Ten-year follow-up on efficacy,immunogenicity and safety of two doses of a combined measles-mumps-rubella-varicella vaccine or one dose of monovalent varicella vaccine: Results from five East European countries

BackgroundWe assessed the 10-year efficacy, immunogenicity and safety of two doses of a combined measles-mumps-rubella-varicella vaccine (MMRV) or one dose of a monovalent varicella vaccine (V) in children from Czech Republic, Lithuania, Poland, Romania and Slovakia.MethodsThis was a phase IIIB follow-up of an observer-blind, randomized, controlled trial (NCT00226499). In phase A, healthy children aged 12–22 months from 10 European countries were randomized in a 3:3:1 ratio to receive two doses of MMRV (MMRV group), one dose of MMR followed by one dose of V (MMR + V group), or two doses of MMR (MMR; control group), 42 days apart. Vaccine efficacy (VE) against varicella (confirmed by viral DNA detection or epidemiological link and clinical assessment) was calculated with 95% confidence intervals using Cox proportional hazards regression model. Immunogenicity was assessed as seropositivity rates and geometric mean concentrations (GMCs). Solicited and unsolicited adverse events (AEs) and serious AEs (SAEs) were recorded.ResultsA total of 3705 children were vaccinated (1590, MMRV group; 1586, MMR + V group; 529, MMR group). There were 663 confirmed varicella cases (47, MMRV group; 349, MMR + V group; 267, MMR group). VE ranged between 95.4% (Lithuania) and 97.4% (Slovakia) in the MMRV group and between 59.3% (Lithuania) and 74% (Slovakia) in the MMR + V group. At year 10, seropositivity rates were 99.5%–100% in the MMRV group, 98%–100% in the MMR + V group and 50%–100% in the MMR control group, and the anti-VZV antibody GMCs were comparable between MMRV and MMR + V groups. The occurrence of solicited and unsolicited AEs was similar across groups and no SAE was considered as vaccination-related. No new safety concerns were identified.ConclusionsOur results indicated that two doses of varicella zoster virus-containing vaccine provided better protection than one dose against varicella and induced antibody responses that persisted 10 years post-vaccination.     

Incidence of herpes zoster among varicella-vaccinated children,by number of vaccine doses and simultaneous administration of measles,mumps, and rubella vaccine

IntroductionChildren may receive measles-mumps-rubella (MMR) and varicella (VAR) vaccines separately or as measles-mumps-rubella-varicella (MMRV). We examined whether pediatric herpes zoster (HZ) incidence varied by pattern of varicella vaccine administration.MethodsIn six integrated health systems, we examined HZ incidence among children turning 12 months old during 2003–2008. All received varicella and MMR vaccines on recommended schedules. Cases were identified through 2014 using ICD-9 codes. Incidence was examined by number of varicella vaccine doses and same-day MMR.ResultsAmong 199,797 children, overall HZ incidence was 18.6/100,000 person-years in the first-dose MMR + VAR group, 17.9/100,000 person-years in the MMRV group, and 7.5/100,000 person-years in the VAR-alone group. HZ incidence was lower following the second dose than before the second dose in all first-dose groups.ConclusionsHZ incidence was not meaningfully different between the MMRV and MMR + VAR first-dose groups. Overall and within first-dose groups, HZ incidence was lower among children receiving two varicella vaccine doses.     

Second dose of measles-mumps-rubella-varicella vaccine (MMRV) and the risk of febrile convulsions

IntroductionStudies have shown an increased risk of febrile convulsions (FC) after first immunization with the quadrivalent measles-mumps-rubella-varicella vaccine (MMRV) compared to a first dose of measles-mumps-rubella vaccine (MMR) only or in combination with separately administered varicella vaccine (MMR + V). Therefore, it is recommended to give MMR + V at first dose and MMRV or MMR + V at second dose. Little is known on the risk of FC after MMRV at second dose, especially whether the risk depends on age, sex, history of FC or type of first dose vaccine.MethodsA retrospective cohort study using claims data from the German Pharmacoepidemiological Research database (GePaRD) was performed in children born between January 1st, 2004 and October 31st, 2015 who received two doses of MMRV, MMR + V or MMR. Cases were defined as hospitalization with a diagnosis of FC without neurological conditions coded as main discharge diagnosis. Unadjusted and adjusted odds ratios (OR) with 95% confidence intevals (CIs) were calculated to compare the risk of FC. Stratified analyses were performed to examine potential effect modification by age, sex, history of FC or type of first dose vaccine.ResultsIn the first 30 days after second dose vaccination, 464 FCs were observed in a cohort of 528,639 children with a median age of 17 months. After adjustment for potential confounders, the adjusted OR for FC in the 30 days after vaccination was 1.25 (95% CI 0.67–2.30) for MMRV compared to MMR + V and 1.04 (0.82–1.32) for MMRV compared to MMR. History of FC was the most important risk factor with an OR of 36.26 (29.30–44.89). We found no effect modification by age, sex, history of FC, or type of first dose vaccine.ConclusionUse of MMRV at second dose is not associated with an increased risk of FC compared to MMR + V or MMR, irrespective of age, sex, history of FC, or type of first dose vaccine.     

Reactogenicity and immunogenicity of a live attenuated tetravalent measles-mumps-rubella-varicella (MMRV) vaccine

In countries where routine varicella vaccination is implemented, it is usually given at the same age as that recommended for measles-mumps-rubella (MMR) vaccination. A combined multivalent measles-mumps-rubella-varicella (MMRV) vaccine would offer the convenience of a single injection and facilitate implementation of varicella vaccination into routine childhood immunisation schedules. We evaluated the immunogenicity and reactogenicity of a tetravalent MMRV candidate vaccine compared to an extemporaneous mix of a measles-mumps-rubella vaccine and varicella vaccine (MMR/V), and to a measles-mumps-rubella (MMR) vaccine alone. A multicentre study was conducted in which a total of 240 healthy children aged 12 months (80 per group) were randomised to receive MMRV, MMR/V, or MMR alone. Active surveillance for adverse events was undertaken for 43 days post-vaccination. Blood samples were taken prior to vaccination and at 60 days post-vaccination. There were no significant differences between groups in rates of pain, redness, or swelling at the site of vaccination. There was no significant difference in the rate of any fever (axillary temperature >or=37.5 degrees C) and grade 3 fever (axillary temperature >39.0 degrees C) between the groups receiving MMRV and MMR during the 43-day follow-up period. Although, a significant increase was found for fever of any cause with onset between days 0 and 14 for MMRV compared to the MMR group, there was no significant difference in grade 3 fever rates during the same period. With respect to immunogenicity, MMRV and MMR/V demonstrated similar seroconversion rates to each component compared to MMR alone, with at least 91.9% of subjects in all groups seroconverting to each vaccine component 60 days after vaccination. Decreased GMTs for varicella antibody at day 60 indicated that there may have been inhibition of this response compared to MMR/V. This tetravalent MMRV candidate vaccine showed promising results, although further examination of the possible increase in minor fever and decreased varicella immunogenicity should be assessed in future studies.     

A combined measles,mumps, rubella and varicella vaccine (Priorix-Tetra™): Immunogenicity and safety profile

Priorix-Tetra™ (GlaxoSmithKline Biologicals) is a combined measles, mumps, rubella and varicella (MMRV) vaccine. Eight studies involving more than 3000 children were reviewed. Compared with co-administration of MMR (Priorix™) and varicella (Varilrix™) vaccines, the MMRV vaccine showed: similar immunogenicity, with immunity shown up to 3 years post-vaccination; a higher rate of fever after the first dose; a slight increase in mild local reactions after the second dose. This MMRV vaccine can be used either as a two-dose vaccine or as a second dose in children primed with separate MMR and/or varicella vaccines, offering a convenient way to introduce varicella vaccination into routine vaccination programmes.     

Risk of febrile seizure after measles–mumps–rubella–varicella vaccine: A systematic review and meta-analysis

BackgroundConsidering the febrile seizure rate, there is no longer a clear preference for use of measles–mumps–rubella–varicella (MMRV) vaccine over separate measles–mumps–rubella (MMR) and varicella (V) vaccine. This work was undertaken to assess the risk of febrile seizure after MMRV vaccine in children.MethodsWe searched PubMed, Embase, BIOSIS Previews, Scopus, Web of Science, Cochrane Library and other databases through 12 December 2014. Meta-analysis was conducted using R version 3.1.2 and Stata version 12.0.ResultsA total of thirty-nine studies were included. Thirty-one published or unpublished clinical trials involving about 40,000 subjects did not show significant differences in incidence of febrile seizure or vaccine related febrile seizure between MMRV and MMR with or without varicella vaccine after any doses, in the risk windows of 0–28, 0–42 or 0–56 days and 7–10 days. In addition, these studies showed that the receipt of concomitant use of MMRV and other pediatric vaccines was not a significant predictor of febrile seizure. Eight post-marketing observations involving more than 3,200,000 subjects were included. No evidence suggested elevated risk of febrile seizure associated with MMRV vaccine among children aged 4–6 years old during 7–10 days or 0–42 days after vaccination. However, an approximately 2-fold increase in risk of seizure or febrile seizure during 7–10 days or 5–12 days after MMRV vaccination was found among children aged 10–24 months, although the highest incidence of seizure was still lower than 2.95‰.ConclusionsFirst MMRV vaccine dose in children aged 10–24 months was associated with an elevated risk of seizure or febrile seizure. Further post-marketing restudies based on more rigorous study design are needed to confirm the findings.     

Parental acceptance of and preferences for administration of routine varicella vaccination in the UK: A study to inform policy

ObjectivesTo explore acceptability of and preferences for the introduction of varicella vaccination to the UK childhood immunisation schedule.DesignWe conducted an online cross-sectional survey exploring parental attitudes towards vaccines in general, and varicella vaccine specifically, and their preferences for how the vaccine should be administered.Participants596 parents (76.3% female, 23.3% male, 0.4% other; mean age 33.4 years) whose youngest child was aged 0–5 years.Main outcome measuresWillingness to accept the vaccine for their child and preferences for how the vaccine should be administered (in combination with the MMR vaccine [MMRV], on the same day as the MMR vaccine but as a separate injection [MMR + V], on a separate additional visit).Results74.0% of parents (95% CI 70.2% to 77.5%) were extremely/somewhat likely to accept a varicella vaccine for their child if one became available, 18.3% (95% CI 15.3% to 21.8%) were extremely/somewhat unlikely to accept it and 7.7% (95% CI 5.7% to 10.2%) were neither likely nor unlikely. Reasons provided by parents likely to accept the vaccine included protection from complications of chickenpox, trust in the vaccine/healthcare professionals, and wanting their child to avoid their personal experience of chickenpox. Reasons provided by parents who were unlikely included chickenpox not being a serious illness, concern about side effects, and believing it is preferable to catch chickenpox as a child rather than as an adult. A combined MMRV vaccination or additional visit to the surgery were preferred over an additional injection at the same visit.ConclusionsMost parents would accept a varicella vaccination. These findings highlight parents’ preferences for varicella vaccine administration, information needed to inform vaccine policy and practice and development of a communication strategy.     

Febrile seizures following measles and varicella vaccines in young children in Australia

BackgroundFebrile seizures (FS) are common in childhood with incidence peaking in the second year of life when measles and varicella-containing vaccines are administered. This study aimed to examine the vaccine-attributable risk of FS following separate administration of MMR and monovalent varicella vaccines (VV) prior to a planned change to MMRV as the second dose of measles-containing vaccine at 18 months of age.MethodsAll FS cases in children aged <5 years from 1st January 2012 to 30th April 2013 were identified from emergency department (ED) and inpatient databases at five Australian tertiary paediatric hospitals participating in PAEDS (Paediatric Active Enhanced Disease Surveillance). Immunization records were obtained from the Australian Childhood Immunization Register (ACIR). The relative incidence (RI) of FS following MMR dose 1 (MMR1) and VV in children aged 11–23 months was determined using the self-controlled case series (SCCS) method and used to calculate attributable risk.ResultsThere were 2013 FS episodes in 1761 children. The peak age at FS was 18 months. The risk of FS was significantly increased 5–12 days post receipt of MMR1 at 12 months (RI = 1.9 [95% CI: 1.3–2.9]), but not after VV at 18 months (RI = 0.6 [95% CI: 0.3–1.2]. The estimated excess annual number of FS post MMR1 was 24 per 100,000 vaccinated children aged 11–23 months (95% CI = 7–49 cases per 100,000) or 1 per 4167 doses.ConclusionsOur study detected the expected increased FS risk post MMR1 vaccine at 12 months, but monovalent varicella vaccine at age 18 months was not associated with increased risk of FS. This provides baseline data to assess the risk of FS post MMRV, introduced in Australia as the second dose of measles-containing vaccine at 18 months of age in July 2013.     

Safety and immunogenicity of a measles–mumps–rubella–varicella vaccine given as a second dose in children up to six years of age

Two doses of measles–mumps–rubella vaccine (MMR) are widely recommended and consideration is being given to a similar schedule for varicella vaccine. A combined measles–mumps–rubella–varicella vaccine (MMRV) could be considered for this second dose in children previously vaccinated separately with MMR and varicella vaccines. Healthy children (N = 390) aged 15–75 months (median 54 months) previously immunized with MMR and varicella vaccines were randomly allocated to receive MMRV or separate injections of MMR and varicella vaccines. Before administration of study vaccines, seropositivity rates were 96.4% for measles, 94.3% for mumps, 99.5% for rubella, and 97.9% for varicella. Post-immunization, seropositivity rates were 99.5% for measles and mumps and 100% for rubella and varicella in the MMR + varicella group and 100% for all four antigens in the MMRV group; a 26.2- and 27.2-fold increase in varicella titer was observed in the MMR + varicella vaccine and MMRV groups, respectively. Except for more frequent pain in the MMRV group (33.3% vs. 23.7%, p = 0.043), there were no differences in the incidence of local and solicited symptoms between groups. In children primed with MMR and varicella vaccine, MMRV had non-inferior immunogenicity and similar safety profiles as a second dose of licensed MMR and varicella vaccine administered concomitantly.     

Immunogenicity and safety of measles-mumps-rubella-varicella (MMRV) vaccine followed by one dose of varicella vaccine in children aged 15 months–2 years or 2–6 years primed with measles-mumps-rubella (MMR) vaccine

In this open, randomized, comparative study (105908/NCT00353288), 458 age-stratified children (15 months–2 years and 2–6 years) previously primed with MMR received one dose of either a combined MMRV vaccine (Priorix-Tetra™, MMRV group) or concomitant MMR and varicella vaccines (Priorix™ and Varilrix™, MMR + V group), followed 42–56 days later by another dose of varicella vaccine (Varilrix™) in both groups. Post-vaccination measles, mumps and rubella seropositivity rates and antibody geometric mean titers (GMTs) were high (99.5% for anti-measles and 100% for anti-mumps and anti-rubella) in both vaccine groups. In the two age strata, varicella seroconversion rates were, post-dose 1: ≥97.6% (MMRV), ≥96.6% (MMR + V) and, post-dose 2: 100% in both groups. Post-dose 2, anti-varicella GMTs increased respectively 14.1- and 12.6-fold (MMRV), and 9.8- and 13.1-fold (MMR + V). Both vaccine regimens were well-tolerated. Post-dose 1, the incidence of any solicited local symptom during the 4-days follow-up was ≤28.2% (MMRV) and ≤19.8% (MMR + V) and the incidence of fever >39.5 °C (rectal temperature) within 15 days was ≤2.8% (MMRV) and ≤2.6% (MMR + V). This MMRV vaccine appears an immunogenic and safe substitute for a second dose of MMR vaccine in young children. The increase in anti-varicella antibodies observed after a second dose of varicella vaccine supports a two-dose schedule for varicella-containing vaccine.     

Assessment of pre-specified adverse events following varicella vaccine: A population-based self-controlled risk interval study

BackgroundClinical trials and spontaneous reporting systems have revealed rare but biologically plausible adverse events following varicella immunization. Few post-marketing controlled studies have been conducted to assess the relationship between the varicella vaccine and these outcomes.ObjectivesTo evaluate the risk of pneumonia, idiopathic thrombocytopenic purpura (ITP), meningitis, encephalitis and ischemic stroke following varicella immunization.Materials and methodsThis nationwide observational study was based on Taiwan National Health Insurance data and National Immunization Information System from 2004 through 2014. Primary analysis included children aged 12–35 months who received the single varicella vaccine on the date of administration. The self-controlled risk interval design compared the incidence of pre-specified outcomes during a risk interval of 1–42 days post-vaccination and a control interval of 43–84 days. The outcomes of interest were defined as admitted pneumonia, ITP, meningitis, encephalitis, and ischemic stroke, as well as fracture as a negative control. Conditional Poisson regression was used to assess the incidence rate ratio (aIRR) with adjustments for age and seasonal effects.ResultsAmong 1,194,189 children, who receiving the varicella vaccine, there was no observed increase in the risk for ITP (aIRR 1.00; 95% CI, 0.76–1.33), meningitis (aIRR 1.21; 95% CI, 0.49–2.95), encephalitis (aIRR 1.00; 95% CI, 0.62–1.60), or ischemic stroke (aIRR 1.24; 95% CI, 0.31–4.95). A clustering feature with pneumonia occurred during days 36–42 post-vaccination (aIRR 1.10; 95% CI, 1.02–1.18). An increase in the risk for ITP was observed in children receiving the varicella and MMR vaccines concomitantly (aIRR 1.70; 95% CI, 1.19–2.43), but not among those receiving the varicella vaccine only.ConclusionsWe detected a small risk of incidental pneumonia associated with varicella vaccine in the 6th week after immunization. There was no increase in the risk of other pre-specified adverse events.     

Frequency and cost of live vaccines administered too soon after prior live vaccine in children aged 12 months through 6 years, 2014–2017

ObjectiveTo identify number of children who received live vaccines outside recommended intervals between doses and calculate corrective revaccination costs.MethodsWe analyzed >1.6 million vaccination records for children aged 12 months through 6 years from six immunization information system (IIS) Sentinel Sites from 2014–15 when live attenuated influenza vaccine (LAIV, FluMist® Quadrivalent) was recommended for use, and from 2016–17, when not recommended for use. Depending on the vaccine, insufficient intervals between live vaccine doses are less than 24 or 28 days from a preceding live vaccine dose. Private and public purchase costs of vaccines were used to determine revaccination costs of live vaccine doses administered during the live vaccine conflict interval. Measles, mumps, rubella (MMR), varicella, combined MMRV, and LAIV were live vaccines evaluated in this study.ResultsAmong 946,659 children who received at least one live vaccine dose from 2014–15, 4,873 (0.5%) received at least one dose too soon after a prior live vaccine (revaccination cost, $786,413) with a median conflict interval of 16 days. Among 704,591 children who received at least one live vaccine dose from 2016–17, 1,001 (0.1%) received at least one dose too soon after a prior live vaccine (revaccination cost, $181,565) with a median conflict interval of 14 days. The live vaccine most frequently administered outside of the recommended intervals was LAIV from 2014–15, and varicella from 2016–17.ConclusionsLive vaccine interval errors were rare (0.5%), indicating an adherence to recommendations. If all invalid doses were corrected by revaccination over the two time periods, the cost within the IIS Sentinel Sites would be nearly one million dollars. Provider awareness about live vaccine conflicts, especially with LAIV, could prevent errors, and utilization of clinical decision support functionality within IISs and Electronic Health Record Systems can facilitate better vaccination practices.     

Chickenpox: sufficient reasons for the introduction of vaccination

The incidence of chickenpox and its complications is high enough to favour introducing varicella vaccination into the Dutch immunisation programme for children, although current Dutch figures may even underestimate the incidence. Safe and effective MMRV vaccines, in which varicella (V) vaccine is combined with measles, mumps and rubella (MMR), could well replace the MMR vaccine used at present. MMRV vaccines should be administered subcutaneously in two doses. Ten years after the introduction of varicella vaccination in the United States of America, the incidence of complications has decreased impressively. An effect on the incidence of herpes zoster has not (yet) been seen.     

Influences on immunization rates: Vaccination coverage of mumps,measles, rubella and varicella before and after the STIKO intervention 2011 – A retrospective study

BackgroundIn September 2011, the German Standing Committee on Vaccinations (STIKO) changed their recommendation regarding the mumps–measles–rubella–varicella vaccination (MMRV). We compared the immunization rates against MMRV in Germany before and after the STIKO intervention.MethodsWe recorded the immunization status of children born between 09/2008 and 08/2012 in 35 selected doctor’s surgeries in Germany.ResultsAfter the STIKO intervention, the ratio of the combined MMRV vaccine as the first dose immunization was reduced to approximately 25% of the initial value. A slight increase in the number of children not sufficiently vaccinated against varicella (1.2%) was observed, but the immunization rates against measles, mumps, rubella and varicella did not significantly decrease.ConclusionsThe STIKO intervention led to a significant change in physicians’ vaccination procedures. The separate administration MMR + V vaccination may be a helpful option to improve the immunization rates in general.     

Priming with MF59 adjuvanted versus nonadjuvanted seasonal influenza vaccines in children – A systematic review and a meta-analysis

BackgroundIdentifying optimal priming strategies for children <2 years could substantially improve the public health benefits of influenza vaccines. Adjuvanted seasonal influenza vaccines were designed to promote a better immune response among young vaccine-naïve children.MethodsWe systematically reviewed randomized trials to assess hemagglutination inhibition (HAI) antibody response to MF59-adjuvanted inactivated influenza vaccine (aIIV) versus nonadjuvanted IIV among children. We estimated pooled ratios of post-vaccination HAI geometric mean titer (GMT) for aIIV versus IIV and confidence intervals (CIs) using the pooled variances derived from reported CIs.ResultsMean age was 28 months (range, 6–72 months). Children received vaccines with either 7.5 μg (6–35 months) or 15 μg (≥36 months) hemagglutinin of each strain depending on age. Seven of eight trials administered trivalent vaccines and one used quadrivalent vaccine. Pooled post-vaccination GMT ratios against the three influenza vaccine strains were 2.5–3.5 fold higher after 2-dose-aIIV versus 2-dose-IIV among children 6–72 months, and point estimates were higher among children 6–35 months compared with older children. When comparing 1-dose-aIIV to 2-dose-IIV doses, pooled GMT ratios were not significantly different against A/H1N1 (1.0; 95% CI: 0.5–1.8; p = 0.90) and A/H3N2 viruses (1.0; 95% CI: 0.7–1.5; p = 0.81) and were significantly lower against B viruses (0.6; 95% CI: 0.4–0.8; p < 0.001) for both age groups. Notably, GMT ratios for vaccine-mismatched heterologous viruses after 2-dose-aIIV compared with 2-dose-IIV were higher against A/H1N1 (2.0; 95% CI: 1.1–3.4), A/H3N2 (2.9; 95% CI: 1.9–4.2), and B-lineage viruses (2.1; 95% CI: 1.8–2.6).ConclusionsTwo doses of adjuvanted IIV consistently induced better humoral immune responses against Type A and B influenza viruses compared with nonadjuvanted IIVs in young children, particularly among those 6–35 months. One adjuvanted IIV dose had a similar response to two nonadjuvanted IIV doses against Type A influenza viruses. Longer-term benefits from imprinting and cell-mediated immunity, including trials of clinical efficacy, are gaps that warrant investigation.     

Risk factors and familial clustering for fever 7–10 days after the first dose of measles vaccines

BackgroundSeven to ten days after a first dose of a measles-containing vaccine (MCV; i.e., MMR or MMRV), children have elevated fever risk which can be associated with febrile seizures. This study investigated individual and familial factors associated with fever 7–10 days after MCV.MethodsRetrospective cohort study among children who were <36 months of age at receipt of MCV in six sites of the Vaccine Safety Datalink from 1/1/2000 to 12/31/2012. We evaluated medically-attended clinic or emergency department visits with a code for fever 7–10 days after any MCV (“MCV- associated”). We evaluated factors associated with MCV-associated fever using χ² and multivariable logistic regression analyses.ResultsAmong 946,806 children vaccinated with MCV, we identified 7480 (0.8%) MCV-associated fever visits. Compared with children without fever after MCV, children with MCV-associated fever were more likely to have received MMRV than MMR (OR 1.3 95% CI 1.2, 1.5), have had medically attended fever both following previous vaccines (OR 1.3 95% CI 1.1, 1.6) and at any other previous time (OR 1.7 95% CI 1.6, 1.8), have had at least 1 prior seizure (OR 2.2 95% CI 1.7, 2.7), and have had >3 medical visits within the 6 months before MCV (OR 1.7 95% CI 1.6, 1.8). In families with multiple MCV-immunized children, after adjusting for healthcare seeking behavior care for fever, those whose siblings had MCV-associated fever were more likely to also have MCV-associated fever (OR 3.5 95% CI 2.5, 4.8).DiscussionChildren who received MMRV vaccine or who had prior medically-attended fevers and seizures during the first year of life had increased risk of fever after a first dose of measles vaccine. After adjusting for familial propensity to seek care, MCV-associated fever still clustered within families, suggesting a possible genetic basis for susceptibility to developing fever due to measles vaccines.     

Decline of varicella vaccination in German surveillance regions after recommendation of separate first-dose vaccination for varicella and measles–mumps–rubella

Background

Germany introduced routine varicella (V) vaccination in 2004. Due to a slightly increased risk of febrile convulsions after first-dose application of combined measles–mumps–rubella–varicella (MMRV) vaccine separate first-dose vaccinations with MMR and monovalent V vaccine were recommended in September 2011.

Methods

We compared V and MMR vaccinations in paediatric practices from two surveillance regions (Munich and Würzburg) one year before and after the change in the recommendation.

Results

A total of 1405/326 monthly reports were provided by a monthly average of 79/14 practices participating in Munich/Würzburg. V first-dose vaccinations (monovalent V or MMRV vaccine) declined by 12% in Munich (from 10.1 to 8.9 vaccinations per month and practice; p < 0.005) and by 4% in Würzburg (from 9.9 to 9.5; p = 0.620), respectively. First-dose vaccinations for MMR (MMR or MMRV vaccine) did not change significantly in both regions.

Conclusion

Acceptance of V vaccination depends in part on the use of combination vaccine.     

Risk of febrile convulsions after MMRV vaccination in comparison to MMR or MMR+V vaccination

Background

In July 2006, Priorix-Tetra™, a combined measles-mumps-rubella-varicella (MMRV) vaccine, was licensed in Germany. Since a postlicensure study had shown a more than twofold elevated risk of febrile convulsions (FC) after first dose vaccination with the combined MMRV vaccine ProQuad^® compared to separately administered MMR and V vaccines (MMR+V), the Paul-Ehrlich-Institute, the German regulatory agency for vaccine licensing and safety, requested a study investigating the risk of FC for Priorix-Tetra™.

Methods

We performed a matched cohort study based on claims data of more than 17 million insurees in the German Pharmacoepidemiological Research Database. All children born between 01.01.2004 and 31.12.2008 who received a 1st dose of MMRV vaccine were matched to children vaccinated with MMR, MMR+V and MMR or MMR+V (combined group), respectively, by sex, age, month of vaccination and statutory health insurance. The primary outcome was defined as hospitalization with a diagnosis of FC without any alternative plausible cause of FC, e.g. an infection or neurological condition, coded as main discharge diagnosis. The secondary outcome excluded only neurological conditions to provide a more comparable outcome definition to the one used in the ProQuad^® study. Numbers needed to harm (NNH), risk ratios and confounder adjusted odds ratios (ORs) with 95% CIs were estimated to compare the exposure groups.

Results

In the main risk period 5–12 days after immunization, the adjusted ORs of the primary endpoint for immunization with MMRV vaccine relative to the comparator vaccine indicated in brackets were 4.1 [95% CI 1.3–12.7; MMR], 3.5 [0.7–19.0; MMR+V], and 4.1 [1.5–11.1; MMR and MMR+V]. The corresponding ORs for the secondary outcome were 2.3 [1.4–3.9; MMR], 1.5 [0.8–2.9; MMR+V] and 2.4 [1.5–3.9; MMR and MMR+V].

Conclusions

This study in children younger than 5 years, 90% of them between 11 and 23 months, shows a risk of FC similar in magnitude for Priorix-Tetra™ as has previously been reported for ProQuad^® suggesting a class effect for these quadrivalent vaccines.     

The immunogenicity and safety of a tetravalent measles-mumps-rubella-varicella vaccine when co-administered with conjugated meningococcal C vaccine to healthy children: A phase IIIb,randomized, multi-center study in Italy

IntroductionMultiple vaccination visits and administrations can be stressful for infants, parents and healthcare providers. Multivalent combination vaccines can deliver the required number of antigens in fewer injections and clinic visits, while vaccine co-administration can also reduce the number of visits. This non-inferiority study was undertaken to evaluate the feasibility of co-administering a combined measles-mumps-rubella-varicella (MMRV) vaccine with conjugated meningococcal C (MenC) vaccine in a large cohort of healthy Italian toddlers.MethodsHealthy subjects aged 13–15 months were randomized (2:1:1) to receive single doses of either: co-administered MMRV + MenC at the same visit (MMRV + MenC group); or MMRV followed 42 days later by MenC (MMRV group); or MenC followed 42 days later by MMRV (MenC group). Blood samples were collected before and 43 days after vaccination. Antibody titers against MMRV were measured using ELISA. Functional-anti-meningococcal-serogroup activity (rSBAMenC) was assessed using a serum bactericidal test. Solicited local and general reactions were recorded for up to 4 and 42 days post-vaccination, respectively. Non-inferiority of MMRV + MenC to MMRV (post-dose-1 seroconversion rates) and MMRV + MenC to MenC (post-dose-1 seroprotection rates) was achieved if the lower limit (LL) of the 95% confidence interval (CI) for the group difference was ⩾−10% for each antigen.Results716 subjects were enrolled in the study. At 42 days post-vaccination, the MMRV seroconversion rates were 99.3% (measles), 94.5% (mumps), 100% (rubella) and 99.7% (varicella) in the MMRV + MenC group, and 99.4%, 93.2%, 100% and 100%, respectively, in the MMRV group. The seroprotection rates against rSBA-MenC were 98.3% in the MMRV + MenC group and 99.3% in the MenC group. Non-inferiority was reached for all the vaccine antigens. The safety profiles were as expected for these vaccines.ConclusionThe immune responses elicited by co-administered MMRV + MenC were non-inferior to those elicited by MMRV or MenC alone and support vaccination of children with both vaccines at a single visit.Clinical Trials registration: NCT01506193.     

Association of the use of MMRV in infants by pediatric infectious disease specialists with that of other affiliated providers

Background

In an effort to maximize vaccine acceptance by minimizing adverse events following immunization associated with fever, including seizures, the Advisory Committee on Immunization Practices (ACIP) recommended in 2009 the use of measles, mumps and rubella vaccine (MMR) and varicella vaccines (V) given separately (MMR + V) rather than combination MMRV as the first dose of MMR-containing vaccine to infants. We evaluated factors associated with continued administration of MMRV as the first dose in many infants despite the ACIP recommendation.

Methods

Children 12 to 23 months of age who received MMRV or MMR + V between May 1, 2010 and April 30, 2011 were identified. Patient, provider and facility characteristics associated with MMRV or MMR + V administration were analyzed by bivariate and by multilevel multivariable logistic regression analysis.

Results

Altogether, 30,017 children received the first dose of MMRV or MMR + V at 12 to 23 months of age between May 1, 2010 and April 30, 2011. Of these, 10.2% received MMRV while 89.8% received MMR + V. MMRV was more likely to be administered to children who were non-compliant with vaccine recommendations at age one (adjusted odds ratio = 1.48, 95%CI = 1.28, 1.71). In addition, administration of MMRV by a Pediatric Infectious Disease specialist affiliated with a clinic was significantly associated with an increased likelihood of administration of MMRV by other providers at that clinic (interval odds ratio 80 = 2.18, 675.94, P(OR > 1) = 95%).

Conclusions

These data suggest that while most providers followed the ACIP recommendation to administer MMR and V separately, Pediatric Infectious Disease specialists’ vaccination practices may impact compliance with ACIP recommendations by other providers. Further study of the drivers behind the use of MMRV rather than MMR + V as the first dose of measles-containing vaccine is needed to determine if reinforcement or if clarification of ACIP recommendations is needed to elucidate when MMRV might be preferred over MMR + V.