Development of Next-Generation COVID-19 Vaccines: BARDA Supported Phase 2b Study Designs.

In response to the COVID-19 pandemic, vaccines were quickly and successfully developed and deployed, saving millions of lives globally. While first generation vaccines are safe and effective in preventing disease caused by SARSCoV-2, next-generation vaccines have the potential to improve efficacy and safety. Vaccines delivered by a mucosal route may elicit greater protective immunity at respiratory surfaces thereby reducing transmission. Inclusion of viral antigens in addition to the spike protein may enhance protection against emerging variants of concern. Next-generation vaccine platforms with a new mechanism of action may necessitate efficacy trials to fulfill regulatory requirements. The Biomedical Advanced Research and Development Authority (BARDA) will be supporting Phase 2b clinical trials of candidate next-generation vaccines. The primary endpoint will be improved efficacy in terms of symptomatic disease relative to a currently approved COVID-19 vaccine. In this paper, we discuss the planned endpoints and potential challenges to this complex program.

Assessment of safety in newborns of mothers participating in clinical trials of vaccines administered during pregnancy.

A panel of experts convened by the Division of Microbiology and Infectious Diseases, National Institute of Allergy and Infectious Diseases, National Institutes of Health, developed proposed guidelines for the evaluation of adverse events in newborns of women participating in clinical trials of maternal immunization in the United States.

Designing drug trials: considerations for pregnant women.

Clinical pharmacology studies that describe the pharmacokinetics and pharmacodynamics of drugs in pregnant women are critical for informing on the safe and effective use of drugs during pregnancy. That being said, multiple factors have hindered the ability to study drugs in pregnant patients. These include concerns for maternal and fetal safety, ethical considerations, the difficulty in designing appropriate trials to assess the study objectives, and funding limitations. This document summarizes the recommendations of a panel of experts convened by the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases, National Institutes of Health. These experts were charged with reviewing the issues related to the development of preclinical and clinical drug studies in pregnant women and to develop strategies for addressing these issues. These findings may also be utilized in the development of future drug studies involving pregnant women and their fetus/neonate.

Assessment of congenital anomalies in infants born to pregnant women enrolled in clinical trials.

In 2011 and 2012, the Division of Microbiology and Infectious Diseases at the National Institute of Allergy and Infectious Diseases, National Institutes of Health, held a series of meetings to provide guidance to investigators regarding study design of clinical trials of vaccines and antimicrobial medications that enroll pregnant women. Assessment of congenital anomalies among infants born to women enrolled in these trials was recognized as a challenging issue, and a workgroup with expertise in epidemiology, pediatrics, genetics, dysmorphology, clinical trials, and infectious diseases was formed to address this issue. The workgroup considered 3 approaches for congenital anomalies assessment that have been developed for use in other studies: (1) maternal report combined with medical records review, (2) standardized photographic assessment and physical examination by a health professional who has received specific training in congenital anomalies, and (3) standardized physical examination by a trained dysmorphologist (combined with maternal interview and medical records review). The strengths and limitations of these approaches were discussed with regard to their use in clinical trials. None of the approaches was deemed appropriate for use in all clinical trials. Instead, the workgroup acknowledged that decisions regarding the optimal method of assessment of congenital anomalies will likely vary depending on the clinical trial, its setting, and the agent under study; in some cases, a combination of approaches may be appropriate. The workgroup recognized the need for more research on approaches to the assessment of congenital anomalies to better guide investigators in optimal design of clinical trials that enroll pregnant women.

Immunogenicity and efficacy of influenza immunization during pregnancy: recent and ongoing studies.

Pregnant women and young infants are at increased risk from influenza. The World Health Organization and public health guidelines from Australia, Canada, and the United States recommend immunizing pregnant women with trivalent inactivated influenza vaccine. However, there are multiple barriers to the uptake of this recommendation. Additionally, current vaccines are not licensed for infants <6 months of age. Immunizing pregnant women would provide protection to both mothers and infants. The Bill & Melinda Gates Foundation (BMGF) and the National Institute of Allergy and Infectious Diseases (NIAID) are trying to address some of the issues associated with maternal immunization, which could be an effective intervention in both high- and low-resource settings to combat the significant maternal and infant morbidity and mortality due to influenza. BMGF and NIAID efforts are complementary to each other, focusing on evaluating the immunogenicity, efficacy, and safety of influenza vaccines during pregnancy; and the potential effect of maternal immunization on outcomes in infants in low-resource populations.

Duration of Cellular and Humoral Responses after Quadrivalent Human Papillomavirus Vaccination in Healthy Female Adults with or without Prior Type 16 and/or 18 Exposure.

Human papillomavirus virus (HPV) vaccines aim to provide durable protection and are ideal to study the association of cellular with humoral responses. We assessed the duration and characteristics of immune responses provided by the quadrivalent HPV (4vHPV) vaccine in healthy female adults with or without prior exposure with type 16 and 18 HPV. In a prospective cohort, vaccine naïve females received three doses of 4vHPV vaccine and were followed for two years to assess cellular (intracellular cytokine staining, proliferation and B cell ELISpot assays) and humoral (multiplex L1/L2 viral-like particles (VLP) and M4 ELISAs) responses. Frequencies of vaccine-specific CD4+ T cells correlated with antibody responses. Higher HPV antibody titers were found at all time points in participants previously exposed to HPV, except for anti-HPV-18 at Day 187 (one week post the third vaccination). Retrospective cohorts enrolled females who had previously received two or three 4vHPV doses and tested antibody titers by M4 ELISA and pseudovirion neutralization assay along with memory B cells (MBCs). Almost all women enrolled in a retrospective cohort with two prior doses and all women enrolled in a retrospective cohort with three prior doses had sustained antibody and memory responses. Our findings indicate that HPV vaccination induces a long-lasting, robust cellular and humoral immune responses.

Phase 1/2 double-blind, placebo-controlled, dose escalation, safety, and pharmacokinetic study of pagibaximab (BSYX-A110), an antistaphylococcal monoclonal antibody for the prevention of staphylococcal bloodstream infections, in very-low-birth-weight neonates.

Staphylococcal sepsis is a major cause of morbidity and mortality in very-low-birth-weight (VLBW) infants. A human chimeric monoclonal antibody, pagibaximab, was developed against staphylococcal lipoteichoic acid. We evaluated the safety, tolerability, and pharmacokinetics of pagibaximab in VLBW neonates. A phase 1/2, randomized, double-blind, placebo-controlled, dose escalation study was conducted in VLBW infants (700 to 1,300 g) 3 to 7 days old. Patients received two doses 14 days apart of intravenous pagibaximab (10, 30, 60, or 90 mg/kg of body weight) or placebo in a 2:1 ratio. Blood and urine samples were obtained pre- and postinfusion for analysis of safety and pharmacokinetics, and data on adverse events were gathered. Staphylococcal organisms causing sepsis were collected and evaluated. Fifty-three patients received at least one dose of pagibaximab or placebo. The average gestational age was 27.6 weeks; the average birth weight was 1,003 g. All serious adverse events were deemed unrelated or probably not drug related. Morbidity and mortality were similar across treatment groups. No evidence of immunogenicity of pagibaximab was detected. Pagibaximab pharmacokinetics was linear. The mean clearance (CL), volume of distribution, and elimination half-life of pagibaximab were independent of dose. The serum half-life was 20.5 +/- 6.8 days. Pagibaximab enhanced serum opsonophagocytic activity. All staphylococci causing sepsis were opsonizable by pagibaximab. Two infusions of pagibaximab, administered 2 weeks apart to high-risk neonates appeared safe and tolerable, and pharmacokinetics were linear. Evaluation of more frequent doses, at the highest doses tested, in neonates at high-risk of staphylococcal sepsis, is warranted.

Maternal and neonatal characteristics associated with neonatal neutropenia in hypertensive pregnancies.

The purpose of this study was to identify maternal and neonatal characteristics affecting marked neonatal neutropenia in pregnancies complicated by hypertension. A single institution retrospective chart review over 2 years of singleton and multifetal pregnancies with hypertensive disorders meeting American College of Obstetricians and Gynecologists criteria was performed. Neutropenia and sepsis occurring within the first 16 days of life (DOL) were studied. Neutropenia was defined as an absolute neutrophil count of <1500/microL and sepsis as any positive blood, cerebrospinal fluid, or urine culture. The study group contained neonates with neutropenia. From all other hypertensive pregnancies, a presumed nonneutropenic control group was randomly generated with a 4:1 ratio; these neonates may or may not have had a complete blood count (CBC) performed because they were clinically stable. Multiple gestations were separately analyzed and compared with hypertensive multifetal neonates with confirmed CBCs showing no neutropenia. Chi-square, Mann-Whitney U, and regression analyses were performed. Five hundred forty-three hypertensive pregnancies representing 633 births, 173 (27.3%) of which were from multiple gestations, were studied. There were 32 (5.9%) cases of neutropenia, with 22 (68.8%) from multiple gestations. Of premature multiple gestations, 45.2% born between 24 and 34 weeks' gestation developed neutropenia. The median time to diagnosis of neutropenia was 1.2 hours with 80.6% detected on the first DOL. Resolution of neutropenia occurred within 7 days in 84.4% of surviving neonates. Univariate analysis showed significant associations of neutropenia with gestational age at delivery, multiple gestations, birth weight, severe preeclampsia, and development of neonatal sepsis. When multiple gestations were analyzed, linear regression showed only sepsis to be significantly associated with neutropenia (p = 0.027). Hypertensive disorders of pregnancy and premature delivery are common in multiple gestations and are associated with neutropenia (12.7% versus 2.2% neutropenia in singletons (p < 0.001). Furthermore, multiple gestations with neutropenia had a higher incidence of sepsis than singletons with neutropenia.

Neonatal cord blood subsets and cytokine response to bacterial antigens.

We compared lymphocyte subsets and cytokine responses to bacteria among term, preterm infants, and adults. Lymphocyte subset percentages in cord blood (22 preterm, 27 term neonates) and peripheral blood from 21 adults and cytokine/chemokine interleukin (IL)-6, IL-8, IL-10, IL-12, interferon gamma (IFN gamma) responses to Escherichia coli, group B Streptococcus (GBS), Staphylococcus epidermidis, and Lactobacillus plantarum (Lp299v) were assessed by flow cytometry. Preterm compared with term infants had increased CD8 (+) T cells (p = 0.02) and reduced naïve CD4 (+) T cells (p < 0.0001). Memory T and natural killer (NK) T cells were reduced (p < 0.001) in neonates; NK and CD56 (+)161 (+) NK cells were increased (p < 0.001). CD56 (+)CD8 (+) NK cells were higher in preterm compared with term infants. Despite individual exceptions, cytokine responses in neonates were weaker than adults except for IL-8 response to E. coli in preterm and IL-12 response to Lp299v in term infants. IL-10 responses were weaker in preterm (p = 0.01) and term (p = 0.005) infants to S. epidermidis and to E. coli (p = 0.03 for both) compared with adults. Differences in regulatory subpopulations of NK and T cells between neonates and adults and term compared with preterm infants were observed. These differences rather than intrinsic functional deficiency may account for neonatal cytokine responses to bacteria.

Genetic basis of preterm birth.

Epidemiologic data show that women who deliver prematurely often have a personal and/or family history of preterm birth (PTB) and that racial and ethnic differences influence the incidence of PTB. This may indicate genetic predisposition to PTB. However, since races and ethnic groups tend to share environmental factors (exposure to toxins, living conditions, diet, smoking), epidemiologic data may just confirm environmental influences on PTB. Alternatively, PTB may represent a consequence of gene-environment interactions. Infection and inflammation correlate with increased risk for preterm premature rupture of amniotic membranes (PPROM) and PTB. Immunomodulatory molecules and their receptors regulate these processes and many of them are products of polymorphic genes. Single nucleotide polymorphisms (SNPs) of a gene may lead to a differential expression of its product. So far, SNPs for several genes have been implicated in PTB. If it is confirmed that polymorphism(s) in particular gene(s) correlates with PTB, it may become possible to develop targeted diagnostic and therapeutic approaches tailored towards unique genetic characteristics of a mother/fetus pair.

Staphylococcal vaccines and immunotherapy: to dream the impossible dream?

Staphylococcal infections not only remain an important cause of morbidity and mortality in both the community and the clinic, but the emergence of a global pandemic of community-associated methicillin-resistant Staphylococcus aureus, involving what purports to be a more virulent strain of this organism, has also led several in the infectious disease community to call for improved disease prevention strategies (in addition to novel therapeutics) in what could be thought of as the microbiological version of pre-emption. In this case, Staphylococcus aureus possesses "weapons of mass destruction" and appears to be using them effectively as part of anti-immunization insurgency.

Effect of antiseptic handwashing vs alcohol sanitizer on health care-associated infections in neonatal intensive care units.

BACKGROUND: The Centers for Disease Control and Prevention, Atlanta, Ga, recommend use of waterless alcohol hand products in lieu of traditional handwashing for patient care, but there are few data demonstrating the impact of this recommendation on health care-associated infections. OBJECTIVE: To compare the effect of 2 hand hygiene regimens on infection rates and skin condition and microbial counts of nurses' hands in neonatal intensive care units. DESIGN, SETTING, AND PARTICIPANTS: Clinical trial using a crossover design in 2 neonatal intensive care units in Manhattan, NY, from March 1, 2001, to January 31, 2003, including 2932 neonatal hospital admissions (51 760 patient days) and 119 nurse participants. INTERVENTION: Two hand hygiene products were tested: a traditional antiseptic handwash and an alcohol hand sanitizer. Each product was used for 11 consecutive months in each neonatal intensive care unit in random order. RESULTS: After adjusting for study site, birth weight, surgery, and follow-up time, there were no significant differences in neonatal infections between the 2 products; odds ratios for alcohol compared with handwashing were 0.98 (95% confidence interval [CI], 0.77-1.25) for any infection, 0.99 (95% CI, 0.77-1.33) for bloodstream infections, 1.61 (95% CI, 0.57-5.54) for pneumonia, 1.78 (95% CI, 0.94-3.37) for skin and soft tissue infections, and 1.26 (95% CI, 0.42-3.76) for central nervous system infections. The skin condition of participating nurses was significantly improved during the alcohol phase (P = .02 and P = .049 for observer and self-assessments, respectively), but there were no significant differences in mean microbial counts on nurses' hands (3.21 and 3.11 log(10) colony-forming units for handwashing and alcohol, respectively; P = .38). CONCLUSIONS: Infection rates and microbial counts on nurses' hands were equivalent during handwashing and alcohol phases, and nurses' skin condition was improved using alcohol. However, assessing the impact on infection rates of a single intervention is challenging because of multiple contributory factors such as patient risk, unit design, and staff behavior. Other practices such as frequency and quality of hand hygiene are likely to be as important as product in reducing risk of cross-transmission.

Passive immunization as prophylaxis: when and where will this work?

The strict definition of passive immunoprophylaxis includes the administration of exogenously produced antibodies (polyclonal and monoclonal) to prevent infections in exposed individuals, inactivate bacterial toxins or "correct" hypogammaglobulinemia in immunocompromised hosts. This definition can be broadened to include modulators of the immune system. Despite advances in chemotherapy and vaccine development, suitable treatment is not currently available for many pathogens. As a result, passive immunization is an appropriate therapeutic option for many organisms.

Gram-negative bacilli associated with catheter-associated and non-catheter-associated bloodstream infections and hand carriage by healthcare workers in neonatal intensive care units.

OBJECTIVE: Bloodstream infections caused by Gram-negative bacilli are a substantial cause of morbidity and mortality in infants in neonatal intensive care units. This study describes the species of Gram-negative bacilli causing bloodstream infections in two neonatal intensive care units, compares characteristics of catheter-related and non-catheter-related bloodstream infections, and compares species and antibiotic resistance patterns of these organisms with those isolated from the hands of nurses working in the same neonatal intensive care units. DESIGN: Interventional study. SETTING: Two high-risk neonatal intensive care units. PATIENTS: Neonates hospitalized for >or =24 hrs. INTERVENTIONS: Prospective surveillance for bloodstream infections was performed in two neonatal intensive care units from March 2001 to January 2003. Hand cultures were obtained quarterly from participating nurses immediately after they performed hand hygiene. MEASUREMENTS AND MAIN RESULTS: There were 298 episodes of bloodstream infections among 2,935 admissions (5.75 episodes per 1,000 patient-days); 77 of 298 (26%) episodes were caused by Gram-negative bacilli. Among these, 47 (61.0%) were catheter-related bloodstream infections (2.61 episodes per 1,000 catheter-days). Eleven and 24 Gram-negative bacilli species were isolated from neonates and nurses, respectively. The most common Gram-negative bacilli causing bloodstream infections were Klebsiella pneumoniae (38.7%), Escherichia coli (21.2%), Enterobacter cloacae (11.2%), and Serratia marcescens (11.2%). In contrast, Acinetobacter lwoffi (18.1%), K. pneumoniae (11.7%), E. cloacae (10.6%), K. oxytoca (10.6%), and Pseudomonas spp. (7.4%) were most commonly isolated from hands of nurses. E. coli, P. aeruginosa, E. cloacae, and E. aerogenes were significantly more likely to cause bloodstream infections than to be isolated from nurses' hands (all p < .001). Although 39% of bloodstream infections were non-catheter-related, there were no significant differences in types of organisms or antimicrobial resistance patterns between catheter-related bloodstream infections and non-catheter-related bloodstream infections (all p > or = .35). Resistance patterns were similar between Gram-negative bacilli isolates from neonates and nurses' hands except for a significantly higher proportion of resistance to cefotaxime and gentamicin among neonatal isolates of K. pneumoniae (p < .05). CONCLUSIONS: Gram-negative bacilli species isolated from neonatal bloodstream infections and nurses' hands varied significantly. Clean hands of providers are an unlikely source of endemic Gram-negative bacilli, suggesting that prevention strategies should focus more on control of endogenous neonatal flora or environmental sources.

Vaccine monitoring systems: A potential model for medications in pregnancy.

Multiple vaccine safety systems contribute to monitor and assess the safety of vaccines given to pregnant women and their offspring. This article presents a review of the strengths and limitations of several national vaccine safety systems. The review concludes that the present framework of vaccine safety systems offers lessons to be learned toward the design of a system for monitoring and assessing the safety of medications administered to pregnant women in clinical practice and research.

Maternal immunization efforts of the National Institutes of Health.

Over the last 35 years, efforts at the National Institutes of Health (NIH) to protect mothers and their infants against infectious diseases have involved a bench-to-bedside approach. Basic and translational research that provided a foundation for clinical trials of vaccines in pregnancy include natural history and vaccine antigen identification studies. Development of laboratory assays and reagents have been funded by NIAID; these are critical for the advancement of vaccine candidates through the preclinical and clinical steps along the maternal immunization research pathway to support vaccine efficacy. Animal models of maternal immunization have been developed to evaluate efficacy of vaccine candidates. Clinical studies required development of maternal immunization protocols to address specific pregnancy related issues, for enrollment and safety assessment of mothers and their infants. NIH has organized and participated in meetings, workshops and other collaborative efforts with partners have advanced maternal immunization efforts. Partners have included many institutes and offices at NIH as well as other Department of Health and Human Services agencies and offices (Food and Drug Administration, Centers for Disease Control and Prevention, National Vaccine Program Office), World Health Organization, academic investigators, Biotech and pharmaceutical companies, and nonprofit organizations such as the Bill and Melinda Gates Foundation. These research and development partnership are essential for advancing maternal immunization. Continued efforts are needed to promote maternal immunization to protect pregnant women and their infants against vaccine-preventable infectious disease, especially in resource-limited settings where the burden of infections is high.

Entry inhibitors SCH-C, RANTES, and T-20 block HIV type 1 replication in multiple cell types.

The small-molecule CCR5 antagonist SCH-C (SCH 351125) was tested for its ability to inhibit HIV-1 replication in peripheral blood mononuclear cells (PBMCs), cord blood mononuclear cells, immature dendritic cells (DCs), and macrophages. Inhibition of infection of PBMCs by virus associated with mature DC in trans was also studied. For comparison, the peptide-based fusion inhibitor T-20 and the CC-chemokine RANTES were also evaluated. Although some cell type-dependent differences in potency were observed, each of the three entry inhibitors was active against the replication of three different CCR5-using primary isolates in each cell type. CCR5-dependent HIV-1 infectivity, whether DC associated or not, is thus vulnerable to inhibitors that block the virus-cell fusion process by different mechanisms. Together, these results suggest that SCH-C and other entry inhibitors should be evaluated for their clinical potential as inhibitors of HIV-1 replication in several settings, including the prevention of maternal-infant transmission and the prevention of sexual transmission by topical application as a microbicide.

Comparison of recombinant granulocyte colony-stimulating factor, recombinant human granulocyte-macrophage colony-stimulating factor and placebo for treatment of septic preterm infants.

BACKGROUND: To reduce morbidity and mortality adjuvant cytokine therapy was administered to septic neonates with variable results. The objective of this case series was to compare the effectiveness of recombinant human granulocyte-macrophage colony-stimulating factor (rhuGM-CSF) and recombinant granulocyte colony-stimulating factor (rG-CSF) with that of placebo in correcting neutropenia induced by sepsis. METHODS: Symptomatic, septic premature neonates with or without a positive blood culture were eligible. Twenty-eight patients were randomized: 10 received rG-CSF (5 microg/kg/dose i.v. twice a day); 10 received rhuGM-CSF (4 microg/kg/dose i.v. twice a day) and 8 received placebo for a maximum of 7 days, or until an absolute neutrophil count (ANC) of 10,000 cells/mm was reached. RESULTS: A significant increase in the ANC above the baseline was present on Day 2 in the rG-CSF group (P = 0.015) and on Day 5 in the rhuGM-CSF (P = 0.002) and placebo (P = 0.027) groups. The ANC of the rG-CSF group was significantly above that in the rhuGM-CSF and placebo groups on Day 7 (P = 0.03). Mortality and neonatal intensive care unit morbidity was not significantly different between the groups. CONCLUSION: The neutrophil count in the rG-CSF-treated group increased significantly faster than that in the placebo or rhuGM-CSF group.

Emergence of resistant staphylococci on the hands of new graduate nurses.

OBJECTIVE: To describe the aerobic microbial flora on the hands of experienced and new graduate nurses over time. DESIGN: A prospective cohort design that examined the relationship between duration of employment in an intensive care unit (ICU) and the microbial flora on the hands of experienced and new graduate nurses during a 23-month period. SETTING: A 50-bed, level III-IV neonatal ICU in New York City. PARTICIPANTS: Twelve experienced nurses and 9 new graduate nurses working full time in the NICU. INTERVENTION: One hundred fifty samples were obtained from the clean, dominant hands of the nurses. Cultures were performed at baseline and then quarterly for each experienced and new graduate nurse. Baseline and final cultures of Staphylococcus epidermidis were further examined using pulsed-field gel electrophoresis. RESULTS: At baseline, a significantly larger proportion of the experienced nurses had methicillin-resistant, coagulase-negative staphylococci isolated from their hands compared with the new graduate nurses (95% and 33%, respectively; P = .0004). For a second culture, performed 1 to 4 months later, there were no longer significant differences between the two groups (82% and 54%, respectively; P = .12). By the last culture, all staphylococcal isolates were methicillin resistant in both groups of nurses; 3 were methicillin-resistant S. aureus. CONCLUSIONS: Colonization with methicillin-resistant staphylococci occurred after brief exposure to the hospital environment, despite the use of antiseptic hand hygiene agents. Furthermore, at final culture, the two groups shared one dominant hospital-acquired strain of S. epidermidis.

Adverse reactions associated with an alcohol-based hand antiseptic among nurses in a neonatal intensive care unit.

BACKGROUND: Alcohol-based hand antiseptics are strongly recommended in the 2002 Centers for Disease Control and Prevention's hand-hygiene guideline. In a study comparing 2 hand-hygiene regimes, an alcohol-based (61% ethyl) antiseptic and a detergent containing 2% chlorhexidine gluconate in 2 neonatal intensive care units, we noted adverse reactions associated with the alcohol-based antiseptic. METHODS: A prospective study was conducted of the skin condition of 58 nurses using an alcohol-based product from March 2001 to January 2002. Adverse reactions to the alcohol-based product were noted and the Fisher exact test was used to determine factors associated with these reactions. Nurses with reactions to the alcohol product who were available to follow-up were patch tested to the product. RESULTS: Of 58 (1.1/100 nursing mo) nurses, 7 were evaluated by occupational health services for dermatologic symptoms that varied from mild to severe after use of the alcohol product, but 4 of 7 have resumed use. Nurses who had adverse reactions develop had been employed on the study unit and in the nursing profession for significantly less time than those with no reactions (P =.037 and P =.002, respectively), and were significantly more likely to report a history of itchy, sore skin (P =.047). A positive patch-test result was noted in 3 of 4 nurses with a previous reaction to the product. CONCLUSION: This case series will alert users in the United States and elsewhere to the nature of reactions to alcohol products and how these reactions differ from reactions to traditional hand antiseptic products.