear cell (PBMC) exert very low but detectable cytolytic activity against both human (K562) and pig (PAEC, J2) target cells, and this activity is enhanced within 4 h of treatment with IL-2. Like human NK cells, many baboon PBMC express the lytic enzymes granzyme A, granzyme B, and perforin. Based on these markers, we identified a subpopulation of CD3(-) baboon lymphocytes that are CD8(dim) and CD16(bright) that likely represents the baboon NK cells. These cells also are characterized by expression of the natural cytotoxicity receptor NKp46. Baboon CD3(-)NKp46(+) cells purified by flow cytometric cell sorting have high cytolytic capacity that can be further enhanced by IL-2 stimulation. These baboon NK cells can be expanded in vitro and retain extremely high cytolytic capacity. While fresh baboon lymphocytes express very little CD56, the expanded baboon NK cells are predominantly CD56(+); approximately 10% of the expanded NK cells are CD56(dim), and the remainder are CD56(bright). CONCLUSIONS: Baboon NK cells that are IL-2 responsive can be identified on the basis of a CD3(-)NKp46(+)CD8(dim)CD16(+/-) or CD3(-)CD8(dim)CD16(bright) phenotype and can be isolated and expanded in culture. These results may allow for a more accurate representation of the human innate immune system in baboon models and more accurate analyses of the role of the baboon innate immune system cells in preclinical models.

Improving GP diabetes management - A PDSA audit cycle in Western Australia.

BACKGROUND: Tight glucose, blood pressure and lipid control in patients with diabetes can reduce morbidity and mortality from macro- and micro-vascular complications. However, treatment targets are not being met in a large proportion of patients. Clinical audit involves cycles of evaluation of current activity against standards. It allows problems to be identified and action to be taken to address them. METHODS: Annual retrospective audits over 3 years of random samples of up to 20 patient medical records from 13 general practitioners in the midwest region of Western Australia (n=807). Statistical tests compared the second and third audits with the first in regard to completeness of screening, health indicators, and the proportion of patients within The Royal Australian College of General Practitioners and Diabetes Australia guidelines targets. RESULTS: While there was a significant improvement in lipid monitoring over the study period (p<0.001), monitoring of HbA1c and blood pressure (BP) remained unchanged. Between the first and third audits, a reduction in mean HbA1c (p<0.001), mean total cholesterol (p=0.017), mean LDL cholesterol (p=0.014) and mean systolic BP (p=0.002) was seen. There was an improvement in the proportion of patients achieving cholesterol goals (measured by LDL and reaching a target of HbA1c <7%) between the first and third audits; however the proportion with BP within target declined. In the third audit, 11% of patients on diet alone, 36% on an oral hypoglycaemic agent, 90% on three oral hypoglycaemic agents and 84% of those on insulin were outside the target HbA1c. In the same audit, of those outside target BP, 53% were on no treatment and 65% were only on one type of medication. Eighty-seven percent of patients outside target cholesterol levels had not been prescribed a statin. DISCUSSION: Many of the audited GPs in our study undertreated BP, HbA1c and cholesterol. Improvement in some areas was seen over the study period, which may have been due to the quality assurance activities undertaken. These results reveal a therapeutic opportunity for reducing cardiovascular events in patients with diabetes. More aggressive management of BP and lipids by GPs may see rewards in terms of reducing cardiovascular events in patients with diabetes.

Characterization and expansion of baboon CD4+CD25+ Treg cells for potential use in a non-human primate xenotransplantation model.

BACKGROUND: It is well established that CD4(+)CD25(+) regulatory T (Treg) cells can modulate allogeneic immune responses. Xenotransplantation, proposed as a means to address the critical shortage of human organs, may also benefit from similar approaches to avert rejection. Baboons are a preferred preclinical animal model for xenogeneic organ transplantation experiments, and the characterization of baboon Treg cells will be beneficial to future tolerance studies in this animal model. METHODS: We analyzed CD4(+)CD25(+) T cells from baboon lymph nodes, spleens, and blood by flow cytometry, then purified and expanded porcine antigen-specific baboon CD4(+)CD25(high) cells in vitro to evaluate their regulatory activity in the baboon anti-pig xenogeneic responses. RESULTS: CD4(+)CD25(high) T cells were 1.7%, 3.1%, and 1.9% of baboon splenic, lymph node, and blood T cells, respectively. The CD4(+)CD25(high) T cells expressed the Treg cell-associated transcription factor, FoxP3. Proliferation/suppression assays using irradiated pig peripheral blood mononuclear cells as stimulators showed that Treg cells suppressed the vigorous baboon CD4(+)CD25(-) T-cell anti-pig proliferation response and cytokine secretion. Expanded baboon Treg cells suppressed baboon anti-pig CD4(+)CD25(-) T-cell proliferation approximately 4- to 10-fold more than freshly isolated Treg cells. Expanded Treg cells suppressed proliferation to primary cells from the same pig used for expansion more effectively than proliferation to stimulators from a different strain of pig, suggesting a level of antigen specificity. CONCLUSION: We demonstrate that baboon Treg cells suppress immune responses to xenogeneic stimulation. These studies suggest that adoptive transfer of expanded Treg cells into transplant recipients may provide an approach to prevent cell-mediated rejection of grafts and potentially induce tolerance in the pig to baboon xenotransplantation preclinical model.

Could heme-oxygenase-1 have a role in modulating the recipient immune response to embryonic stem cells?

Pluripotent human embryonic stem cells (hESCs) may provide a potential source of cellular therapies, but as allogeneic cells may require evading the recipient's immune response. Using an NIH-registry hESC line, it was found that undifferentiated hESCs induce a reduced proliferative response compared to PBMC and demonstrate that this diminished response correlates with the activity of heme oxygenase-1 (HO-1). Inhibition of HO-1 significantly increases T cell proliferation against hESC, indicating the potential suppression of these cells during transplantation of allogeneic hESC. These data suggest the hypothesis that HO-1 provides a mechanism for protecting hESCs in vivo.

Lipophilic statins suppress cytotoxicity by freshly isolated natural killer cells through modulation of granule exocytosis.

NK cells, a component of the innate immune system, provide a first line of defense against viral infections and malignancies, interact with the adaptive immune system and have a role in rejection of allogeneic bone marrow transplants and solid allo- and xenotransplants. Immunoregulatory activity by the anti-hypercholesterolemia agents, 3-hydroxy-3-methyl-glutaryl Coenzyme A (HMG-CoA) reductase inhibitors, known as statins, has recently been reported. We analyzed the effects of three statins on human NK cell cytotoxicity. Two lipophilic statins (simvastatin and fluvastatin) suppressed the cytotoxic activity of fresh and IL-2-stimulated NK cells, while pravastatin, a hydrophilic statin, did not. Suppression was not associated with changes in intracellular perforin, granzyme A or granzyme B levels, or with changes in expression of leukocyte function-associated antigen-1, an integrin known to regulate NK activity and reported to be altered by statin treatment. Decreased cytotoxicity was associated with decreased CD107a surface expression, indicating that the exocytosis pathway was compromised by simvastatin and fluvastatin but not by pravastatin. Mevalonate, the immediate downstream product of HMG-CoA reductase, partially reversed the effect of lipophilic statins on cytotoxicity and CD107a expression. Lipophilic statins also suppressed the release of the granule component, granzyme B, by IL-2-activated NK cells following stimulation with K562. That lipophilic statins suppress NK cell activity through inhibition of the exocytosis pathway suggest an additional potential role for statins in inhibition of transplantation responses.