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

Abstract

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).

Keywords: Human serum albumin; Non-inferiority; Safety; Varicella vaccine.

Conflict of interest statement

Ethics approval and consent to participate

This study was approved by independent ethics committees/institutional review boards at each site (University of Tartu, Office of Research and Development; Landesarztekammer Baden-Wurttemberg Medical Board; National Institute of Pediatrics, Coyoacan; Medical Care and Research, Merida; Faculty of Medicine, Chulalongkorn University; NHS, Health Research Authority, North West-Liverpool East Research Ethics Committee) and conducted in accordance with provisions of the Declaration of Helsinki. Written informed consent was obtained from all children’s parents prior to enrolment in the study.

Consent for publication

Not applicable.

Competing interests

MLR, OH, CB, MP and PG are employees of the GSK group of companies, and OH and PG hold shares in the GSK group of companies as part of their employee remuneration. CB was employed by the GSK group of companies during the conduct of this study and is a current employee of Sanofi Pasteur. She holds shares in the GSK group of companies and Sanofi Pasteur. SNF declares that his institution received grants from the GSK group of companies for the conduct of this trial. SNF also declares support through his institution for the conduct of other trials (from the GSK group of companies, Sanofi-Pasteur, Pfizer, AstraZeneca, MedImmune, Alios, Ablynx and Merck). SNF declares that his institution received other support from Pfizer, AstraZeneca, MedImmune, Sanofi, Sequerius and Merck for advisory board participation. MDS declares that his institution received grants from the GSK group of companies for the conduct of this trial. MDS also declares support through his institution for the conduct of other trials (from the GSK group of companies, Sanofi-Pasteur, Pfizer, MedImmune, Novavax and Johnson and Johnson). CP, MA RW, KC, UB, JB, KH and CE MP have indicated they have no financial relationship or conflict of interest relevant to this article to disclose.

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Figures

Fig. 1

Focus on the patient

Fig. 2

Participant flow chart. Group Var-HSA, participants receiving varicella vaccine produced without HSA (human serum albumin); Group Var + HSA, participants receiving varicella vaccine containing HSA; N, number of participants; ATP, according-to-protocol. Note: a Immunogenicity analyses were only planned in a sub-cohort of ~ 200 participants in each group. b Not due to an adverse event

Fig. 3

Percentage of participants with solicited local and general adverse events, post-each dose (total vaccinated cohort). Group Var-HSA, participants receiving varicella vaccine produced without HSA (human albumin serum); Group Var + HSA, participants receiving varicella vaccine containing HSA. Note: Error bars represent 95% confidence intervals. Grade 3 adverse events were defined as: cried when limb was moved/spontaneously painful for pain; diameter > 20 mm for swelling/redness; temperature > 39.5 °C for fever; > 150 lesions for varicella-like rash; prevented normal, everyday activities and leading to seeking medical advice (all other events). *Two grade 3 varicella-like rashes were reported in this study, both of which were following dose 1 in the Var + HSA group