Immunogenicity and reactogenicity following MMR vaccination in 5-7-month-old infants: a double-blind placebo-controlled randomized clinical trial in 6540 Danish infants.

Background: Measles is a highly contagious viral disease. Vaccinated mothers transfer fewer antibodies during pregnancy, resulting in shortened infant immunity. Earlier primary vaccination might avert the gap in protection. Methods: Healthy 5-7-month-old Danish infants were assigned in a 1:1 ratio to M-M-RVaxPro or placebo (solvent) in a double-blind, randomized trial between April 15, 2019 and November 1, 2021 (ClinicalTrials.govNCT03780179, EudraCT 2016-001901-18). Eligibility criteria were birth weight >1000 g and gestational age ≥32 weeks.Immunogenicity was measured by plaque reduction neutralization test (PRNT) and IgG ELISA before intervention, four weeks after intervention and routine MMR. Reactogenicity data were collected for six weeks and measured by hazard ratios (HR). Findings: 647 and 6540 infants participated in the immunogenicity and reactogenicity study, respectively; 87% and 99% completed follow-up. After early MMR, seroprotection rates (SPRs) were 47% (13%) in measles PRNT; 28% (2%), 57% (8%) in mumps and rubella IgG (placebo). For measles PRNT, geometric mean ratio was 4.3 (95% CI: 3.4-5.3) between randomization groups after intervention and 1.5 (95% CI: 1.3-1.9) after routine MMR.Reactogenicity was independent of randomization (HR, 1.0; 95% CI: 0.9-1.1). Severe adverse events occurred in 25 infants (HR, 1.8; 95% CI: 0.8-4.0); none deemed vaccine related. Interpretation: Early MMR elicited low SPRs but did not negatively impact short-term responses to a subsequent MMR. MMR at 5-7 months was safe and not associated with higher rates of reactogenicity than placebo. Funding: Innovation Fund Denmark.

Genetics and measles, mumps and rubella vaccine response in childhood and adolescence-A systematic review.

Measles, mumps and rubella (MMR) are contagious infectious diseases that can be prevented by immunization. However, MMR infections can occur in previously immunized individuals. The vaccine response is, among other factors, influenced by the combined effects of many genes. This systematic review investigates the genetic influence on measles, mumps and rubella antibody responses after childhood vaccination. In accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA), systematic literature searches were conducted in the medical databases PubMed, EMBASE and PsycINFO. Search strings were adjusted for each database. Citations were included if they measured and compared the immune response with immunogenetics after vaccination with a vaccine containing one or more of the following components: measles, mumps and/or rubella, MMR. The measure of vaccine response studied was antibodies after vaccination. Forty-eight articles were included in the final analysis. The results suggest that genetic determinants, including host genes, and single nucleotide polymorphisms in immune-related genes influence the MMR antibody responses after vaccination. Specifically, replicated associations were found between HLA, CD46, RARB, IRF9, EIF2AK2, cytokine genes and MMR vaccine-induced humoral immune responses. This knowledge can be useful in understanding and predicting immune responses and may have implications for future vaccine strategies.

Measles, mumps, and rubella vaccine at age 6 months and hospitalisation for infection before age 12 months: randomised controlled trial.

OBJECTIVE: To test for potential non-specific effects of an additional, early measles, mumps, and rubella (MMR) vaccine at age 5-7 months on risk of infection related hospitalisation before age 12 months. DESIGN: Randomised, double blinded, placebo controlled trial. SETTING: Denmark, a high income setting with low exposure to MMR. PARTICIPANTS: 6540 Danish infants aged 5 to 7 months. INTERVENTIONS: Infants were randomly allocated 1:1 to intramuscular injection with standard titre MMR vaccine (M-M-R VaxPro) or placebo (solvent only). MAIN OUTCOME MEASURES: Hospitalisations for infection, defined as all hospital contacts of infants referred from primary care for hospital evaluation and with an infection diagnosed, analysed as recurrent events, from randomisation to 12 months of age. In secondary analyses implications of censoring for date of subsequent diphtheria, tetanus, pertussis, polio, Haemophilus influenzae type B, and immunisation with pneumococci conjugate vaccine (DTaP-IPV-Hib+PCV), potential effect modification by sex, prematurity (<37 weeks' gestation), season, and age at randomisation were tested, and the secondary outcomes of hospitalisations ≥12 hours and antibiotic use were evaluated. RESULTS: 6536 infants were included in the intention-to-treat analysis. 3264 infants randomised to MMR vaccine experienced 786 hospitalisations for infection before age 12 months compared with 762 for the 3272 infants randomised to placebo. In the intention-to-treat analysis the rate of hospitalisations for infection did not differ between the MMR vaccine and placebo groups (hazard ratio 1.03, 95% confidence interval 0.91 to 1.18). For infants randomised to MMR vaccine compared with those randomised to placebo, the hazard ratio of hospitalisations for infection with a duration of at least 12 hours was 1.25 (0.88 to 1.77), and for prescriptions of antibiotics was 1.04 (0.88 to 1.23). No significant effect modifications were found by sex, prematurity, age at randomisation, or season. The estimate did not change when censoring at the date infants received DTaP-IPV-Hib+PCV after randomisation (1.02, 0.90 to 1.16). CONCLUSION: Findings of this trial conducted in Denmark, a high income setting, do not support the hypothesis that live attenuated MMR vaccine administered early to infants aged 5-7 months decreases the rate of hospitalisations for non-targeted infection before age 12 months. TRIAL REGISTRATION: EU Clinical Trials Registry EudraCT 2016-001901-18 and ClinicalTrials.gov NCT03780179.

Ventilation inhomogeneity and NO and CO diffusing capacity in ex-premature school children.

AIM: Ex-premature school children show mild-to-moderate airway obstruction and decreased CO diffusing capacity. Multiple breath nitrogen washout (N2MBW) and NO diffusing capacity (DLNO) measurements may provide new insight into long-term pulmonary and vascular impairment in bronchopulmonary dysplasia (BPD). METHODS: We examined a randomly selected group of 70 ex-premature children (gestational age <28 weeks or birth weight <1500 g; 42 with and 28 without BPD) and 38 term-born healthy controls of 8-13 years of age. Subjects performed N2MBW (lung clearance index, LCI; Sacin, and Scond), DLNO (membrane related diffusing capacity, Dm and pulmonary capillary volume, Vc), Fractional exhaled NO, CO diffusing capacity, conventional spirometry (FEV1, FVC, FEF25-75) and plethysmography (RV, TLC). Respiratory symptoms were assessed by questionnaire. RESULTS: Compared to healthy controls, the BPD group had higher z-scores for lung clearance index (P = 0.003), Sacin (P = 0.005), lower CO diffusing capacity (P = 0.025), DLNO (P = 0.022), DLNO/VA z-scores (P = 0.025) and a significant larger proportion had respiratory complaints. Amongst ex-premature children, the BPD group did not differ from the non-BPD group except for a decreased Dm (P = 0.023). Ex-premature with BPD showed predominantly airway obstruction (FEV1/FVC; P < 0.0001), signs of hyperinflation (RV/TLC-ratio; P = 0.028), and 25% had a positive bronchodilator response (>12% in FEV1). CONCLUSION: Ex-premature school children exhibited relatively mild but significant long-term respiratory symptoms and pulmonary peripheral impairment judged by N2MBW and DLNO measurements along with well-known airway obstruction. Larger longitudinal studies are needed to assess the clinical use of these advanced methods of assessing ventilation inhomogeneity and DLNO.