Phase 1 Open-Label Dose Escalation Trial for the Development of a Human Bacillus Calmette-Guérin Challenge Model for Assessment of Tuberculosis Immunity In Vivo.

BACKGROUND: A controlled human infection model for assessing tuberculosis (TB) immunity can accelerate new vaccine development. METHODS: In this phase 1 dose escalation trial, 92 healthy adults received a single intradermal injection of 2 × 106 to 16 × 106 colony-forming units of Bacillus Calmette-Guérin (BCG). The primary endpoints were safety and BCG shedding as measured by quantitative polymerase chain reaction, colony-forming unit plating, and MGIT BACTEC culture. RESULTS: Doses up to 8 × 106 were safe, and there was evidence for increased BCG shedding with dose escalation. The MGIT time-to-positivity assay was the most consistent and precise measure of shedding. Power analyses indicated that 10% differences in MGIT time to positivity (area under the curve) could be detected in small cohorts (n = 30). Potential biomarkers of mycobacterial immunity were identified that correlated with shedding. Transcriptomic analysis uncovered dose- and time-dependent effects of BCG challenge and identified a putative transcriptional TB protective signature. Furthermore, we identified immunologic and transcriptomal differences that could represent an immune component underlying the observed higher rate of TB disease incidence in males. CONCLUSIONS: The safety, reactogenicity, and immunogenicity profiles indicate that this BCG human challenge model is feasible for assessing in vivo TB immunity and could facilitate the vaccine development process. CLINICAL TRIALS REGISTRATION: NCT01868464 (ClinicalTrials.gov).

Immunogenicity of a 2-Dose Regimen of Moderna mRNA Beta/Omicron BA.1 Bivalent Variant Vaccine Boost in a Randomized Clinical Trial.

We compared the serologic responses of 1 dose versus 2 doses of a variant vaccine (Moderna mRNA-1273 Beta/Omicron BA.1 bivalent vaccine) in adults. A 2-dose boosting regimen with a variant vaccine did not increase the magnitude or the durability of the serological responses compared to a single variant vaccine boost.

Immunogenicity of a Two Dose Regimen of Moderna mRNA Beta/Omicron BA.1 Bivalent Variant Vaccine Boost in a Randomized Clinical Trial.

In this brief report, we compare the magnitude and durability of the serologic response of one versus two doses (separated by 56 days) of a variant vaccine (Moderna mRNA-1273 Beta/Omicron BA.1 bivalent vaccine) in adults.

Immunogenicity of the BA.1 and BA.4/BA.5 SARS-CoV-2 Bivalent Boosts: Preliminary Results from the COVAIL Randomized Clinical Trial.

In a randomized clinical trial, we compare early neutralizing antibody responses after boosting with bivalent SARS-CoV-2 mRNA vaccines based on either BA.1 or BA.4/BA.5 Omicron spike protein combined with wildtype spike. Responses against SARS-CoV-2 variants exhibited the greatest reduction in titers against currently circulating Omicron subvariants for both bivalent vaccines.

Immunogenicity of the BA.1 and BA.4/BA.5 Severe Acute Respiratory Syndrome Coronavirus 2 Bivalent Boosts: Preliminary Results From the COVAIL Randomized Clinical Trial.

In a randomized clinical trial, we compare early neutralizing antibody responses after boosting with bivalent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) messenger RNA (mRNA) vaccines based on either BA.1 or BA.4/BA.5 Omicron spike protein combined with wild-type spike. Responses against SARS-CoV-2 variants exhibited the greatest reduction in titers against currently circulating Omicron subvariants for both bivalent vaccines.

Immune correlates analysis of a phase 3 trial of the AZD1222 (ChAdOx1 nCoV-19) vaccine.

In the phase 3 trial of the AZD1222 (ChAdOx1 nCoV-19) vaccine conducted in the U.S., Chile, and Peru, anti-spike binding IgG concentration (spike IgG) and pseudovirus 50% neutralizing antibody titer (nAb ID50) measured four weeks after two doses were assessed as correlates of risk and protection against PCR-confirmed symptomatic SARS-CoV-2 infection (COVID-19). These analyses of SARS-CoV-2 negative participants were based on case-cohort sampling of vaccine recipients (33 COVID-19 cases by 4 months post dose two, 463 non-cases). The adjusted hazard ratio of COVID-19 was 0.32 (95% CI: 0.14, 0.76) per 10-fold increase in spike IgG concentration and 0.28 (0.10, 0.77) per 10-fold increase in nAb ID50 titer. At nAb ID50 below the limit of detection (< 2.612 IU50/ml), 10, 100, and 270 IU50/ml, vaccine efficacy was -5.8% (-651%, 75.6%), 64.9% (56.4%, 86.9%), 90.0% (55.8%, 97.6%) and 94.2% (69.4%, 99.1%). These findings provide further evidence towards defining an immune marker correlate of protection to help guide regulatory/approval decisions for COVID-19 vaccines.

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 Third Dose of SARS-CoV-2 mRNA Vaccine - An Interim Analysis.

Waning immunity after two SARS-CoV-2 mRNA vaccinations and the emergence of variants precipitated the need for a third dose of vaccine. We evaluated early safety and immunogenicity after a third mRNA vaccination in adults who received the mRNA-1273 primary series in the Phase 1 trial approximately 9 to 10 months earlier. The booster vaccine formulations included 100 mcg of mRNA-1273, 50 mcg of mRNA-1273.351 that encodes Beta variant spike protein, and bivalent vaccine of 25 mcg each of mRNA-1273 and mRNA-1273.351. A third dose of mRNA vaccine appeared safe with acceptable reactogenicity. Vaccination induced rapid increases in binding and neutralizing antibody titers to D614G, Beta, and Delta variants that were similar or greater than peak responses after the second dose. Spike-specific CD4+ and CD8+ T cells increased to similar levels as after the second dose. A third mRNA vaccination was well tolerated and generated robust humoral and T cell responses. ClinicalTrials.gov numbers NCT04283461 (mRNA-1273 Phase 1) and NCT04785144 (mRNA-1273.351 Phase 1).

Multi-site observational maternal and infant COVID-19 vaccine study (MOMI-vax): a study protocol.

BACKGROUND: Pregnant women were excluded from investigational trials of COVID-19 vaccines. Limited data are available to inform pregnant and postpartum women on their decisions to receive a COVID-19 vaccine. METHODS: The goal of this observational, prospective cohort study is to evaluate the immunogenicity and safety of various Emergency Use Authorization (EUA) or licensed COVID-19 vaccines administered to pregnant or lactating women and describe the transplacental antibody transfer and kinetics of antibodies in mothers and infants. The study is adaptive, allowing additional groups to be added as new vaccines or vaccine regimens are authorized. Up to 20 clinical research institutions in the United States (U.S.) will be included. Approximately 200 pregnant women and 65 postpartum women will be enrolled per EUA or licensed COVID-19 vaccine formulation in the U.S. This study will include pregnant and postpartum women of all ages with and without chronic medical conditions. Their infants will be enrolled and followed beginning at birth in the pregnant cohort and beginning at the earliest possible time point in the postpartum cohort. Blood samples will be collected for immunogenicity outcomes and pregnancy and birth outcomes assessed among women and infants. Primary analyses will be descriptive and done by vaccine type and/or platform. DISCUSSION: Given the long-standing and legitimate challenges of enrolling pregnant individuals into clinical trials early in the vaccine development pipeline, this study protocol describes our current study and provides a template to inform the collection of data for pregnant individuals receiving COVID-19 or other vaccines. TRIAL REGISTRATION: NCT05031468 .

Durability of mRNA-1273 vaccine-induced antibodies against SARS-CoV-2 variants.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) mutations may diminish vaccine-induced protective immune responses, particularly as antibody titers wane over time. Here, we assess the effect of SARS-CoV-2 variants B.1.1.7 (Alpha), B.1.351 (Beta), P.1 (Gamma), B.1.429 (Epsilon), B.1.526 (Iota), and B.1.617.2 (Delta) on binding, neutralizing, and angiotensin-converting enzyme 2 (ACE2)­competing antibodies elicited by the messenger RNA (mRNA) vaccine mRNA-1273 over 7 months. Cross-reactive neutralizing responses were rare after a single dose. At the peak of response to the second vaccine dose, all individuals had responses to all variants. Binding and functional antibodies against variants persisted in most subjects, albeit at low levels, for 6 months after the primary series of the mRNA-1273 vaccine. Across all assays, B.1.351 had the lowest antibody recognition. These data complement ongoing studies to inform the potential need for additional boost vaccinations.

Phase 1 Study of the Effects of the Tuberculosis Treatment Pretomanid, Alone and in Combination With Moxifloxacin, on the QTc Interval in Healthy Volunteers.

Tuberculosis (TB) continues to be a serious threat to public health throughout the world. Newer treatments are needed that could offer simplified regimens with activity against both drug-sensitive and drug-resistant bacilli, while optimizing safety. Pretomanid (PA-824), a nitroimidazooxazine compound, is a new drug for the treatment of pulmonary TB that was recently approved in the United States and Europe in the context of a regimen combined with bedaquiline and linezolid. This phase 1 double-blind, randomized, placebo-controlled crossover study specifically examined the effect of single-dose administration of pretomanid 400 or 1000 mg and pretomanid 400 mg plus moxifloxacin 400 mg on the QTc interval in 74 healthy subjects. Subjects were fasting at the time of drug administration. Pretomanid concentrations following single 400- or 1000-mg doses were not associated with any QT interval prolongation of clinical concern. Moxifloxacin did not alter the pharmacokinetics of pretomanid, and the effect of pretomanid 400 mg plus moxifloxacin 400 mg on the individually corrected QT interval was consistent with the effect of moxifloxacin alone. Both drugs were generally well tolerated. Although supratherapeutic exposure of pretomanid relative to the now-recommended dosing with food was not achieved, these findings contribute to the favorable assessment of cardiac safety for pretomanid.

Safety and Immunogenicity of SARS-CoV-2 mRNA-1273 Vaccine in Older Adults.

BACKGROUND: Testing of vaccine candidates to prevent infection with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in an older population is important, since increased incidences of illness and death from coronavirus disease 2019 (Covid-19) have been associated with an older age. METHODS: We conducted a phase 1, dose-escalation, open-label trial of a messenger RNA vaccine, mRNA-1273, which encodes the stabilized prefusion SARS-CoV-2 spike protein (S-2P) in healthy adults. The trial was expanded to include 40 older adults, who were stratified according to age (56 to 70 years or ≥71 years). All the participants were assigned sequentially to receive two doses of either 25 µg or 100 µg of vaccine administered 28 days apart. RESULTS: Solicited adverse events were predominantly mild or moderate in severity and most frequently included fatigue, chills, headache, myalgia, and pain at the injection site. Such adverse events were dose-dependent and were more common after the second immunization. Binding-antibody responses increased rapidly after the first immunization. By day 57, among the participants who received the 25-µg dose, the anti-S-2P geometric mean titer (GMT) was 323,945 among those between the ages of 56 and 70 years and 1,128,391 among those who were 71 years of age or older; among the participants who received the 100-µg dose, the GMT in the two age subgroups was 1,183,066 and 3,638,522, respectively. After the second immunization, serum neutralizing activity was detected in all the participants by multiple methods. Binding- and neutralizing-antibody responses appeared to be similar to those previously reported among vaccine recipients between the ages of 18 and 55 years and were above the median of a panel of controls who had donated convalescent serum. The vaccine elicited a strong CD4 cytokine response involving type 1 helper T cells. CONCLUSIONS: In this small study involving older adults, adverse events associated with the mRNA-1273 vaccine were mainly mild or moderate. The 100-µg dose induced higher binding- and neutralizing-antibody titers than the 25-µg dose, which supports the use of the 100-µg dose in a phase 3 vaccine trial. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 Study ClinicalTrials.gov number, NCT04283461.).

An mRNA Vaccine against SARS-CoV-2 - Preliminary Report.

BACKGROUND: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged in late 2019 and spread globally, prompting an international effort to accelerate development of a vaccine. The candidate vaccine mRNA-1273 encodes the stabilized prefusion SARS-CoV-2 spike protein. METHODS: We conducted a phase 1, dose-escalation, open-label trial including 45 healthy adults, 18 to 55 years of age, who received two vaccinations, 28 days apart, with mRNA-1273 in a dose of 25 µg, 100 µg, or 250 µg. There were 15 participants in each dose group. RESULTS: After the first vaccination, antibody responses were higher with higher dose (day 29 enzyme-linked immunosorbent assay anti-S-2P antibody geometric mean titer [GMT], 40,227 in the 25-µg group, 109,209 in the 100-µg group, and 213,526 in the 250-µg group). After the second vaccination, the titers increased (day 57 GMT, 299,751, 782,719, and 1,192,154, respectively). After the second vaccination, serum-neutralizing activity was detected by two methods in all participants evaluated, with values generally similar to those in the upper half of the distribution of a panel of control convalescent serum specimens. Solicited adverse events that occurred in more than half the participants included fatigue, chills, headache, myalgia, and pain at the injection site. Systemic adverse events were more common after the second vaccination, particularly with the highest dose, and three participants (21%) in the 250-µg dose group reported one or more severe adverse events. CONCLUSIONS: The mRNA-1273 vaccine induced anti-SARS-CoV-2 immune responses in all participants, and no trial-limiting safety concerns were identified. These findings support further development of this vaccine. (Funded by the National Institute of Allergy and Infectious Diseases and others; mRNA-1273 ClinicalTrials.gov number, NCT04283461).

Partnerships to Design Novel Regimens to Treat Childhood Tuberculosis, Sui Generis: The Road Ahead.

There has been a recent expansion of preclinical models to predict the efficacy of regimens to treat adults with tuberculosis. Despite increasing global interest in childhood tuberculosis, these same tools have not been employed to develop pediatric regimens. Children differ from adults in bacillary burden, spectrum of disease, the metabolism and distribution of antituberculosis drugs, and the toxicity experienced. The studies documented in this series describe a proof-of-concept approach to pediatric regimen development. We propose a program of investigation that would take this forward into a systematic and comprehensive method to find optimal drug combinations to use in children, ideal exposures, and required dosing. Although the number of possible drug combinations is extensive, a series of principles could be employed to select likely effective regimens. Regimens should avoid drugs with overlapping toxicity or linked mechanisms of resistance and should aim to include drugs with different mechanisms of action and ones that are able to target different subpopulations of mycobacteria. Finally drugs should penetrate into body sites necessary for treating pediatric disease. At an early stage, this body of work would need to engage with regulatory agencies and bodies that formulate guidelines, so that once regimens and dosages are identified, translation into clinical studies and clinical practice can be rapid. The development of child-friendly drug formulations would need to be carried out in parallel so that pharmacokinetic studies can be undertaken as formulations are created. Significant research and development would be required and a wide range of stakeholders would need to be engaged. The time is right to consider a more thoughtful and systematic approach toward identifying, testing, and comparing combinations of drugs for children with tuberculosis.

A Blueprint to Address Research Gaps in the Development of Biomarkers for Pediatric Tuberculosis.

Childhood tuberculosis contributes significantly to the global tuberculosis disease burden but remains challenging to diagnose due to inadequate methods of pathogen detection in paucibacillary pediatric samples and lack of a child-specific host biomarker to identify disease. Accurately diagnosing tuberculosis in children is required to improve case detection, surveillance, healthcare delivery, and effective advocacy. In May 2014, the National Institutes of Health convened a workshop including researchers in the field to delineate priorities to address this research gap. This blueprint describes the consensus from the workshop, identifies critical research steps to advance this field, and aims to catalyze efforts toward harmonization and collaboration in this area.

Towards early inclusion of children in tuberculosis drugs trials: a consensus statement.

Children younger than 18 years account for a substantial proportion of patients with tuberculosis worldwide. Available treatments for paediatric drug-susceptible and drug-resistant tuberculosis, albeit generally effective, are hampered by high pill burden, long duration of treatment, coexistent toxic effects, and an overall scarcity of suitable child-friendly formulations. Several new drugs and regimens with promising activity against both drug-susceptible and drug-resistant strains have entered clinical development and are either in various phases of clinical investigation or have received marketing authorisation for adults; however, none have data on their use in children. This consensus statement, generated from an international panel of opinion leaders on childhood tuberculosis and incorporating reviews of published literature from January, 2004, to May, 2014, addressed four key questions: what drugs or regimens should be prioritised for clinical trials in children? Which populations of children are high priorities for study? When can phase 1 or 2 studies be initiated in children? What are the relevant elements of clinical trial design? The consensus panel found that children can be included in studies at the early phases of drug development and should be an integral part of the clinical development plan, rather than studied after regulatory approval in adults is obtained.