Grippol Supplementary Files

A systematic review of clinical trials conducted with a low-dose inactivated influenza vaccine adjuvanted by azoximer bromide (AZB, Polyoxidonium), was performed to compare vaccine reactogenicity against non-adjuvant vaccines. We also assessed whether lower amounts of antigen per viral strain in AZB-adjuvanted vaccines affected antibody responses. A robust search strategy identified scientific publications reporting 30 clinical trials, comprising data on 11,736 participants and 86 trial arms, for inclusion in the analysis. Local reaction rates (R_lr) appeared to be lower in AZB-adjuvanted vaccine treatment arms versus comparator vaccine treatment arms. Meta‑regression analysis revealed that AZB did not contribute to vaccine reactogenicity. Post-vaccination geometric mean titres in those exposed to AZB-adjuvanted vaccine and comparator vaccine treatment arms were similar in both children and adults aged 18–60 years, implying an antigen-sparing effect by AZB.

Methods

Data identification, selection criteria and extraction

This study was conducted according to the principles of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) [24]. A literature search was performed in English- and Russian-language databases (United States National Library of Medicine at the National Institutes of Health PubMed database, Cochrane Database of Systematic Reviews, Russian National Medical Library) to identify any public records or reports of clinical trials conducted with AZB-SU between 1998 and 2018. Relevant articles were identified by searching the terms: ‘influenza’ AND ‘vaccin*’ AND ‘[‘azoximer bromide’ OR ‘polyoxidonium’ OR ‘Grippol’]. The online search was performed in January 2019 and updated in August 2019.

Manual search of existing lists of references, provided by the manufacturer, NPO Petrovax Pharm (Moscow, Russia), was performed, and assessments included original trial reports and trial compilations produced by the manufacturer. Study reports were rejected if a full text was not openly available or in case of pre-clinical studies, field studies or post-marketing reports on rare events or individual cases.

Reports from studies with at least one of the following assessments were included:

• Reactogenicity: Participants were followed for at least 5–6 days after intervention (vaccine or placebo), and local and systemic vaccine reactions were recorded.
• Safety: Serious adverse events (SAEs) were recorded within at least 3–4 weeks after intervention.
• Immunogenicity: Antibody titres against vaccine strains were determined with a standard hemagglutination inhibition assay, in sera drawn before and 3–4 weeks after intervention.

A data extraction form was used based on the PRISMA recommendations. Titles and abstracts identified from searches were screened by two independent reviewers. They also independently reviewed full‐text versions of marked articles that met the predefined criteria. Each study was provided with a unique identifier number (Study reference number). All extracted data were independently reviewed by two researchers and finalised after consultation and agreement on inclusion and exclusion assignment was unanimous. Data extracted from included studies comprised: authors and date of study, population characteristics (including age, medical history and previous vaccinations), trial design and intervention arms, vaccines used (formulations, virus strains, amount of HA per strain and per dose), numbers or percentages of participants with post-vaccination local or systemic reactions and the numbers of participants who experienced SAEs. Immunogenicity data, i.e. pre- and post-vaccination geometric mean titre (GMT) and variance (e.g., confidence interval [CI]) and serologic Committee for Proprietary Medicinal Products (CPMP) variables (see below), were collected for efficacy analyses. All entry data were critically assessed for eligibility by the reviewers.