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The evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in variants that can escape neutralization by therapeutic antibodies. Here, we describe AZD3152, a SARS-CoV-2-neutralizing monoclonal antibody designed to provide improved potency and coverage against emerging variants. AZD3152 binds to the back left shoulder of the SARS-CoV-2 spike protein receptor binding domain and prevents interaction with the human angiotensin-converting enzyme 2 receptor. AZD3152 potently neutralized a broad panel of pseudovirus variants, including the currently dominant Omicron variant JN.1 but has reduced potency against XBB subvariants containing F456L. In vitro studies confirmed F456L resistance and additionally identified T415I and K458E as escape mutations. In a Syrian hamster challenge model, prophylactic administration of AZD3152 protected hamsters from weight loss and inflammation-related lung pathologies and reduced lung viral load. In the phase 1 sentinel safety cohort of the ongoing SUPERNOVA study (ClinicalTrials.gov: NCT05648110), a single 600-mg intramuscular injection of AZD5156 (containing 300 mg each of AZD3152 and cilgavimab) was well tolerated in adults through day 91. Observed serum concentrations of AZD3152 through day 91 were similar to those observed with cilgavimab and consistent with predictions for AZD7442, a SARS-CoV-2-neutralizing antibody combination of cilgavimab and tixagevimab, in a population pharmacokinetic model. On the basis of its pharmacokinetic characteristics, AZD3152 is predicted to provide durable protection against symptomatic coronavirus disease 2019 caused by susceptible SARS-CoV-2 variants, such as JN.1, in humans.

Introduction: The phase 3 PROVENT and STORM CHASER studies evaluated AZD7442 (tixagevimab/cilgavimab) for pre-exposure and post-exposure prophylaxis of symptomatic coronavirus disease 2019 (COVID-19). We report the final 15-month results of both studies., Methods: In PROVENT, participants were randomized 2:1 to receive 300 mg AZD7442 (n = 3460) or placebo (n = 1737). In STORM CHASER, participants were enrolled within 8 days of exposure to a severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected individual and randomized 2:1 to receive 300 mg AZD7442 (n = 749) or placebo (n = 372)., Results: In PROVENT, the relative risk reduction (RRR) in symptomatic COVID-19 for AZD7442 versus placebo was 76.7% at primary analysis [95% confidence interval (CI) 46.1, 90.0; p < 0.001], 83.0% at day 183 (95% CI 67.3, 91.2; nominal p < 0.001), and 46.3% at day 366 (95% CI 23.1, 62.4; nominal p < 0.001). Severe/critical COVID-19 was reduced by 91.4% with AZD7442 versus placebo by day 366 (95% CI 61.3, 98.1; nominal p < 0.0001). Adverse events (AEs) occurred in 58.2% and 58.0% of participants administered AZD7442 or placebo, respectively; serious AEs (SAEs) occurred in 6.2% and 5.6%, respectively. In STORM CHASER, the RRR in symptomatic COVID-19 for AZD7442 versus placebo was 33.3% at primary analysis (95% CI - 25.9, 64.7; p = 0.212), 43.3% at day 183 (95% CI 1.4, 67.4; nominal p = 0.044) and 3.4% at day 366 (95% CI - 35.6, 31.2; nominal p = 0.842). Severe/critical COVID-19 did not occur in participants receiving AZD7442 versus 0.5% of participants receiving placebo by day 366. AEs occurred in 46.5% and 51.9% of participants administered AZD7442 or placebo, respectively; SAEs occurred in 2.7% and 4.3%, respectively. In both studies, serum concentration-time profiles over 457 days were similar for tixagevimab and cilgavimab and consistent with the extended half-life reported for AZD7442 (approximately 90 days)., Conclusion: This analysis provides proof of concept supporting long-term safety of intramuscularly administered AZD7442 for prevention of symptomatic/severe COVID-19. A graphical abstract is available with this article., Gov Identifiers: PROVENT (NCT04625725) and STORM CHASER (NCT04625972)., (© 2024. The Author(s).)

Background: This phase 3 trial assessed AZD7442 (tixagevimab/cilgavimab) for post-exposure prophylaxis against symptomatic coronavirus disease 2019 (COVID-19)., Methods: Adults without prior severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or COVID-19 vaccination were enrolled within 8 days of exposure to a SARS-CoV-2-infected individual and randomized 2:1 to a single 300-mg AZD7442 dose (one 1.5-mL intramuscular injection each of tixagevimab and cilgavimab) or placebo. Primary end points were safety and first post-dose SARS-CoV-2 reverse-transcription polymerase chain reaction (RT-PCR)-positive symptomatic COVID-19 event before day 183., Results: A total of 1121 participants were randomized and dosed (AZD7442, n = 749; placebo, n = 372). Median (range) follow-up was 49 (5-115) and 48 (20-113) days for AZD7442 and placebo, respectively. Adverse events occurred in 162 of 749 (21.6%) and 111 of 372 (29.8%) participants with AZD7442 and placebo, respectively, mostly mild/moderate. RT-PCR-positive symptomatic COVID-19 occurred in 23 of 749 (3.1%) and 17 of 372 (4.6%) AZD7442- and placebo-treated participants, respectively (relative risk reduction, 33.3%; 95% confidence interval [CI], -25.9 to 64.7; P = .21). In predefined subgroup analyses of 1073 (96%) participants who were SARS-CoV-2 RT-PCR-negative (n = 974, 87%) or missing an RT-PCR result (n = 99, 9%) at baseline, AZD7442 reduced RT-PCR-positive symptomatic COVID-19 by 73.2% (95% CI, 27.1 to 90.1) vs placebo., Conclusions: This study did not meet the primary efficacy end point of post-exposure prevention of symptomatic COVID-19. However, analysis of participants who were SARS-CoV-2 RT-PCR-negative or missing an RT-PCR result at baseline support a role for AZD7442 in preventing symptomatic COVID-19. Clinical Trials Registration. NCT04625972., Competing Interests: Potential conflicts of interest. M. J. L. reports research support from GSK, Johnson & Johnson, Moderna, and Novavax; consultancy for Dynavax, GSK, Merck & Co, Pfizer, and Seqirus; and participation on a data and safety monitoring board (DSMB)/advisory board for GSK. A. U. reports honoraria/speaker fees from Sanofi, Merck, Janssen, GSK, Roche, ViiV, and Gilead; advisory boards for Gilead, Merck, and ViiV/GSK; and participation on a DSMB for COV-Boost study, Flare study, and for Vicore. S. D. P. reports that the USU Infectious Diseases Clinical Research Program (IDCRP), a US Department of Defense institution, and HJF were funded under a cooperative research and development agreement to help conduct the STORM CHASER study, sponsored by AstraZeneca. The HJF, in support of the USU IDCRP, was also funded by the Department of Defense Joint Program Executive Office for Chemical, Biological, Radiological, and Nuclear Defense to augment the conduct of an unrelated phase 3 vaccine trial sponsored by AstraZeneca. Both of these trials were part of the US government COVID-19 response. M. T. E. reports patents planned, issued, or pending by AstraZeneca on AZD7442. P. G. reports consulting fees from Medicago and Takeda Vaccines as senior medical director; a leadership or fiduciary role as a full member of the Academy of Medicine in Rio de Janeiro, Brazil; and stock or stock options in Takeda Pharmaceuticals, AstraZeneca. All authors report medical writing assistance provided by Prime Global. S. T., A. T., Y. Y., S. S., R. H. A., R. B., K. D., P. G., E. J. K., G. C. K. W. K., S. I., K. A. N., A. S., K. S., M. N. P., and M. T. E. are employees of and hold or may hold stock in AstraZeneca. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed., (© The Author(s) 2022. Published by Oxford University Press on behalf of Infectious Diseases Society of America.)

Objectives: In Sweden, pneumococcal serotype distribution in adults with community-acquired pneumonia (CAP) and potential coverage of currently licensed pneumococcal conjugate vaccines (PCVs) is unknown., Methods: During 2016-2018, patients aged ≥18 years hospitalized with radiologically confirmed (RAD+) CAP were enrolled at Skåne University Hospital in a study on the etiology of CAP in Sweden (ECAPS). Urine samples and blood cultures were collected per-protocol. Streptococcus pneumoniae (Spn) culture isolates were serotyped and urine samples tested for the pan-pneumococcal urinary antigen (PUAT) and multiplex urine antigen detection (UAD) assay, detecting 24 serotypes., Results: Analyses included 518 participants with RAD+CAP; 67.4% were ≥65 years of age, 73.4% were either immunocompromised or had an underlying chronic medical condition. The proportion of CAP due to Spn identified by any method was 24.3% of which 9.3% was detected by UAD alone. The most frequently identified serotypes were 3 (26 cases, 5.0% of all CAP), and 8, 11A and 19A (10 cases each, 1.9%). In individuals aged 18-64 and ≥65 years, respectively, PCV20 serotypes contributed to 35 of 169 (20.7%) and 53 of 349 cases of all CAP (15.2%), and PCV13 serotypes caused 21 of 169 (12.4%) and 35 of 349 (10.0%) cases. PCV15 coverage was 23 of 169 (13.6%) and 42 of 349 (12.0%) in individuals aged 18-64 and ≥65 years, respectively. Overall, PCV20 increases the coverage of all CAP from 10.8% (PCV13) to 17.0%., Conclusion: Compared to earlier pneumococcal vaccines, PCV20 expands the coverage of all-cause CAP. Routine diagnostic tests underestimate the proportion of CAP caused by Spn., Competing Interests: CT, KP, AP, QJ, BG, and JS are full time employees of Pfizer Vaccines and hold stock and/or stock options. RB is a former employee of Pfizer and holds stock and/or stock options. JA and KR are participating in projects supported by Pfizer. KR is collaborating with Moderna, collaborated with GSK and has been a scientific advisor to MSD and GSK. JA has received payments for lectures and/or participated in advisory boards for from AstraZeneca, GSK, MSD, MEDA, and Pfizer. KR has received payment for lectures from Pfizer. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Hansen, Rünow, Torisson, Theilacker, Palmborg, Pan, Jiang, Southern, Beavon, Gessner, Riesbeck and Ahl.)

Pneumococcal community-acquired pneumonia (CAP) is a leading cause of mortality. Following the introduction of pneumococcal conjugate vaccines (PCVs) in children, a decrease in the burden of the disease was reported. In parallel, an increase in non-vaccine serotypes was also noted. The objective of this study was to assess the current serotype-specific epidemiology of pneumococci among Italian older adults hospitalized for CAP. A prospective study was conducted between 2017 and 2020 in four Italian regions. Subjects aged ≥65 years hospitalized with confirmed CAP were tested for pneumococci using both pneumococcal urinary antigen and serotype-specific urine antigen tests able to identify all 24 serotypes included in the available vaccines. Of the 1155 CAP cases, 13.1% were positive for pneumococci. The most prevalent serotypes were 3 (2.0%), 8 (1.7%), 22F (0.8 %) and 11A (0.7%). These serotypes are all included in the newly licensed PCV20. The serotypes included in PCV13, PCV15 and PCV20 contributed to 3.3%, 4.4% and 7.5% of the CAP cases, respectively. In the context of a low PCV13 coverage among older adults and a high PCV coverage in children, a substantial proportion of CAP is caused by PCV13 serotypes. Higher valency PCV15 and PCV20 may provide additional benefits for the prevention of CAP in vaccinated older adults., Competing Interests: The authors declare the following financial interests/personal relationships, which may be regarded as potential competing interests: E.B., C.T., B.G., R.B. and E.A.M. were employees of Pfizer at the time of this study and may hold Pfizer stock or stock options; A.O., A.D., S.M., M.O., L.S., R.P., D.M., F.F., F.V., F.T., V.B. and T.B. have no conflicts of interests to declare.

Rationale: Streptococcus pneumoniae serotype 3 (SPN3) is a cause of invasive pneumococcal disease and associated with low carriage rates. Following the introduction of pediatric 13-valent pneumococcal conjugate vaccine (PCV13) programs, SPN3 declines are less than other vaccine serotypes and incidence has increased in some populations coincident with a shift in predominant circulating SPN3 clade, from I to II. A human challenge model provides an effective means for assessing the impact of PCV13 on SPN3 in the upper airway. Objectives: To establish SPN3's ability to colonize the nasopharynx using different inoculum clades and doses, and the safety of an SPN3 challenge model. Methods: In a human challenge study involving three well-characterized and antibiotic-sensitive SPN3 isolates (PFESP306 [clade Ia], PFESP231 [no clade], and PFESP505 [clade II]), inoculum doses (10,000, 20,000, 80,000, and 160,000 cfu/100 μl) were escalated until maximal colonization rates were achieved, with concurrent acceptable safety. Measurement and Main Results: Presence and density of experimental SPN3 nasopharyngeal colonization in nasal wash samples, assessed using microbiological culture and molecular methods, on Days 2, 7, and 14 postinoculation. A total of 96 healthy participants (median age 21, interquartile range 19-25) were inoculated ( n  = 6-10 per dose group, 10 groups). Colonization rates ranged from 30.0-70.0% varying with dose and isolate. 30.0% (29/96) reported mild symptoms (82.8% [24/29] developed a sore throat); one developed otitis media requiring antibiotics. No serious adverse events occurred. Conclusions: An SPN3 human challenge model is feasible and safe with comparable carriage rates to an established Serotype 6B human challenge model. SPN3 carriage may cause mild upper respiratory symptoms.

Greece introduced a 13-valent pneumococcal conjugate vaccine (PCV13) into the infant national immunization program in 2010 (3 + 1 schedule until June 2019). Since 2015, PCV13 has been recommended for adults aged 19-64 years with comorbidities and adults ≥65 years sequentially with 23-valent pneumococcal polysaccharide vaccine (PPSV23). We examined pneumococcal serotype distribution among Greek adults aged ≥19 years hospitalized with community-acquired pneumonia (CAP) during November 2017-April 2019. This was an interim analysis of EGNATIA, a prospective study of adult hospitalized CAP in the cities of Ioannina and Kavala. Pneumococcus was identified using cultures, BinaxNow®, serotype-specific urinary antigen detection assays (UAD-1/2). Our analysis included overall 482 hospitalized CAP patients (mean age: 70.5 years; 56.4% male). 53.53% of patients belonged to the highest pneumonia severity index (PSI) classes (IV-V). Pneumococcus was detected in 65 (13.5%) patients, with more than half (57%) of cases detected only by UAD. Approximately two-thirds of pneumococcal CAP occurred in those aged ≥65 years (n = 40, 8.3% of CAP). More than half of pneumococcal CAP (n = 35, 53.8%) was caused by PCV13 serotypes. Most frequently detected PCV13 serotypes were 3, 19A, 23F, collectively accounting for 83% of PCV13 vaccine-type (VT) CAP and 6% of all-cause CAP. Overall, 82.9% of PCV13 VT CAP occurred among persons with an indication (age/risk-based) for PCV13 vaccination. Even with a mature PCV13 childhood immunization program, a persistent burden of PCV13 VT CAP exists in Greek adults. Strategies to increase PCV13 (and higher-valency PCVs, when licensed) coverage in adults should be implemented to reduce the disease burden.

Background: The monoclonal-antibody combination AZD7442 is composed of tixagevimab and cilgavimab, two neutralizing antibodies against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) that have an extended half-life and have been shown to have prophylactic and therapeutic effects in animal models. Pharmacokinetic data in humans indicate that AZD7442 has an extended half-life of approximately 90 days., Methods: In an ongoing phase 3 trial, we enrolled adults (≥18 years of age) who had an increased risk of an inadequate response to vaccination against coronavirus disease 2019 (Covid-19), an increased risk of exposure to SARS-CoV-2, or both. Participants were randomly assigned in a 2:1 ratio to receive a single dose (two consecutive intramuscular injections, one containing tixagevimab and the other containing cilgavimab) of either 300 mg of AZD7442 or saline placebo, and they were followed for up to 183 days in the primary analysis. The primary safety end point was the incidence of adverse events after a single dose of AZD7442. The primary efficacy end point was symptomatic Covid-19 (SARS-CoV-2 infection confirmed by means of reverse-transcriptase-polymerase-chain-reaction assay) occurring after administration of AZD7442 or placebo and on or before day 183., Results: A total of 5197 participants underwent randomization and received one dose of AZD7442 or placebo (3460 in the AZD7442 group and 1737 in the placebo group). The primary analysis was conducted after 30% of the participants had become aware of their randomized assignment. In total, 1221 of 3461 participants (35.3%) in the AZD7442 group and 593 of 1736 participants (34.2%) in the placebo group reported having at least one adverse event, most of which were mild or moderate in severity. Symptomatic Covid-19 occurred in 8 of 3441 participants (0.2%) in the AZD7442 group and in 17 of 1731 participants (1.0%) in the placebo group (relative risk reduction, 76.7%; 95% confidence interval [CI], 46.0 to 90.0; P<0.001); extended follow-up at a median of 6 months showed a relative risk reduction of 82.8% (95% CI, 65.8 to 91.4). Five cases of severe or critical Covid-19 and two Covid-19-related deaths occurred, all in the placebo group., Conclusions: A single dose of AZD7442 had efficacy for the prevention of Covid-19, without evident safety concerns. (Funded by AstraZeneca and the U.S. government; PROVENT ClinicalTrials.gov number, NCT04625725.)., (Copyright © 2022 Massachusetts Medical Society.)

BackgroundAlthough recent epidemiological data suggest that pneumococci may contribute to the risk of SARS-CoV-2 disease, cases of coinfection with Streptococcus pneumoniae in patients with coronavirus disease 2019 (COVID-19) during hospitalization have been reported infrequently. This apparent contradiction may be explained by interactions of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and pneumococci in the upper airway, resulting in the escape of SARS-CoV-2 from protective host immune responses.MethodsHere, we investigated the relationship of these 2 respiratory pathogens in 2 distinct cohorts of health care workers with asymptomatic or mildly symptomatic SARS-CoV-2 infection identified by systematic screening and patients with moderate to severe disease who presented to the hospital. We assessed the effect of coinfection on host antibody, cellular, and inflammatory responses to the virus.ResultsIn both cohorts, pneumococcal colonization was associated with diminished antiviral immune responses, which primarily affected mucosal IgA levels among individuals with mild or asymptomatic infection and cellular memory responses in infected patients.ConclusionOur findings suggest that S. pneumoniae impair host immunity to SARS-CoV-2 and raise the question of whether pneumococcal carriage also enables immune escape of other respiratory viruses and facilitates reinfection.Trial registrationISRCTN89159899 (FASTER study) and ClinicalTrials.gov NCT03502291 (LAIV study).

Background: Community-acquired pneumonia is an important cause of morbidity and mortality in adults. Approximately one-third of pneumonia cases can be attributed to the pneumococcus. Pneumococcal conjugate vaccines (PCVs) protect against colonisation with vaccine-type serotypes. The resulting decrease in transmission of vaccine serotypes leads to large indirect effects. There are limited data from developing countries demonstrating the impact of childhood PCV immunisation on adult pneumonia. There are also insufficient data available on the burden and severity of all-cause pneumonia and respiratory syncytial virus (RSV) in adults from low resource countries. There is currently no recommendation for adult pneumococcal vaccination with either pneumococcal polysaccharide vaccine or PCVs in Mongolia. We describe the protocol developed to evaluate the association between childhood 13-valent PCV (PCV13) vaccination and trends in adult pneumonia., Methods: PCV13 was introduced into the routine childhood immunisation schedule in Mongolia in a phased manner from 2016. In March 2019 we initiated active hospital-based surveillance for adult pneumonia, with the primary objective of evaluating trends in severe hospitalised clinical pneumonia incidence in adults 18 years and older in four districts of Ulaanbaatar. Secondary objectives include measuring the association between PCV13 introduction and trends in all clinically-defined pneumonia, radiologically-confirmed pneumonia, nasopharyngeal carriage of S. pneumoniae and pneumonia associated with RSV or influenza. Clinical questionnaires, nasopharyngeal swabs, urine samples and chest radiographs were collected from enrolled patients. Retrospective administrative and clinical data were collected for all respiratory disease-related admissions from January 2015 to February 2019., Discussion: Establishing a robust adult surveillance system may be an important component of monitoring the indirect impact of PCVs within a country. Monitoring indirect impact of childhood PCV13 vaccination on adult pneumonia provides additional data on the full public health impact of the vaccine, which has implications for vaccine efficiency and cost-effectiveness. Adult surveillance in Mongolia will contribute to the limited evidence available on the burden of pneumococcal pneumonia among adults in low- and middle-income countries, particularly in the Asia-Pacific region. In addition, it is one of the few examples of implementing prospective, population-based pneumonia surveillance to evaluate the indirect impact of PCVs in a resource-limited setting., (© 2021. The Author(s).)

Background: The 13-valent pneumococcal conjugate vaccine (PCV13) entered Cameroon's childhood national immunization programme (NIP) in July 2011 under a 3-dose schedule (6, 10, 14 weeks of age) without any catch-up. We described the impact of PCV13 onserotype distribution among pneumococcal meningitis cases over time., Methods: We used laboratory-based sentinel surveillance data to identify meningitis cases among 2- to 59-month-old children with clinically-suspected bacterial meningitis (CSBM) admitted to hospitals in Yaoundé (August 2011-December 2018). Purulent meningitis cases had a cerebrospinal fluid (CSF) white blood cell (WBC) count ≥20 per mm3. Pneumococcal meningitis cases had S. pneumoniae identified from CSF, with serotyping by polymerase chain reaction. Years 2011-2014 were described as early PCV13 era (EPE) and years 2015-2018 as late PCV13 era (LPE) impact periods., Results: Among children hospitalized with CSBM who had a lumbar puncture obtained, there was no significant change from the EPE versus the LPE in the percentage identified with purulent meningitis: 7.5% (112/1486) versus 9.4% (154/1645), p = 0.0846. The percentage of pneumococcal meningitis cases due to PCV13 vaccine-serotype (VST) decreased from 62.0% (31/50) during the EPE to 35.8% (19/53) in the LPE, p = 0.0081. The most frequent pneumococcal meningitis VSTs during the EPE were 6A/6B (30%) and 5 (6%), and during the LPE were 14 (13.2%), 3 (7.6%), 4 (5.6%) and 18C (5.6%)., Conclusion: Four to seven years after PCV13 introduction, the proportion of pneumococcal meningitis due to vaccine serotypes has declined, mainly due to reductions of serotypes 6A/6B, 1, 19A, and 23F; nevertheless, PCV13 VSTs remain common. Because the analyzed surveillance system was not consistent or population based, we could not estimate incidence or overall impact; this emphasizes the need for improved surveillance to document further the utility of PCV13 immunization in Cameroon., Competing Interests: Some of the co-authors (MA, BB, JS, MAF, RB and BG) are employed by Pfizer, Inc and may own stock or stock options. The authors adhere to PLOS ONE policies on sharing data and materials.