Randomized Study of Rivaroxaban vs Placebo on Disease Progression and Symptoms Resolution in High-Risk Adults With Mild Coronavirus Disease 2019.

BACKGROUND: Severe acute respiratory syndrome coronavirus 2 infection may be associated with a prothrombotic state, predisposing patients for a progressive disease course. We investigated whether rivaroxaban, a direct oral anticoagulant factor Xa inhibitor, would reduce coronavirus disease 2019 (COVID-19) progression. METHODS: Adults (N = 497) with mild COVID-19 symptoms and at high risk for COVID-19 progression based on age, body mass index, or comorbidity were randomized 1:1 to either daily oral rivaroxaban 10 mg (N = 246) or placebo equivalent (N = 251) for 21 days and followed to day 35. Primary end points were safety and progression. Absolute difference in progression risk was assessed using a stratified Miettinen and Nurminen method. RESULTS: The study was terminated after 497 of the target 600 participants were enrolled due to a prespecified interim analysis of the first 200 participants that crossed the futility boundary for the primary efficacy end point in the intent-to-treat population. Enrollees were 85% aged <65 years; 60% female; 27% Hispanic, Black, or other minorities; and 69% with ≥2 comorbidities. Rivaroxaban was well tolerated. Disease progression rates were 46 of 222 (20.7%) in rivaroxaban vs 44 of 222 (19.8%) in placebo groups, with a risk difference of -1.0 (95% confidence interval, -6.4 to 8.4; P = .78). CONCLUSIONS: We did not demonstrate an impact of rivaroxaban on disease progression in high-risk adults with mild COVID-19. There remains a critical public health gap in identifying scalable effective therapies for high-risk people in the outpatient setting to prevent COVID-19 progression.

Why Child Health and Mortality Prevention Surveillance?

Recognizing the need for better primary data on the causes of global child mortality, the Bill & Melinda Gates Foundation made an unusually long funding commitment toward a surveillance system using pathology to identify opportunities to prevent child deaths and promote equity.

Successes and Opportunities during the Pandemic: Reflections and Revelations from a Vaccine Development Perspective.

The Centre of Regulatory Excellence (CoRE) launched an annual lecture series in 2021 in Singapore to honor the memory of the late Professor Sir Alasdair Breckenridge, CoRE's founding Chair, and foster dialogue on global biomedical and regulatory perspectives, challenges, and advances. The 2022 Sir Alasdair Breckenridge Lecture "Success and Opportunities in the Pandemic" was delivered by Dr Penny M Heaton, former CEO of the Bill & Melinda Gates Foundation Research Institute and current Global Therapeutics Lead for Vaccines at Johnson & Johnson. Dr Heaton highlighted key lessons on the importance of trust, collaboration, and transparency in the context of health care and vaccine production.

Newcastle disease virus-like particles containing respiratory syncytial virus G protein induced protection in BALB/c mice, with no evidence of immunopathology.

Respiratory syncytial virus (RSV) is the leading cause of serious respiratory infections in children as well as a serious cause of disease in elderly and immunosuppressed populations. There are no licensed vaccines available to prevent RSV disease. We have developed a virus-like particle (VLP) vaccine candidate for protection from RSV. The VLP is composed of the NP and M proteins of Newcastle disease virus (NDV) and a chimeric protein containing the cytoplasmic and transmembrane domains of the NDV HN protein and the ectodomain of the human RSV G protein (H/G). Immunization of mice with 10 or 40 microg total VLP-H/G protein by intraperitoneal or intramuscular inoculation stimulated antibody responses to G protein which were as good as or better than those stimulated by comparable amounts of UV-inactivated RSV. Immunization of mice with two doses or even a single dose of these particles resulted in the complete protection of mice from RSV replication in the lungs. Immunization with these particles induced neutralizing antibodies with modest titers. Upon RSV challenge of VLP-H/G-immunized mice, no enhanced pathology in the lungs was observed, although lungs of mice immunized in parallel with formalin-inactivated RSV (FI-RSV) showed the significant pathology that has previously been documented after immunization with FI-RSV. Thus, the VLP-H/G candidate vaccine was immunogenic in BALB/c mice and prevented replication of RSV in murine lungs, with no evidence of immunopathology. These data support further development of virus-like particle vaccine candidates for protection against RSV.

Efficacy of the pentavalent rotavirus vaccine, RotaTeq® (RV5), between doses of a 3-dose series and with less than 3 doses (incomplete regimen).

Post-hoc analyses of the Rotavirus Efficacy and Safety Trial (REST) were conducted to determine whether the pentavalent rotavirus vaccine (RV5) confers early protection against rotavirus gastroenteritis (RVGE) before completion of the 3-dose regimen. To evaluate the efficacy of RV5 between doses in reducing the rates of RVGE-related hospitalizations and emergency department (ED) visits in infants who ultimately received all 3 doses of RV5/placebo, events occurring from 2 weeks after the first and second doses to receipt of the subsequent dose (Analysis A) and events occurring from 2 weeks after the first and second doses to 2 weeks after the subsequent dose (Analysis B) were analyzed. In Analysis A, RV5 reduced the rates of combined hospitalizations and ED visits for G1-G4 RVGE or RVGE regardless of serotype between doses 1 and 2 by 100% (95% confidence interval [CI]: 72-100%) or 82% (95% CI: 39-97%), respectively, and between doses 2 and 3, RV5 reduced the rates of combined hospitalizations and ED visits for G1-G4 RVGE or RVGE regardless of serotype by 91% (95% CI: 63-99%) or 84% (95% CI: 54-96%), respectively. Similar rate reductions were observed in Analysis B. These data suggest that RV5 provides a high level of protection between doses against hospitalizations and ED visits for RVGE starting as early as 14 days after the first dose.

Bringing Preventive RSV Monoclonal Antibodies to Infants in Low- and Middle-Income Countries: Challenges and Opportunities.

Respiratory syncytial virus (RSV) is the leading cause of acute lower respiratory tract infections (LRTIs) in infants. Most deaths occur in infants under 3 months old, and those living in low and middle-income countries (LMICs). There are no maternal or infant RSV vaccines currently approved. An RSV monoclonal antibody (mAb) could fill the gap until vaccines are available. It could also be used when a vaccine is not given, or when there is insufficient time to vaccinate and generate an antibody response. The only currently approved RSV mAb, palivizumab, is too costly and needs monthly administration, which is not possible in LMICs. It is imperative that a safe, effective, and affordable mAb to prevent severe RSV LRTI be developed for infants in LMICs. Next generation, half-life extended mAbs in clinical development, such as nirsevimab, show promise in protecting infants against RSV LRTI. Given that a single dose could cover an entire 5-month season, there is an opportunity to make RSV mAbs affordable for LMICs by investing in improvements in manufacturing efficiency. The challenges of using RSV mAbs in LMICs are the complexities of integrating them into existing healthcare delivery programs and surveillance systems, both of which are needed to define seasonal patterns, and monitor for escape mutants. Collaboration with key stakeholders such as the World Health Organization and Gavi, the Vaccine Alliance, will be essential for achieving this goal.

Age dependence of the risk of intussusception following [corrected] rhesus-human reassortant rotavirus tetravalent vaccine: is it beyond doubt?

The relation between the risk of intussusception and age at the time of receipt of the first dose of rhesus-human reassortant rotavirus tetravalent vaccine (RRV-TV) has been studied extensively on the basis of Centers for Disease Control and Prevention (CDC) matched case-control study data, using various statistical methods, including conditional logistic regression and quadratic smoothing splines. However, different conclusions have been reported in published analyses regarding the dependence of the risk of intussusception on age at first dose. The authors reanalyzed the CDC matched case-control data set using unrestricted and restricted quadratic smoothing spline methods for various exposure windows (i.e., intervals postvaccination). These analyses indicated that the use of different models may lead to different conclusions. The restricted quadratic smoothing spline with appropriately chosen knot locations showed a statistically significant increased risk of intussusception associated with RRV-TV for the exposure window 3-14 days after the first dose at an age as young as 49 days, the youngest age in the data set at which vaccine was administered; this implies an increased risk of intussusception associated with RRV-TV at all ages studied.

Robustness of the healthcare utilization results from the Rotavirus Efficacy and Safety Trial (REST) evaluating the human-bovine (WC3) reassortant pentavalent rotavirus vaccine (RV5).

BACKGROUND: The Rotavirus Efficacy and Safety Trial was a placebo-controlled Phase III study that evaluated the safety and efficacy of a three-dose pentavalent rotavirus vaccine (RV5) including its effect on healthcare utilization for rotavirus gastroenteritis (RVGE). The per-protocol (PP) analyses, which counted events occurring 14 days after dose 3 among infants without protocol violations, have already been published. This paper evaluates the consistency of the healthcare utilization results based on the modified intention to treat (MITT) analyses with the PP analyses. The MITT analyses include all infants receiving at least one dose of vaccine or placebo and follow-up begins after dose 1. The paper also explores the consistency of the results for different subgroups of the study population with different types of surveillance. METHODS: Data on healthcare utilization for acute gastroenteritis were collected via telephone interviews after administration of the first dose. Parents were either contacted every 6 weeks or every 2 weeks depending on the substudy in which they were enrolled. Those contacted every 2 weeks were also asked to complete symptom diaries. Poisson regression was used to evaluate the effect of RV5 on the rates of RVGE-associated healthcare encounters in all of the analyses. RESULTS: In the first 2 years after vaccination, RV5 reduced the combined rate of hospitalizations and emergency department (ED) visits 88.9% (95% CI: 84.9, 91.9) for all RVGE regardless of serotype in the MITT analysis compared with a 94.5% (95% CI: 91.2, 96.6) reduction based on the G1-G4 PP analysis. By type of surveillance, the rate reductions for the G1-G4 PP analysis were 91.0% (95% CI: 81.7, 95.5) and 95.9% (95% CI: 92.2, 97.8) among parents contacted every 2 weeks (number evaluable = 4,451) and every 6 weeks (number evaluable = 52,683) respectively. CONCLUSIONS: Our analyses demonstrated that the effect of RV5 on reducing the rate of hospitalizations and ED visits based on the MITT analyses were generally consistent with the PP analyses. The rate of events for subgroups with different intensities of surveillance differed but the effect of RV5 on the relative rate reductions were consistent with the results that have already been published. TRIAL REGISTRATION: ClinicalTrials.gov number, NCT00090233.

Challenges of Developing Novel Vaccines With Particular Global Health Importance.

Six of the top ten leading causes of death in low resource settings could potentially be prevented by vaccination. Development of vaccines for individuals in these populations is difficult because of the biological complexity of the prevalent pathogens and the challenges inherent to development of any vaccine. This review discusses those challenges and promising advances to address them and highlights recent progress in development of vaccines against several pathogens of interest.

Clinical trials in the pandemic age: What is fit for purpose?

It is critical to ensure that COVID-19 studies provide clear and timely answers to the scientific questions that will guide us to scalable solutions for all global regions. Significant challenges in operationalizing trials include public policies for managing the pandemic, public health and clinical capacity, travel and migration, and availability of tests and infrastructure. These factors lead to spikes and troughs in patient count by location, disrupting the ability to predict when or if a trial will reach recruitment goals. The focus must also be on understanding how to provide equitable access to these interventions ensuring that interventions reach those who need them the most, be it patients in low resource settings or vulnerable groups.  We introduce a website to be used by The Bill & Melinda Gates Foundation, Wellcome Trust, and other funders of the COVID Therapeutics Accelerator that accept proposals for future clinical research. The portal enables evaluations of clinical study applications that focus on study qualities most likely to lead to informative outcomes and completed studies.

Safety and efficacy of a pentavalent human-bovine (WC3) reassortant rotavirus vaccine.

BACKGROUND: Rotavirus is a leading cause of childhood gastroenteritis and death worldwide. METHODS: We studied healthy infants approximately 6 to 12 weeks old who were randomly assigned to receive three oral doses of live pentavalent human-bovine (WC3 strain) reassortant rotavirus vaccine containing human serotypes G1, G2, G3, G4, and P[8] or placebo at 4-to-10-week intervals in a blinded fashion. Active surveillance was used to identify subjects with serious adverse and other events. RESULTS: The 34,035 infants in the vaccine group and 34,003 in the placebo group were monitored for serious adverse events. Intussusception occurred in 12 vaccine recipients and 15 placebo recipients within one year after the first dose including six vaccine recipients and five placebo recipients within 42 days after any dose (relative risk, 1.6; 95 percent confidence interval, 0.4 to 6.4). The vaccine reduced hospitalizations and emergency department visits related to G1-G4 rotavirus gastroenteritis occurring 14 or more days after the third dose by 94.5 percent (95 percent confidence interval, 91.2 to 96.6 percent). In a nested substudy, efficacy against any G1-G4 rotavirus gastroenteritis through the first full rotavirus season after vaccination was 74.0 percent (95 percent confidence interval, 66.8 to 79.9 percent); efficacy against severe gastroenteritis was 98.0 percent (95 percent confidence interval, 88.3 to 100 percent). The vaccine reduced clinic visits for G1-G4 rotavirus gastroenteritis by 86.0 percent (95 percent confidence interval, 73.9 to 92.5 percent). CONCLUSIONS: This vaccine was efficacious in preventing rotavirus gastroenteritis, decreasing severe disease and health care contacts. The risk of intussusception was similar in vaccine and placebo recipients. (ClinicalTrials.gov number, NCT00090233.)

Concomitant use of the 3-dose oral pentavalent rotavirus vaccine with a 3-dose primary vaccination course of a diphtheria-tetanus-acellular pertussis-hepatitis B-inactivated polio-Haemophilus influenzae type b vaccine: immunogenicity and reactogenicity.

BACKGROUND: The pentavalent rotavirus vaccine (PRV), RotaTeq, can be concomitantly administered with most routine childhood vaccines. This study evaluated the immunogenicity and reactogenicity of PRV when used concomitantly with a hexavalent vaccine containing diphtheria, tetanus, acellular pertussis, hepatitis B, inactivated poliovirus, and Haemophilus influenzae type b. METHODS: Healthy infants (N = 403) received hexavalent vaccine concomitantly with either PRV or placebo at 2, 3, and 4 months of age. Antibody responses were measured immediately before and 42 +/- 3 days after vaccination. Parents/legal guardians recorded all adverse events for 14 days after vaccination. RESULTS: Seroprotective titers for hepatitis B (hepatitis B surface antigen > or =10 mIU/mL) were achieved by 97.8% of subjects in both vaccine treatment groups. Seroprotective titers to H. influenzae type b (polyribosylribitol phosphate > or =0.15 microg/mL) were achieved by 91.4% of subjects receiving both vaccines and 95.1% of subjects receiving only hexavalent vaccine. Seroprotective titers to diphtheria, tetanus, and poliovirus were also comparable between the vaccine treatment groups, as were geometric mean antibody titers to the pertussis antigens. Among PRV recipients, 92% had a > or =3-fold rise in serum antirotavirus immunoglobulin A levels. Concomitant administration was well tolerated. The incidence of adverse events was similar for both groups, with no statistically significant increases in fever, vomiting, diarrhea, or irritability. CONCLUSIONS: In this study, concomitant administration of PRV with hexavalent vaccine was well tolerated and the immune responses to the antigens of the hexavalent vaccine were noninferior when compared with those of the control group. In addition, PRV was immunogenic when administered concomitantly with hexavalent vaccine.

Efficacy of pentavalent human-bovine (WC3) reassortant rotavirus vaccine based on breastfeeding frequency.

The efficacy of a live, oral, pentavalent rotavirus vaccine against G1-4 rotavirus gastroenteritis (RVGE) was retrospectively assessed based on breastfeeding frequency among 5098 infants in a placebo-controlled trial. The efficacy against any RVGE severity for infants never breastfed, sometimes breastfed, or exclusively breastfed was 68.3%, 82.2%, and 68.0%, respectively. The efficacy against severe RVGE was 100%, 95.4%, and 100%, respectively. Breastfeeding did not seem to adversely impact the efficacy of pentavalent rotavirus vaccine.

Concomitant use of the oral pentavalent human-bovine reassortant rotavirus vaccine and oral poliovirus vaccine.

OBJECTIVES: The live oral pentavalent rotavirus vaccine (PRV) is well tolerated and highly efficacious against rotavirus gastroenteritis. This open-label, multicenter study evaluated the immunogenicity and safety of coadministering oral poliovirus vaccine (OPV) with PRV. METHODS: From 2005 to 2006, healthy 6- to 12-week-old Latin American infants were randomized to PRV and OPV concomitantly or PRV 2-4 weeks before OPV. Three doses of each vaccine were administered 8-10 weeks apart. Subjects did not receive OPV at birth. Routine licensed pediatric vaccines were allowed. Antibody responses to PRV and OPV were evaluated 42 days after the last dose of each vaccine. Adverse events were recorded for 14 days after each study visit. RESULTS: In the concomitant-use group (n = 372), more than 98% of subjects achieved serum-neutralizing antibody titer > or = 1:8 against poliovirus types 1, 2, and 3. The poliovirus seroprotection rate in the concomitant-use group was statistically noninferior to the staggered-use group (n = 363). The immunoglobulin A (IgA) antirotavirus geometric mean titer was 46% lower in the concomitant-use group than in the staggered-use group. However, concomitant use elicited a > or = 3-fold increase (from predose 1 to postdose 3) in serum antirotavirus IgA in 93% of subjects and achieved the definition of noninferiority. Both regimens were similarly well tolerated. CONCLUSIONS: PRV did not interfere with immune responses to OPV. Although coadministration with OPV reduced serum antirotavirus IgA geometric mean titer, seroresponse rates were high and consistent with those observed in previous studies showing high vaccine efficacy. These results support including PRV in vaccination schedules involving OPV.

Estimating the cost of vaccine development against epidemic infectious diseases: a cost minimisation study.

BACKGROUND: The Coalition for Epidemic Preparedness Innovations was established in 2016, to develop vaccines that can contribute to preparedness for outbreaks of epidemic infectious diseases. Evidence on vaccine development costs for such diseases is scarce. Our goal was to estimate the minimum cost for achieving vaccine research and development preparedness targets in a portfolio of 11 epidemic infectious diseases, accounting for vaccine pipeline constraints and uncertainty in research and development preparedness outcomes. METHODS: We assembled a pipeline of 224 vaccine candidates from preclinical through to phase 2 for 11 priority epidemic infectious diseases. We used a linear regression model to identify drivers of development costs from preclinical through to end of phase 2a. Drawing from published estimates of vaccine research and development probabilities of success, we simulated costs for advancing these 224 vaccine candidates through to the end of phase 2a. We combined these findings to determine minimum costs for progressing at least one vaccine through to the end of phase 2a per epidemic infectious disease by means of a stochastic optimisation model. FINDINGS: The cost of developing a single epidemic infectious disease vaccine from preclinical trials through to end of phase 2a is US$31-68 million (US$14-159 million range), assuming no risk of failure. We found that previous licensure experience and indirect costs are upward drivers of research and development costs. Accounting for probability of success, the average cost of successfully advancing at least one epidemic infectious disease vaccine through to the end of phase 2a can vary from US$84-112 million ($23 million-$295 million range) starting from phase 2 to $319-469 million ($137 million-$1·1 billion range) starting from preclinical. This cost includes the cumulative cost of failed vaccine candidates through the research and development process. Assuming these candidates and funding were made available, progressing at least one vaccine through to the end of phase 2a for each of the 11 epidemic infectious diseases would cost a minimum of $2·8-3·7 billion ($1·2 billion-$8·4 billion range). INTERPRETATION: Our analysis provides new evidence on vaccine research and development pipelines and associated costs for 11 epidemic infectious diseases, highlighting both funding needs and research and development gaps for achieving vaccine research and development preparedness targets. FUNDING: This work was partly supported by the Research Council of Norway through the Global Health and Vaccination Programme GLOBVAC.

Vaccines: the pentavalent rotavirus vaccine: discovery to licensure and beyond.

Twenty-five years passed between the discovery of the parent strain (WC3) of the pentavalent human-bovine reassortant rotavirus vaccine (PRV) in 1981 and the licensure of PRV in 2006. This orally administered liquid vaccine, which is given as a 3-dose series, is indicated for the prevention of rotavirus gastroenteritis, caused by the G serotypes contained in the vaccine, in infants and children. PRV is recommended by the Advisory Committee on Immunization Practices and the American Academy of Pediatrics for administration to all infants in the United States. These recommendations are supported by the results of the phase III studies, which demonstrated that PRV is well tolerated and efficacious. PRV reduced rotavirus-related hospitalizations by 96% and was not associated with an increased incidence of serious adverse events, including intussusception. This report focuses on the safety and efficacy data from the late-phase studies of PRV and discusses plans for providing this vaccine to the developing world.