Immunogenicity and safety of coadministration of COVID-19 and influenza vaccination among healthcare workers
Authors: Wagenhäuser Isabell , Reusch Julia , Gabel Alexander , Höhn Anna , Lâm Thiên-Trí , Almanzar Giovanni , Prelog Martina , Krone Lukas B. , Frey Anna , Schubert-Unkmeir Alexandra , Dölken Lars , Frantz Stefan , Kurzai Oliver , Vogel Ulrich , Petri Nils , Krone Manuel 
Published: June 2022

ABSTRACTBackgroundA third dose of COVID-19 vaccination (‘COVID booster vaccination’) has become established as an important measure to strengthen the immune response against SARS-CoV-2. In contrast, seasonal influenza vaccination has been an important infection prevention measure for years, especially among highly exposed healthcare workers (HCWs). Coadministration of vaccines against COVID-19 and seasonal influenza could be an efficient strategy to protect HCWs from two major viral respiratory infections. Yet, the immunogenicity and safety of coadministration remains to be evaluated.MethodsThis study examines the differences in Anti-SARS-CoV-2-Spike IgG antibody formation as well as side effects based on a digital questionnaire after a third COVID-19 vaccination with or without coadministration of a seasonal quadrivalent influenza vaccine (Influvac Tetra vaccine 2021/2022). 1,231 HCWs were recruited who received a mRNA-based booster COVID-19 vaccination (mRNA-1273 or BNT162b2mRNA) after basic immunisation with BNT162b2mRNA twice. Anti-SARS-CoV-2-Spike IgG levels were determined at least 14 days after vaccination by SERION ELISA agile SARS-CoV-2 IgG.FindingsAnti-SARS-CoV-2-Spike IgG concentrations were by 25·4% lower in individuals with coadministration of the seasonal quadrivalent influenza vaccination than without (p<0·01). There was no statistically significant difference in the reported side effects. The concentration of Anti-SARS-CoV-2-Spike IgG was higher in HCWs who had received the influenza vaccine concomitantly with mRNA-1273 than with BNT162b2mRNA as third COVID-19 vaccine (p<0·0001).InterpretationCoadministration of the seasonal quadrivalent influenza vaccine significantly limits the levels in Anti-SARS-CoV-2-Spike IgG levels, with a more restricted elevation in case of a BNT162b2mRNA booster vaccination compared with mRNA-1273 vaccine. The reduced humoral immune response in case of coadministration needs to be considered in seasonal vaccination recommendations, although the consequences of lower Anti-SARS-CoV-2-Spike IgG levels for the protection against SARS-CoV-2 infection and severe COVID-19 disease course are currently unknown. An augmented mRNA-based COVID-19 vaccine dosage may compensate for the restricted immunogenicity in case of coadministration.FundingThis study was funded by the Federal Ministry for Education and Science (BMBF) through a grant provided to the University Hospital of Wuerzburg by the Network University Medicine on COVID-19 (B-FAST, grant-No 01KX2021) as well as by the Free State of Bavaria with COVID-research funds provided to the University of Wuerzburg, Germany. Nils Petri is supported by the German Research Foundation (DFG) funded scholarship UNION CVD.Research in contextEvidence before this studyFor evaluation of the previously published evidence, PubMed and medRxiv were searched for the terms “influenza vaccination”, “influenza vaccine”, “influenza”, “flu”, “seasonality”, combined with “coadministration”, “concomitant”, “COVID-19 vaccination”, “COVID-19 vaccine”, “SARS-CoV-2”, in title or abstract, published between 1st of January 2020 and 18th of May 2022.To date, it is unclear if coadministration of COVID-19 and influenza vaccine is effective and safe, particularly in the cohort of healthcare workers (HCWs) as key public health stakeholders. For the subunit COVID-19 vaccine NVX-CoV2373, an impairment of Anti-SARS-CoV-2-Spike IgG levels has been shown in individuals coadministered with a seasonal influenza vaccine. The two previously published studies on coadministration of a mRNA-based COVID-19 and a seasonal quadrivalent influenza vaccine have reported a restriction of humoral Anti-SARS-CoV-2-Spike immune response in the coadministration group. These examinations were conducted with limited correspondence to real-life conditions and in smaller cohorts. Additionally, these former studies do not consider the important aspect of side effects as a possible direct effect of the prevention measure on the availability of public health care in combination with Anti-SARS-CoV-2-Spike IgG levels. In summary, the humoral immunogenicity and side effects of a coadministered third COVID-19 and a seasonal influenza vaccine are still unclear and the limited available data is not transferable to the general public.Added value of this studyWe performed the first large-scale real-life evaluation of humoral immunogenicity and side effects of COVID-19 and influenza vaccine coadministration in HCWs. Anti-SARS-CoV-2-Spike IgG levels were significantly lower in the coadministered cohort compared to the not coadministered control group, stratified by third COVID-19 vaccine (BNT162b2mRNA or mRNA-1273). Anti-SARS-CoV-2-Spike IgG post-vaccine elevation was lower among BNT162b2mRNA vaccinated HCWs than in those vaccinated with mRNA-1273 as a third COVID-19 vaccination. The influence of the seasonal quadrivalent influenza vaccine is evaluated in a cohort including 1,231 HCWs in total, covering a broad age range. Coadministration did not lead to an increase in side effects, which is a central requirement for considering the option of coadministration, given the role of HCWs as key personnel in maintaining health care capacities.Implications of all the available evidenceOur data suggest, that coadministration of third mRNA-based COVID-19 and quadrivalent seasonal influenza vaccine is safe and immunogenic, although it leads to a slightly reduced Anti-SARS-CoV-2-Spike antibody formation. While the clinical impact of the observed reduction in humoral Anti-SARS-CoV-2-Spike immune response for protection against SARS-CoV-2 infection and severe COVID-19 disease is still unclear, influenza vaccination remains an important infection prevention measure, especially among highly exposed HCWs. The coadministration does not increase side effects but may improve vaccination rate. A higher-dosed mRNA-based COVID-19 vaccine may compensate for the restricted immunogenicity in case of seasonal influenza vaccine coadministration. Our results will support the development of public health recommendations for coadministration of COVID-19 and influence vaccines in anticipation of the imminent infection waves in the coming winter season.