Utility of MF-non coding region for measles molecular surveillance during post-elimination phase, Spain, 2017-2020

Background: In countries entering the post-elimination phase for measles, the study of variants by sequencing of 450 nucleotides of the N gene (N450) does not always allow the tracing of chains of transmission. Indeed, between 2017 and 2020, most measles virus sequences belonged to either the MVs/Dublin.IRL/8.16 (B3-Dublin) or the MVs/Gir Somnath.IND/42.16 (D8-Gir Somnath) variants. We evaluated the additional use of a non-coding region (MF-NCR) as a tool to enhance resolution and infer case origin, chains of transmission and characterize outbreaks. Methods: We obtained 115 high-quality MF-NCR sequences from strains collected from Spanish patients infected with either B3-Dublin or D8-Gir Somnath variants between 2017 and 2020, performed epidemiological, phylogenetic and phylodynamic analyses and applied a mathematical model to determine relatedness among identified clades. Results: Applying this model allowed us to identify phylogenetic clades potentially derived from concomitant importations of the virus rather than single chain of transmission, inferred based on only N450 and epidemiology data. In a third outbreak, we found two related clades that corresponded to two chains of transmission. Discussion: Our results show the ability of the proposed method to improve identification of simultaneous importations in the same region which could trigger enhanced contact tracing. Moreover, the identification of further transmission chains indicates that the size of import-related outbreaks was smaller than previously found, supporting the interpretation that endemic measles transmission was absent in Spain between 2017 and 2020. We suggest considering the use of the MF-NCR region in conjunction with the study of N450 variants in future WHO recommendations for measles surveillance.This work was supported by the “Instituto de Salud Carlos III” (PI15CIII/00023, PI19ICIII/0041). AG was funded by CIBER de Epidemiología y Salud Pública (CIBERESP), ISCIII. CJ was funded by the ECDC/EUPHEM fellowship.S

Safety and immunogenicity of an upper-range release titer measles-mumps-rubella vaccine in children vaccinated at 12 to 15 months of age: a phase III, randomized study

The titer of live attenuated viral vaccines, such as MMR vaccines, varies between batches and over the shelf-life of a batch, with the highest titer expected at batch release. As higher titers may theoretically lead to increased reactogenicity, we compared the safety profile of an upper-range release titer MMR-RIT lot with commercial MMR II lots in a phase III, randomized, controlled study (NCT02184572). We vaccinated 1736 children with MMR-RIT (N = 1164) or MMR II (N = 572), both administered as first doses with varicella, hepatitis A, and pneumococcal conjugate vaccines at 12–15 months of age. The incidence of fever 5–12 days post-vaccination was comparable following MMR-RIT and MMR II vaccination: 4.2% vs 3.1% (difference: 1.1%) for fever > 39.0°C and 18.2% vs 17.1% (difference: 1.1%) for fever ≥ 38.0°C, which met the primary objective. Two cases of febrile convulsions (one considered vaccination-related) were reported within 43 days post-MMR-RIT. During Days 0–42, rashes were reported for 24.4% (MMR-RIT) and 27.4% (MMR II) of children; measles/rubella-like rashes for 5.8% and 4.7%, respectively. Measles-like illnesses were reported for 1.5% (MMR-RIT) and 0.9% (MMR II) of children 5–12 days post-vaccination. One serious adverse event, immune thrombocytopenic purpura following MMR II vaccination, was considered vaccination-related. Immune responses were similar in both groups. In summary, the safety profile of an upper-range release titer MMR-RIT lot was in line with that of commercial MMR II lots, with similar rates of fever and other MMR-specific symptoms and low rates of measles-like illnesses reported with both vaccines

A second dose of a measles-mumps-rubella vaccine administered to healthy four-to-six-year-old children: a phase III, observer-blind, randomized, safety and immunogenicity study comparing GSK MMR and MMR II with and without DTaP-IPV and varicella vaccines co-administration

In many countries, a second dose of a combined measles, mumps, and rubella (MMR) vaccine is recommended at 4–6 years of age – similarly to the booster of diphtheria, tetanus, acellular pertussis, and inactivated polio vaccine (DTaP-IPV) and the second dose of varicella vaccine (VV). Vaccine co-administration is generally encouraged if no interferences exist among the vaccines. This phase IIIa, randomized, controlled trial (NCT01621802) evaluated the immunogenicity and safety of MMR-RIT (Priorix, GSK) when given as a second dose with or without co-administration of DTaP-IPV and VV, using MMR II (M-M-R II, Merck & Co Inc.) as comparator. Antibody geometric mean concentrations or titers (GMCs/GMTs) and response rates to the components of all the administered vaccines were assessed. Solicited, unsolicited, and serious adverse events were recorded. Four thousand eleven children aged 4–6 years were enrolled. MMR-RIT elicited immune responses that were not inferior to those of MMR II in terms of GMCs and seroresponse rates when administered alone or when co-administered with DTaP-IPV and VV. The immune responses to the co-administered vaccines in MMR-RIT recipients were non-inferior to those in MMR II recipients. MMR-RIT and MMR II demonstrated similar reactogenicity profiles; the most frequent solicited adverse events across vaccine groups and sub-cohorts were local pain and fever. In conclusion, the immunogenicity and safety profiles of MMR-RIT administered with or without DTaP-IPV and VV were similar to those of MMR II

Reactogenicity and immunogenicity of a new combined Measles-Mumps-Rubella vaccine: results of a multicentre trial

A large single blind, multi-centre study involving 1779 children was performed in Italy. Infants, aged between 12 and 27 months were divided between two groups: group A received a single dose of a new MMR vaccine, 'Priorix'(3), while group B received a widely used MMR vaccine, Triviraten(4). Solicited local and general symptoms were recorded using diary cards and antibody levels were measured, prior to and 60 days post-vaccination, using ELISA assays. The incidence of solicited symptoms (evaluated in 1754 subjects) was comparable between groups, with the exception of fever which was significantly lower in group B. Immunogenicity was evaluated in 686 subjects. Of note, was the significantly higher anti-mumps seroconversion rate (p<0.001) observed in group A (97.0%) compared to group B (35.4%). However the anti-measles and anti-rubella seroconversion rates were equivalent between groups. Significantly higher (p<0.001) post-vaccination GMTs were in group A vs group B for anti-measles (2830 vs 784 IU/ml) and anti-mumps (1640 vs 469 U/ml), however the anti-rubella GMTs were significantly higher (p<0.001) in group B (117.6 IU/ml) compared to group A (92.6 IU/ml). The persistence of antibodies in 35 subjects was assessed 1 year after vaccination and the results showed no appreciable decline in titres with either vaccine. The trial demonstrates 'Priorix' is well tolerated and highl

Reactogenicity and immunogenicity of a new combined Measles-Mumps-Rubella vaccine: results of a multicenter trial

A large single blind, multi-centre study involving 1779 children was performed in Italy. Infants, aged between 12 and 27 months were divided between two groups: group A received a single dose of a new MMR vaccine, 'Priorix'(3), while group B received a widely used MMR vaccine, Triviraten(4). Solicited local and general symptoms were recorded using diary cards and antibody levels were measured, prior to and 60 days post-vaccination, using ELISA assays. The incidence of solicited symptoms (evaluated in 1754 subjects) was comparable between groups, with the exception of fever which was significantly lower in group B. Immunogenicity was evaluated in 686 subjects. Of note, was the significantly higher anti-mumps seroconversion rate (p<0.001) observed in group A (97.0%) compared to group B (35.4%). However the anti-measles and anti-rubella seroconversion rates were equivalent between groups. Significantly higher (p<0.001) post-vaccination GMTs were in group A vs group B for anti-measles (2830 vs 784 IU/ml) and anti-mumps (1640 vs 469 U/ml), however the anti-rubella GMTs were significantly higher (p<0.001) in group B (117.6 IU/ml) compared to group A (92.6 IU/ml). The persistence of antibodies in 35 subjects was assessed 1 year after vaccination and the results showed no appreciable decline in titres with either vaccine. The trial demonstrates 'Priorix' is well tolerated and highly immunogenic