A Phase 2 Clinical Trial to Evaluate the Safety, Reactogenicity, and Immunogenicity of Different Prime-Boost Vaccination Schedules of 2013 and 2017 A(H7N9) Inactivated Influenza Virus Vaccines Administered With and Without AS03 Adjuvant in Healthy US Adults.

INTRODUCTION: A surge of human influenza A(H7N9) cases began in 2016 in China from an antigenically distinct lineage. Data are needed about the safety and immunogenicity of 2013 and 2017 A(H7N9) inactivated influenza vaccines (IIVs) and the effects of AS03 adjuvant, prime-boost interval, and priming effects of 2013 and 2017 A(H7N9) IIVs. METHODS: Healthy adults (n = 180), ages 19-50 years, were enrolled into this partially blinded, randomized, multicenter phase 2 clinical trial. Participants were randomly assigned to 1 of 6 vaccination groups evaluating homologous versus heterologous prime-boost strategies with 2 different boost intervals (21 vs 120 days) and 2 dosages (3.75 or 15 µg of hemagglutinin) administered with or without AS03 adjuvant. Reactogenicity, safety, and immunogenicity measured by hemagglutination inhibition and neutralizing antibody titers were assessed. RESULTS: Two doses of A(H7N9) IIV were well tolerated, and no safety issues were identified. Although most participants had injection site and systemic reactogenicity, these symptoms were mostly mild to moderate in severity; injection site reactogenicity was greater in vaccination groups receiving adjuvant. Immune responses were greater after an adjuvanted second dose, and with a longer interval between prime and boost. The highest hemagglutination inhibition geometric mean titer (95% confidence interval) observed against the 2017 A(H7N9) strain was 133.4 (83.6-212.6) among participants who received homologous, adjuvanted 3.75 µg + AS03/2017 doses with delayed boost interval. CONCLUSIONS: Administering AS03 adjuvant with the second H7N9 IIV dose and extending the boost interval to 4 months resulted in higher peak antibody responses. These observations can broadly inform strategic approaches for pandemic preparedness. Clinical Trials Registration. NCT03589807.

A Multicenter, Controlled Human Infection Study of Influenza A(H1N1)pdm09 in Healthy Adults.

BACKGROUND: We evaluated the associations between baseline influenza virus-specific hemagglutination inhibition (HAI) and microneutralization (MN) titers and subsequent symptomatic influenza virus infection in a controlled human infection study. METHODS: We inoculated unvaccinated healthy adults aged 18-49 years with an influenza A/California/04/2009/H1N1pdm-like virus (NCT04044352). We collected serial safety labs, serum for HAI and MN, and nasopharyngeal swabs for reverse-transcription polymerase chain reaction (RT-PCR) testing. Analyses used the putative seroprotective titer of ≥40 for HAI and MN. The primary clinical outcome was mild-to-moderate influenza disease (MMID), defined as ≥1 postchallenge positive qualitative RT-PCR test with a qualifying symptom/clinical finding. RESULTS: Of 76 participants given influenza virus challenge, 54 (71.1%) experienced MMID. Clinical illness was generally very mild. MMID attack rates among participants with baseline titers ≥40 by HAI and MN were 64.9% and 67.9%, respectively, while MMID attack rates among participants with baseline titers <40 by HAI and MN were 76.9% and 78.3%, respectively. The estimated odds of developing MMID decreased by 19% (odds ratio, 0.81 [95% confidence interval, .62-1.06]; P = .126) for every 2-fold increase in baseline HAI. There were no significant adverse events. CONCLUSIONS: We achieved a 71.1% attack rate of MMID. High baseline HAI and MN were associated with protection from illness. Clinical Trials Registration. NCT04044352.

Safety and Immunogenicity of a monovalent inactivated influenza A/H5N8 virus vaccine given with and without AS03 or MF59 adjuvants in healthy adults.

BACKGROUND: Avian influenza A/H5N8 virus infections have been circulating widely in wild and domestic bird populations with transmission to a few human poultry workers. This phase 1, randomized, blinded trial evaluated the safety and immunogenicity of a monovalent inactivated influenza A/H5N8 virus vaccine (H5N8 IIV) given with and without AS03 or MF59 adjuvants. METHODS: 275 healthy adults, ages 19-64 years, were randomized to one of five groups to receive two doses of 15 µg unadjuvanted influenza A/gyrfalcon/Washington/41088-6/2014(H5N8) (clade 2.3.4.4c) virus vaccine or two doses of 7.5 or 15 µg of vaccine adjuvanted with AS03 or MF59. Immunogenicity was assessed through 21 days following the second dose of vaccine using hemagglutination inhibition (HAI) and microneutralization (MN) assays for the homologous influenza A/H5N8 and three heterologous influenza A/H5 viruses. Safety was assessed through 1 year. RESULTS: The vaccines were well tolerated. Only modest immune responses were seen following receipt of a single dose of vaccine. Seroprotection (HAI titers ≥40) was more common in groups that received AS03 plus 7.5 or 15 µg of vaccine (89% and 93%, respectively) compared to the MF59-adjuvanted groups (56% and 73%), while unadjuvanted vaccine showed a poor response (27%). Higher antigen content resulted in modestly improved immune responses. HAI and MN GMTs and seroconversion rates were low across all study groups for all three heterologous strains of influenza A/H5 virus. CONCLUSIONS: AS03 or MF59-adjuvanted H5N8 IIV generated strong immunogenic responses following two doses. There was poor cross-reactivity for the three antigenically drifted H5N1 strains tested.

Topical Imiquimod Does Not Provide an Adjuvant Effect When Administered With Inactivated Influenza A/H5N1 Vaccine in Healthy Young Adults.

BACKGROUND: Safe, effective, and easy to deploy adjuvants are needed for influenza prepandemic preparedness. Based on recent reports, we hypothesized that preapplication of topical imiquimod followed by intradermal (ID) vaccination with monovalent inactivated influenza A/H5N1 vaccine (MIV A/H5N1) results in improved serologic responses. METHODS: We randomized 50 healthy adults in a 1:1 ratio to receive topical imiquimod (group 1) or control cream (group 2) followed by ID injection of 9 µg of the hemagglutinin MIV A/H5N1 in 2 doses, 21 days apart. Subjects were followed for safety and serologic responses as measured by the hemagglutination inhibition (HAI) and microneutralization (MN) assays. RESULTS: Solicited and unsolicited adverse events were comparable between groups 1 and 2, and were mostly mild to moderate in severity. At 21 days after dose 2, the geometric mean titers (GMTs) of HAI antibodies against the vaccine strain were 16.2 and 24.3 in groups 1 and 2, respectively. The MN antibody GMTs were 9.3 and 10.7 in groups 1 and 2, respectively. There were no significant differences in antibody levels between groups at study time points. CONCLUSIONS: Topical imiquimod administration combined with ID MIV A/H5N1 was safe but did not result in improved serologic responses to the vaccine.Clinical Trials Registration. NCT03472976.

Use of Anthrax Vaccine in the United States: Recommendations of the Advisory Committee on Immunization Practices, 2019.

This report updates the 2009 recommendations from the CDC Advisory Committee on Immunization Practices (ACIP) regarding use of anthrax vaccine in the United States (Wright JG, Quinn CP, Shadomy S, Messonnier N. Use of anthrax vaccine in the United States: recommendations of the Advisory Committee on Immunization Practices [ACIP)], 2009. MMWR Recomm Rep 2010;59[No. RR-6]). The report 1) summarizes data on estimated efficacy in humans using a correlates of protection model and safety data published since the last ACIP review, 2) provides updated guidance for use of anthrax vaccine adsorbed (AVA) for preexposure prophylaxis (PrEP) and in conjunction with antimicrobials for postexposure prophylaxis (PEP), 3) provides updated guidance regarding PrEP vaccination of emergency and other responders, 4) summarizes the available data on an investigational anthrax vaccine (AV7909), and 5) discusses the use of anthrax antitoxins for PEP. Changes from previous guidance in this report include the following: 1) a booster dose of AVA for PrEP can be given every 3 years instead of annually to persons not at high risk for exposure to Bacillus anthracis who have previously received the initial AVA 3-dose priming and 2-dose booster series and want to maintain protection; 2) during a large-scale emergency response, AVA for PEP can be administered using an intramuscular route if the subcutaneous route of administration poses significant materiel, personnel, or clinical challenges that might delay or preclude vaccination; 3) recommendations on dose-sparing AVA PEP regimens if the anthrax vaccine supply is insufficient to vaccinate all potentially exposed persons; and 4) clarification on the duration of antimicrobial therapy when used in conjunction with vaccine for PEP.These updated recommendations can be used by health care providers and guide emergency preparedness officials and planners who are developing plans to provide anthrax vaccine, including preparations for a wide-area aerosol release of B. anthracis spores. The recommendations also provide guidance on dose-sparing options, if needed, to extend the supply of vaccine to increase the number of persons receiving PEP in a mass casualty event.

Progress toward the Development of a NEAT Protein Vaccine for Anthrax Disease.

Bacillus anthracis is a sporulating Gram-positive bacterium that is the causative agent of anthrax and a potential weapon of bioterrorism. The U.S.-licensed anthrax vaccine is made from an incompletely characterized culture supernatant of a nonencapsulated, toxigenic strain (anthrax vaccine absorbed [AVA]) whose primary protective component is thought to be protective antigen (PA). AVA is effective in protecting animals and elicits toxin-neutralizing antibodies in humans, but enthusiasm is dampened by its undefined composition, multishot regimen, recommended boosters, and potential for adverse reactions. Improving next-generation anthrax vaccines is important to safeguard citizens and the military. Here, we report that vaccination with recombinant forms of a conserved domain (near-iron transporter [NEAT]), common in Gram-positive pathogens, elicits protection in a murine model of B. anthracis infection. Protection was observed with both Freund's and alum adjuvants, given subcutaneously and intramuscularly, respectively, with a mixed composite of NEATs. Protection correlated with an antibody response against the NEAT domains and a decrease in the numbers of bacteria in major organs. Anti-NEAT antibodies promote opsonophagocytosis of bacilli by alveolar macrophages. To guide the development of inactive and safe NEAT antigens, we also report the crystal structure of one of the NEAT domains (Hal) and identify critical residues mediating its heme-binding and acquisition activity. These results indicate that we should consider NEAT proteins in the development of an improved antianthrax vaccine.

Safety and Immunogenicity of a Subvirion Monovalent Unadjuvanted Inactivated Influenza A(H3N2) Variant Vaccine in Healthy Persons ≥18 Years Old.

BACKGROUND: Variant influenza A(H3N2) viruses (H3N2v) have transmitted recently from pigs to humans in the United States. Vaccines strategies are needed. METHODS: Healthy adults received 2 doses of subvirion H3N2v vaccine (15 µg of hemagglutinin/dose) 21 days apart in this open-label trial. Serum hemagglutination inhibition (HAI) and neutralizing (Neut) antibody (Ab) titers were measured before and 8 and 21 days after each dose. Memory B-cell (MBC) responses were assessed. RESULTS: Vaccine was well tolerated. A total of 40% of subjects had an HAI Ab titer of ≥40 before vaccination. Eight-seven percent (95% confidence interval [CI], 79%-93%) and 73% (95% CI, 63%-81%) of subjects 18-64 years old (98 subjects) and ≥65 years old (90 subjects), respectively, had an HAI titer of ≥40 21 days after dose 1 (P = .01); 51% (95% CI, 41%-61%) and 52% (95% CI, 41%-62%) of younger and older subjects, respectively, developed ≥4-fold rises in titer (P = not significant). Neut Ab response patterns were similar. Geometric mean titers were higher in younger subjects. Dose 2 provided no significant enhancement in responses. Cross-reactive MBCs were detected before vaccination and expanded after vaccination. Preexisting H3N2v-specific MBCs positively correlated with early increases in vaccine-induced Ab. CONCLUSIONS: In most healthy adults, one 15-µg dose of vaccine elicited levels of HAI Abs associated with protection. Studies in children and elderly individuals are indicated to define the immunization needs of these groups. CLINICAL TRIALS REGISTRATION: NCT01746082.

Safety and Immunogenicity of a Single Low Dose or High Dose of Clade 2 Influenza A(H5N1) Inactivated Vaccine in Adults Previously Primed With Clade 1 Influenza A(H5N1) Vaccine.

Influenza A(H5N1) vaccination strategies that improve the speed of the immunological response and cross-clade protection are desired. We compared the immunogenicity of a single 15-µg or 90-µg dose of A/H5N1/Indonesia/05/05 (clade 2) vaccine in adults who were previously primed with A/H5N1/Vietnam/1203/2004 (clade 1) vaccine. High-dose vaccine resulted in significantly higher titers to both clade 1 and 2 antigens. Clade 2 titers were unaffected by the previous dose of clade 1 vaccine. Low-dose priming with a mismatched pandemic influenza A(H5N1) vaccine would improve the rapidity, magnitude, and cross-reactivity of the immunological response following a single high-dose, unadjuvanted, pandemic vaccine.

Effect of Varying Doses of a Monovalent H7N9 Influenza Vaccine With and Without AS03 and MF59 Adjuvants on Immune Response: A Randomized Clinical Trial.

IMPORTANCE: Human infections with the avian influenza A(H7N9) virus were first reported in China in 2013 and continue to occur. Hemagglutinin H7 administered alone is a poor immunogen necessitating evaluation of adjuvanted H7N9 vaccines. OBJECTIVE: To evaluate the immunogenicity and safety of an inactivated H7N9 vaccine with and without AS03 adjuvant, as well as mixed vaccine schedules that included sequential administration of AS03- and MF59-containing formulations and of adjuvanted and unadjuvanted formulations. DESIGN, SETTING, AND PARTICIPANTS: Double-blind, phase 2 trial at 5 US sites enrolled 980 adults aged 19 through 64 years from September 2013 through November 2013; safety follow-up was completed in January 2015. INTERVENTIONS: The H7N9 vaccine was given on days 0 and 21 at nominal doses of 3.75 µg, 7.5 µg, 15 µg, and 45 µg of hemagglutinin with or without AS03 or MF59 adjuvant mixed on site. MAIN OUTCOMES AND MEASURES: Proportions achieving a hemagglutination inhibition antibody (HIA) titer of 40 or higher at 21 days after the second vaccination; vaccine-related serious adverse events through 12 months after the first vaccination; and solicited signs and symptoms after vaccination through day 7. RESULTS: Two doses of vaccine were required to induce detectable antibody titers in most participants. After 2 doses of an H7N9 formulation containing 15 µg of hemagglutinin given without adjuvant, with AS03 adjuvant, or with MF59 adjuvant, the proportion achieving an HIA titer of 40 or higher was 2% (95% CI, 0%-7%) without adjuvant (n = 94), 84% (95% CI, 76%-91%) with AS03 adjuvant (n = 96), and 57% (95% CI, 47%-68%) with MF59 adjuvant (n = 92) (P < .001 for comparison of the AS03 and MF59 schedules). The 2 schedules alternating AS03-and MF59-adjuvanted formulations led to lower geometric mean titers (GMTs) of (41.5 [95% CI, 31.7-54.4]; n = 92) and (58.6 [95% CI, 44.3-77.6]; n = 96) than the group induced by 2 AS03-adjuvanted formulations (n = 96) (103.4 [95% CI, 78.7-135.9]; P < .001) but higher GMTs than 2 doses of MF59-adjuvanted formulation (n = 94) (29.0 [95% CI, 22.4-37.6]; P < .001). CONCLUSIONS AND RELEVANCE: The AS03 and MF59 adjuvants augmented the immune responses to 2 doses of an inactivated H7N9 influenza vaccine, with AS03-adjuvanted formulations inducing the highest titers. This study of 2 adjuvants used in influenza vaccine formulations with adjuvant mixed on site provides immunogenicity information that may be informative to influenza pandemic preparedness programs. TRIAL REGISTRATION: clinicaltrials.gov Identifier: NCT01942265.

Safety of zoster vaccine in elderly adults following documented herpes zoster.

BACKGROUND: After completion of the Shingles Prevention Study (SPS; Department of Veterans Affairs Cooperative Studies Program Number 403), SPS participants who had initially received placebo were offered investigational zoster vaccine without charge. This provided an opportunity to determine the relative safety of zoster vaccine in older adults following documented herpes zoster (HZ). METHODS: A total of 13 681 SPS placebo recipients who elected to receive zoster vaccine were followed for serious adverse events (SAE) for 28 days after vaccination. In contrast to the SPS, a prior episode of HZ was not a contraindication to receiving zoster vaccine. The SPS placebo recipients who received zoster vaccine included 420 who had developed documented HZ during the SPS. RESULTS: The mean interval between the onset of HZ and the receipt of zoster vaccine in the 420 recipients with prior HZ was 3.61 years (median interval, 3.77 years [range, 3-85 months]); the interval was <5 years for approximately 80% of recipients. The proportion of vaccinated SPS placebo recipients with prior HZ who developed ≥ 1 SAE (0.95%) was not significantly different from that of vaccinated SPS placebo recipients with no prior history of HZ (0.66%), and the distribution of SAEs in the 2 groups was comparable. CONCLUSIONS: These results demonstrate that the general safety of zoster vaccine in older persons is not altered by a recent history of documented HZ, supporting the safety aspect of the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices recommendation to administer zoster vaccine to all persons ≥ 60 years of age with no contraindications, regardless of a prior history of HZ.

Delays in Hepatitis A vaccination in people with HIV in Houston, Texas between 2010 and 2018.

Background: Studies have demonstrated low hepatitis A virus (HAV) vaccination rates among persons with HIV (PWH). Methods: We conducted a retrospective study of persons entering HIV care at two clinics in Houston, Texas between 2010 and 2018. We defined those eligible for HAV vaccination as those who had no history of HAV vaccination and had a negative anti-HAV IgG at entry to care. Kaplan-Meier curves summarized time to receipt of HAV vaccines. The proportions of patients who received 1 and 2 HAV vaccines at 6, 12, and 24 months were estimated. Cox proportional hazards regression evaluated associations between patient characteristics and vaccination. Significant factors were included in a multivariable Cox proportional hazards model. Results: Of 6,515 patients, 1372 were eligible for HAV vaccination. Of eligible patients, 29.2 % received 1 HAV vaccination at 6 months, 37.1 % at 12 months, and 47.8 % at 24 months. At 6 months, 10 % received 2 HAV vaccinations, 21.1 % at 12 months, and 33.4 % at 24 months. In multivariable analysis, men who have sex with men (adjusted HR 1.35, 95 % CI 1.06, 1.73) or those who had CD4 count ≥ 200 cells/µl (adjusted HR 2.52, 95 % CI 1.89, 3.37) had their second vaccination sooner than those who were not men who have sex with men or who had CD4 counts < 200 cells/µl, respectively. Patients > 50 years of age had their second vaccination sooner than those aged 30-50 years (adjusted HR 1.47, 95 % CI 1.08, 1.99). Those with active substance history had a longer time to second vaccination compared to those with no substance use history (adjusted HR 0.57, 95 % CI 0.40, 0.82). Conclusions: HAV vaccination rates were low and highlight the need for effective solutions to address HAV immunization gaps in PWH, especially among young patients, those with active substance use disorders, and those with significant immunocompromise.

Effects of infection and disease with Mycobacterium tuberculosis on serum antibody to glucan and arabinomannan: two surface polysaccharides of this pathogen.

BACKGROUND: The role of the surface capsular polysaccharides (CPs) of Mycobacterium tuberculosis (Mtb) in the pathogenesis of infection and disease, as well their potential for use as diagnostic reagents and vaccine antigens, are unknown. METHODS: Serum antibody to two CPs of Mtb, arabinomannan (AM) and glucan (Glu), were studied in samples from 52 18-74 year-old HIV-seronegative, immunocompetent individuals in Houston Texas. The effects of Mtb exposure, infection and disease upon the levels of antibodies to these CPs were assessed. Subjects were grouped according to the standard international classification. RESULTS: IgA anti-Glu levels were significantly higher in the active and treated TB compared to a group that was PPD-negative without TB exposure history (p<0.05). Antibodies against AM demonstrated a similar pattern, with the exception that IgG anti-AM was higher in groups who had active TB or previously documented active TB, and IgA anti-AM was higher in subjects with previously documented active TB compared to the level in an unexposed, PPD-negative group (p<0.05). Serum IgG anti-Glu levels were higher in subjects with active TB or previously documented active TB than in the unexposed PPD-negative group, but the differences were not significant. CONCLUSIONS: These data suggest that the evaluation of antibody responses to the CP of Mtb may have utility for TB serodiagnosis, and that vaccines designed to induce humoral responses to TB CPs should be tested for their capacity to evoke anti-tuberculosis protective immunity.

Direct comparison of an inactivated subvirion influenza A virus subtype H5N1 vaccine administered by the intradermal and intramuscular routes.

BACKGROUND: Direct comparisons of similar doses of a novel influenza virus antigen administered by the intradermal route and the intramuscular route have not been reported. METHODS: A total of 227 healthy adults aged 18-49 years were randomized to receive 2 doses 1 month apart of a subvirion inactivated influenza A virus subtype H5N1 (rgA/Vietnam/1203/2004) vaccine containing 38.7 µg of H5N1 hemagglutinin (HA), by the intramuscular route or by the intradermal route using the Mantoux technique. Clinical and serologic responses were assessed. RESULTS: Injection site reactions were more frequent in the intradermal group. Immune responses and the geometric mean titer of serum hemagglutination inhibition and neutralizing antibodies 1 month after receipt of the first dose were similar and low but were significantly higher after 2 doses of vaccine in both groups. CONCLUSIONS: Intramuscular and intradermal delivery of vaccine were both well tolerated. Immune responses after 2 doses of this influenza A/H5N1 HA (38.7 µg) were low and not significantly different when given by the intradermal or intramuscular route. Evaluation of higher dosages, alternative intradermal delivery methods, and the addition of adjuvants will be needed to enhance the immunogenicity of inactivated influenza A/H5N1 vaccines by the intradermal route. CLINICAL TRIALS REGISTRATION: NCT00439335.

Higher antigen content improves the immune response to 2009 H1N1 influenza vaccine in HIV-infected adults: a randomized clinical trial.

BACKGROUND: The immunogenicity of a high hemagglutinin (HA) dose or a second dose of influenza vaccine in human immunodeficiency virus (HIV)-infected individuals has not been fully explored. METHODS: One hundered ninety-two HIV-infected individuals aged 18-64 years were stratified by CD4 cell count (<200 cells/mL or ≥200 cells/mL) and randomized to receive 2 doses of 15 µg or 30 µg HA 2009 H1N1 vaccine 21 days apart. Hemagglutination inhibition (HAI) and microneutralization (MN) antibodies were measured on days 0, 10, 21, 31, 42, and 201. RESULTS: Recipients of 30 µg HA had significantly higher HAI geometric mean titers (GMTs), compared with recipients of 15 µg HA on days 10 (139.0 vs 51.9; P = .01), 21 (106.7 vs 51.9; P = .001), and 31 (130.0 vs 73.7; P = .03) but not on days 42 (91.8 vs 61.6; P = .11) and 201 (43.0 vs 27.0; P = .08). When analyzed by CD4 cell count stratum, HAI GMTs were significantly higher among 30 µg HA recipients than among 15 µg HA in the CD4 cell count <200 cells/mL stratum on days 21 and 31 and the MN GMTs on days 10, 21, 31, and 42 (P < .05). In the CD4 cell count ≥200 cells/mL stratum, MN GMTs were significantly higher among recipients of 30 µg HA than among recipients of 15 µg HA on day 10 (P = .03). CONCLUSION: Increasing the HA dose of the 2009 H1N1 vaccine improves the vaccine's immunogenicity in HIV-infected individuals. CLINICAL TRIALS REGISTRATION: NCT00992433.

Delays in Hepatitis B Immunization Series Completion in People With Human Immunodeficiency Virus.

Background: Studies have demonstrated low hepatitis B virus (HBV) vaccine series completion among persons with human immunodeficiency virus (HIV). Methods: We conducted a retrospective record review of persons entering HIV care at 2 clinics in Houston, Texas, between 2010 and 2018. Kaplan-Meier curves summarized time to receipt of HBV vaccines for those eligible for vaccination. We estimated the proportions of patients who had received 1, 2, or 3 HBV vaccine doses at 12 and 24 months after entry to care. A Prentice Williams and Peterson total time model was used to evaluate associations between patient characteristics and time to vaccination. Results: Of the 5357 patients who entered care, 2718 were eligible for HBV vaccination. After 2 years of follow-up, 51.2% of those eligible had received 1 HBV vaccine, 43.2% had received 2, and 28.4% received 3 vaccines. With adjustment for significant cofactors, patients whose CD4 cell count was ≥200/µL (adjusted hazard ratio [aHR], 1.43 [95% confidence interval (CI), 1.29-1.59]) and transgender patients (1.49 [1.08-2.04]) received any given vaccine dose sooner than those with CD4 cell counts <200/µL or cisgender patients, respectively. Compared with non-Hispanic whites, Hispanic patients were vaccinated sooner (aHR, 1.28 [95% CI, 1.07-1.53]). Those with an active substance use history had a significantly longer time to vaccination than those with no substance use history (aHR, 0.73 [95% CI, .62-.85]). Conclusions: Strategies are needed to increase HBV vaccine completion rates in our study population, particularly among those with CD4 cell counts <200/µL or with a substance use disorder.

Safety and immunogenicity of Multimeric-001 (M-001) followed by seasonal quadrivalent inactivated influenza vaccine in young adults - A randomized clinical trial.

BACKGROUND: The continuing evolution of influenza viruses poses a challenge to vaccine prevention, highlighting the need for a universal influenza vaccine. We evaluated the safety and immunogenicity of one such candidate, Multimeric-001 (M-001), when used as a priming vaccine prior to administration of quadrivalent inactivated influenza vaccine (IIV4). METHODS: Healthy adults 18 to 49 years of age were enrolled in a phase 2 randomized, double-blind placebo-controlled trial. Participants received two doses of either 1.0-mg M-001 or saline placebo (60 per study arm) on Days 1 and 22 followed by a single dose of IIV4 on about Day 172. Safety, reactogenicity, cellular immune responses and influenza hemagglutination inhibition (HAI) and microneutralization (MN) were assessed. RESULTS: The M-001 vaccine was safe and had an acceptable reactogenicity profile. Injection site tenderness (39% post-dose 1, 29% post-dose 2) was the most common reaction after M-001 administration. Polyfunctional CD4+ T cell responses (perforin-negative, CD107α-negative, TNF-α+, IFN-γ+, with or without IL-2) to the pool of M-001 peptides increased significantly from baseline to two weeks after the second dose of M-001, and this increase persisted through Day 172. However, there was no enhancement of HAI or MN antibody responses among M-001 recipients following IIV4 administration. CONCLUSIONS: M-001 administration induced a subset of polyfunctional CD4+ T cells that persisted through 6 months of follow-up, but it did not improve HAI or MN antibody responses to IIV4. (clinicaltrials.gov NCT03058692).

Efficacy and safety of azithromycin versus placebo to treat lower respiratory tract infections associated with low procalcitonin: a randomised, placebo-controlled, double-blind, non-inferiority trial.

BACKGROUND: Lower respiratory tract infections are frequently treated with antibiotics, despite a viral cause in many cases. It remains unknown whether low procalcitonin concentrations can identify patients with lower respiratory tract infection who are unlikely to benefit from antibiotics. We aimed to compare the efficacy and safety of azithromycin versus placebo to treat lower respiratory tract infections in patients with low procalcitonin. METHODS: We conducted a randomised, placebo-controlled, double-blind, non-inferiority trial at five health centres in the USA. Adults aged 18 years or older with clinically suspected non-pneumonia lower respiratory tract infection and symptom duration from 24 h to 28 days were eligible for enrolment. Participants with a procalcitonin concentration of 0·25 ng/mL or less were randomly assigned (1:1), in blocks of four with stratification by site, to receive over-encapsulated oral azithromycin 250 mg or matching placebo (two capsules on day 1 followed by one capsule daily for 4 days). Participants, non-study clinical providers, investigators, and study coordinators were masked to treatment allocation. The primary outcome was efficacy of azithromycin versus placebo in terms of clinical improvement at day 5 in the intention-to-treat population. The non-inferiority margin was -12·5%. Solicited adverse events (abdominal pain, vomiting, diarrhoea, allergic reaction, or yeast infections) were recorded as a secondary outcome. This trial is registered with ClinicalTrials.gov, NCT03341273. FINDINGS: Between Dec 8, 2017, and March 9, 2020, 691 patients were assessed for eligibility and 499 were enrolled and randomly assigned to receive azithromycin (n=249) or placebo (n=250). Clinical improvement at day 5 was observed in 148 (63%, 95% CI 54 to 71) of 238 participants with full data in the placebo group and 155 (69%, 61 to 77) of 227 participants with full data in the azithromycin group in the intention-to-treat analysis (between-group difference -6%, 95% CI -15 to 2). The 95% CI for the difference did not meet the non-inferiority margin. Solicited adverse events and the severity of solicited adverse events were not significantly different between groups at day 5, except for increased abdominal pain associated with azithromycin (47 [23%, 95% CI 18 to 29] of 204 participants) compared with placebo (35 [16%, 12 to 21] of 221; between-group difference -7% [95% CI -15 to 0]; p=0·066). INTERPRETATION: Placebo was not non-inferior to azithromycin in terms of clinical improvement at day 5 in adults with lower respiratory tract infection and a low procalcitonin concentration. After accounting for both the rates of clinical improvement and solicited adverse events at day 5, it is unclear whether antibiotics are indicated for patients with lower respiratory tract infection and a low procalcitonin concentration. FUNDING: National Institute of Allergy and Infectious Diseases, bioMérieux.