Serious neurological adverse events in immunocompetent children and adolescents caused by viral reactivation in the years following varicella vaccination.

Serious adverse events following vaccination include medical complications that require hospitalisation. The live varicella vaccine that was approved by the Food and Drug Administration in the United States in 1995 has an excellent safety record. Since the vaccine is a live virus, adverse events are more common in immunocompromised children who are vaccinated inadvertently. This review includes only serious adverse events in children considered to be immunocompetent. The serious adverse event called varicella vaccine meningitis was first reported in a hospitalised immunocompetent child in 2008. When we carried out a literature search, we found 15 cases of immunocompetent children and adolescents with varicella vaccine meningitis; the median age was 11 years. Eight of the children had received two varicella vaccinations. Most of the children also had a concomitant herpes zoster rash, although three did not. The children lived in the United States, Greece, Germany, Switzerland, and Japan. During our literature search, we found five additional cases of serious neurological events in immunocompetent children; these included 4 cases of progressive herpes zoster and one case of acute retinitis. Pulses of enteral corticosteroids as well as a lack of herpes simplex virus antibody may be risk factors for reactivation in immunocompetent children. All 20 children with adverse events were treated with acyclovir and recovered; 19 were hospitalised and one child was managed as an outpatient. Even though the number of neurological adverse events remains exceedingly low following varicella vaccination, we recommend documentation of those caused by the vaccine virus.

Upregulation of keratin 15 is required for varicella-zoster virus replication in keratinocytes and is attenuated in the live attenuated vOka vaccine strain.

Varicella-zoster virus (VZV) is the etiological agent of chickenpox and shingles, diseases characterised by epidermal virus replication in skin and mucosa and the formation of blisters. We have previously shown that VZV infection has a profound effect on keratinocyte differentiation, altering the normal pattern of epidermal gene expression. In particular, VZV infection reduces expression of suprabasal keratins 1 and 10 and desmosomal proteins, disrupting epidermal structure to promote expression of a blistering phenotype. Here, we extend these findings to show that VZV infection upregulates the expression of keratin 15 (KRT15), a marker expressed by basal epidermal keratinocytes and hair follicles stem cells. We demonstrate that KRT15 is essential for VZV replication in the skin, since downregulation of KRT15 inhibits VZV replication in keratinocytes, while KRT15 exogenous overexpression supports viral replication. Importantly, our data show that VZV upregulation of KRT15 depends on the expression of the VZV immediate early gene ORF62. ORF62 is the only regulatory gene that is mutated in the live attenuated VZV vaccine and contains four of the five fixed mutations present in the VZV Oka vaccine. Our data indicate that the mutated vaccine ORF62 is not capable of upregulating KRT15, suggesting that this may contribute to the vaccine attenuation in skin. Taken together our data present a novel association between VZV and KRT15, which may open a new therapeutic window for a topical targeting of VZV replication in the skin via modulation of KRT15.

Varicella vaccine effectiveness evaluation in Wuxi, China: A retrospective cohort study.

Varicella is a vaccine-preventable infectious disease. Since 1 December 2018, the varicella vaccine has been included in the local Expanded Programme on Immunization (EPI) in Wuxi, China, and children born after 1 December 2014 are eligible for free vaccination. To evaluate the effect of varicella vaccination in Wuxi city, we selected 382 397 children born from 2012 to 2016 as subjects. Their disease data were obtained from the Chinese Disease Prevention and Control Information System, and their vaccination data were obtained from the Jiangsu Province Vaccination Integrated Service Management Information System. The incidence of breakthrough varicella cases increased in the first 4 years and reached the peak in the fifth year. With the increase of vaccination rate, the incidence of varicella decreased significantly. The vaccine effectiveness (VE) was found to be 88.17%-95.78% for one dose and 98.65%-99.93% for two doses. Although the VE per dose decreased from 99.57% in the first year to 93.04% in the eighth year, it remained high. These findings confirmed the effectiveness of varicella vaccination in children, supported the use of a two-dose varicella vaccination strategy to achieve better protection, and provided important insights into the optimal vaccination strategy for varicella prevention in children.

Varicella-Zoster Virus Pretransplant Vaccination and Posttransplant Infections Among Pediatric Solid Organ Recipients in the Two-Dose Varicella Era: A Single-Center, Multi-Organ Retrospective Study.

BACKGROUND: Varicella-zoster virus (VZV) pretransplant immunization rates, exposures, and posttransplant disease are poorly characterized among pediatric solid organ transplant (SOT) recipients in the two-dose varicella vaccine era. METHODS: A retrospective analysis of the electronic health records among children <18 years old who received SOT from January 1, 2011 through December 31, 2021, was performed at a single center to assess for missed pretransplant varicella vaccination opportunities, characterize VZV exposures, and describe posttransplant disease. RESULTS: Among 525 children, 444 were ≥6 months old (m.o.) at SOT with a documented VZV vaccine status. Eighty-five (19%) did not receive VZV Dose One; 30 out of 85 (35%) could have been immunized. Infants 6-11 m.o. accounted for 14 out of 30 (47%) missed opportunities. Among children ≥12 m.o. with documented Dose Two status (n = 383), 72 had missed vaccination opportunities; 57 out of 72 (79%) were children 1-4 years old. Most children had unclassifiable pre-SOT serostatus as varicella serology was either not obtained/documented (n = 171) or the possibility of passive antibodies was not excluded (n = 137). Of those with classified serology (n = 188), 69 were seroimmune. Forty-seven of 525 (9%) children had recorded VZV exposures; two developed varicella-neither had documented pre-SOT seroimmunity nor had received post-exposure prophylaxis. Nine additional children had medically attended disease: four primary varicella and five zoster. Of the 11 cases, 10 had cutaneous lesions without invasive disease; one had multi-dermatomal zoster with transaminitis. Seven (64%) received treatment exclusively outpatient. CONCLUSIONS: VZV exposure and disease still occur. Optimizing immunization among eligible candidates and ensuring patients have a defined VZV serostatus pretransplantation remain goals of care.

Incomplete Immunity for Varicella and Measles in Pediatric Organ Transplant Candidates. Real World Experience From an Infectious Diseases Pre-Transplantation Clinic.

BACKGROUND: Vaccinating pediatric solid organ transplant candidates against measles and varicella is crucial due to the risk of severe disease in immunosuppressed recipients and general avoidance of live virus vaccines post-transplantation. The world saw a resurgence of measles starting 2012 prompting the American Society of Transplantation in 2015 to release guidelines on recognition, prevention, and post-exposure prophylaxis of this disease in solid transplant recipients. This study aims to assess the extent of incomplete immunity to these viruses in candidates and the approach to immunity optimization during a period of heightened awareness. METHODS: A cross-sectional study from 2012 to 2016 at Cleveland Clinic Children's included pediatric solid organ transplant candidates. Data on vaccination history, serology, and demographics were collected. Incomplete immunity was defined by incomplete vaccination or seronegativity. RESULTS: Among 91 candidates, 54.9% had complete varicella vaccination. Serological varicella immunity among patients tested varied by age: < 7 years, 50.0% positive in patients with complete schedules, none in the incomplete; ≥ 7 years, 50.0% positive in patients with complete schedules, 65.5% in the incomplete. For measles, 69.2% had complete vaccination, with immunity varying by age among those tested: < 7 years, 84.6% positive in patients with complete schedules, 42.9% in the incomplete; ≥ 7 years, 81.0% with complete, 62.5% with incomplete. Only 31.1% of those who qualified for a varicella additional dose and 28% who qualified for an additional measles dose received it, respectively. CONCLUSIONS: Incomplete immunity to varicella and measles was prevalent in pediatric solid organ transplant candidates at our center during the study period. Despite an increase in global measles activity, our efforts to optimize immunity through additional vaccine doses were only partially successful. Future research should focus on addressing strategies and understanding barriers to ensure timely vaccination for this vulnerable population prior to transplant, especially during periods of increased viral activity.

Immunogenicity and safety of a quadrivalent meningococcal tetanus toxoid-conjugate vaccine administered concomitantly with other paediatric vaccines in toddlers: a phase III randomised study.

Invasive meningococcal disease has high morbidity and mortality, with infants and young children among those at greatest risk. This phase III, open-label, randomised study in toddlers aged 12-23 months evaluated the immunogenicity and safety of meningococcal tetanus toxoid-conjugate vaccine (MenACYW-TT), a tetanus toxoid conjugated vaccine against meningococcal serogroups A, C, W and Y, when coadministered with paediatric vaccines (measles, mumps and rubella [MMR]; varicella [V]; 6-in-1 combination vaccine against diphtheria, tetanus, pertussis, polio, hepatitis B and Haemophilus influenzae type b [DTaP-IPV-HepB-Hib] and pneumococcal conjugate vaccine [PCV13])(NCT03205371). Immunogenicity to each meningococcal serogroup was assessed by serum bactericidal antibody assay using human complement (hSBA). Vaccine safety profiles were described up to 30 days post-vaccination. A total of 1183 participants were enrolled. The proportion with seroprotection (hSBA ≥1:8) to each meningococcal serogroup at Day 30 was comparable between the MenACYW-TT and MenACYW-TT + MMR + V groups (≥92 and ≥96%, respectively), between the MenACYW-TT and MenACYW-TT + DTaP-IPV-HepB-Hib groups (≥90% for both) and between the MenACYW-TT and MenACYW-TT + PCV13 groups (≥91 and ≥84%, respectively). The safety profiles of MenACYW-TT, and MMR + V, DTaP-IPV-HepB-Hib, and PCV13, with or without MenACYW-TT, were generally comparable. Coadministration of MenACYW-TT with paediatric vaccines in toddlers had no clinically relevant effect on the immunogenicity and safety of any of the vaccines.

Long -term persistence of antibodies against varicella in fully immunized healthcare workers: an Italian retrospective cohort study.

BACKGROUND: Chickenpox is a highly contagious disease caused by the varicella zoster virus (VZV), and in infants, adolescents, adults, pregnant women, and the immunocompromised it can be serious. The best way to prevent chickenpox is immunization with the varicella vaccine. Protective levels of antibodies induced by the varicella vaccine decline over time, but there is currently no formal recommendation for testing anti-varicella zoster virus (VZV) IgG levels in immunized healthcare workers (HCWs). METHODS: The aims of this study were to evaluate the seroprevalence of circulating anti-VZV IgG in a sample a sample of students and residents of the medical school of the University of Bari, the long-term immunogenicity of the varicella vaccine, and the effectiveness of a strategy consisting of a third vaccine booster dose. The study population was screened as part of a biological risk assessment conducted between April 2014 and October 2020. A strategy for the management of non-responders was also examined. RESULTS: The 182 students and residents included in the study had a documented history of immunization (two doses of varicella vaccine). The absence of anti-VZV IgG was determined in 34% (62/182; 95%CI = 27.2-41.4%), with serosusceptibility more common among males than females (p < 0.05). After a third varicella dose, seroconversion was achieved in 100% of this previously seronegative group. No serious adverse events were recorded. CONCLUSIONS: One-third of the study population immunized against VZV lacked a protective antibody titer, but a third dose of vaccine restored protection. Since it is highly unlikely that VZV will be eliminated in the immediate future, the loss of immunity in a substantial portion of the population implies a risk of varicella outbreaks in the coming years. Screening for varicella immunity in routine assessments of the biological risk of medical students and HCWs may help to prevent nosocomial VZV infections.

Acceptance of universal varicella vaccination among Swiss pediatricians and general practitioners who treat pediatric patients.

BACKGROUND: Over the last two decades, several countries have initiated universal varicella vaccination (UVV) programs in infants. In 2019, the Swiss National Immunization Technical Advisory Group (NITAG) decided to start evaluating the introduction of universal varicella vaccination. There is a theoretical concern that suboptimal vaccination coverage could lead to a shift in the varicella incidence to older age groups, thereby potentially increasing complication rates. To achieve a high vaccination coverage rate, it is important that practicing physicians comply with a potential recommendation for UVV. We studied the perception of varicella and the current vaccination behavior among Swiss pediatricians and general practitioners (GPs) who treat children. We also assessed their intention to advise parents to vaccinate their children against varicella in the event the Swiss NITAG will recommend UVV. METHODS: Primary data was collected through a structured, 20-min online survey with Swiss pediatricians and GPs who treat children. RESULTS: 150 physicians participated in the study: 40 GPs in the German-speaking part, 20 GPs in the French-speaking part, 67 pediatricians in the German-speaking part, and 23 pediatricians in the French-speaking part. The majority (64%) of all participants reported that they currently recommend varicella vaccination for risk groups according to the national immunization plan. About one third of physicians (35%) - predominantly pediatricians - currently already recommend it for all infants. In these situations, a measles, mumps, rubella, varicella combination vaccine is currently used by 58% for the first dose and by 59% for the second dose. 86% of participants stated that they would advise parents to have their children vaccinated against varicella in case of a recommendation for UVV by the Swiss NITAG. 68% responded that they expect many questions from parents and 65% agreed that they have good arguments to convey the importance of varicella vaccination. CONCLUSIONS: The survey study results show that most participating pediatricians and GPs indicated a favorable attitude towards childhood vaccination against varicella in the setting of a Swiss NITAG recommendation for UVV. This data shows the importance of NITAG recommendations in influencing vaccine education and supporting achievement of high coverage of varicella vaccination.

Lack of persisting antibody in a post-transplant patient after vaccine-strain varicella.

BACKGROUND: LAVV have historically been avoided in children after solid organ transplantation. However, it has been reported that post-transplant, children without severe immunosuppression can generate anti-varicella antibody after immunization but the duration of the response is not clear. Furthermore, the origin of the varicella virus in immunosuppressed patients who develop varicella after vaccination is often unclear. CLINICAL PROGRESS: A female child received LAVV 30 months after a living donor liver transplant at the age of 2 months. Varicella rash appeared on the trunk 16 days after vaccination and gradually spread over the body. The patient was treated with intravenous acyclovir followed by oral therapy and recovered fully. The virus detected in blisters was derived from the vaccine-type strain. Paired sera before and after the onset of varicella showed an increase in antibody titer. However, 2 years after onset, the antibody titer decreased to undetectable again. CONCLUSIONS: This was an informative case of varicella due to vaccine strain attenuated virus. Antibody levels were not maintained over many years. Although varicella was caused by the vaccine-type strain, repeated vaccinations may be necessary for post-transplant patients who develop varicella.

Safety of LAVs administered after pediatric LT.

Recent guidelines suggest that LAVs may be given to LT recipients meeting certain criteria. However, information is still limited. We sought to evaluate the safety of LAVs, including measles, mumps, rubella, and varicella to LT recipients following our clinically based immunization protocol for LT recipients. We conducted a case-series analysis on safety of LAVs for measles, rubella, varicella, and mumps given to LT recipients at our institution from July 2010 to July 2019. Patients who underwent LT at age <20 years who visited our immunization clinic were included. LT recipients were vaccinated if 2 years had lapsed from LT, had no signs of rejection within 6 months, and were on minimal immunosuppressants. Patient demographics, underlying diseases, type and number of vaccines administered, date of vaccination, and adverse events occurring within 4 weeks after vaccination were extracted from their medical records. During the study period, LAVs were administered 422 times to 209 patients who met criteria and included 225 doses of MR combination vaccine, 224 doses of varicella vaccine, and 215 doses of mumps vaccine. Underlying diseases included cholestatic liver diseases (n = 125), followed by metabolic diseases (n = 33) and acute liver failure (n = 19). Nine non-critical adverse events (2.1%) possibly associated with LAVs were reported, but there were no serious adverse events, including hospitalizations or deaths. In conclusion, LAVs administered to LT recipients were safe without any serious adverse events following our relatively simple institutional protocol.

Waning Effectiveness of One-dose Universal Varicella Vaccination in Korea, 2011-2018: a Propensity Score Matched National Population Cohort.

BACKGROUND: Despite high coverage (~98%) of universal varicella vaccination (UVV) in the Republic of Korea since 2005, reduction in the incidence rate of varicella is not obvious. The study aimed to evaluate the vaccine effectiveness (VE) of one-dose UVV by timeline and severity of the disease. METHODS: All children born in Korea in 2011 were included for this retrospective cohort study that analyzed insurance claims data from 2011-2018 and the varicella vaccination records in the immunization registry. Adjusted hazard ratios by Cox proportional hazard models were used to estimate the VE through propensity score matching by the month of birth, sex, healthcare utilization rate, and region. RESULTS: Of the total 421,070 newborns in the 2011 birth cohort, 13,360 were matched for age, sex, healthcare utilization rate, and region by the propensity score matching method. A total of 55,940 (13.29%) children were diagnosed with varicella, with the incidence rate 24.2 per 1000 person-year; 13.4% of vaccinated children and 10.4% of unvaccinated children. The VE of one-dose UVV against any varicella was 86.1% (95% confidence interval [CI], 81.4-89.5) during the first year after vaccination and 49.9% (95% CI, 43.3-55.7) during the 6-year follow-up period since vaccination, resulting in a 7.2% annual decrease of VE. The overall VE for severe varicella was 66.3%. The VE of two-dose compared to one-dose was 73.4% (95% CI, 72.2-74.6). CONCLUSION: We found lower long-term VE in one-dose vaccination and waning of effectiveness over time. Longer follow ups of the vaccinated children as well as appropriately designed studies are needed to establish the optimal strategy in preventing varicella in Korea.

Why are vaccines against many human viral diseases still unavailable; an historic perspective?

The number of new and improved human viral vaccines licensed in recent years contrasts sharply with what could be termed the golden era (1955-1990) when vaccines against polio-, measles, mumps, rubella, and hepatitis B viruses first became available. Here, we attempt to explain why vaccines, mainly against viruses other than human immunodeficiency virus and hepatitis C virus, are still unavailable. They include human herpesviruses other than varicella-zoster virus, respiratory syncytial and most other respiratory, enteric and arthropod-borne viruses. Improved oral poliovirus vaccines are also urgently required. Their unavailability is attributable to regulatory/economic factors and the properties of individual viruses, but also to an absence of relevant animal models and ethical problems for the conduct of clinical of trials in pediatric and other critical populations. All are portents of likely difficulties for the licensing of effective vaccines against emerging pathogens, such as avian influenza, Ebola, and Zika viruses.

Severe and Complicated Varicella and Associated Genotypes 10 Years After Introduction of a One-Dose Varicella Vaccine Program.

Background: This national, sentinel prospective study aimed to identify children with severe hospitalized varicella, despite availability of universal 1-dose vaccination since 2005, and determine associations between virus genotypes and disease severity. Methods: Children with varicella or zoster from 5 Paediatric Active Enhanced Disease Surveillance hospitals were enrolled. Lesions were swabbed for genotyping. Associations with disease severity were analyzed using multiple regression. Results: From 2007 to 2015, 327 children with confirmed varicella (n = 238) or zoster (n = 89) were enrolled. Two hundred three (62%) were immunocompetent children; including 5 of 8 children who required intensive care unit management. Eighteen percent (36 of 203) of immunocompetent children had been previously vaccinated. Vaccinated children aged >18 months were less likely to have severe disease (9%; 5 of 56) than unvaccinated children (21%; 21 of 100; P = .05). Three of 126 children who had virus genotyping (2 immunocompromised) had varicella (n = 2) or zoster (n = 2) due to the Oka/vaccine strain. European origin clades predominated and were independently associated with more severe disease (odds ratio = 3.2; 95% confidence interval, 1.1- 9.5; P = .04). Conclusions: Severe hospitalized varicella still occurs with a 1-dose varicella program, although predominantly in unvaccinated children. Most 1-dose vaccine recipients were protected against severe disease. Viral genotyping in complex hospitalized cases is important to assist in monitoring disease due to Oka-vaccine strain.

The Epidemiology of Herpes Zoster in the United States During the Era of Varicella and Herpes Zoster Vaccines: Changing Patterns Among Older Adults.

Historic herpes zoster incidence trends in US adults have been hard to interpret. Using administrative databases, we extended previous descriptions of these trends through 2016. We observed an age-specific transition, with ongoing increases among younger adults but deceleration in older adults. The patterns are not readily explained.

The Epidemiology of Herpes Zoster in the United States During the Era of Varicella and Herpes Zoster Vaccines: Changing Patterns Among Children.

Varicella vaccination can have complex direct and indirect influences on the epidemiology of herpes zoster among children. We evaluated pediatric herpes zoster trends using administrative databases. The incidence has declined in a step-wise pattern since the varicella vaccination program's introduction, suggesting that rates may eventually decline in the entire population.

Measles, mumps, rubella (vaccine) and varicella vaccines in pediatric liver transplant: An initial analysis of post-transplant immunity.

Varicella and measles infection represents a significant source of morbidity and mortality for pediatric LT recipients. We evaluated the prevalence and correlates of post-transplant immunity in pediatric LT recipients previously immunized against measles (n = 72) and varicella (n = 67). Sixteen of seventy-two (22%) patients were measles non-immune, and 42/67 (63%) were varicella non-immune after LT. Median time from LT to titers for measles and varicella was 4.0 and 3.3 years, respectively. In the measles cohort, non-immune patients received fewer pretransplant vaccine doses (P = 0.026) and were younger at both time of vaccination (P = 0.006) and LT (P = 0.004) compared with immune patients. Upon multivariable analysis, weight > 10 kg at LT (OR 5.91, 95% CI 1.27-27.41) and technical variant graft (OR 0.07, 95% CI 0.01-0.37) were independently, significantly associated with measles immunity. In the varicella cohort, non-immune patients received fewer pretransplant vaccine doses (P = 0.028), were younger at transplant (P = 0.022), and had less time lapse between their last vaccine and transplant (P = 0.012) compared with immune patients. Upon multivariate analysis, time > 1 year from last vaccine to LT was independently, significantly associated with varicella immunity (OR 3.78, CI 1.30-11.01). This study demonstrates that non-immunity to measles and varicella is a prevalent problem after liver transplantation in children and identifies 3 unique risk factors for non-immunity in this high-risk population.

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).

Immunogenicity and safety of the combined vaccine for measles, mumps, and rubella isolated or combined with the varicella component administered at 3-month intervals: randomised study.

BACKGROUND: Field testing required to license the combined measles, mumps, and rubella (MMR) vaccine must take into account the current recommendation of the vaccine in Brazil: first dose at 12 months and second dose at 15 months of age in combination with a varicella vaccine. OBJECTIVES: This study aimed to evaluate the clinical consistency, immunogenicity, and reactogenicity of three batches of MMR vaccine prepared with active pharmaceutical ingredients (API) from Bio-Manguinhos, Fiocruz (MMR-Bio), and compare it to a vaccine (MMR produced by GlaxoSmithKline) with different API. METHODS: This was a phase III, randomised, double-blind, non-inferiority study of the MMR-Bio administered in infants immunised at health care units in Pará, Brazil, from February 2015 to January 2016. Antibody levels were titrated by immunoenzymatic assays. Adverse events were recorded in diaries. FINDINGS: Seropositivity levels after MMR-Bio were 97.6% for measles, 84.7% for mumps, and 98.0% for rubella. After the MMRV vaccine, seroconversion rates and GMT increased substantially for mumps. In contrast, approximately 35% of the children had no detectable antibodies to varicella. Systemic adverse events were more frequent than local events. CONCLUSION: The demonstration of batch consistency and non-inferiority of the Bio-MMR vaccine completed the technology transfer. This is a significant technological achievement with implications for immunisation programs.