Immunogenicity and safety of different dosing schedules of trivalent inactivated influenza vaccine in pregnant women with HIV: a randomised controlled trial

Marta C Nunes, Clare L Cutland, Andrew Moultrie, Stephanie Jones, Justin R Ortiz, Kathleen M Neuzil, Keith P Klugman, Eric A F Simões, Adriana Weinberg, Shabir A Madhi, Maternal Flu Trial Team, A Hugo, P Sithole, L-A Stoltenkamp, Y Abdoola, N van Niekerk, F Treurnicht, Marta C Nunes, Clare L Cutland, Andrew Moultrie, Stephanie Jones, Justin R Ortiz, Kathleen M Neuzil, Keith P Klugman, Eric A F Simões, Adriana Weinberg, Shabir A Madhi, Maternal Flu Trial Team, A Hugo, P Sithole, L-A Stoltenkamp, Y Abdoola, N van Niekerk, F Treurnicht

Abstract

Background: Standard-dose, seasonal, trivalent, inactivated influenza vaccine induces moderate-to-low haemagglutination-inhibition antibody responses in people living with HIV. This study assessed the immunogenicity and safety of different dosing schedules of inactivated influenza vaccine in pregnant women living with HIV in South Africa.

Methods: In this double-blind, randomised, controlled trial, we recruited pregnant women with HIV from seven antenatal clinics in Soweto, South Africa. Pregnant women were eligible if they were aged 18-38 years, infected with HIV, and had an estimated gestational age of 12-36 weeks. Women were randomly assigned (1:1:1), using a computer-generated randomisation list, to receive inactivated influenza vaccine containing 15 μg of each of the three seasonal influenza strains for that year, as a single dose, a double dose, or two single doses 1 month apart. Participants and study personnel were masked to group allocation. Haemagglutination-inhibition antibody responses were measured for all groups in the mothers at enrolment and at 1 month after each vaccine dose, and in the single-dose and double-dose groups within 7 days of birth in the neonates. Immunogenicity analyses only included women with visits 28-35 days apart and infants who were born at least 28 days after maternal immunisation. The primary was seroconversion rate to each of the vaccine strains in the mothers 1 month after completion of the dosing schedule, and the primary safety outcomes were frequency of local and systemic reactions. Safety was assessed in mothers and infants until 24 weeks post partum and analysed in all participants who received at least one dose of vaccine. This study is registered with ClinicalTrials.gov, NCT01527825, and is closed to accrual.

Findings: Between Feb 11, and June 6, 2013, 800 pregnant women living with HIV were enrolled and randomly assigned to the single-dose (n=266), double-dose (n=265), or two-single-doses (n=269) group. In the analysable population, seroconversion rates in mothers 1 month after the final vaccine dose were significantly higher in the double-dose group (n=230; ranging from 29% to 65% for the three vaccine strains) than in the single-dose group (n=230; ranging from 18% to 49%; p≤0·019 for the three vaccine strains), but were similar between the two-single-doses group (n=220; ranging from 23% to 52%) and the single-dose group (p≥0·20 for the three vaccine strains). Safety outcomes were similar in the three groups, except for more injection-site reactions in recipients in the double-dose group.

Interpretation: A regimen of double-dose inactivated influenza vaccine gave slightly greater immunogenicity than did a single-dose regimen in pregnant women living with HIV. However, immunogenicity in the double-dose group was still lower than historical data from the same setting in pregnant women without HIV. More immunogenic vaccines are needed for pregnant women living with HIV to enhance transplacental transfer of vaccine-induced protective antibodies to their newborn infants.

Funding: Bill & Melinda Gates Foundation.

Copyright © 2020 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.

Figures

Figure
Figure
Trial profile for mothers (A) and their infants (B) Visit 1 is the enrolment and first injection visit, visit 2 is the second injection visit, and visit 3 is the visit 1 month after the second injection. HAI=hemagglutination-inhibition antibody.
Figure
Figure
Trial profile for mothers (A) and their infants (B) Visit 1 is the enrolment and first injection visit, visit 2 is the second injection visit, and visit 3 is the visit 1 month after the second injection. HAI=hemagglutination-inhibition antibody.

References

    1. Phadke VK, Omer SB. Maternal vaccination for the prevention of influenza: current status and hopes for the future. Expert Rev Vaccines. 2016;15:1255–1280.
    1. Zaman K, Roy E, Arifeen SE. Effectiveness of maternal influenza immunization in mothers and infants. N Engl J Med. 2008;359:1555–1564.
    1. Tapia MD, Sow SO, Tamboura B. Maternal immunisation with trivalent inactivated influenza vaccine for prevention of influenza in infants in Mali: a prospective, active-controlled, observer-blind, randomised phase 4 trial. Lancet Infect Dis. 2016;16:1026–1035.
    1. Steinhoff MC, Katz J, Englund JA. Year-round influenza immunisation during pregnancy in Nepal: a phase 4, randomised, placebo-controlled trial. Lancet Infect Dis. 2017;17:981–989.
    1. Madhi SA, Cutland CL, Kuwanda L. Influenza vaccination of pregnant women and protection of their infants. N Engl J Med. 2014;371:918–931.
    1. Nunes MC, Cutland CL, Dighero B. Kinetics of hemagglutination-inhibiting antibodies following maternal influenza vaccination among mothers with and those without HIV infection and their infants. J Infect Dis. 2015;212:1976–1987.
    1. Zanetti AR, Amendola A, Besana S, Boschini A, Tanzi E. Safety and immunogenicity of influenza vaccination in individuals infected with HIV. Vaccine. 2002;20(suppl 5):B29–B32.
    1. Kroon FP, Rimmelzwaan GF, Roos MT. Restored humoral immune response to influenza vaccination in HIV-infected adults treated with highly active antiretroviral therapy. AIDS. 1998;12:F217–F223.
    1. Durando P, Fenoglio D, Boschini A. Safety and immunogenicity of two influenza virus subunit vaccines, with or without MF59 adjuvant, administered to human immunodeficiency virus type 1-seropositive and -seronegative adults. Clin Vaccine Immunol. 2008;15:253–259.
    1. Richardson K, Weinberg A. Reduced immunogenicity of influenza vaccines in HIV-infected compared with uninfected pregnant women is associated with regulatory T cells. AIDS. 2011;25:595–602.
    1. El Sahly HM, Davis C, Kotloff K. Higher antigen content improves the immune response to 2009 H1N1 influenza vaccine in HIV-infected adults: a randomized clinical trial. J Infect Dis. 2012;205:703–712.
    1. McKittrick N, Frank I, Jacobson JM. Improved immunogenicity with high-dose seasonal influenza vaccine in HIV-infected persons: a single-center, parallel, randomized trial. Ann Intern Med. 2013;158:19–26.
    1. Lagler H, Grabmeier-Pfistershammer K, Touzeau-Römer V. Immunogenicity and tolerability after two doses of non-adjuvanted, whole-virion pandemic influenza A (H1N1) vaccine in HIV-infected individuals. PLoS One. 2012;7
    1. Launay O, Desaint C, Durier C. Safety and immunogenicity of a monovalent 2009 influenza A/H1N1v vaccine adjuvanted with AS03A or unadjuvanted in HIV-infected adults: a randomized, controlled trial. J Infect Dis. 2011;204:124–134.
    1. Cooper C, Thorne A, Klein M. Immunogenicity is not improved by increased antigen dose or booster dosing of seasonal influenza vaccine in a randomized trial of HIV infected adults. PLoS One. 2011;6
    1. Cooper C, Klein M, Walmsley S. High-level immunogenicity is achieved vaccine with adjuvanted pandemic H1N1(2009) and improved with booster dosing in a randomized trial of HIV-infected adults. HIV Clin Trials. 2012;13:23–32.
    1. Soonawala D, Rimmelzwaan GF, Gelinck LB, Visser LG, Kroon FP. Response to 2009 pandemic influenza A (H1N1) vaccine in HIV-infected patients and the influence of prior seasonal influenza vaccination. PLoS One. 2011;6
    1. Abzug MJ, Nachman SA, Muresan P. Safety and immunogenicity of 2009 pH1N1 vaccination in HIV-infected pregnant women. Clin Infect Dis. 2013;56:1488–1497.
    1. National Department of Health . National Department of Health; Pretoria: 2013. The 2012 national antenatal sentinel HIV and herpes simplex type-2 prevalence survey, South Africa.
    1. National Institute for Communicable Diseases, Division of the National Health Laboratory Services; 2014. National Institute for Communicable Diseases monthly surveillance report. Report for 1 January to 31 January 2014.
    1. Weinberg A, Song LY, Walker R. Anti-influenza serum and mucosal antibody responses after administration of live attenuated or inactivated influenza vaccines to HIV-infected children. J Acquir Immune Defic Syndr. 2010;55:189–196.
    1. Harris PA, Taylor R, Thielke R, Payne J, Gonzalez N, Conde JG. Research electronic data capture (REDCap)—a metadata-driven methodology and workflow process for providing translational research informatics support. J Biomed Inform. 2009;42:377–381.
    1. Zhang W, Sun H, Atiquzzaman M, Sou J, Anis AH, Cooper C. Influenza vaccination for HIV-positive people: systematic review and network meta-analysis. Vaccine. 2018;36:4077–4086.
    1. Effros RB, Fletcher CV, Gebo K. Aging and infectious diseases: workshop on HIV infection and aging: what is known and future research directions. Clin Infect Dis. 2008;47:542–553.
    1. Lange CG, Lederman MM, Medvik K. Nadir CD4+ T-cell count and numbers of CD28+ CD4+ T-cells predict functional responses to immunizations in chronic HIV-1 infection. AIDS. 2003;17:2015–2023.
    1. Blanchard-Rohner G, Meier S, Bel M. Influenza vaccination given at least 2 weeks before delivery to pregnant women facilitates transmission of seroprotective influenza-specific antibodies to the newborn. Pediatr Infect Dis J. 2013;32:1374–1380.
    1. Madhi SA, Briner C, Maswime S. Causes of stillbirths among women from South Africa: a prospective, observational study. Lancet Glob Health. 2019;7:e503–e512.
    1. Malaspina A, Moir S, Orsega SM. Compromised B cell responses to influenza vaccination in HIV-infected individuals. J Infect Dis. 2005;191:1442–1450.
    1. Madhi SA, Maskew M, Koen A. Trivalent inactivated influenza vaccine in African adults infected with human immunodeficient virus: double blind, randomized clinical trial of efficacy, immunogenicity, and safety. Clin Infect Dis. 2011;52:128–137.
    1. Grohskopf LA, Sokolow LZ, Broder KR, Walter EB, Fry AM, Jernigan DB. Prevention and control of seasonal influenza with vaccines: recommendations of the Advisory Committee on Immunization Practices-United States, 2018–19 Influenza Season. MMWR Recomm Rep. 2018;67:1–20.

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