Natalie I Mazur, MD et al.
Respiratory syncytial virus is the second most common cause of infant mortality and a major cause of morbidity and mortality in older adults (aged >60 years). Efforts to develop a respiratory syncytial virus vaccine or immunoprophylaxis remain highly active. 33 respiratory syncytial virus prevention candidates are in clinical development using six different approaches: recombinant vector, subunit, particle-based, live attenuated, chimeric, and nucleic acid vaccines; and monoclonal antibodies. Nine candidates are in phase 3 clinical trials. Understanding the epitopes targeted by highly neutralising antibodies has resulted in a shift from empirical to rational and structure-based vaccine and monoclonal antibody design. An extended half-life monoclonal antibody for all infants is likely to be within 1 year of regulatory approval (from August, 2022) for high-income countries. Live-attenuated vaccines are in development for older infants (aged >6 months). Subunit vaccines are in late-stage trials for pregnant women to protect infants, whereas vector, subunit, and nucleic acid approaches are being developed for older adults. Urgent next steps include ensuring access and affordability of a respiratory syncytial virus vaccine globally. This review gives an overview of respiratory syncytial virus vaccines and monoclonal antibodies in clinical development highlighting different target populations, antigens, and trial results.
Alaa Ahmad, Ph.D., Kingsley Eze, B.Sc., Nicolas Noulin, Ph.D., Veronika Horvathova, M.B., Ch.B., Bryan Murray, M.B., B.S., Mark Baillet, B.Sc., C.Stat., Laura Grey, Ph.D., Julie Mori, Ph.D., and Nathalie Adda
Adda et al. investigated a potential inhibitor of respiratory syncytial virus (RSV) in a human challenge study. An inhibitor, known as EDP-938, would act in such a way whereby it would alter and interfere with a protein that allows for RSV to replicate in the human body. A study was set up to evaluate how participants would react in terms of the viral load (total amount of virus a person has in them) and clinical symptoms (mucus production) after receiving either EDP-938 or a placebo. The participants received the interventions only after they tested positive with the inoculated modified strain of RSV. The results between the different groups showed that the viral load as well as the presentation of symptoms were lower in the groups receiving EDP-938 than in those receiving the placebo. Furthermore, the safety profiles were similar between the inhibitor and the placebo groups. This study supports further exploration of EDP-938 activity and better understanding of potential treatments against RSV.
You Li, PhD, Xin Wang, PhD, Bingbing Cong, BMed, Shuyu Deng, BMed, Daniel R Feikin, MD, Harish Nair, PhD
You Li and co-workers investigated why RSV has rebounded after the expected local RSV season in several countries during the COVID-19 pandemic. The RSV epidemic was late in the 18 countries included, and 11 observed a rebound before September 2021. The risk of observing a rebound of RSV was 23 times higher after re-opening schools. On the contrary, an increase in temperature of 5°C decreased the risk of RSV rebound by 37%. The risk of RSV rebound increased over time, suggesting a role of the accumulation of individuals susceptible to RSV through new births and waning immunity. Increased susceptibility of the population and full re-opening of schools may override the effect of high temperature. Countries that did not yet observe a rebound in RSV should prepare for it, especially in the weeks after re-opening schools and when temperature drops. This study will be instrumental for policy makers to understand impact of distinct non-pharmaceutical interventions to control the COVID pandemic.
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.