Elsevier

Journal of Infection

Volume 83, Issue 3, September 2021, Pages 354-360
Journal of Infection

Seasonal trivalent inactivated influenza vaccine with topical imiquimod in immunocompromised patients: A randomized controlled trial

https://doi.org/10.1016/j.jinf.2021.07.010Get rights and content

Highlights

Abstract

Background

The effect of the Toll-like receptor 7 agonist imiquimod before intradermal (ID) or intramuscular (IM) influenza vaccine in immunocompromised hosts is unknown.

Methods

In this open-label randomized controlled trial, kidney transplant recipients (KT) and people living with HIV (PLWH) were randomized to receive IM trivalent inactivated influenza vaccine alone (IM), IM vaccine after topical imiquimod (imi+IM) or ID vaccine after topical imiquimod (imi+ID). Immunogenicity was assessed by hemagglutination inhibition assay. The primary outcome was vaccine response, defined as seroconversion to at least one viral strain at day 21.

Results

Seventy patients (35 KT and 35 PLWH) received IM (24), imi+IM (22), or imi+ID (24) vaccine. Vaccine response was 61% (14/23) with IM, 59% (13/22) with imi+IM, and 65% (15/23) with imi+ID vaccine (P = 0.909). Vaccine response was associated with HIV infection compared to kidney transplantation (adjusted-OR 3.74, 95% CI 1.25 – 11.23, P = 0.019), but not with imiquimod application nor ID injection. After vaccination, seroprotection to all viral strains was 79% (19/24) with IM, 68% (15/22) with imi+IM, and 70% (16/23) with imi+ID (P = 0.657). We did not observe any vaccine-related severe adverse event.

Conclusions

In our study, topical imiquimod did not improve the immunogenicity of influenza vaccine in KT and in PLWH.

Introduction

Influenza is responsible each year for up to 600 000 respiratory deaths worldwide, and immunocompromised hosts are at increased risk for more severe infections.1,2 In particular, among solid organ transplant (SOT) recipients with influenza, hospital and intensive care unit admission, and mortality rates of 70%, 11%, and 5%, as well as impaired graft failure-free survival have been reported.3,4 The advent of combined antiretroviral therapy (cART) led to a substantial decline of mortality rate due to influenza in people living with HIV (PLWH), however HIV infection was still associated with an increased hospitalization rate during the 2009 influenza A H1N1 pandemic.5,6

Although seasonal influenza vaccination is strongly recommended and remains the best preventive strategy against influenza, the immunogenicity of the standard inactivated trivalent influenza vaccine containing 15 µg of influenza antigens per strain and administered by intramuscular injection is reduced in SOT recipients and PLWH.7 Therefore, alternative strategies aiming to improve the immunogenicity of the influenza vaccine are needed in these populations.

Imiquimod is a synthetic Toll-like receptor 7 (TLR7) agonist that stimulates both the innate and the adaptative immune system inducing cytokines production and the recruitment and activation of plasmacytoid dendritic cells and the production of interferon-α in the skin.8,9 In animal models, imiquimod has been shown to improve immune response to influenza vaccine.10 Imiquimod is currently used for the topical treatment, without significant systemic absorption, of dermatologic conditions such as anogenital warts, molluscum contagiosum, actinic keratosis, or superficial basocellular carcinoma.8

In clinical studies, topical application of imiquimod before seasonal intradermal influenza vaccination has recently been shown to boost the humoral immune response in elderly adults with comorbidities and in young healthy volunteers.11,12 Yet, the impact of imiquimod in immunocompromised patients, in particular SOT recipients and PLWH, has not been assessed.

We conducted an open-label randomized controlled trial aiming to compare the immunogenicity and safety of the standard intramuscular influenza vaccine to the intradermal vaccine after topical imiquimod application in kidney transplant (KT) recipients and PLWH. We additionally aimed to assess whether the potential booster effect of imiquimod was also present if influenza vaccine was administered intramuscularly instead of intradermally.

Section snippets

Study designs and participants

In this single-center, open-label, randomized controlled clinical trial, we assigned participants in a 1:1:1 ratio to receive intramuscular injection of the trivalent inactivated influenza vaccine alone (IM vaccine, standard treatment), intramuscular injection of the trivalent inactivated influenza vaccine after topical application of a cream containing imiquimod (imi+IM vaccine), or intradermal injection of the trivalent inactivated influenza vaccine after topical application of a cream

Study population

Among 166 patients screened, we enrolled 35 KT recipients and 35 PLWH: 24 participants received the IM vaccine, 22 the imi+IM vaccine and 24 the imi+ID vaccine (Fig. 1). Baseline characteristics of study participants are shown in Table 1. Thirty-four percent of the KT recipients were within the first year after transplantation (50% [6/12] in the IM, 18% [2/11] in the imi+IM, and 33% [4/12] in the imi+ID groups, respectively). In KT recipients, maintenance immunosuppression mostly consisted of

Discussion

We performed the first randomized controlled clinical trial assessing the immunogenicity and safety of topical application of the TLR7 agonist imiquimod before intramuscular or intradermal injection of the seasonal influenza vaccine in immunocompromised patients. In our study conducted in KT recipients and PLWH, topical imiquimod application did not improve vaccine response (defined as seroconversion to at least one viral strain 21 days after vaccination). All immunogenicity parameters

Funding

This work was supported by the “Bourse de la relève 2016″ of the Leenaards Foundation awarded to OM.

CRediT authorship contribution statement

Matteo Mombelli: Visualization, Data curation, Formal analysis, Writing – original draft, Writing – review & editing. Katja Hoschler: Data curation, Formal analysis, Writing – review & editing. Matthias Cavassini: Writing – review & editing. Manuel Pascual: Writing – review & editing. Oriol Manuel: Visualization, Writing – review & editing.

Declaration of Competing Interest

OM reports grants from Lophius Biosciences, personal fees from MSD, personal fees from Gilead, outside the submitted work. MC reports grants from Gilead, MSD and Viiv, outside the submitted work paid to his institution. All other authors report no potential conflicts. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest.

Acknowledgments

We thank all study participants. We are particularly grateful to Mrs Deolinda Alves for logistical and technical support during the whole study. We thank the Transplantation center outpatients’ clinic staff for assistance during the study. This work was presented in part at the 28th European Congress of Clinical Microbiology and Infectious Diseases (ECCMID), 21–24th April 2018, Madrid, Spain (Abstract P0037).

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