Combined measles-mumps-rubella-varicella vaccine and febrile convulsions: the risk considered in the broad context.

INTRODUCTION: Studies on quadrivalent measles, mumps, rubella, and varicella (MMRV) vaccines have indicated a twofold increased relative risk of febrile convulsion (FC) after the first dose compared to MMR and V administered at the same medical visit (MMR+V). AREAS COVERED: This narrative review contextualizes FC occurrence after the first MMRV vaccine dose from a clinical perspective and outlines approaches to attenuate FC occurrence post-vaccination. EXPERT OPINION: While the relative FC risk increases after the first dose of MMRV compared to MMR+V vaccine in measles-naïve infants, the attributable risk is low versus the overall FC risk in the pediatric population triggered by other causes, like natural exposure to pathogens or routine vaccination. No increased risk of FC has been reported after MMRV co-administration with other routine vaccines compared to MMRV alone. Based on our findings and considering the MMRV vaccination benefits (fewer injections, higher coverage, better vaccination compliance), the overall benefit-risk profile of MMRV vaccine is considered to remain positive. Potential occurrence of FC in predisposed children (e.g. with personal/family history of FC) may be attenuated if they receive MMR+V instead of MMRV as the first dose. It is also important to monitor vaccinees for fever during the first 2 weeks post-vaccination.

Children under 5 years of age can sometimes have convulsions when they get a fever during illness or after vaccination. These are called febrile convulsions, and, in most cases, they leave no lasting damage, and the child outgrows them. After a combined vaccine against four childhood illnesses (measles, mumps, rubella, and varicella) became available, concerns appeared that measles-naïve children who received a first dose of this vaccine had a higher risk of febrile convulsions than children vaccinated with two separate vaccines (one against measles, mumps, and rubella, and one against varicella) administered during the same medical visit. However, this risk is low: during the first or the second week after the first vaccine dose, 1 additional child out of approximately 2500 children who receive the combined vaccine will have a febrile convulsion compared to those receiving 2 separate vaccines. In comparison, febrile convulsions due to any cause will appear in 1 out of 25 children younger than 5 years, and in 1 out of 43 children with measles. The combined vaccine has certain advantages over separate vaccines: children receive fewer injections and are more likely to be fully vaccinated against all four diseases. Children who had febrile convulsions before, or with a close relative who had febrile convulsions could be at higher risk of febrile convulsions after the first dose of the combined vaccine. Provided the informed consent from their parents or legal guardians, these children must receive separate vaccines, while all other children may receive the combined vaccine.

Clinical trials show similar safety outcomes including febrile convulsion rates for GSK's and Merck's measles-mumps-rubella (MMR) vaccines.

Combined measles-mumps-rubella (MMR) vaccines produced by GSK (GSK-MMR) and Merck (Merck-MMR) have demonstrated effectiveness and an acceptable safety profile, as documented over decades of post-licensure use in various regions worldwide. In the United States, 2 doses of the MMR vaccine are recommended at the ages of 12-15 months and 4-6 years. All-cause febrile convulsions have the highest incidence at 12-18 months of age, when the first MMR vaccine dose is administered. Because febrile convulsions can also occur rarely after MMR vaccine administration, we reviewed safety data of the GSK-MMR compared to the Merck-MMR vaccine from 4 clinical trials that evaluated a first dose in 12-15-month-olds and 2 clinical trials that evaluated a second dose in ≥4-year-olds. Overall frequencies of febrile convulsions were ≤0.4% across studies and vaccine groups. The frequency of febrile convulsions occurring 7-10 days post-vaccination with the GSK-MMR vaccine (5.7/10,000) was generally consistent with previously published data. The other safety outcomes were similar between the GSK-MMR and Merck-MMR vaccines in both age groups. Hence, as recommended by the Advisory Committee on Immunization Practices, the GSK-MMR vaccine can also be used for routine immunization of children according to the current immunization schedule in the United States to prevent MMR.

Safety and reactogenicity of a liquid formulation of human rotavirus vaccine (porcine circovirus-free): A phase III, observer-blind, randomized, multi-country study.

BACKGROUND: The introduction of rotavirus vaccines in national immunization programs has decreased mortality and hospitalizations due to diarrhea. GSK's live-attenuated, human rotavirus vaccine (HRV) is a 2-dose vaccine for oral administration. Following the detection of porcine circovirus type 1 (PCV-1) in HRV, a PCV-free (no detection of PCV-1 and PCV-2 according to the detection limits of tests used) HRV was developed. The immunogenicity, reactogenicity and safety of a liquid (liq) PCV-free HRV were assessed in two prior studies. The present study aimed to generate additional reactogenicity and safety data. METHODS: This phase III, observer-blind, randomized, controlled multi-country study enrolled healthy 6-12-week-old infants. Infants were randomized to receive 2 doses of either the liq PCV-free HRV (N = 677) or the lyophilized (lyo) HRV (N = 674) 1-2 months apart. Solicited adverse events (AEs) were recorded for 8 days after each dose, unsolicited AEs for 31 days and serious AEs (SAEs) from dose 1 until the end of the 6-month safety follow-up. RESULTS: The occurrence of solicited general AEs was comparable between the liq PCV-free HRV and the lyo HRV groups, with irritability/fussiness being the most frequently reported (74.9% [95% confidence interval: 71.4-78.1] and 72.1% [68.6-75.5]). Unsolicited AEs were reported for 29.7% (26.3-33.3) and 30.6% (27.1-34.2) of infants in the liq PCV-free HRV and the lyo HRV group. A total of 39 and 38 infants reported at least one SAE, respectively. The most common SAEs were upper respiratory tract (0.7% and 0.9%) and urinary tract infections (0.9% and 0.6%). One SAE (constipation) in the liq PCV-free HRV group was considered as potentially causally related to vaccination by the investigator. No deaths were reported. CONCLUSIONS: The study showed that the reactogenicity and safety profiles of the liq PCV-free HRV and the lyo HRV are similar. CLINICALTRIALS: gov identifier: NCT0395474.

Review of Over 15 Years Postmarketing Safety Surveillance Spontaneous Data for the Human Rotavirus Vaccine (Rotarix) on Intussusception.

INTRODUCTION: Rotavirus (RV) is the most common cause of acute gastroenteritis in children <5 years of age worldwide, and vaccination reduces the disease burden. Evidence from postmarketing surveillance studies suggested an increased risk of intussusception (IS) in infants post-RV vaccination. An overall positive benefit-risk balance for the human RV vaccine (HRV) Rotarix (GlaxoSmithKline [GSK], Belgium) has been established and recent findings indicate an indirect effect of reduced IS over the long term. OBJECTIVE: The aim of this study was to discuss spontaneous data from the GSK worldwide safety database on IS post-Rotarix administration. METHODS: The database was reviewed for all spontaneous IS cases from 2004 to 2020. Additionally, an observed versus expected (O/E) analysis was done for adverse events attributed to IS. Data were reviewed as overall worldwide and stratified by region (Europe/USA/Japan) and dose. RESULTS: A male predominance of IS patients was observed, consistent with earlier reports. The most frequently reported events in confirmed IS cases (Brighton Collaboration Working Group [BCWG] level 1) with time to onset ≤ 30 days post-vaccination were vomiting (55.8%), haematochezia (47.2%), and crying (21.1%). The observations from the IS spontaneous cases review and results of the O/E analysis are consistent with the known IS safety profile of RV vaccines: a transient increased incidence of IS post-vaccination (primarily in Europe/Japan/worldwide), mostly within 7 days postdose 1. CONCLUSION: Since the outcomes of early IS management are favourable over delayed management, healthcare professionals should inform parents about the importance of seeking immediate medical advice in case of unusual behaviour of the vaccinated infant. GSK continues to monitor the IS risk post-Rotarix administration through routine pharmacovigilance activities.

Rotavirus (RV) is the most common cause of acute gastroenteritis and a major cause of death in young children worldwide. Vaccination has been instrumental in reducing the impact of RV disease. Real-world evidence suggests an increased risk of intussusception (an infrequent type of bowel obstruction) in infants following RV vaccination. We reviewed IS cases reported spontaneously worldwide in children following a two-dose vaccination with the human RV vaccine (Rotarix, GlaxoSmithKline [GSK]) since its launch in 2004. We observed that (1) IS occurred more frequently 7 days after the first dose and, to a lesser extent, after the second dose; (2) boys were more frequently affected than girls (56.3%); (3) of 862 confirmed reported cases, 557 required hospitalisation; and (4) surgical intervention was required for 294 of 557 hospitalised cases. We used statistical analysis to assess whether the number of cases observed would be higher or lower than the natural occurrence of IS (irrespective of vaccination). These results were in line with the known RV vaccine safety profile. It is important to constantly monitor the real-world safety profile of RV vaccines in the postmarketing setting. Since the outcomes of early management of IS are favourable compared with delayed management, healthcare professionals should inform parents to seek immediate medical advice if they observe unusual behaviour in their vaccinated child. In conclusion, our analyses on data of a large patient pool for this rare event reinforce the favourable safety profile of human RV vaccine and the benefits of vaccination in young children.

Phase 2b Controlled Trial of M72/AS01E Vaccine to Prevent Tuberculosis.

BACKGROUND: A vaccine to interrupt the transmission of tuberculosis is needed. METHODS: We conducted a randomized, double-blind, placebo-controlled, phase 2b trial of the M72/AS01E tuberculosis vaccine in Kenya, South Africa, and Zambia. Human immunodeficiency virus (HIV)-negative adults 18 to 50 years of age with latent M. tuberculosis infection (by interferon-γ release assay) were randomly assigned (in a 1:1 ratio) to receive two doses of either M72/AS01E or placebo intramuscularly 1 month apart. Most participants had previously received the bacille Calmette-Guérin vaccine. We assessed the safety of M72/AS01E and its efficacy against progression to bacteriologically confirmed active pulmonary tuberculosis disease. Clinical suspicion of tuberculosis was confirmed with sputum by means of a polymerase-chain-reaction test, mycobacterial culture, or both. RESULTS: We report the primary analysis (conducted after a mean of 2.3 years of follow-up) of the ongoing trial. A total of 1786 participants received M72/AS01E and 1787 received placebo, and 1623 and 1660 participants in the respective groups were included in the according-to-protocol efficacy cohort. A total of 10 participants in the M72/AS01E group met the primary case definition (bacteriologically confirmed active pulmonary tuberculosis, with confirmation before treatment), as compared with 22 participants in the placebo group (incidence, 0.3 cases vs. 0.6 cases per 100 person-years). The vaccine efficacy was 54.0% (90% confidence interval [CI], 13.9 to 75.4; 95% CI, 2.9 to 78.2; P=0.04). Results for the total vaccinated efficacy cohort were similar (vaccine efficacy, 57.0%; 90% CI, 19.9 to 76.9; 95% CI, 9.7 to 79.5; P=0.03). There were more unsolicited reports of adverse events in the M72/AS01E group (67.4%) than in the placebo group (45.4%) within 30 days after injection, with the difference attributed mainly to injection-site reactions and influenza-like symptoms. Serious adverse events, potential immune-mediated diseases, and deaths occurred with similar frequencies in the two groups. CONCLUSIONS: M72/AS01E provided 54.0% protection for M. tuberculosis-infected adults against active pulmonary tuberculosis disease, without evident safety concerns. (Funded by GlaxoSmithKline Biologicals and Aeras; ClinicalTrials.gov number, NCT01755598 .).

Heptral (ademetionine) in patients with intrahepatic cholestasis in chronic liver disease due to non-alcoholic liver disease: results of a multicentre observational study in India.

The observational study was aimed at assessing the effectiveness and tolerability of Heptral (brand of ademetionine 1,4-butane disulfonate) in Indian patients presenting with intrahepatic cholestasis (IHC) due to chronic Non alcoholic liver disease (NALD). The study also aimed at understanding the prescribing practices of physicians as well as the profile of patients being prescribed Heptral. This Prospective observational study included 250 patients across 23 sites in India. The assessments of health-economic parameters, liver biochemistry, signs and symptoms of IHC (fatigue, jaundice, and pruritus) were performed at two visits, i.e., at baseline and after six weeks of Ademetionine treatment. Ademetionine was prescribed as part of the routine medical treatment as per the local label and not as a study intervention. Full analysis set (FAS) population included 244 patients. The mean age was 43.75 +/- 11.14 years and 75.5% (184/244) patients were males. 30.7% (75/244) of FAS population presented with cirrhosis. Concomitant medications were recommended to 44.4% (108/243) patients. Ademetionine treatment resulted in statistically significant reduction (p < 0.0001) in burden of disease parameters (number of days off work and number of visits to doctor), levels of biochemical markers and signs and symptoms of IHC. Physicians had favourable opinion for effectiveness and tolerability of Ademetionine for majority of the patients. Administration of Heptral in patients with NALD and IHC resulted in significant improvement in burden of disease, laboratory markers, signs and symptoms of cholestasis. The treatment was well tolerated.