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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.

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, By repurposing humoral and cell-mediated immunogenicity data from a large multinational trial enrolling adults aged ≥50 years, we found no consistent evidence of differences in varicella-zoster virus exposure between countries with widely circulating varicella versus countries with universal vaccination.

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

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%

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.

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.

© 2022 GlaxoSmithKline Biologicals S.A.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.

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.

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.

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., Data from a phase 3 clinical trial of measles-mumps-rubella vaccines show a moderate correlation between the anti-mumps antibody measurements derived by enzyme-linked immunosorbent assay and plaque reduction neutralization test, reflecting different aspects of the serological response measured by each assay.

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.

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., When compared with the MMR II vaccine (M-M-R-II) currently available in the United States, a first dose of MMR-RIT (Priorix) given to 1-year-old children elicited robust immunoresponses and raised no safety concerns.

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 Vazquez 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.

Background Porcine circovirus type 1 (PCV-1) material was detected in the human rotavirus vaccine (HRV) in 2010. Although no safety risk was identified for infants vaccinated with HRV, a PCV-free HRV (no detection of PCV-1 and PCV-2 according to the limit of the tests used) was developed, which showed comparable immunogenicity and safety profile to the initial HRV. We assessed the non-inferiority of immune responses elicited by routine vaccines (co-)administered with either liquid (Liq) PCV-free HRV or lyophilized (Lyo) HRV, and the immunogenicity and safety of HRVs in infants. Methods In this phase 3, randomized, single-blind study (NCT03207750) in the United States, healthy infants aged 6–12 weeks received 2 doses of Liq PCV-free HRV or Lyo HRV at study month (M)0, M2 and routine vaccines at M0, M2, M4 (Figure 1). Co-primary objectives were to hierarchically demonstrate non-inferiority of immune responses to routine vaccine antigens when (co-)administered with Liq PCV-free HRV compared to Lyo HRV, 1 month post-dose 3 of the routine vaccines and to rule out a 10% decrease in seroresponse to pertussis antigens. Immunogenicity and safety of HRVs were also evaluated (Figure 1). Figure 1. Study design Results 1272 infants were vaccinated and 990 (Liq PCV-free HRV: 489; Lyo HRV: 501) were included in the per-protocol set. All statistical criteria were met for the 2 co-primary objectives (Table 1). Seroprotection/seropositivity rates were ≥ 99.3% for all DTaP-HBV-IPV antigens, ≥ 97.4% for Hib and ≥ 90.8% for most PCV13 serotypes. Geometric mean concentrations/titers for the routine vaccine antigens were comparable between groups (Table 2). 76.3% of infants in Liq PCV-free HRV and 78.9% in Lyo HRV had anti-RV antibody concentration ≥ 20 U/mL. The incidence of solicited (Figure 2) and unsolicited adverse events (AEs) were similar in both groups. Of 75 serious AEs (SAEs), 2 (Lyo HRV: abdominal distension; intussusception) were considered vaccine-related by investigator; 1 fatal SAE (Liq PCV-free HRV: sudden infant death syndrome) was considered non-vaccine related by investigator. Table 1. Non-inferiority of the immune responses to routine vaccine antigens when (co-)administered with HRV (Liq PCV-free HRV vs Lyo HRV) and exclusion of 10% decrease in seroresponse to pertussis antigens, 1 month post-dose 3 (per-protocol set) Table 2. Seroprotection/seropositivity rates and geometric mean concentrations/titers for the routine vaccines antigens 1 month post-dose 3 (per-protocol set) Figure 2. The incidence of solicited adverse events occurring within 7 days post-vaccination (overall/infant, exposed set) Conclusion Routine vaccines (co-)administered with Liq PCV-free HRV showed non-inferior immune responses and similar safety profiles compared to (co-)administration with Lyo HRV. Funding GlaxoSmithKline Biologicals SA Disclosures Remon Abu-Elyazeed, MD, PhD, GSK group of companies (Employee) Nicola P. Klein, MD, PhD, GSK group of companies (Research Grant or Support)Merck (Grant/Research Support)Pfizer (Grant/Research Support)Protein Science (now SP) (Grant/Research Support)Sanofi Pasteur (Grant/Research Support) Leentje Moerman, PhD, GSK group of companies (Employee) Michael Povey, MSc, GSK group of companies (Employee) Shelly Senders, MD, Pfizer (Grant/Research Support) Dan Bi, MD, MPH, GSK group of companies (Employee)

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).

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.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.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.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.GlaxoSmithKline Biologicals.

Background M-M-RTMII (MMRII; Merck & Co) is currently the only measles-mumps-rubella (MMR) vaccine licensed in the United States. Another licensed vaccine would reinforce MMR supply. This study assessed the immunogenicity of a candidate vaccine (PriorixTM, GlaxoSmithKline Vaccines [MMR-RIT]) when used as a first dose among eligible children in the United States. Methods In this exploratory Phase-2, multicenter, observer-blind study, 1220 healthy subjects aged 12–15 months were randomized (3:3:3:3) and received 1 dose of 1 of 3 MMR-RIT lots with differing mumps virus titers (MMR-RIT-1 [4.8 log10]; MMR-RIT-2 [4.1 log10]; MMR-RIT-3 [3.7 log10] CCID50) or MMRII co-administered with hepatitis A vaccine (HAV), varicella vaccine (VAR) and 7-valent pneumococcal conjugate vaccine (PCV7). Immune response to measles, mumps, and rubella viruses was evaluated at Day 42 post-vaccination. Incidence of solicited injection site, general, and serious adverse events was assessed. Results Seroresponse rates for MMR vaccine viral components in MMR-RIT lots were 98.3–99.2% (measles), 89.7–90.7% (mumps), and 97.5–98.8% (rubella), and for MMRII were 99.6%, 91.1%, and 100%, respectively. Immune responses to HAV, VAR, and PCV7 were similar when co-administered with any of the 3 MMR-RIT lots or MMRII. There were no apparent differences in solicited or serious adverse events among the 4 groups. Conclusions Immune responses were above threshold levels for projected protection against the 3 viruses from MMR-RIT lots with differing mumps virus titers. MMR-RIT had an acceptable safety profile when co-administered with HAV, VAR, and PCV7. Clinical Trials Registration NCT00861744; etrack; 111870

Introduction Multiple 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. Methods Healthy 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. Results 716 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. Conclusion The 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 .

Background A randomized, controlled, long-term varicella vaccine efficacy study (NCT00226499) was conducted in several European countries with no universal varicella vaccination. The control group allows studying the immunological response profiles to natural varicella exposure and disease in children from 1 year of age onwards. Methods Of 5,803 subjects enrolled in the study, 744 were vaccinated with 2 doses of measles-mumps-rubella vaccine as active control. Follow-up lasted for up to 10 years. Varicella case ascertainment was done by combining PCR testing of skin lesions, epidemiological context and blinded clinical case adjudication by independent experts. A confirmed case required a positive PCR result or a positive epidemiological context with a positive case adjudication. Results In the control group, a total of 352 confirmed varicella episodes were captured; of which, 339 had an available serum sample taken before and after the episode at any of the year 1 or bi-yearly visits scheduled per protocol. All subjects were seronegative for anti-VZV antibodies before vaccination. The immunological profile showed that 96% of subjects with varicella episodes experienced an 8-fold increase of the anti-VZV titers when comparing the sample available after the episode vs. the one before the episode. The data indicate that the GMC levels were similar to that induced by 2-dose immunization with varicella vaccines, and persisted over many years after the varicella episode without indication of waning (figure). In subjects without any reported varicella episode, 8-fold increases of the anti-VZV titers between 2 successive blood samples were measured in up to 34% of consecutive pairs of serum samples. Conclusion To our knowledge, this is the first long-term analysis of the immunological history of anti-varicella immunological profile in young children exposed to a high varicella force of infection. About one-third of subjects not vaccinated against varicella developed an anti-VZV immune response although no varicella disease was reported. Sub-clinical varicella may occur more frequently than anticipated. The total incidence of varicella infections might be under-estimated by syndromic surveys only. Funding: GlaxoSmithKline Biologicals SA. Disclosures P. Gillard, GSK: Employee and Shareholder, Salary. M. Povey, GSK: Employee, Salary. S. Carryn, GSK: Employee and Shareholder, Restricted shares, and Salary.

Background Immunogenicity and safety of varicella vaccine (Varilrix™ [Oka-RIT]; GlaxoSmithKline Vaccines) in adults who had undergone autologous hematopoietic stem cell transplantation (HSCT) were assessed (September 2003 to September 2007; NCT00792623). Methods Two Oka-RIT doses were given at 4.5 and 6.5 months post transplantation. Humoral immune responses were assessed using an immunofluorescence assay (anti-varicella zoster virus [VZV] antibody; cutoff 1:4) after each vaccine dose. Solicited local (8 day) and general (43 day), unsolicited (until day 43) adverse events (AEs) after each vaccine dose and serious adverse events (SAEs) (until 17.5 months post dose 2) were recorded. Results Of 45 patients, 19 were included in the according to protocol cohort for immunogenicity; 15 patients had pre- and post-vaccination serum samples positive for anti-VZV antibodies. Vaccine responses (anti-VZV antibody titer ≥1:4 in seronegative patients, and ≥4-fold increase in anti-VZV antibody titer in seropositive patients) were elicited by only 2 patients 2 months post dose 1, and by a single patient 1.5 months post dose 2. Although no major safety signals were detected, any and Grade 3 solicited AEs that were causally related to vaccination were reported by 44.8% and 10.3% patients, respectively. During the 43-day follow-up period, 3 patients developed varicella-like rash (1 vaccine-type VZV). Beyond 43 days, herpes zoster was reported in 2 patients and wild-type varicella infection in 2 patients (1 was breakthrough infection). Four non-fatal SAEs were reported by patients and considered causally unrelated to vaccination. Conclusion Oka-RIT was poorly immunogenic but safe when given to adults up to 6 months post autologous HSCT, and alternative strategies are required to prevent VZV-associated complications in these populations.

Aim: This study evaluated the immunogenicity and safety of tetravalent measles-mumps-rubella-varicella (MMRV) vaccine produced with measles and rubella monovalent bulks derived from a newly established working seed virus stock (MMRVnew WS) compared with the combined MMRV vaccine derived from the current seed virus stock, in Taiwanese and Singaporean children (NCT00892775). Methods:Healthy children aged 11–22 mo were randomized to receive two doses of either the MMRV new WS vaccine or the MMRV vaccine. Antibody titers against measles, mumps and rubella were measured using ELISA and against varicella using an immunofluorescence assay. The primary objective was to demonstrate non-inferiority of MMRVnew WS to MMRV in terms of post-dose-1 seroconversion rates, defined as a group difference with a lower limit of the 95% confidence interval greater than -10% for each antigen. Parents/guardians recorded symptoms in diary cards for 43 d after each vaccine dose. Results:Non-inferiority of MMRV new WS to MMRV was achieved for all vaccine antigens. The lower limits of the 95% confidence intervals for group differences (MMRVnew WS group vs. MMRV) for measles (99.4% vs 100%), mumps (89.7% vs 90.4%), rubella (99.7% vs 100%) and varicella (97.6% vs 92.9%) seroconversion rates were greater than -10%. Mild symptoms including a peak in fever between days 5 and 12, post-dose-1, was observed in both groups. Conclusion:The immune responses elicited by the MMRV new WS vaccine were non-inferior to that elicited by the MMRV vaccine for all antigens. Both vaccines exhibited an acceptable safety profile in Taiwanese and Singaporean children.

Objective This study (NCT00969436) compared the immunogenicity and safety of measles-mumps-rubella (MMR) followed by MMR+varicella (V) vaccines to (1) 2 doses of combined MMRV and (2) MMR followed by MMRV, in Indian children. Design Phase III, open, randomised, non-inferiority study. Setting 6 tertiary care hospitals located in India. Participants Healthy participants aged 9–10 months not previously vaccinated against/exposed to measles, mumps, rubella and varicella or without a history of these diseases. Interventions Participants were randomised (2:2:1) to receive 2 doses of either MMRV (MMRV/MMRV group) or MMR followed by MMRV (MMR/MMRV group) or MMR followed by MMR+V (MMR/MMR+V, control group) at 9 and 15 months of age. Antibody titres against measles, mumps and rubella were measured using ELISA and against varicella using an immunofluorescence assay. Main outcome measures To demonstrate non-inferiority of the 2 vaccination regimens versus the control in terms of seroconversion rates, defined as a group difference with a lower bound of the 95% CI >−10% for each antigen, 43 days postdose 2. Parents/guardians recorded solicited local and general symptoms for a 4-day and 43-day period after each vaccine dose, respectively. Results Seroconversion rates postdose 1 ranged from 87.5% to 93.2% for measles, 83.3% to 86.1% for mumps and 98.7% to 100% for rubella across the 3 vaccine groups. The seroconversion rates postdose 2 were 100% for measles, mumps and rubella and at least 95.8% for varicella across the 3 vaccine groups. Non-inferiority of MMRV/MMRV and MMR/MMRV to MMR/MMR+V was achieved for all antigens, 43 days postdose 2. The 3 vaccination regimens were generally well tolerated in terms of solicited local and general symptoms. Conclusions The immune responses elicited by the MMRV/MMRV and MMR/MMRV vaccination regimens were non-inferior to those elicited by the MMR/MMR+V regimen for all antigens. The 3 vaccination schedules also exhibited an acceptable safety profile in Indian children. Trial registration number NCT00969436.

Purpose This study (NCT00751348) evaluated the immunogenicity and safety of a combined measles-mumps-rubella-varicella (MMRV) vaccine compared to co-administration of measles-mumps-rubella and varicella (MMR+V) vaccines in Korean children during their second year of life. Materials and Methods Healthy children aged 11-24 months received one dose of MMRV or MMR+V. Antibody titers against measles, mumps and rubella were measured using enzyme-linked immunosorbent assay and against varicella using an immunofluorescence assay. Parents/guardians recorded adverse events in diary cards for up to 43 days post-vaccination. The primary objective was to demonstrate non-inferiority of MMRV to MMR+V for all antigens in terms of seroconversion rates (SCRs), defined as a group difference with a lower limit of the 95% confidence interval (CI)>-10%. Results Of 474 subjects enrolled, 458 (MMRV, 301; MMR+V, 157) were included in the according-to-protocol cohort. For measles (98.0% vs. 99.4%), rubella (99.7% vs. 100%) and varicella (98.9% vs. 100%) SCRs, the lower limits of the 95% CIs for group differences were greater than -10%; however, for mumps SCRs (88.8% vs. 94.2%), it was -10.40%. The primary objective of non-inferiority in mumps SCRs was therefore not met, although the observed group difference in a post-hoc analysis of anti-mumps antibodies using a plaque reduction neutralization assay was 0.39% with a 95% CI lower limit of -4.03%. Adverse events occurred at comparable frequencies for both groups, except for more frequent fever in MMRV recipients. Conclusion Based on the pre-specified non-inferiority criterion, SCRs of the MMRV vaccine were non-inferior to that elicited by MMR+V vaccines for all antigens except mumps.

GSK’s varicella vaccine contains human serum albumin (HSA) which is used to stabilize the virus and prevent immunogens from adhering to the injection vial walls. However, because HSA is derived from human blood, there is a theoretical risk that it might contain infectious agents which could be unsafe for humans. Given this concern, a study was undertaken to compare the immunogenicity and safety of a new formulation without HSA with the currently licensed varicella vaccine in the Czech Republic and Hungary. Healthy children aged 11–21 months received two doses of the varicella vaccine either with or without HSA. Antibody titres against varicella-zoster virus (anti-VZV) were measured 42 days after each dose, using an immunofluorescence assay (IFA, cut-off = 4dilution−1) and enzyme linked immunosorbent assay (ELISA, cut-off = 25 mIU/ml). Solicited local symptoms were recorded during a 4-day post-vaccination follow-up period; solicited general and unsolicited symptoms were recorded during a 43-day post-vaccination follow-up period and serious adverse event (SAEs) were recorded throughout the study. Of 244 children (mean age = 15.2 months [SD = 3.2]) vaccinated in the study, 233 (vaccine without HSA N = 117; vaccine containing HSA N = 116) formed the according-to-protocol immunogenicity cohort. Observed seroconversion/seroresponse rates were >98 and 100 %, 42 days after doses 1 and 2, respectively. The rates were within the same range in both groups, irrespective of the testing assay. The varicella vaccine without HSA was non-inferior to the licensed vaccine in terms of anti-VZV antibody Geometric Mean Titre/Concentration ratio (1.12 [95 % CI:0.86–1.46] by IFA; 1.12 [95 % CI:0.93–1.33] by ELISA) approximately six weeks after the first dose of the 2-dose vaccination course. The incidence of solicited and unsolicited symptoms was similar after both vaccines; low-grade fever was numerically higher after the first dose of the varicella vaccine without HSA. Seven SAEs were reported, none of which were fatal or considered to be vaccine-related. The first dose of a new varicella vaccine without HSA was immunologically non-inferior to the licensed varicella vaccine. After two doses, both vaccines had acceptable safety profiles in children aged 11–21 months in the Czech Republic and Hungary. NCT00568334 , registered on 5 December 2007 ( www.clinicaltrials.gov ).