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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.

ABSTRACT: 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.

SUBMITTER: Namazova-Baranova L

PROVIDER: S-EPMC9067519 | biostudies-literature | 2022 Jan

REPOSITORIES: biostudies-literature

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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.

Namazova-Baranova Leyla L Habib Md Ahsan MA Povey Michael M Efendieva Kamilla K Fedorova Olga O Fedoseenko Marina M Ivleva Tatyana T Kovshirina Yulia Y Levina Julia J Lyamin Artem A Ogorodova Ludmila L Reshetko Olga O Romanenko Viktor V Ryzhenkova Inna I Sidorenko Irina I Yakovlev Yakov Y Zhestkov Aleksandr A Tatochenko Vladimir V Scherbakov Michael M Shpeer Evgeniy L EL Casabona Giacomo G

Human vaccines & immunotherapeutics 20210826 1

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-rubel ...[more]

PMID: 34435933

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Project description:Older age is associated with increased infectious morbidity and decreased immune responses to vaccines, but the mechanisms that mediate this effect are incompletely understood. The efficacy and immunogenicity of the live attenuated zoster vaccine (ZVL) have a very-well-described negative association with the age of the vaccinee. In a study of 600 ZVL recipients 50 to >80 years of age, we investigated immunological factors that might explain the effect of age on the immunogenicity of ZVL. Using FluoroSpot assays and flow cytometry, we determined that varicella-zoster virus (VZV)-specific peak T helper 1 (VZV-Th1) responses to ZVL were independently predicted by prevaccination VZV-Th1 responses, regulatory T cells (Treg), and PD1-expressing immune checkpoint T cells (Tcheck) but not by the age of the vaccinee. Persistence of VZV-Th1 1 year after vaccination was independently predicted by the factors mentioned above, by peak VZV-Th1 responses to ZVL, and by the age of the vaccinee. We further demonstrated by ex vivo blocking experiments the mechanistic role of PD1 and CTLA4 as modulators of decreased VZV-Th1 responses in the study participants. VZV-specific cytotoxic T cell (VZV-CTL) and T follicular helper responses to ZVL did not correlate with age, but similar to other Th1 responses, VZV-CTL peak and baseline responses were independently correlated. These data expand our understanding of the factors affecting the magnitude and kinetics of T cell responses to ZVL in older adults and show the importance of prevaccination Treg and Tcheck in modulating the immunogenicity of ZVL. This presents new potential interventions to increase vaccine responses in older adults.IMPORTANCE Vaccination is the most effective method to protect older adults against viral infections. However, the immunogenicity of viral vaccines in older adults is notoriously poor. The live attenuated zoster vaccine (ZVL) provides the best example of a gradual decrease of vaccine immunogenicity with every 10-year age increase above 50 years. Here we show that the abundance of regulatory T cells before vaccine administration to older adults has a significant inhibitory effect on immune responses to ZVL and, together with baseline immunity to varicella-zoster virus, explains the effect of age on the immunogenicity of ZVL. Moreover, in vitro blockade of regulatory T cell mechanisms of action with biologic modulators restores immune responses to varicella-zoster virus in vaccinees. Collectively, these observations suggest that immune modulators that block regulatory T cell activity may increase responses to viral attenuated vaccines in older adults.

Project description:Two herpes zoster (HZ) vaccines licensed in the United States are recommended by the Advisory Committee on Immunization Practices (ACIP): (i) live-attenuated vaccine (ZVL) using vOka strain varicella-zoster virus (VZV) and (ii) recombinant adjuvanted vaccine (RZV) containing recombinant varicella-zoster virus (VZV) glycoprotein E (gE). Two phase 3 clinical trials of RZV led the Advisory Committee on Immunization Practices (ACIP) to recommend it with preferred status. VZV T cell-mediated immunity (CMI), but not humoral immunity, is considered essential for protection against HZ. Published studies of humoral immunity focused on VZV-specific IgG concentration. To complement reports comparing the CMI responses to these vaccines, we compared humoral responses in ZVL and RZV recipients, emphasizing functional qualities (avidity and neutralization). Baseline avidities to a VZV glycoprotein mixture (gp) were near the upper limit of detection, but avidity to gE was much lower. Small increases in gp avidity were observed for both RZV and ZVL vaccination (19 and 12 avidity index units [AIU], respectively). RZV boosted both gE avidity and VZV neutralizing antibody significantly more than ZVL (mean gE avidity boost, 47 AIU versus 22 AIU; mean neutralizing antibody boost, 22-fold versus 8-fold). Increases in neutralizing antibodies strongly correlated with gE avidity increases (r = 0.5) and moderately with gp avidity increases (r = 0.23). After 1 year, 81% of RZV recipients and only 18% of ZVL recipients retained >50% of their peak avidity boosts. These results are consistent with the CMI responses to these vaccines: RZV responses are skewed to long-term memory, whereas ZVL preferentially induces transient effector responses.IMPORTANCE These observations further distinguish the immunogenicity and duration of the immune response of the two vaccines. In addition, measurements of functional humoral immunity (IgG avidity and neutralizing antibody) in response to zoster immunization, alone or combined with other immune markers, might contribute to practical in vitro correlates of protection. Combined with previous observations of the cell-mediated response to these vaccines, this study suggests that vaccine development will benefit from more expansive and granular assessments of acquired immunity during early phase 1 immunogenicity trials.

Project description:ObjectivesTo examine the reported incidence and features of disseminated varicella zoster virus (VZV) infection following live attenuated herpes zoster vaccine live (ZVL: Zostavax, Merck) in immunocompromised people in Australia.Design and settingZVL was funded in 2016 in Australia for people aged 70 years, with a catch-up programme for those 71-79 years. From 2016 to 2020, three deaths due to disseminated vaccine-strain VZV infection occurred following inadvertent ZVL administration in individuals with varying levels of immunocompromise. This descriptive study examined 4 years of national surveillance data reported to the Therapeutic Goods Administration's Adverse Event Monitoring System (AEMS). Denominator data for rates were from doses recorded in the Australian Immunisation Register.ParticipantsIndividuals vaccinated between 1 November 2016 and 31 December 2020 who experienced adverse event(s) following immunisation (AEFI) after ZVL recorded in the AEMS.Primary and secondary outcome measuresRates and outcomes of confirmed (Oka strain positive) or probable disseminated VZV infection, and inadvertent administration of ZVL in immunocompromised individuals.Results854 AEFI were reported from 1 089 966 doses of ZVL administered (78.4 per 100 000 doses). Of those, 14 were classified as confirmed (n=6, 0.55 per 100 000) or probable (n=8) disseminated VZV infection. The confirmed cases were all hospitalised, and most (5/6) were immunocompromised; three cases died. Thirty-seven individuals were reported as vaccinated despite a contraindication due to immunocompromise (3.4 per 100 000), with 12/37 (32%) hospitalised.ConclusionsDisseminated VZV is potentially life-threatening and occurs mostly in those with severe immunocompromise. Inadvertent administration of ZVL to immunocompromised individuals has occurred despite initial provider guidance and education. Multiple additional strategies to assist providers to identify contraindications have been implemented to prevent adverse outcomes.

Dataset Information

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.

Publications

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.

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