Daily Respiratory Research Analysis
Durable respiratory protection and therapeutics advanced today: a phase 3 trial shows the RSVPreF3 OA vaccine maintains efficacy against RSV lower respiratory tract disease across three seasons in adults 60+, while a pediatric phase 3 trial demonstrates clinical benefit of the antiviral ziresovir in hospitalized infants ≤6 months. A nationwide cohort from Brazil quantifies persistent excess mortality up to 10 years after tuberculosis diagnosis, with risk concentrating in specific subgroups and c
Summary
Durable respiratory protection and therapeutics advanced today: a phase 3 trial shows the RSVPreF3 OA vaccine maintains efficacy against RSV lower respiratory tract disease across three seasons in adults 60+, while a pediatric phase 3 trial demonstrates clinical benefit of the antiviral ziresovir in hospitalized infants ≤6 months. A nationwide cohort from Brazil quantifies persistent excess mortality up to 10 years after tuberculosis diagnosis, with risk concentrating in specific subgroups and causes shifting to cardiovascular, cancer, and non-TB respiratory diseases.
Research Themes
- RSV immunization durability and revaccination strategy
- Pediatric RSV antiviral therapy effectiveness
- Long-term excess mortality after tuberculosis and risk stratification
Selected Articles
1. Efficacy, safety, and immunogenicity of the AS01
In a multinational, phase 3, randomized, observer-blind trial in adults ≥60 years, a single dose of RSVPreF3 OA conferred 62.9% cumulative efficacy against RSV-LRTD over three consecutive seasons, with efficacy against both RSV A and B. Protection waned over time, and revaccination at one year produced efficacy in the same range as a single dose. Safety was clinically acceptable.
Impact: This is among the first rigorous demonstrations of multi-season durability for an RSV vaccine in older adults, directly informing immunization policy and revaccination strategies.
Clinical Implications: Supports adoption of RSVPreF3 OA for adults ≥60 with expected protection across at least three seasons; clinicians should anticipate waning and watch for forthcoming guidance on optimal revaccination timing.
Key Findings
- Single-dose RSVPreF3 OA showed 62.9% cumulative efficacy against RSV-LRTD over three seasons (median follow-up 30.6 months).
- Efficacy was demonstrated against both RSV A (69.8%) and RSV B (58.6%) related LRTD.
- Efficacy waned over time; revaccination at 1 year yielded efficacy within the same range as a single dose; safety profile was acceptable with <1% serious adverse events judged related.
Methodological Strengths
- Randomized, observer-blind, placebo-controlled, multicountry phase 3 design across 17 countries and 275 sites
- Pre-specified analyses by subtype and sustained multi-season follow-up with adequate power
Limitations
- Efficacy waned over time; optimal revaccination interval remains undefined.
- Severe outcomes and subgroup safety signals are not fully detailed in the abstract and require full-text appraisal.
Future Directions: Define optimal revaccination schedules (interval and target subgroups), assess durability against severe RSV-LRTD and hospitalization, and evaluate coadministration with other seasonal vaccines.
BACKGROUND: Duration of protection after respiratory syncytial virus (RSV) vaccination is unknown. This study aimed to evaluate efficacy and safety over three RSV seasons of the AS01 METHODS: In this randomised, observer-blind, placebo-controlled, phase 3 trial (AReSVi-006), participants aged 60 years or older in 275 centres (ie, GP practices and clinical research sites) across 17 countries in Africa, Asia, Oceania, Europe, and North America were randomly assigned (1:1) to receive RSVPreF3 OA or placebo before RSV season one. RSVPreF3 OA recipients were re-randomly assigned (1:1) before RSV season two to receive a second RSVPreF3 OA dose (RSV revaccination group) or placebo (RSV single-dose group). Recipients of placebo before RSV season one also received placebo before season two (placebo group). The primary objective (efficacy against first occurrence of RSV-LRTD over one RSV season) was reported previously. Confirmatory secondary objectives were to demonstrate efficacy over three RSV seasons of a single RSVPreF3 OA dose and of a first dose followed by revaccination 1 year later, against RSV-LRTD, overall and by RSV subtype (success criteria: lower limits of two-sided CIs around efficacy estimates >20% [RSV-LRTD] and >0% [RSV-LRTD by RSV subtype]). This study is registered with ClinicalTrials.gov, NCT04886596, and is complete. FINDINGS: Participants were enrolled between May 25, 2021, and Jan 31, 2022. Efficacy analyses included 12 468 RSVPreF3 OA recipients and 12 498 placebo recipients. Cumulative efficacy over three seasons of one RSVPreF3 OA dose was 62·9% (97·5% CI 46·7-74·8) against RSV-LRTD, 69·8% (42·2-85·7) against RSV A-related LRTD, and 58·6% (35·9-74·1) against RSV B-related LRTD (median follow-up from day 15 post-dose one 30·6 months [IQR 26·2-32·0]). Efficacy was observed over three seasons among participants aged 60-69 years, participants aged 70-79 years, pre-frail participants (ie, those with a walking speed of 0·4-0·99 m/s in a gait speed test), and participants with pre-existing conditions that increase the RSV-LRTD risk. Efficacy against RSV-LRTD decreased over time. A first RSVPreF3 OA dose followed by revaccination 1 year later had an efficacy that was within the same range as that of one dose. RSVPreF3 OA showed a clinically acceptable safety profile. Between dose one and trial end, eight (<1%) participants in the RSV single-dose group, 12 (<1%) in the RSV revaccination group, and 12 (<1%) in the placebo group had a serious adverse event considered to be related to the trial intervention by the investigator. Five deaths were assessed as related to the trial intervention by the investigator: three in the vaccine groups (cardiopulmonary failure, cardiac arrest, and left ventricular failure) and two in the placebo group (death of unknown cause and pulmonary embolism). INTERPRETATION: A single RSVPreF3 OA dose was efficacious against RSV-LRTD over three RSV seasons in people aged 60 years or older, despite a decrease in efficacy over time. Further research is needed to establish the optimal revaccination strategy. These results support the favourable benefit-risk profile of RSVPreF3 OA to help protect against RSV-LRTD for at least three RSV seasons. FUNDING: GSK.
2. Efficacy and safety of ziresovir in hospitalised infants aged 6 months or younger with respiratory syncytial virus infection in China: findings from a phase 3 randomised trial with 24-month follow-up.
In hospitalized infants ≤6 months with PCR-confirmed RSV, oral ziresovir produced a greater improvement in the Wang bronchiolitis clinical score at day 3 versus placebo (LS mean difference −1.2, p=0.0004) with no drug-related serious adverse events. This prespecified subgroup analysis demonstrates early clinical benefit and a favorable safety profile over a 5-day treatment window with 24 months of follow-up.
Impact: High-quality randomized evidence for an RSV antiviral in the most vulnerable age group is rare; these findings open the door to therapeutic options complementing prevention in infants.
Clinical Implications: Ziresovir may offer an early clinical benefit for hospitalized infants with RSV and a favorable safety profile; larger global trials powered for hard outcomes (oxygen requirement, LOS, ICU) should guide adoption.
Key Findings
- At day 3, ziresovir improved WBCS more than placebo (LS mean change −3.5 vs −2.2; difference −1.2; p=0.0004) in the ITT-infected population ≤6 months.
- No drug-related serious adverse events or deaths occurred; drug-related TEAEs were 18% (ziresovir) vs 11% (placebo).
- Trial included 24-month safety follow-up; the prespecified infant subgroup analysis supports early symptomatic benefit.
Methodological Strengths
- Randomized, double-blind, placebo-controlled phase 3 design across 28 hospitals
- Prespecified analysis of infants ≤6 months with PCR-confirmed RSV and standardized clinical scoring
Limitations
- Primary endpoint is a short-term clinical score at 48 hours post-baseline, not hard outcomes (e.g., oxygen days, hospitalization length).
- Subgroup limited to infants ≤6 months in China; generalizability and effect in severe disease require confirmation.
Future Directions: Conduct larger, multinational trials powered for clinically meaningful endpoints (oxygen use, LOS, ICU admission, mortality), evaluate resistance, and define optimal timing with supportive care.
BACKGROUND: Respiratory syncytial virus (RSV) is a particularly dangerous infection in some populations, including very young infants. This study examined the efficacy and safety of ziresovir in hospitalised infants aged 6 months or younger with RSV infection. METHODS: In this double-blind, randomised, placebo-controlled trial conducted across 28 hospitals in China, patients aged 1-24 months hospitalised for virologically confirmed RSV infection were randomly allocated (2:1) to receive ziresovir (10-40 mg by weight twice daily) or placebo orally for 5 days, with 2 years of follow-up. Patients were included if they had a Wang bronchiolitis clinical score (WBCS) of at least 5 at first dosing and were administered their first dose of study drug within 7 days of the onset of symptoms of RSV infection. In this prespecified subanalysis of patients aged 6 months and younger at randomisation, we analysed the primary endpoint (change from baseline in WBCS on day 3 [48 h post-baseline]) in the intention-to-treat infected (ITT-i) population (comprising patients who received at least one dose of study drug and who had PCR-confirmed RSV infection). Safety endpoints were assessed in all patients who received at least one dose. This study is registered with ClinicalTrials.gov (NCT04231968) and is completed. FINDINGS: Participants were recruited from Sept 22, 2020, to Jan 19, 2022, and followed up to Feb 4, 2024. Among patients aged 6 months or younger, 188 participants (125 in the ziresovir group and 63 in the placebo group) received at least one dose of study drug and were included in the safety analysis, while the ITT-i population included 150 patients (100 in the ziresovir group and 50 in the placebo group). In the ziresovir group, 33 (26%) of 125 patients were female, 92 (74%) were male, mean age was 3·4 months (SD 1·4), and mean baseline WBCS was 6·8 (SD 1·7). In the placebo group, 15 (24%) of 63 patients were female, 48 (76%) were male, mean age was 3·3 months (1·5), and mean baseline WBCS was 6·9 (1·8). The least-squares mean change in WBCS from baseline to day 3 was -3·5 points (95% CI -3·9 to -3·1) with ziresovir versus -2·2 points (-2·8 to -1·7) with placebo (difference -1·2 [95% CI -1·9 to -0·6], p=0·0004). Drug-related treatment-emergent adverse events occurred in 22 (18%) of 125 patients who received ziresovir and seven (11%) of 63 patients who received placebo. No drug-related serious adverse events were observed and no deaths occurred. INTERPRETATION: Ziresovir had a favourable safety profile and was associated with a significant clinical benefit during the treatment period compared with placebo in patients aged 6 months or younger. FUNDING: Shanghai Ark Biopharmaceutical, National Clinical Research Center for Respiratory Diseases, and National Major Science and Technology Projects of China.
3. Long-term mortality trends among individuals with tuberculosis: a retrospective cohort study of individuals diagnosed with tuberculosis in Brazil.
Linkage of national TB notifications with mortality records in Brazil (n=834,594; 4.1 million person-years) shows markedly elevated mortality after TB diagnosis: MRR 11.28 in year 1, declining to 1.46 by year 10, with cumulative excess mortality of 9.9% at 10 years. Excess risk concentrates in ages 30–44, relapse, loss to follow-up, and co-prevalent HIV and alcohol use disorder; causes of death shift over time to cardiovascular, cancer, and non-TB respiratory diseases.
Impact: This large-scale, nationally representative analysis quantifies persistent excess mortality after TB and identifies modifiable risk factors, informing post-TB care models and health policy.
Clinical Implications: Post-TB care should extend beyond treatment completion to long-term risk management, including cardiovascular prevention, malignancy screening as appropriate, optimized HIV care, and addressing alcohol use; targeted surveillance is warranted for relapse and those lost to follow-up.
Key Findings
- Mortality rate ratio was 11.28 in year 1 after TB diagnosis, declining to 3.59 in year 2 and 1.46 by year 10.
- Cumulative excess mortality reached 6.12% at 1 year and 9.90% at 10 years post-diagnosis.
- Excess mortality was highest among ages 30–44, and associated with relapse, loss to follow-up, HIV, and alcohol use disorder; causes of death shifted toward CVD, cancer, and non-TB respiratory diseases over time.
Methodological Strengths
- Very large national cohort (834,594 individuals) with 4.1 million person-years and linked mortality data
- Age/sex/year/state matched comparisons to general population and cause-of-death characterization
Limitations
- Observational retrospective design with potential residual confounding and misclassification of causes of death.
- Generalizability beyond Brazil may vary due to healthcare system differences; some risk factors may be under-ascertained.
Future Directions: Implement and evaluate post-TB care packages targeting cardiovascular risk, mental health and substance use, and track long-term outcomes; investigate causal pathways and interventions in high-risk subgroups.
BACKGROUND: Even after successful treatment, individuals surviving tuberculosis (TB) disease experience elevated mortality rates. However, there is limited evidence on how these risks vary over time and by individual characteristics. METHODS: We conducted a retrospective cohort study of individuals diagnosed with TB in Brazil, using national TB notifications and linked mortality records for 2007-2016. We estimated mortality rate ratios (MRRs) and cumulative mortality by year since TB diagnosis, compared to general population mortality matched on age, sex, year, and state. We identified clinical and sociodemographic factors associated with elevated post-TB mortality, and compared the distribution of causes of death to the general population. RESULTS: The study sample included 834,594 individuals, with 4.1 million person-years of follow-up (average: 4.9 years). The TB cohort had elevated mortality compared to the general population, particularly in the first year post-diagnosis (MRR 11.28, 95%CI: 11.18-11.37). Post-TB MRRs declined from 3.59 (3.53-3.64) in year 2 to 1.46 (1.34-1.59) in year 10. Cumulative excess mortality was 6.12% (6.07-6.17) after 1 year and 9.90% (9.58-10.24) after 10 years. MRRs were highest for individuals 30-44 years-old at diagnosis. Relapse, loss to follow-up, and co-prevalent conditions like HIV and alcohol use disorder were strongly associated with higher MRRs. Over time, major causes of death in the TB cohort shifted from TB and HIV to cardiovascular disease, cancer, and non-TB respiratory diseases. CONCLUSIONS: Individuals developing TB disease face elevated mortality up to 10 years after diagnosis. These excess risks vary across demographic and clinical characteristics.