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.

A randomized trial assessing the efficacy, immunogenicity, and safety of vaccination with live attenuated varicella zoster virus-containing vaccines: ten-year follow-up in Russian children.

In Russia, a universal varicella vaccination (UVV) program has not been implemented, and varicella vaccination coverage is low. We assessed the efficacy, antibody persistence, and safety of one- and two-dose varicella vaccination schedules in Russian children with a ten-year follow-up period, as part of an international phase IIIB, observer-blind, randomized, controlled trial (NCT00226499). Children aged 12-22 months were randomized (3:3:1) to receive two doses of tetravalent measles-mumps-rubella-varicella vaccine (V2 group), one dose trivalent measles-mumps-rubella (MMR) vaccine and one dose of varicella vaccine (V1 group), or two doses of MMR vaccine (V0 [control] group), 42 days apart. Main study outcomes were: vaccine efficacy (VE) against confirmed varicella cases, anti-varicella zoster virus (VZV) seropositivity rates and geometric mean concentrations, and reporting of (serious) adverse events ([S]AEs). The total vaccinated cohort in Russia comprised 1000 children; 900 were followed up until study end (year [Y] 10). VE estimates against confirmed varicella (Y10) were 92.4% in the V2 group and 74.7% in the V1 group. Anti-VZV seropositivity rates remained ≥99.4% in the V2 group and ≥89.7% in the V1 group from day 42 post-vaccination 2 until Y10. Occurrence of (un)solicited AEs and SAEs was similar across groups and confirmed the safety profile of the vaccines. No vaccination-related SAEs or deaths were reported. These results are consistent with the global trial results, i.e., the highest VE estimates observed following the two-dose schedule compared to the one-dose schedule. These data may inform decision-making related to potential implementation of a UVV program.

What is the context?Varicella is a common childhood disease caused by the highly contagious varicella zoster virus.Varicella vaccines have been used for more than three decades.A large clinical trial conducted in ten countries assessed the efficacy and safety of one dose of monovalent varicella vaccine or two doses of combined varicella vaccine (MMRV). The enrolled children were also followed up for a ten-year period to evaluate the persistence of the immune response and the long-term efficacy of the vaccine.What is new?Here, we present the long-term efficacy, immunogenicity, and safety results in the cohort of children enrolled in Russia, as part of the global ten-year follow-up study. We found that:The monovalent and combined vaccines reduced the number of varicella cases.The MMRV two-dose regimen displayed higher efficacy in preventing varicella of all severities compared to the one-dose regimen.The immune response conferred by the vaccine persisted up to ten years post-vaccination.No vaccination-related deaths occurred, and no safety concerns were raised.What is the impact?Vaccination against varicella resulted in long-term protective efficacy and antibody persistence over ten years post-vaccination in Russian children.Although one-dose varicella vaccination was effective at protecting against varicella, a two-dose schedule provided a more complete protection. This could inform health policy decisions regarding the implementation of varicella vaccination in routine immunization program in Russia.

Randomised controlled trial showed long-term efficacy, immunogenicity and safety of varicella vaccines in Norwegian and Swedish children.

AIM: Several countries, such as Norway and Sweden, have not implemented universal varicella vaccination. We present data for Norway and Sweden that were generated by a paediatric multi-country Phase III study over a 10-year period. This assessed the efficacy, antibody persistence and safety of two varicella vaccines containing the same Oka strain. METHODS: This was an observer-blind, controlled trial conducted in 10 European countries. Children aged 12-22 months (n = 5803) were randomised 3:3:1 and vaccinated between 1 September 2005 and 10 May 2006. The two-dose group received two tetravalent measles-mumps-rubella-varicella vaccine doses. The one-dose group received one monovalent varicella vaccine dose after a measles-mumps-rubella vaccine dose. Control group participants received two measles-mumps-rubella vaccine doses. Main study outcomes were vaccine efficacy against confirmed varicella cases and incidence of adverse events. RESULTS: Vaccine efficacy in the two-dose group was ≥92.1% in both Norwegian and Swedish children compared to 72.3% in Norway and 58.0% in Sweden in the one-dose group. Incidences of adverse events and serious adverse events were similar in the Norwegian and Swedish study populations. CONCLUSION: Consistent with overall study results, high efficacy against varicella and acceptable safety profiles of the two varicella vaccines were observed in Norwegian and Swedish populations. These findings highlight the benefits of varicella vaccines, particularly when administered as a two-dose schedule.

No Consistent Evidence of Decreased Exposure to Varicella-Zoster Virus Among Older Adults in Countries with Universal Varicella Vaccination.

BACKGROUND: Universal varicella vaccination might reduce opportunities for varicella-zoster virus (VZV) exposure and protective immunological boosting, thus increasing herpes zoster incidence in latently infected adults. We assessed humoral and cell-mediated immunity (CMI), as markers of VZV exposure, in adults aged ≥50 years. METHODS: We repurposed data from placebo recipients in a large multinational clinical trial (ZOE-50). Countries were clustered based on their varicella vaccination program characteristics, as having high, moderate, or low VZV circulation. Anti-VZV antibody geometric mean concentrations, median frequencies of VZV-specific CD4 T cells, and percentages of individuals with increases in VZV-specific CD4 T-cell frequencies were compared across countries and clusters. Sensitivity analyses using a variable number of time points and different thresholds were performed for CMI data. RESULTS: VZV-specific humoral immunity from 17 countries (12 high, 2 moderate, 3 low circulation) varied significantly between countries (P < .0001) but not by VZV circulation. No significant differences were identified in VZV-specific CMI between participants from 2 high versus 1 low circulation country. In 3/5 sensitivity analyses, increases in CMI were more frequent in high VZV circulation countries (.03 ≤ P < .05). CONCLUSIONS: We found no consistent evidence of reduced VZV exposure among older adults in countries with universal varicella vaccination. CLINICAL TRIALS REGISTRATION: NCT01165177.

Clinically- versus serologically-identified varicella: A hidden infection burden. A ten-year follow-up from a randomized study in varicella-endemic countries.

Varicella-zoster virus (VZV) infections cause a substantial disease burden, which is underestimated due to incomplete reporting data and lack of serological surveillance. In this post-hoc analysis of a randomized, Phase IIIb clinical trial (NCT00226499) with a ten-year follow-up period, we report anti-VZV antibody levels and persistence in non-vaccinated children, as a varicella infection estimate in ten European countries with endemic varicella. The present analysis specifically focuses on clinical and serological data from the control group, which included 827 healthy participants aged 12-22 months who received two doses of measles-mumps-rubella (MMR) vaccine. The per-protocol cohort included 744 children for whom varicella occurrence was evaluated by clinical definitions, epidemiological links and PCR test outcomes. Anti-VZV antibody levels were assessed by ELISA. The primary objective of this analysis was to correlate varicella occurrence with anti-VZV antibody levels. Varicella was confirmed in 47% of MMR recipients. Among participants without reported varicella, the percentage of anti-VZV seropositive children increased to 75% and average anti-VZV antibody concentrations increased to 250 mIU/mL at year ten after vaccination, suggesting infection or exposure. An eight-fold increase in anti-VZV antibody concentrations between two consecutive visits, which is also observed after confirmed varicella, was detected in 37% of these participants during the follow-up period. About one-third of children not vaccinated against varicella and not diagnosed with varicella developed an anti-VZV immune response, suggesting subclinical varicella occurrence. Longitudinal studies combining serology and disease incidence are necessary to reliably estimate total varicella burden of infection.

Effectiveness of "Priorix" Against Measles and Mumps Diseases in Children Born After 2004 in the United Kingdom: A Retrospective Case-control Study Using the Clinical Practice Research Datalink GOLD Database.

BACKGROUND: Evidence on vaccine effectiveness (VE) may encourage vaccination and help fight the reemergence of measles and mumps in Europe. However, limited data exist on real-life effectiveness of individual measles, mumps and rubella (MMR) vaccines. This study evaluated VE of GSK's MMR vaccine ("Priorix") against measles and mumps. METHODS: This retrospective, case-control study used UK data from the Clinical Practice Research Datalink GOLD linked to the Hospital Episode Statistics database to identify children 1-13 years old diagnosed with measles or mumps from January 2006 to December 2018. Cases were matched to controls according to birth month/year and practice region. Cases were identified using clinical codes (without laboratory confirmation). "Priorix" exposure was identified using vaccine batch identifiers. Children exposed to other MMR vaccines were excluded. Adjusted VE was estimated for ≥1 vaccine dose in all children, and for 1 dose and ≥2 doses in children ≥4 years at diagnosis. RESULTS: Overall, 299 measles cases matched with 1196 controls (87.6% <4 years old), and 243 mumps cases matched with 970 controls (74.2% <4 years old) were considered. VE for ≥1 dose in all children was 78.0% (97.5% confidence interval: 67.2%-85.3%) for measles and 66.7% (48.1%-78.6%) for mumps. In children ≥4 years old, VE after 1 dose was 74.6% (-21.7% to 94.7%) for measles and 82.3% (32.7%-95.3%) for mumps, and VE after ≥2 doses was 94.4% (79.7%-98.5%) for measles and 86.5% (64.0%-94.9%) for mumps. CONCLUSIONS: "Priorix" is effective in preventing measles and mumps in real-life settings.

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.

BACKGROUND: We 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. METHODS: This 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. RESULTS: A 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. CONCLUSIONS: Our 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.

Correlation of protection against varicella in a randomized Phase III varicella-containing vaccine efficacy trial in healthy infants.

BACKGROUND: Varicella vaccination confers high and long-lasting protection against chickenpox and induces robust immune responses, but an absolute correlate of protection (CoP) against varicella has not been established. This study models the relationship between varicella humoral response and protection against varicella. METHODS: This was a post-hoc analysis of data from a Phase IIIb, multicenter, randomized trial (NCT00226499) conducted in ten varicella-endemic European countries. Healthy children aged 12-22 months were randomized 3:3:1 to receive one dose of measles-mumps-rubella and one dose of varicella vaccine (one-dose group) or two doses of measles-mumps-rubella-varicella vaccine (two-dose group) or two doses of measles-mumps-rubella vaccine (control group) six weeks apart. The study remained observer-blind until completion, except in countries with obligatory additional immunizations. The objective was to correlate varicella-specific antibody concentrations with protection against varicella and probability of varicella breakthrough, using Cox proportional hazards and Dunning and accelerated failure time statistical models. The analysis was guided by the Prentice framework to explore a CoP against varicella. RESULTS: The trial included 5803 participants, 5289 in the efficacy (2266: one-dose group, 2279: two-dose group and 744: control group) and 5235 (2248, 2245 and 742 in the same groups) in the immunogenicity cohort. The trial ended in 2016 with a median follow-up time of 9.8 years. Six weeks after vaccination with one- or two-dose varicella-containing vaccine, more than 93.0% of vaccinees were seropositive for varicella-specific antibodies. Estimated vaccine efficacy correlated positively with antibody concentrations. The fourth Prentice CoP criterion was not met, due to predicted positive vaccine efficacy in seronegative participants. Further modelling showed decreased probability of moderate to severe varicella breakthrough with increasing varicella-specific antibody concentrations (ten-year probability <0.1 for antibody concentrations ≥2-fold above the seropositivity cut-off). CONCLUSIONS: Varicella-specific antibody concentrations are a good predictor of protection, given their inverse correlation with varicella occurrence. CLINICAL TRIAL: NCT00226499.

Concomitant administration of a liquid formulation of human rotavirus vaccine (porcine circovirus-free) with routine childhood vaccines in infants in the United States: Results from a phase 3, randomized trial.

BACKGROUND: In response to the detection of porcine circovirus type 1 (PCV-1) in the human rotavirus vaccine (HRV), a PCV-free HRV (no detection of PCV-1 and PCV-2 according to the detection limit of tests used) was developed. Liquid (Liq) PCV-free HRV previously showed immunogenicity and safety profiles comparable to lyophilized (Lyo) HRV. METHODS: This was a phase 3a, randomized, single-blind study (NCT03207750) conducted in the United States. Healthy infants aged 6-12 weeks received 2 doses (0, 2 months) of either Liq PCV-free HRV or Lyo HRV with routine vaccines (0, 2, 4 months): diphtheria-tetanus-acellular pertussis, hepatitis B and inactivated poliovirus combination vaccine (DTaP-HBV-IPV), monovalent tetanus toxoid-conjugated vaccine against Haemophilus influenzae type b (Hib-TT), and 13-valent pneumococcal conjugate vaccine. Co-primary objectives were: (i) to assess non-inferiority of immune responses to routine vaccine antigens 1 month post-dose 3 following co-administration with Liq PCV-free HRV compared to Lyo HRV; (ii) to rule out a 10% decrease in seroresponse to pertussis antigens after dose 3. Other objectives were to evaluate immunogenicity and safety of HRV vaccines. RESULTS: Of 1272 vaccinated infants, 990 (489 in Liq PCV-free HRV and 501 in Lyo HRV group) were included in the per-protocol set. All statistical criteria were met, thus co-primary objectives were demonstrated. Seroprotection/seropositivity rates in both groups were high: 100% for diphtheria/tetanus, ≥99.3% for HBV, ≥99.8% for polio, ≥99.8% for each pertussis antigen, ≥90.8% for all pneumococcal serotypes except serotype 3 (≥69.1%), and ≥ 97.4% for Hib. Most infants seroconverted for anti-RV antibodies (76.3% of Liq PCV-free HRV and 78.9% of Lyo HRV recipients). Geometric mean concentrations/titers were comparable between groups. Incidences of adverse events and serious adverse events were similar between groups. CONCLUSION: Routine pediatric vaccines co-administered with Liq PCV-free HRV showed non-inferior immune responses and similar safety profiles to those following co-administration with Lyo HRV.

Comparison of a glycoprotein E-based ELISA with a varicella-zoster whole-virus ELISA for the quantification of varicella vaccine immune responses in young children.

Antibody response against varicella-zoster virus (VZV) is frequently assessed by whole-virus- (anti-VZV) or glycoprotein-based ELISAs. This study compared antibody concentrations measured by an assay quantifying anti-VZV glycoprotein E (anti-gE) and anti-VZV ELISA in 12-23-month-olds, receiving two varicella vaccine doses in a phase III trial (NCT02570126). Samples (pre- and 42 days post-each vaccination) initially tested with anti-VZV ELISA were re-tested with anti-gE ELISA. Of 1138 samples from 397 children, 757 were positive by anti-VZV (antibody concentration ≥25 mIU/mL) and 758 by anti-gE ELISA (≥97 mIU/mL). There were 375 double-negative and only 11 discrepant samples. The overall agreement was 99.03% (95% confidence interval: 98.28-99.52; McNemar p-value = 1). The ratio between antibody geometric mean concentrations (anti-gE/anti-VZV) for the 752 double-positive samples was 3.78 overall, 4.75 post-first, and 3.01 post-second vaccination. The anti-gE ELISA is a valid alternative for trials assessing antibody response to new varicella vaccines versus established ones, used as control.

Immunogenicity and Safety of a Measles-Mumps-Rubella Vaccine Administered as a First Dose to Children Aged 12 to 15 Months: A Phase III, Randomized, Noninferiority, Lot-to-Lot Consistency Study.

BACKGROUND: MMR II (M-M-R II [Merck & Co, Inc.]) is currently the only measles, mumps, and rubella (MMR) vaccine licensed in the United States. A second MMR vaccine would mitigate the potential risk of vaccine supply shortage or delay. In this study, we assessed the immunogenicity and safety of another MMR vaccine (MMR-RIT [Priorix, GlaxoSmithKline]) compared with those of the MMR II in 12- to 15-month-old children who received it as a first dose. METHODS: In this phase III, observer-blinded, noninferiority, lot-to-lot consistency clinical trial (ClinicalTrials.gov identifier NCT01702428), 5003 healthy children were randomly assigned to receive 1 dose of MMR-RIT (1 of 3 production lots) or MMR II along with other age-recommended routine vaccines. We evaluated the immunogenicity of all vaccines in terms of antibody concentrations (by using an enzyme-linked immunosorbent assay or electrochemiluminescence assay) and/or seroresponse rates 43 days after vaccination. We also assessed the reactogenicity and safety of the vaccines. RESULTS: Immunoresponses after vaccination with MMR-RIT were robust and noninferior to those after vaccination with the MMR II. Immunogenicity of the 3 production lots of MMR-RIT was consistent; more than 97% of the children had a seroresponse to MMR components. The coadministered vaccines elicited similar immunoresponses in the MMR-RIT and MMR II groups. Both MMR vaccines resulted in comparable reactogenicity profiles, and no safety concerns were detected. CONCLUSIONS: If licensed, the MMR-RIT could provide a valid option for the prevention of measles, mumps, and rubella in children in the United States and would reduce potential risks of a vaccine shortage.

Assessment of Mumps Virus-Specific Antibodies: Comparison of Plaque Reduction Neutralization Test and Enzyme-Linked Immunosorbent Assay Estimates.

BACKGROUND: The plaque reduction neutralization test (PRNT), which measures a subset of immunoglobulin antibodies (functional neutralizing antibodies), and the enzyme-linked immunosorbent assay (ELISA), which measures total immunoglobulin (neutralizing and nonneutralizing antibodies), characterize different aspects of the anti-mumps virus antibody response after vaccination. METHODS: Data from a recent phase 3 clinical trial (NCT01681992) of 2 measles-mumps-rubella vaccines were used to compare anti-mumps antibody responses measured using an unenhanced PRNT (GSK; seropositivity cutoff and threshold, 2.5 and 4 times the 50% end-point dilution, respectively) with those estimated using an ELISA (thresholds, 5 and 10 ELISA units/mL, respectively). RESULTS: Of 3990 initially seronegative samples, 3284 (82.3%) were seropositive after vaccination for anti-mumps antibodies in both assays. The Pearson correlation coefficient for double-positive samples was 0.57, indicative of a moderate correlation. Receiver operating characteristic curve analysis showed that an ELISA threshold of 51.7 ELISA units/mL best corresponded to the PRNT seroresponse threshold. There was no obvious vaccine brand effect on the correlation between assays. CONCLUSIONS: The moderate correlation between the anti-mumps antibody measurements obtained with PRNT and ELISA reflects different aspects of the serological response. In the absence of a well-defined protective serological threshold, PRNT provides complementary information on the antibody response, whereas ELISA remains a critically useful measurement of vaccine immunogenicity.

Long-term immunogenicity of measles, mumps and rubella-containing vaccines in healthy young children: A 10-year follow-up.

Measles and mumps outbreaks still occur in countries that have successfully implemented universal routine immunization programs. Measles outbreaks are mostly associated to absent or incomplete vaccination, whereas for mumps outbreaks the combined effects of waning of immunity and circulating new strains are incriminated. It is therefore increasingly useful to characterize the long-lasting immunity induced by measles-, mumps, and rubella (MMR)-containing vaccines. In this 10-year study, 1887 healthy children aged 12-22 months, randomized to receive 1 or 2 doses of MMR-containing vaccines (Priorix or Priorix-Tetra; GSK), were included in an antibody persistence analysis. A total of 364 children in the 1-dose group received a second dose out of study according to their local vaccination schedule between Years 4 and 10 post-dose 1, and were included in a separate post-hoc analysis to evaluate the effect of the second dose when given later. Anti-measles, -mumps and -rubella antibody titers were measured by commercial ELISA kits (Enzygnost, Siemens) after each vaccine dose and at Years 1, 2, 4, 6, 8 and 10 post-vaccination. Antibodies against measles and rubella declined moderately after vaccination but remained well above the seropositivity threshold after 10 years. The anti-measles antibody titers elicited by Priorix-Tetra remained about 2-fold higher throughout the study as compared with Priorix. A second dose of MMR vaccine later in life had a minor and transient effect on anti-measles and anti-rubella waning titers. In contrast, anti-mumps antibody levels remained relatively stable over the 10-year follow-up and a second dose of MMR vaccine, given anytime over the 10-year period, had a boosting effect on anti-mumps antibody titers and seropositivity rates. In conclusion, 1 or 2 doses of MMR-containing vaccines given to children in their second year of life induced antibody responses against measles, mumps and rubella viruses that persisted at least up to 10 years post-vaccination. Clinical trial registration number: NCT00226499.

Safety and immunogenicity of a varicella vaccine without human serum albumin (HSA) versus a HSA-containing formulation administered in the second year of life: a phase III, double-blind, randomized study.

BACKGROUND: A new formulation of the live-attenuated varicella vaccine Varilrix (GSK) produced without human serum albumin (HSA) was developed to minimize a theoretical risk of transmission of infectious diseases. A previous study showed that the vaccine was immunologically non-inferior to the HSA-containing vaccine and well-tolerated in toddlers; low-grade fever was numerically higher in children receiving the vaccine without HSA, but the study lacked power to conclude on this difference. METHODS: In this phase III, double-blind, multi-center study, healthy 12-23-month-olds were randomized (1:1) to receive two doses of the varicella vaccine without (Var-HSA group) or with HSA (Var + HSA group) at days 0 and 42. The primary objective compared safety of the vaccines in terms of incidence of fever > 39.0 °C in the 15-day period post-first vaccination. The objective was considered met if the upper limit of the 95% confidence interval for the between-group difference in the incidence of fever > 39.0 °C was ≤5% (Var-HSA group minus Var + HSA group). Safety, reactogenicity and immune responses were evaluated. RESULTS: Six hundred fifteen children in the Var-HSA group and 616 in the Var + HSA group received ≥1 vaccination. Fever > 39.0 °C was reported in 3.9 and 5.2% of participants in the Var-HSA and Var + HSA groups, with a between-group difference of - 1.29 (95% confidence interval: - 3.72-1.08); therefore, the primary objective was achieved. Fever rates post-each dose and the incidence of solicited local and general adverse events (AEs) were comparable between groups. Unsolicited AEs were reported for 43.9 and 36.5% of children in the Var-HSA group and 45.8 and 36.0% of children in the Var + HSA group, during 43 days post-dose 1 and 2, respectively. Serious AEs occurred in 2.1% (group Var-HSA) and 2.4% (group Var + HSA) of children, throughout the study. In a sub-cohort of 364 children, all had anti-varicella-zoster virus antibody concentrations ≥50 mIU/mL post-dose 2; comparable geometric mean concentrations were observed between the groups. CONCLUSIONS: The varicella vaccine formulated without HSA did not induce higher rates of fever during the 15 day-post-vaccination period, as compared with the original HSA-containing vaccine. The two vaccines displayed similar safety and immunogenicity profiles in toddlers. TRIAL REGISTRATION: NCT02570126 , registered on 5 October 2015 (www.clinicaltrials.gov).

Protection against varicella with two doses of combined measles-mumps-rubella-varicella vaccine or one dose of monovalent varicella vaccine: 10-year follow-up of a phase 3 multicentre, observer-blind, randomised, controlled trial.

BACKGROUND: The duration of protection provided by varicella vaccines is unclear. We assessed the 10-year vaccine efficacy of two doses of a combined measles-mumps-rubella-varicella vaccine (MMRV), one live attenuated varicella vaccine (V) dose given after one measles-mumps-rubella vaccine (MMR) dose (MMR + V), versus two MMR doses (control vaccine) for the prevention of confirmed varicella. METHODS: This was a phase 3b follow-up of an observer-blinded, randomised, controlled trial. In phase a, children aged 12-22 months (at first vaccination) from Czech Republic (Czechia), Greece, Italy, Lithuania, Norway, Poland, Romania, Russia, Slovakia, and Sweden were randomly assigned by computer-generated randomisation list (3:3:1) to receive two doses of MMRV, one dose of MMR and one dose of varicella vaccine, or two doses of MMR, 42 days apart. Varicella cases were confirmed by detection of viral DNA, or epidemiological link and clinical assessment, by an independent data monitoring committee; disease severity was based on a modified Vázquez scale. Hazard ratios for MMRV and MMR + V versus MMR estimated in the per-protocol cohort using a Cox proportional hazards regression model were used to calculate vaccine efficacy and 95% CI. Serious adverse events were recorded throughout the study in all vaccinated children. Study objectives were secondary and descriptive. The trial is registered at ClinicalTrials.gov, number NCT00226499. FINDINGS: Between Sept 1, 2005, and May 10, 2006, 5803 children (mean age 14·2 months, SD 2·5) were vaccinated. The per-protocol cohort included 2279 children from the MMRV group, 2266 from the MMR + V group, and 744 from the MMR group. From baseline to a median follow-up of 9·8 years, 76 (3%) children in the MMRV group, 469 (21%) in the MMR + V group, and 352 (47%) in the MMR group had varicella. Vaccine efficacy against all varicella was 95·4% (95% CI 94·0-96·4) for MMRV and 67·2% (62·3-71·5) for MMR + V; vaccine efficacy against moderate or severe varicella was 99·1% (97·9-99·6) for MMRV and 89·5% (86·1-92·1) for MMR + V. During phase b, serious adverse events were reported by 290 (15%) of 1961 children in the MMRV group, 317 (16%) of 1978 in the MMR + V group, and 93 (15%) of 641 in the MMR group. There were no treatment-related deaths. INTERPRETATION: The 10-years vaccine efficacy observed, suggests that a two-dose schedule of varicella vaccine provided optimum long-term protection for the prevention of varicella by offering individual protection against all severities of disease and leading to a potential reduction in transmission, as observed in the US experience with universal mass vaccination. FUNDING: GlaxoSmithKline Biologicals.

Immunogenicity and safety of a second dose of a measles-mumps-rubella vaccine administered to healthy participants 7 years of age or older: A phase III, randomized study.

The introduction of vaccination programs against measles, mumps, and rubella (MMR) led to significant global reduction in morbidity and mortality from these diseases. The currently recommended MMR vaccination schedule in the United States of America comprises 2 vaccine doses typically administered at 12-15 months and 4-6 years, respectively. Considering recent outbreaks in the USA, catch-up vaccination with an additional dose of MMR vaccine could contribute to outbreak control and community protection. This phase III, observer-blind, randomized controlled trial (NCT02058563) assessed the immunogenicity and safety of a dose of the MMR-RIT vaccine (Priorix, GSK) compared to MMR II vaccine (control; M-M-R II, Merck&Co Inc.) in ≥7-year-olds who had received ≥1 previous dose of MMR vaccine. We assessed anti-measles, anti-mumps, and anti-rubella antibody geometric mean concentrations (GMCs; primary endpoint) and seroresponse rates (SRRs) at day 42 post-vaccination. Solicited, unsolicited, and serious adverse events (AEs) were recorded. The according-to-protocol cohort for immunogenicity included 869 participants (MMR-RIT: N = 433; MMR II: N = 436). We observed anti-measles, anti-mumps, and anti-rubella antibody GMCs of 1790.2 mIU/mL, 113.5 EU/mL, and 76.1 IU/mL, respectively, and SRRs of 98.8%, 98.4%, and 99.5%, respectively, after a dose of MMR-RIT; non-inferiority compared to MMR II was demonstrated. Both vaccines showed comparable reactogenicity profiles; the most common solicited AEs were injection site redness and pain, and fever (MMR-RIT: 12.2%, 11.8%, and 3.0%; MMR II: 11.7%, 11.5%, and 5.2%, respectively). The dose of MMR-RIT induced robust immune responses that were not inferior to those of MMR II, and was well tolerated.

One or two doses of live varicella virus-containing vaccines: Efficacy, persistence of immune responses, and safety six years after administration in healthy children during their second year of life.

BACKGROUND: This phase III B follow-up of an initial multicenter study (NCT00226499) will evaluate the ten-year efficacy of two doses of the combined measles-mumps-rubella-varicella vaccine (MMRV) and one dose of the live attenuated varicella vaccine (V) versus a measles-mumps-rubella control group (MMR) for the prevention of clinical varicella disease. Here we present efficacy results for six years post-vaccination. METHODS: In phase A of the study, healthy children aged 12-22 months from ten European countries were randomized (3:3:1) and received either two doses of MMRV, or one dose of combined MMR and one dose of monovalent varicella vaccine (MMR+V), or two doses of the MMR vaccine (control), 42 days apart. Vaccine efficacy against all and against moderate or severe varicella (confirmed by detection of viral DNA or epidemiological link) was assessed from six weeks up to six years post-dose 2 for the MMRV and MMR+V groups, and was calculated with 95% confidence intervals (CI). The severity of varicella was calculated using the modified Vázquez scale (mild ≤ 7; moderately severe = 8-15; severe ≥ 16). Herpes zoster cases were also recorded. RESULTS: 5289 children (MMRV = 2279, mean age = 14.2, standard deviation [SD] = 2.5; MMR+V = 2266, mean age = 14.2, SD = 2.4; MMR = 744, mean age = 14.2, SD = 2.5 months) were included in the efficacy cohort. 815 varicella cases were confirmed. Efficacy of two doses of MMRV against all and against moderate or severe varicella was 95.0% (95% CI: 93.6-96.2) and 99.0% (95% CI: 97.7-99.6), respectively. Efficacy of one dose of varicella vaccine against all and against moderate or severe varicella was 67.0% (95% CI: 61.8-71.4) and 90.3% (95% CI: 86.9-92.8), respectively. There were four confirmed herpes zoster cases (MMR+V = 2, MMR = 2), all were mild and three tested positive for the wild-type virus. CONCLUSIONS: Two doses of the MMRV vaccine and one dose of the varicella vaccine remain efficacious through six years post-vaccination.

Two-year antibody persistence in children vaccinated at 12-15 months with a measles-mumps-rubella virus vaccine without human serum albumin.

One combined measles-mumps-rubella (MMR) vaccine without Human Serum Albumin (HSA) is currently licensed in the USA (M-M-R II; Merck, USA) and another has been developed (Priorix™ [MMR-RIT, GSK, Belgium]). In this follow-up study, children from USA or Puerto Rico, who had received one dose of M-M-R II or MMR-RIT at 12-15 months of age in the primary study (NCT00861744), were followed-up for 2 y post-vaccination. Anti-measles and anti-rubella antibodies were measured using Enzyme-Linked Immunosorbent Assay (ELISA), and anti-mumps antibodies using ELISA and plaque reduction neutralization (PRN) assays. Serious adverse events (SAEs) were recorded during the entire follow-up. The according-to-protocol (ATP) persistence cohort included 752 children (M-M-R II = 186, MMR-RIT = 566), who received primary vaccination at a mean age of 12.3 ( ± 0.67) months. 104 children were revaccinated with MMR-containing vaccines; therefore, serology results for timepoints after revaccination were excluded from the analysis. Seropositivity for measles (Year 1≥ 98.3%; Year 2≥ 99.4%) and rubella (Year 1≥ 98.9%; Year 2 = 100%) remained as high at Year 2 as at Day 42. Similarly, seropositivity for mumps determined by ELISA (Year 1≥ 90.1%; Year 2≥ 94.1%) and PRN assays (Year 1≥ 87.5%; Year 2≥ 91.7%) persisted. Thirty-three SAEs were recorded in 23 children; 2 SAEs (inguinal adenitis and idiopathic thrombocytopenic purpura) and one SAE (febrile convulsion) were considered as potentially related to MMR-RIT and M-M-R II, respectively. This study showed that antibodies against measles, mumps and rubella persisted for up to 2 y post-vaccination with either MMR vaccine in children aged 12-15 months, and that both vaccines were well-tolerated during the follow-up period.