Identification of a recombinant live attenuated respiratory syncytial virus vaccine candidate that is highly attenuated in infants

BACKGROUND: Recombination technology can be used to create live attenuated respiratory syncytial virus (RSV) vaccines that contain combinations of known attenuating mutations. METHODS: Two live attenuated, recombinantly derived RSV vaccine candidates, rA2cp248/404 Delta SH and rA2cp248/404/1030 Delta SH, were evaluated in 31 adults and in 95 children >/=6 months old. rA2cp248/404/1030 Delta SH was subsequently evaluated in 44 infants 1-2 months old. These vaccine candidates share 4 attenuating genetic elements and differ only in a missense mutation (1030) in the polymerase gene. RESULTS: Both vaccines were highly attenuated in adults and RSV-seropositive children and were well tolerated and immunogenic in RSV-seronegative children. Compared with that of rA2cp248/404 Delta SH, replication of rA2cp248/404/1030 Delta SH was restricted in RSV-seronegative children (mean peak titer, 10(4.3) vs. 10(2.5) plaque-forming units [pfu]/mL), indicating that the 1030 mutation had a potent attenuating effect. Although rA2cp248/404/1030 Delta SH was well tolerated in infants, only 44% of infants who received two 10(5.3)-pfu doses of vaccine had detectable antibody responses. However, replication after administration of the second dose was highly restricted, indicating that protective immunity was induced. At least 4 of 5 attenuating genetic elements were retained in recovered vaccine viruses. CONCLUSIONS: rA2cp248/404/1030 Delta SH is the first RSV vaccine candidate to be sufficiently attenuated in young infants. Additional studies are needed to determine whether rA2cp248/404/1030 Delta SH can induce protective immunity against wild-type RSV.     

Association between respiratory syncytial virus outbreaks and lower respiratory tract deaths of infants and young children

The temporal patterns of respiratory virus isolations from 10 laboratories in the USA were compared with that of deaths of children less than 5 years old from July 1975 through June 1984. Isolations of respiratory syncytial virus (RSV) occurred as yearly winter outbreaks; parainfluenza virus 1 and 2 isolations occurred as well-defined outbreaks every other year in the autumn; parainfluenza virus 3 isolations occurred throughout the year with periodic, increased isolations suggestive of outbreaks; and influenza virus isolations (A, B, or A plus B) occurred as yearly winter outbreaks. After data were controlled for seasonal patterns, RSV isolations were strongly correlated with the winter peaks in lower respiratory tract illness (LRI) deaths of infants 1-11 months old; influenza virus isolations were correlated with the winter peak in LRI deaths of children 24-59 months old. The parainfluenza viruses were not correlated with respiratory deaths. This study supports the idea that RSV is a major contributor to winter peaks in LRI deaths of children 1-11 months old.     

Infection by the respiratory syncytial virus in infants and young children at high risk

The respiratory syncytial virus is the most common cause of infection of the lower respiratory tract in infants and young children, and is the leading cause of hospitalisation and death due to viral illness during the first year of life. In otherwise healthy infants, the virus usually causes only mild respiratory illness, but premature babies and infants with chronic lung disease, those with congenitally malformed hearts, or those who are immunodeficient, are at increased risk of serious illness, hospitalisation, and death. Recent infection with the virus is also associated with increased postoperative complications after corrective surgery for congenitally malformed hearts. No effective vaccine is currently available, and treatment is limited to supportive therapy. Prevention in groups deemed to be at high-risk, therefore, is essential. In addition to measures for control of infection, prophylactic immunotherapy is indicated in selected patients. Palivizumab (Synagis) is a monoclonal antibody indicated for the prevention of serious viral disease of the lower respiratory tract in premature infants, those with chronic lung disease, and those with haemodynamically significant congenital cardiac lesions. Palivizumab is given intramuscularly, usually as a monthly injection during the so-called "season". In a recent international, randomised, double-blind, placebo-controlled trial in 1,287 children less than or equal to 2 years old with haemodynamically significant congenital cardiac malformations, prophylaxis achieved a relative reduction of 45 per cent in the incidence of antigen-confirmed viral-related hospitalisation, and reduced the duration of hospital stay by 56 per cent. National and international guidelines, therefore, now recommend routine prophylaxis in the first year of life in children with haemodynamically significant congenital cardiac disease.     

Burden of illness in infants and young children hospitalized for respiratory syncytial virus: A rapid review

Respiratory syncytial virus (RSV) infections are common among young children and represent a significant burden to patients, their families and the Canadian health system. Here we conduct a rapid review of the burden of RSV illness in children 24 months of age or younger. Four databases (Medline, Embase, Cochrane Database of Clinical Trials, ClinicalTrials.gov from 2014 to 2018), grey literature and reference lists were reviewed for studies on the following: children with or without a risk factor, without prophylaxis and with lab-confirmed RSV infection. Of 29 studies identified, 10 provided within-study comparisons and few examined clinical conditions besides prematurity. For infants of 33–36 weeks gestation (wGA) versus term infants, there was low-to-moderate certainty evidence for an increase in RSV-hospitalizations (n=599,535 infants; RR 2.05 [95% CI 1.89–2.22]; 1.3 more per 100 [1.1–1.5 more]) and hospital length of stay (n=7,597 infants; mean difference 1.00 day [95% CI 0.88–1.12]). There was low-to-moderate certainty evidence of little-to-no difference for infants born at 29–32 versus 33–36 wGA for hospitalization (n=12,812 infants; RR 1.20 [95% CI 0.92–1.56]). There was low certainty evidence of increased mechanical ventilation for hospitalized infants born at 29–32 versus 33–35 wGA (n=212 infants; RR 1.58, 95% CI 0.94–2.65). Among infants born at 32–35 wGA, hospitalization for RSV in infancy may be associated with increased wheeze and asthma-medication use across six-year follow-up (RR range 1.3–1.7). Children with versus without Down syndrome may have increased hospital length of stay (n=7,206 children; mean difference 3.00 days, 95% CI 1.95–4.05; low certainty). Evidence for other within-study comparisons was of very low certainty. In summary, prematurity is associated with greater risk for RSV-hospitalization and longer hospital length of stay, and Down syndrome may be associated with longer hospital stay for RSV. Respiratory syncytial virus-hospitalization in infancy may be associated with greater wheeze and asthma-medication use in early childhood. Lack of a comparison group was a major limitation for many studies.     

Pulmonary infections with respiratory syncytial virus and the parainfluenza viruses

Respiratory syncytial virus (RSV) and the parainfluenza viruses (PIVs) are the most important causes of acute lower respiratory illness (LRI) in infants and children under 6 years of age. These enveloped viruses are members of the paramyxovirus family. They infect cells in the epithelium lining the trachea and intrapulmonary airways, and cause croup, bronchitis, bronchiolitis, and bronchopneumonia. RSV causes annual midwinter to early spring outbreaks of respiratory disease in temperate climates; epidemics are heralded by the appearance of increased numbers of cases of bronchiolitis, primarily in children under 2 years of age. PIV serotypes 1 and 2 cause epidemics of croup in the fall months. Infections with PIV serotype 3 can occur in an endemic pattern throughout the year, or may occur as outbreaks, usually in the fall or spring. Croup and bronchiolitis are the most common syndromes of PIV-3 LRI. Infection with these viruses induces short-lived partial resistance to reinfection, but the human host remains susceptible to reinfection with these agents throughout life. While antibody in respiratory secretions is related most directly to resistance to reinfection, cell-mediated immune responses are crucial for limitation and termination of established infection. Current research efforts are directed at more thorough characterization of the developing host immune response to individual viral antigens, and to development of methods for immunization using specific virion peptides. Recently, antiviral therapy has become available for serious RSV infection in young infants.     

Evaluation of a live, cold-passaged, temperature-sensitive, respiratory syncytial virus vaccine candidate in infancy

A live-attenuated, intranasal respiratory syncytial virus (RSV) candidate vaccine, cpts-248/404, was tested in phase 1 trials in 114 children, including 37 1-2-month-old infants-a target age for RSV vaccines. The cpts-248/404 vaccine was infectious at 104 and 105 plaque-forming units in RSV-naive children and was broadly immunogenic in children >6 months old. Serum and nasal antibody responses in 1-2 month olds were restricted to IgA, had a dominant response to RSV G protein, and had no increase in neutralizing activity. Nevertheless, there was restricted virus shedding on challenge with a second vaccine dose and preliminary evidence for protection from symptomatic disease on natural reexposure. The cpts-248/404 vaccine candidate did not cause fever or lower respiratory tract illness. In the youngest infants, however, cpts-248/404 was unacceptable because of upper respiratory tract congestion associated with peak virus recovery. A live attenuated RSV vaccine for the youngest infant will use cpts-248/404 modified by additional attenuating mutations.     

Residential crowding and severe respiratory syncytial virus disease among infants and young children: A systematic literature review

Background

Varicella and herpes zoster are both caused by varicella zoster virus (VZV) infection or reactivation and may lead to complications associated with a (severe) societal burden. Because the epidemiology of VZV-related diseases in the Netherlands remains largely unknown or incomplete, the main objective of this study was to study the primary care incidence, associated complications and health care resource use.

Methods

We investigated the incidence of VZV complications in the Dutch general practitioner (GP) practices and pharmacies in a retrospective population-based cohort study (2004?C2008) based on longitudinal GP data including free text fields, hospital referral and discharge letters from approximately 165,000 patients.

Results

The average annual incidence of varicella GP-consultations was 51.5 per 10,000 (95% CI 44.4-58.7) overall; 465.5 per 10,000 for 0?C1?year-olds; 610.8 per 10,000 for 1?C4?year-olds; 153.5 per 10,000 for 5?C9?year-olds; 8,3 per 10,000 for >10?year olds. When only ICPC coded diagnoses were analyzed the incidence was 27% lower. The proportion of complications among varicella patients was 34.9%. Most frequently complications were upper respiratory tract infections. Almost half of the varicella patients received medication. The referral rate based on GP consultations was 1.7%. The average annual incidence of herpes zoster GP-consultations was 47.5 per 10,000 (95% CI 40.6-54.4). The incidence increased with age; 32.8 per 10,000 for <60?year-olds; 93.1 per 10,000 for 60?C64?year-olds and 113.2 per 10,000 for >65?year olds. When estimating herpes zoster incidence only on ICPC coded information, the incidence was 28% lower. The complication rate of herpes zoster was 32.9%. Post herpetic neuralgia was seen most often. Of patients diagnosed with herpes zoster 67.8% received medication. The referral rate based on GP consultations was 3.5%.

Conclusions

For varicella the highest incidence of GP-consultations was found in 1?C4?year-olds, for herpes zoster in the >65?years olds. The occurrence of complications was not age-dependent but varies per complication. When estimating incidence of VZV-related diseases in primary care, based on diagnostic codes only, one should be aware of a gross underestimation of the incidence. Our analysis may have important implications for the outcomes of upcoming cost-effectiveness analyses on VZV vaccination.     

Comparison of live attenuated cold-adapted and avian-human influenza A/Bethesda/85 (H3N2) reassortant virus vaccines in infants and children

Randomized, placebo-controlled studies with 10(3)-10(7) 50% tissue-culture infectious dose (TCID50) of avian-human (ah) and cold-adapted (ca) influenza A/Bethesda/85 (H3N2) reassortant viruses were completed in 106 seronegative young children 6-48 months of age. Although the reassortants differed in six of eight RNA segments, they exhibited similar properties in level of attenuation, infectivity, immunogenicity, and efficacy. The 50% human infectious dose was 10(4.6) TCID50 for ah and 10(4.4) for ca vaccines. Both reassortants were satisfactorily attenuated with restricted replication and were no more reactogenic than placebo. The mean peak titer of virus shed was 10(1.5) (ah) to 10(2.0) (ca) TCID50/ml, and each of 37 isolates tested retained their characteristic vaccine phenotypes. Infection with ah or ca virus conferred immunity to experimental challenge with homologous virus. These findings indicate that both ah and ca influenza A/Bethesda/85 (H3N2) reassortants should be suitable vaccine candidates for use in healthy infants and young children.     

孟鲁司特钠联合喜炎平注射液治疗小儿呼吸道合胞病毒感染的应用研究

目的 探讨孟鲁司特钠联合喜炎平注射液在治疗小儿呼吸道合胞病毒感染中的临床效果及对粘附分子水平的影响.方法 选取2017年3月—2020年5月在我院诊治的122例小儿呼吸道合胞病毒感染者为研究对象,采用随机数字表法将其分为2组,各61例.对照组采用孟鲁司特钠治疗,观察组在对照组基础上联合喜炎平注射液治疗.治疗2周后评估患...     

Recombinant human deoxyribonuclease in infants with respiratory syncytial virus bronchiolitis

BACKGROUND: Treatment of hospitalized infants with respiratory syncytial virus (RSV) bronchiolitis is mainly supportive. Bronchodilators and systemic steroids are often used but do not reduce the length of hospital stay. Because hypoxia and airways obstruction develop secondary to viscous mucus in infants with RSV bronchiolitis, and because free DNA is present in RSV mucus, we tested the efficacy of the mucolytic drug recombinant human deoxyribonuclease (rhDNase). METHODS: In a multicenter, randomized, double-blind, controlled clinical trial, 225 oxygen-dependent infants admitted to the hospital for RSV bronchiolitis were randomly assigned to receive 2.5 mg bid of nebulized rhDNase or placebo until discharge. The primary end point was length of hospital stay. Secondary end points were duration of supplemental oxygen, improvement in symptom score, and number of intensive care admissions. RESULTS: There were no significant differences between the groups with regard to the length of hospital stay (p = 0.19) or the duration of supplemental oxygen (p = 0.07). The ratio (rhDNase/placebo) of geometric means of length of stay was 1.12 (95% confidence interval, 0.96 to 1.33); for the duration of supplemental oxygen, the ratio was 1.28 (95% confidence interval, 0.97 to 1.68). There were no significant differences in the rate of improvement of the symptom score or in the number of intensive care admissions. CONCLUSIONS: Administration of rhDNase did not reduce the length of hospital stay or the duration of supplemental oxygen in oxygen-dependent infants with RSV bronchiolitis.     

The European Forum for Clinical Management: prophylaxis against the respiratory syncytial virus in infants and young children with congenital cardiac disease

A recent, randomised, double-blind, placebo-controlled trial has demonstrated the effectiveness of palivizumab (Synagis) for prophylaxis against infection by the respiratory syncytial virus in 1,287 young children with congenital cardiac disease. Guidelines for the use of palivizumab in these children considered to be at high risk were published by the American Academy of Pediatrics, followed by similar guidelines from the British Paediatric Cardiac Association, and recommendations from a number of other individual countries, including Canada, Germany, Spain, and France. In May, 2004, further discussion was held between a group of 15 paediatric cardiologists at a European forum for clinical management held in Munich, Germany. The objective of this forum was to define optimal recommendations on prevention of infection by the respiratory syncytial virus in infants and young children with congenital cardiac disease, appropriate to the clinical needs and style of those practising in paediatrics in individual countries. Participants were invited because of their knowledge of the therapeutic area, and for their experience of using palivizumab for prophylaxis against the respiratory syncytial virus in children with congenitally malformed hearts. Measures to educate the carers of children with such congenital malformations on precautions against infection by the respiratory syncytial virus were discussed, along with the many different aspects of best practice for therapeutic prophylaxis with palivizumab. The most appropriate timing of prophylaxis, recommendations for which children are most likely to benefit from prophylaxis, and suggested protocols were among the issues covered. The recommendations resulting from the discussions are presented in this paper, as a step towards reaching consensus.