Bivalent Prefusion F Vaccine in Pregnancy to Prevent RSV Illness in Infants

Summary Background Pneumonia is the leading cause of death among children younger than 5 years. In this study, we estimated causes of pneumonia in young African and Asian children, using novel analytical methods applied to clinical and microbiological findings. Methods We did a multi-site, international case-control study in nine study sites in seven countries: Bangladesh, The Gambia, Kenya, Mali, South Africa, Thailand, and Zambia. All sites enrolled in the study for 24 months. Cases were children aged 1–59 months admitted to hospital with severe pneumonia. Controls were age-group-matched children randomly selected from communities surrounding study sites. Nasopharyngeal and oropharyngeal (NP-OP), urine, blood, induced sputum, lung aspirate, pleural fluid, and gastric aspirates were tested with cultures, multiplex PCR, or both. Primary analyses were restricted to cases without HIV infection and with abnormal chest x-rays and to controls without HIV infection. We applied a Bayesian, partial latent class analysis to estimate probabilities of aetiological agents at the individual and population level, incorporating case and control data. Findings Between Aug 15, 2011, and Jan 30, 2014, we enrolled 4232 cases and 5119 community controls. The primary analysis group was comprised of 1769 (41·8% of 4232) cases without HIV infection and with positive chest x-rays and 5102 (99·7% of 5119) community controls without HIV infection. Wheezing was present in 555 (31·7%) of 1752 cases (range by site 10·6–97·3%). 30-day case-fatality ratio was 6·4% (114 of 1769 cases). Blood cultures were positive in 56 (3·2%) of 1749 cases, and Streptococcus pneumoniae was the most common bacteria isolated (19 [33·9%] of 56). Almost all cases (98·9%) and controls (98·0%) had at least one pathogen detected by PCR in the NP-OP specimen. The detection of respiratory syncytial virus (RSV), parainfluenza virus, human metapneumovirus, influenza virus, S pneumoniae, Haemophilus influenzae type b (Hib), H influenzae non-type b, and Pneumocystis jirovecii in NP-OP specimens was associated with case status. The aetiology analysis estimated that viruses accounted for 61·4% (95% credible interval [CrI] 57·3–65·6) of causes, whereas bacteria accounted for 27·3% (23·3–31·6) and Mycobacterium tuberculosis for 5·9% (3·9–8·3). Viruses were less common (54·5%, 95% CrI 47·4–61·5 vs 68·0%, 62·7–72·7) and bacteria more common (33·7%, 27·2–40·8 vs 22·8%, 18·3–27·6) in very severe pneumonia cases than in severe cases. RSV had the greatest aetiological fraction (31·1%, 95% CrI 28·4–34·2) of all pathogens. Human rhinovirus, human metapneumovirus A or B, human parainfluenza virus, S pneumoniae, M tuberculosis, and H influenzae each accounted for 5% or more of the aetiological distribution. We observed differences in aetiological fraction by age for Bordetella pertussis, parainfluenza types 1 and 3, parechovirus–enterovirus, P jirovecii, RSV, rhinovirus, Staphylococcus aureus, and S pneumoniae, and differences by severity for RSV, S aureus, S pneumoniae, and parainfluenza type 3. The leading ten pathogens of each site accounted for 79% or more of the site's aetiological fraction. Interpretation In our study, a small set of pathogens accounted for most cases of pneumonia requiring hospital admission. Preventing and treating a subset of pathogens could substantially affect childhood pneumonia outcomes. Funding Bill & Melinda Gates Foundation.

Summary Background Respiratory syncytial virus (RSV) is the most common cause of acute lower respiratory infection in young children. We previously estimated that in 2015, 33·1 million episodes of RSV-associated acute lower respiratory infection occurred in children aged 0–60 months, resulting in a total of 118 200 deaths worldwide. Since then, several community surveillance studies have been done to obtain a more precise estimation of RSV associated community deaths. We aimed to update RSV-associated acute lower respiratory infection morbidity and mortality at global, regional, and national levels in children aged 0–60 months for 2019, with focus on overall mortality and narrower infant age groups that are targeted by RSV prophylactics in development. Methods In this systematic analysis, we expanded our global RSV disease burden dataset by obtaining new data from an updated search for papers published between Jan 1, 2017, and Dec 31, 2020, from MEDLINE, Embase, Global Health, CINAHL, Web of Science, LILACS, OpenGrey, CNKI, Wanfang, and ChongqingVIP. We also included unpublished data from RSV GEN collaborators. Eligible studies reported data for children aged 0–60 months with RSV as primary infection with acute lower respiratory infection in community settings, or acute lower respiratory infection necessitating hospital admission; reported data for at least 12 consecutive months, except for in-hospital case fatality ratio (CFR) or for where RSV seasonality is well-defined; and reported incidence rate, hospital admission rate, RSV positive proportion in acute lower respiratory infection hospital admission, or in-hospital CFR. Studies were excluded if case definition was not clearly defined or not consistently applied, RSV infection was not laboratory confirmed or based on serology alone, or if the report included fewer than 50 cases of acute lower respiratory infection. We applied a generalised linear mixed-effects model (GLMM) to estimate RSV-associated acute lower respiratory infection incidence, hospital admission, and in-hospital mortality both globally and regionally (by country development status and by World Bank Income Classification) in 2019. We estimated country-level RSV-associated acute lower respiratory infection incidence through a risk-factor based model. We developed new models (through GLMM) that incorporated the latest RSV community mortality data for estimating overall RSV mortality. This review was registered in PROSPERO (CRD42021252400). Findings In addition to 317 studies included in our previous review, we identified and included 113 new eligible studies and unpublished data from 51 studies, for a total of 481 studies. We estimated that globally in 2019, there were 33·0 million RSV-associated acute lower respiratory infection episodes (uncertainty range [UR] 25·4–44·6 million), 3·6 million RSV-associated acute lower respiratory infection hospital admissions (2·9–4·6 million), 26 300 RSV-associated acute lower respiratory infection in-hospital deaths (15 100–49 100), and 101 400 RSV-attributable overall deaths (84 500–125 200) in children aged 0–60 months. In infants aged 0–6 months, we estimated that there were 6·6 million RSV-associated acute lower respiratory infection episodes (4·6–9·7 million), 1·4 million RSV-associated acute lower respiratory infection hospital admissions (1·0–2·0 million), 13 300 RSV-associated acute lower respiratory infection inhospital deaths (6800–28 100), and 45700 RSV-attributable overall deaths (38 400–55 900). 2·0% of deaths in children aged 0–60 months (UR 1·6–2·4) and 3·6% of deaths in children aged 28 days to 6 months (3·0–4·4) were attributable to RSV. More than 95% of RSV-associated acute lower respiratory infection episodes and more than 97% of RSV-attributable deaths across all age bands were in low-income and middle-income countries (LMICs). Interpretation RSV contributes substantially to morbidity and mortality burden globally in children aged 0–60 months, especially during the first 6 months of life and in LMICs. We highlight the striking overall mortality burden of RSV disease worldwide, with one in every 50 deaths in children aged 0–60 months and one in every 28 deaths in children aged 28 days to 6 months attributable to RSV. For every RSV-associated acute lower respiratory infection in-hospital death, we estimate approximately three more deaths attributable to RSV in the community. RSV passive immunisation programmes targeting protection during the first 6 months of life could have a substantial effect on reducing RSV disease burden, although more data are needed to understand the implications of the potential age-shifts in peak RSV burden to older age when these are implemented. Funding EU Innovative Medicines Initiative Respiratory Syncytial Virus Consortium in Europe (RESCEU).