Linssen RS, Bem RA, Kapitein B, Rengerink KO, Otten MH, den Hollander B, Bont L, van Woensel JBM
High flow oxygen intends to decrease work of breathing and prevent respiratory failure. Despite trials have shown benefit, high flow oxygen has not brought the success hoped for as it did not decrease the need for PICU admissions. This study studied trends in 15,606 pediatric intensive care unit (PICU) admissions for (RSV) bronchiolitis in The Netherlands, France, Scotland, Belgium, Italy and Norway between 2000 and 2019. The authors observed an increase in the annual number of RSV-PICU admissions, as well as in the proportion of RSV-PICU admissions compared to all PICU admissions and the national population-based estimates per 100,000 children. The proportion of children with a risk factor for severe RSV bronchiolitis remained the same and the proportion of intubated children online moderately declined. The authors relate their findings to the widespread introduction of high-flow nasal cannula (HFNC) in the PICU that started around 2009. The increasing PICU burden by RSV bronchiolitis related to high flow oxygen support warrants further attention.
How to use potential RSV preventive interventions wisely? A modelling study on seasonal-approaches of maternal vaccination and passive immunization
Li Y, Hodgson D, Wang X, Atkins KE, Feikin DR, Nair H
As soon as the temperature goes down by the end of summer and the beginning of fall, viruses are lurking around the corner. RSV is also such a virus, which has a clear seasonality in most countries. Maternal vaccination and passive immunization approaches for RSV are currently in development in clinical trials. However, both preventive measures will only offer an infant protection for approximately 3 to 5 months. Timing these defensive strategies right according to when RSV is planning to attack, could lead to an efficient strategy. Li and his colleagues tested this hypothesis with a computational model using efficacy data from the ResVax and nirsevimab trials. For 52 low- and middle-income countries (LMICs), effectiveness of various seasonal- and year-round programs was calculated and compared. One of the main findings was that in countries with clear RSV seasonality, an approach in which passive immunization started 3 months before RSV season onset was able to prevent 49.4% of RSV associated hospital admissions and 38.6% of the RSV-acute lower respiratory infections. Since this approach only averted 16% less of the hospital admissions than a year-round schedule, it was clearly more efficient. As soon as prophylactic medicines are available, it is important to use them in an efficient and feasible way, especially in LMICs, where the burden of RSV is highest and resources can be limited. This research is one of the first to explore different seasonal approaches.
Ruckwardt TJ, Morabito KM, Phung E, Crank MC, Costner PJ, Holman LA, Chang LA, Hickman SP, Berkowitz NM, Gordon IJ, Yamshchikov GV, Gaudinski MR, Lin B, Bailer R, Chen M, Ortega-Villa AM, Nguyen T, Kumar A, Schwartz RM, Kueltzo LA, Stein JA, Carlton K, Gall JG, Nason MC, Mascola JR, Chen G, Graham BS, VRC 317 study team
The Vaccine Research Center of NIH published a randomized, open-label, dose-escalation phase 1 clinical trial of the DS-Cav1 stabilized pre-F subunit vaccine. 95 healthy adults were vaccinated with different dosages and with or without aluminium hydroxide adjuvant. During the 44 weeks follow-up, the DS-Cav1 vaccine was found to be safe and well tolerated. After an initial high vaccine response in RSV F-protein specific antibodies, sustained neutralizing activity against both RSV subtypes A and B was found across all dosage groups with no or only marginal differences between doses and no effect of the aluminium hydroxide adjuvant. Although a second immunization at week 12 was associated with initially higher neutralizing activity, it did not significantly impact the sustainability of the antibody response at week 44 compared to a single immunization. In addition, the vaccine induced an elevation of pre-F-specific IgG and IgA in the nasopharyngeal mucosa. These results give hope for RSV vaccine development and may have predictive value for the ongoing phase 3 trials with RSV pre-F subunit vaccines in pregnant women.
Thomas E, Mattila JM, Lehtinen P, Vuorinen T, Waris M, Heikkinen T
RSV is the number one cause of hospitalization for acute lower respiratory tract infection in infants. Moreover, RSV affects an even bigger group of non-hospitalized children. Thomas and his colleagues decided to investigate the burden of RSV infection in this under-recognized patient group. They prospectively followed 408 newborns in Finland during their first RSV season. Throughout this period, one third of the participants was diagnosed with proven RSV infection. Infants with one or more siblings were infected twice as often as those without siblings. In 76.9% of diseased children, RSV infection was complicated by acute otitis media and 70.9% required antibiotics. As expected, a minority of children (6.7%) with RSV infections was hospitalized. This study shows that RSV illness brings upon a great burden in not only hospitalized, but also outpatient newborns. Future preventive and therapeutic measures might be worth exploring for these infants as well.
Foley DA, Yeoh DK, Minney-Smith CA, Martin AC, Mace AO, Sikazwe CT, Le H, Levy A, Moore HC, Blyth CC
During the current COVID-19 pandemic, RSV infections have fallen of the radar. We have seen a tremendous decrease in RSV infection rates, which usually peak during the fall and winter seasons. This raises the question: what is going to happen when COVID-19 cases decline and public health measures are reduced? Foley and his colleagues highlight the situation in Western Australia in their letter to the editor. Since the end of the winter season, there has been an absence of SARS-COV-2 transmission in Western Australia and hereafter only limited social distancing measures were continued. In their letter, the authors link RSV infection rates in Western Australian children to the simultaneous corona regulations in place. An increase in RSV activity is seen starting from September when safety measures were loosened up. The rising number of cases have exceeded the median seasonal peak from the last 8 years. These findings raise concerns for RSV control in other countries and areas, when moderation of COVID-19 related measures may bring upon a surge in RSV infection.
Sadoff J, De Paepe E, DeVincenzo J, Gymnopoulou E, Menten J, Murray B, Bastian AR, Vandebosch A, Haazen W, Noulin N, Comeaux C, Heijnen E, Eze K, Gilbert A, Lambkin-Williams R, Schuitemaker H, Callendret B
Janssen Pharmaceuticals has shown that a single intramuscular injection with an adenovector (Ad26) -based RSV vaccine is highly immunogenic and able to induce a six-fold increase in RSV A2 neutralizing antibody titers. Viral replication upon RSV A challenge at day 28 after immunization was reduced substantially in vaccinees, although infection was not completely prevented. Similarly, symptom scores were largely reduced upon challenge with RSV A in vaccinated volunteers. However, side effects were seen more often in vaccinees as compared to placebo recipients, which requires further study. No severe side effects were observed. This study shows that an adenovector can be used to elicit prefusion immunity against RSV when containing the RSV-F gene encoding for the protein stabilized in the prefusion conformation. Further field studies are expected to demonstrate efficacy in relevant high risk populations.
Ghazaly MMH, Faddan NHA, Raafat DM, Mohammed NA, Nadel S
Sepsis, trauma, burn, and transfusion related lung injury are known causes of pediatric ARDS, an alveolar disease leading to hypoxemia. Viral respiratory infection has been mentioned as a more rare cause of ARDS, but the role of individual viruses, such as RSV, is understudied. This single-center retrospective observational study shows that acute viral bronchilitis is an important cause of pediatric acute respiratory distress syndrome in children under the age of 2 years. Among 144 children admitted to the PICU with acute viral bronchiolitis, 27% developed acute respiratory distress syndrome. In half of these cases (51%) RSV was found as the triggering pathogen of disease. Bacterial coinfection was a significant risk factor for the development of acute respiratory distress syndrome in children with acute viral bronchiolitis. This study confirms that RSV respiratory infection, commonly considered a disease of the distal respiratory tract, often extends to the alveoli, thereby compromising oxygenation.
Habibi MS, Thwaites RS, Chang M, Jozwik A, Paras A, Kirsebom F, Varese A, Owen A, Cuthbertson L, James P, Tunstall T, Nickle D, Hansel TT, Moffatt MF, Johansson C, Chiu C, Openshaw PJM
Why does RSV exposure in one individual lead to disease, while another individual does not experience symptoms at all? Besides, how can a virus reinfect individuals that already have a specific viral immune response available? In this Science paper, Habibi and his colleagues present mucosal neutrophil activation as a new factor involved in RSV susceptibility and protection. They studied the nasal mucosa by transcriptional and proteomic analyses in 58 healthy volunteers right before RSV inoculation and during the following days of infection. An active neutrophilic inflammatory status in the airways at the time of viral exposure was found to predispose to symptomatic infection. This effect might be mediated by a reduction in antiviral inflammatory responses directly after viral exposure. In addition, an early immune response to the infection with enriched IL-17 signaling and corresponding pathways was associated with protection from RSV-related symptoms. Further experiments in mice showed that chemokine induced neutrophil recruitment to the airway before viral exposure enhances disease severity and leads to an elevated cytotoxic CD8+ T cell response. These findings shed light on mechanisms of viral susceptibility and suggest new targets for RSV intervention. Furthermore, neutrophilic inflammation of the airways might not only be important in RSV infection, but in other viral respiratory diseases as well, such as in the SARS-CoV-2 infection.
Karron RA, Atwell JE, McFarland EJ, Cunningham CK, Muresan P, Perlowski C, Libous J, Spector SA, Yogev R, Aziz M, Woods S, Wanionek K, Collins PL, Buchholz UJ
Live-attenuated RSV vaccines are probably effective in young children. This is an important conclusion from Ruth Karron and co-workers after analyzing data from seven previous trials. According to the PATH snapshot of RSV vaccines, there are seven live-attenuated RSV vaccines in phase 1 clinical trials while none have progressed into phase 2. Karron showed that RSV positive respiratory infections requiring medical attention were reduced by 67% after receiving one of the more promising vaccines in this analysis of past phase I clinical trials. The authors combined data from previous live-attenuated vaccine candidates administered intranasally to 241 children aged 6 to 24 months in total. Five of seven vaccines, referred to as “more promising”, induced a ≥4-fold increase of neutralizing antibodies titers in at least 80% of recipients. Antibody titers of vaccinated children increased by more than 14-fold after being later exposed to wild-type RSV, indicating a substantial memory immune response. While high antibody titers likely reflect a good immune response overall and do not act alone to protect against RSV, one dose might be sufficient to protect infants during RSV season. Based on this study, intranasal live-attenuated vaccines have substantial potential to protects young children after the protection granted by maternal antibodies wears off. It is time for a phase 2 proof-of-concept study demonstrating the full potential of live-attenuated RSV vaccines in young infants.
Madhi SA, Polack FP, Piedra PA, Munoz FM, Trenholme AA, Simões EAF, Swamy GK, Agrawal S, Ahmed K, August A, Baqui AH, Calvert A, Chen J, Cho I, Cotton MF, Cutland CL, Englund JA, Fix A, Gonik B, Hammitt L, Heath PT, de Jesus JN, Jones CE, Khalil A, Kimberlin DW, Libster R, Llapur CJ, Lucero M, Pérez Marc G, Marshall HS, Masenya MS, Martinón‐Torres F, Meece JK, Nolan TM, Osman A, Perrett KP, Plested JS, Richmond PC, Snape MD, Shakib JH, Shinde V, Stoney T, Thomas DN, Tita AT, Varner MW, Vatish M, Vrbicky K, Wen J, Zaman K, Zar HJ, Glenn GM, and Fries LF, for the Prepare Study Group
Novavax shows an almost 40% reduction in medically significant RSV-associated LRTIs, in their phase 3 randomized controlled trial with the support of the Bill and Melinda Gates foundation. They recruited healthy pregnant women, at 28 weeks through 36 weeks of gestation, before the start of the RSV season. They were randomly assigned with an overall 2:1 ratio to receive a RSV fusion (F) protein nanoparticle vaccine or placebo. In total, 4636 women were enrolled. The vaccine was safe, with a percentage of infants with a RSV-associated, medically significant lower respiratory tract infection of 1.5% in the vaccine group versus 2.4% in the placebo group (vaccine efficacy was 39.4%). This difference was not sufficient according to FDA-required prespecified criteria of vaccine efficacy. Interestingly, in the vaccine group RSV-related hospitalisations and all-cause pneumonia were significantly reduced by 44% and approx. 50%, respectively. Adding to that, a higher vaccine efficacy was seen in low- or middle-income countries (LMIC), where prevention of RSV is most needed. An explanation for the differential effect in high income countries versus LMIC is still being sought. For now, the faith of the first safe and efficacious RSV vaccine remains uncertain.
This summary is written by Roy Zuurbier