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In part 1 of a phase 2–3 trial, a 50-μg dose of mRNA-1273 vaccine was safe and immunogenic. In part 2, nearly 4000 6-to-11-year-olds received two doses of vaccine or placebo and were followed for a median of 82 days. The vaccine had mainly mild adverse effects and was immunogenic in 99%, similar to the results in 18-to-25-year-olds. Vaccine efficacy during a delta-variant period was 88%.

Background. Two doses of either trivalent live attenuated or inactivated influenza vaccines (LAIV and TIV, respectively) are approved for young children (>24 months old for LAIV and ≥6 months old for TIV) and induce protective antibody responses. However, whether combinations of LAIV and TIV are safe and equally immunogenic is unknown. Furthermore, LAIV is more protective than TIV in children for unclear reasons. Methods. Children 6-35 months old were administered, 1 month apart, 2 doses of either TIV or LAIV, or combinations of LAIV and TIV in both prime/boost sequences. Influenza-specific antibodies were measured by hemagglutination inhibition (HAI), and T cells were studied in flow cytometric and functional assays. Highly conserved Ml, M2, and NP peptides predicted to be presented by common HLA class I and II were used to stimulate interferon-ã enzyme-linked immunospot responses. Results. All LAIV and/or TIV combinations were well tolerated and induced similar HAI responses. In contrast, only regimens containing LAIV induced influenza-specific CD4⁺, CD8⁺, and γδ T cells, including T cells specific for highly conserved influenza peptides. Conclusions. Prime/boost combinations of LAIV and TIV in young children were safe and induced similar protective antibodies. Only LAIV induced CD4⁺, CD8⁺, and γδ T cells relevant for broadly protective heterosubtypic immunity. Clinical Trials Registration. NCT00231907.

Invasive Staphylococcus aureus infections cause high morbidity and mortality in children and adults. With rising antimicrobial resistance, optimal prevention strategies and novel therapeutics are needed. As an effective vaccine remains elusive, characterization of invasive isolates over time is required to identify determinants of invasive infection. S. aureus isolates recovered from children with invasive infection and those with colonization were obtained. Isolates were examined by whole genome sequencing to evaluate gene repertoire, sequence type, clonal complex, and phylogenetic characterization, and isolate characteristics were correlated to clinical data. 118 children with invasive S. aureus infections were enrolled; 56% of infections were caused by methicillin-susceptible S. aureus (MSSA). Methicillin-resistance (MRSA) was associated with increased inflammation, though clinical outcomes of MRSA vs MSSA did not differ. Colonization isolates exhibited higher sequence type diversity than invasive isolates. Nine distinct clonal complexes (CC) were identified among all isolates; CC8 and CC5 were associated with higher clinical severity scores. Accessory gene regulator locus type 1, Panton-Valentine Leukocidin, and arginine catabolic mobile element declined over time. Staphylokinase and leukocidin ED were associated with invasive infection, while enterotoxin B was more frequent in colonizing isolates. We observed a significant expansion in sequence type diversity among invasive clinical isolates over 12 years with the emergence of newly invasive clones in recent years. The presence of staphylokinase and LukED were associated with invasive infection over time. These findings provide insights into the pathogenesis of invasive S. aureus and may provide putative targets for immunologic approaches to prevention.

Uncomplicated skin infections are a common outpatient clinical problem. In this randomized, controlled trial, clindamycin and trimethoprim–sulfamethoxazole (TMP-SMX) were compared as outpatient therapy for uncomplicated cellulitis or abscess. Skin and skin-structure infections (hereafter referred to as skin infections) are common conditions among patients seeking medical care in the United States, 1 , 2 accounting for approximately 14.2 million outpatient visits in 2005 1 and more than 850,000 hospital admissions. 3 Skin infections are associated with considerable complications, including bacteremia, the need for hospitalization and surgical procedures, and death. 4 , 5 Results of cultures of skin-infection lesions in the United States have shown that most of the infections are caused by methicillin-resistant Staphylococcus aureus (MRSA), 6 , 7 but the efficacy of various antibiotic regimens in areas where community-associated MRSA is endemic has not been defined. . . .

There are limited data on the role of antimicrobials in the treatment of skin abscesses. In this trial, clindamycin or trimethoprim–sulfamethoxazole was found to facilitate more rapid resolution than placebo in the management of skin abscess under 5 cm in diameter. More than 4 in 100 people seek treatment for skin infections annually in the United States. 1 Abscesses are the most common of these infections, and the majority of patients are treated as outpatients. 1 Serious complications, such as bacteremia, occur in rare cases. 1 , 2 Staphylococcus aureus, including methicillin-resistant S. aureus (MRSA) strains, causes most skin infections, 3 , 4 but the appropriate strategy for the treatment of these infections has not been defined. Clindamycin and trimethoprim–sulfamethoxazole (TMP-SMX) are recommended for outpatient treatment of abscesses because of their low cost and in vitro activity against community-associated MRSA and methicillin-susceptible strains, 5 but data on their . . .

The U.S. COVID-19 vaccination program, which commenced in December 2020, has been instrumental in preventing morbidity and mortality from COVID-19 disease. Safety monitoring has been an essential component of the program. The federal government undertook a comprehensive and coordinated approach to implement complementary safety monitoring systems and to communicate findings in a timely and transparent way to healthcare providers, policymakers, and the public. Monitoring involved both well-established and newly developed systems that relied on both spontaneous (passive) and active surveillance methods. Clinical consultation for individual cases of adverse events following vaccination was performed, and monitoring of special populations, such as pregnant persons, was conducted. This report describes the U.S. government’s COVID-19 vaccine safety monitoring systems and programs used by the Centers for Disease Control and Prevention, the U.S. Food and Drug Administration, the Department of Defense, the Department of Veterans Affairs, and the Indian Health Service. Using the adverse event of myocarditis following mRNA COVID-19 vaccination as a model, we demonstrate how the multiple, complementary monitoring systems worked to rapidly detect, assess, and verify a vaccine safety signal. In addition, longer-term follow-up was conducted to evaluate the recovery status of myocarditis cases following vaccination. Finally, the process for timely and transparent communication and dissemination of COVID-19 vaccine safety data is described, highlighting the responsiveness and robustness of the U.S. vaccine safety monitoring infrastructure during the national COVID-19 vaccination program.

Influenza A/H7N9 viruses have pandemic potential. We conducted an open-label, randomized, controlled trial of AS03-adjuvanted 2017 inactivated influenza A/H7N9 vaccine (H7N9 IIV) in healthy adults. Group 1 received H7N9 IIV and seasonal quadrivalent influenza vaccine (IIV4) simultaneously, followed by H7N9 IIV three weeks later. Group 2 received IIV4 alone and then two doses of H7N9 IIV at three-week intervals. Group 3 received one dose of IIV4. We used hemagglutination inhibition (HAI) and microneutralization (MN) assays to measure geometric mean titers and seroprotection (≥1:40 titer) to vaccine strains and monitored for safety. Among 149 subjects, seroprotection by HAI three weeks after H7N9 IIV dose 2 was 51% (95 %CI 37%-65%) for Group 1 and 40% (95 %CI 25%-56%) for Group 2. Seroprotection by MN at the same timepoint was 84% (95 %CI 72%-93%) for Group 1 and 74% (95 %CI 60%-86%) for Group 2. By 180 days after H7N9 IIV dose 2, seroprotection by HAI or MN was low for Groups 1 and 2. Responses measured by HAI and MN against each IIV4 strain three weeks after IIV4 vaccination were similar in all groups. Solicited local and systemic reactions were similar after a single vaccination, while those receiving simultaneous H7N9 and IIV4 had slightly more reactogenicity. There were no serious adverse events or medically-attended adverse events related to study product receipt. Adjuvanted H7N9 IIV was modestly immunogenic whether administered simultaneously or sequentially with IIV4, though responses declined by 180 days. IIV4 was immunogenic regardless of schedule. Clinical Trials Registration: NCT03318315

•BPZE1 is a live, attenuated intranasal pertussis vaccine.•BPZE1 was not associated with clinically significant adverse events after vaccination.•BPZE1 induced both humoral and mucosal antibody responses after vaccination.•No prolonged shedding of BPZE1 was observed. BPZE1 is a live, attenuated pertussis vaccine derived from B. pertussis strain Tohama I modified by genetic removal or inactivation of 3 B. pertussis toxins: pertussis toxin, dermonecrotic toxin, and tracheal cytotoxin. This Phase 2a study evaluated the safety and immunogenicity of liquid or lyophilized BPZE1 vaccine administered intranasally by needleless tuberculin syringe or mucosal atomization device (VaxINatorTM) at two dose levels. Fifty healthy male and non-pregnant female participants 18–49 years of age were enrolled. Participants were randomized 3:3:3:1 to a single lyophilized dose of 107 colony forming units (CFU) BPZE1, 109 CFU BPZE1, placebo via VaxINator device, or a single liquid dose of 109 CFU BPZE1 via tuberculin syringe. Reactogenicity was assessed for 14 days. Blood was obtained pre-vaccination; on Day 8 (safety); and on Days 15, 29, and 181 (immunogenicity). Nasal wick and swab samples were obtained at baseline and on Days 29 and 181 for assessment of mucosal antibody responses and clearance of BPZE1. Across all groups, 35/50 (70 %) experienced at least one local adverse event (AE) and 31/50 (62 %) experienced at least one systemic AE, with similar AE frequencies observed between the highest 109 CFU BPZE1 and placebo groups. There were no severe or serious AEs during the study. At Day 29, seroconversion (≥2-fold rise from baseline in serum IgG or IgA) to at least 2 pertussis antigens was observed in 73 % in the 109 CFU BPZE1 VaxINator group, 60 % in the 109 CFU BPZE1 group delivered via tuberculin syringe, 27 % of participants in the 107 CFU BPZE1 VaxINator group, and 20 % in the placebo VaxINator group. No participants were colonized with BPZE1 at Day 29 post vaccination. Lyophilized BPZE1 vaccine was well tolerated and immunogenic at the highest dose (109 CFU) delivered intranasally by VaxINator device and was not associated with any SAEs or prolonged shedding of BPZE1. Further evaluation of BPZE1 is warranted.

•SA4Ag is a novel multiantigen vaccine that targets S. aureus virulence factors.•A single dose of SA4Ag was well-tolerated in healthy adults aged 18–64years.•A robust functional immune response was elicited to each vaccine component.•Antibody rise was rapid and sustained after one dose of SA4Ag vaccine.•SA4Ag is a promising candidate vaccine to prevent invasive S. aureus infections. A prophylactic Staphylococcus aureus four-antigen vaccine (SA4Ag) is under development for prevention of invasive S. aureus disease. A preliminary S. aureus three-antigen vaccine (SA3Ag) was reformulated to include a novel manganese transporter protein (MntC or rP305A). This study describes the first-in-human dose-finding, safety, and immunogenicity results for SA4Ag. In this double-blind, sponsor-unblind, placebo-controlled, phase 1/2 study, 454 healthy adults aged 18–64years were randomised to receive a single dose of one of three formulations of SA4Ag with escalating dose levels of rP305A or placebo. Functional immune responses were measured using opsonophagocytic activity (OPA) killing and fibrinogen-binding inhibition (FBI) assays; antigen-specific immunogenicity was assessed using a four-plex competitive Luminex® immunoassay (cLIA). A high proportion of SA4Ag recipients met the pre-defined antibody thresholds for each antigen at Day 29. A substantial and dose-level dependent immune response was observed for rP305A, with up to 18-fold rises in cLIA titres at Day 29. Robust functional responses were demonstrated, with >80-fold and >20-fold rises in OPA assay titres at Day 29 using S. aureus strains expressing capsular polysaccharide serotypes 5 and 8, respectively. Durable antibody responses were observed through month 12, gradually waning from peak levels achieved by days 11–15. SA4Ag was well tolerated, and no vaccine-related serious adverse events were reported. Single-dose vaccination of SA4Ag in healthy adults aged 18–64years safely induced rapid and robust functional immune responses that were durable through month 12, supporting further development of this vaccine. Trial registration number: NCT01364571

Staphylococcus aureus capsular polysaccharides (CP) are important virulence factors under evaluation as vaccine antigens. Clinical S. aureus isolates have the biosynthetic capability to express either CP5 or CP8 and an understanding of the relationship between CP genotype/phenotype and S. aureus epidemiology is valuable. Using whole genome sequencing, the clonal relatedness and CP genotype were evaluated for disease-associated S. aureus isolates selected from the Tigecycline Evaluation and Surveillance Trial (T.E.S.T) to represent different geographic regions in the United States (US) during 2004 and 2009-10. Thirteen prominent clonal complexes (CC) were identified, with CC5, 8, 30 and 45 representing >80% of disease isolates. CC5 and CC8 isolates were CP type 5 and, CC30 and CC45 isolates were CP type 8. Representative isolates from prevalent CC were susceptible to in vitro opsonophagocytic killing elicited by anti-CP antibodies, demonstrating that susceptibility to opsonic killing is not linked to the genetic lineage. However, as not all S. aureus isolates may express CP, isolates representing the diversity of disease isolates were assessed for CP production. While approximately 35% of isolates (primarily CC8) did not express CP in vitro, CP expression could be clearly demonstrated in vivo for 77% of a subset of these isolates (n = 20) despite the presence of mutations within the capsule operon. CP expression in vivo was also confirmed indirectly by measuring an increase in CP specific antibodies in mice infected with CP5 or CP8 isolates. Detection of antigen expression in vivo in relevant disease states is important to support the inclusion of these antigens in vaccines. Our findings confirm the validity of CP as vaccine targets and the potential of CP-based vaccines to contribute to S. aureus disease prevention.