Coadministration of seasonal influenza and COVID-19 vaccines: A systematic review of clinical studies

Figures & data

Figure 1. Study selection (PRISMA Flow chart)³⁰.

Figure 2. Study designs of selected randomized controlled trials (N = 3).

(I) Izikson et al.³¹; (L) Lazarus et al.²⁰; (T) Toback et al.²¹

ARs: adverse reactions; HAI: hemagglutinin-inhibiting antibodiegglutinin-inhibiting antibodies; IgG: immunoglobulin G; IS: injection site.

Table 1. Description of the safety & immunogenicity studies reviewed.

Ref.	Izikson et al. (2022)^Citation31	Lazarus et al. (2021)^Citation20	Toback et al. (2022)^Citation21
STUDY INFORMATION
Registration #	ClinicalTrials.gov NCT04969276	EudraCT 2021–001124-18	ClinicalTrials.gov NCT04583995
Sponsor	Sanofi Pasteur	University hospitals Bristol and Weston NHS Foundation Trust	Novavax
Country	USA	UK	UK
Study dates	July/August 2021	April/June 2021	September/November 2020
STUDY DESIGN
	Phase 2	Phase 4	Phase 3
	RCT	RCT	RCT
	Multicenter (6 centers)	Multicenter (12 centers)	Multicenter (33 centers)
	Interim report (on 21 d)		Substudy, 4 centers only
Participants	306 adults:	679 adults:	431 adults:
	≥65 y, 100%	≥65 y, 33%	≥65 y, 7%
	Randomization (1:1:1)	Randomization (1:1)	Not randomized
	3 groups: C+I I+P C+P	2 groups per flu (n = 3), and COVID (n = 2) vaccines Influenza first, C+I/P Placebo first, C+P/I	2 groups: C+I/C I+P/P
	N = 296 C+I, n = 100 C+P, n = 104 I+P, n = 92	N = 679 C+I/P, n = 340 C+P/I, n = 339	N = 431 C+I/C, n = 217 I+P/P, n = 214
Vaccines	I, 1 Flu vaccine: HD-QIV	I, 3 flu vaccines: aTIV (with MF59C) QIVc (cellular) QIVr (recombinant)	I, 2 flu vaccines: aTIV QIVc
	C, 1 COVID vaccine: mRNA-1273	C, 2 COVID vaccines: ChAdOx1 BNT162b2	C, 1 COVID vaccine: NVX-CoV2373
	P, Placebo	P, Placebo	P, Placebo
Vaccination schedule	COVID-19: booster dose (last dose of primary vaccination >5 months)	COVID-19: dose 2 of primary series (last dose >2/3 months ChAdOx1 or >1/3 months BNT162b2)	COVID-19: dose 1 of primary series
	2 injections on Day 0 (C+I, P+I or P+C)	2 injections on Day 0 (C+I, or C+P) 1 injection on Day 21 (P or I)	2 injections on Day 0 (C+I or I+P) 1 injection on Day 21 (C or P)
SAFETY
Reactogenicity	Follow-up: 21 d (Interim analysis)	Follow-up: 21 d after each injection	Follow-up: 35 d after the first injection
	Solicited ISR − 7 d	Solicited ISR − 7 d	Solicited ISR − 7 d
&	Solicited systemic AR − 7 d	Solicited systemic AR − 7 d	Solicited systemic AR − 7 d
Other safety	Unsolicited AE	Unsolicited AE	Unsolicited AE
information	SAE	SAE	SAE
	AESI	AESI	AESI
	MAAE	MAAE	MAAE
IMMUNOGENICITY
Influenza	HI	HI	HI
	A/H1N1; A/H3N2; B/Yamagata; B/Victoria	A/H1N1; A/H3N2; B/Yamagata; B/Victoria	A/H1N1; A/H3N2; B/Yamagata; B/Victoria
	Day 0 & Day 21	Day 0, Day 21, & Day 42	Day 0 & Day 21
	Titer (1/dil)	Titer (1/dil)	Titer (1/dil)
COVID-19	ELISA	ECLIA (Elecsys)	ELISA
	Concentration (BAU/ml) Day 0 & Day 21	Titer (U/ml) Day 0, Day 21, & Day 42	Concentration (ELISA units/ml) Day 0 & Day 35

AESI: adverse event of special interest; AR: adverse reaction; aTIV: adjuvanted trivalent influenza vaccine; BAU: binding antibody units (=ELU (ELISA laboratory units)/ml÷7.9815); C: COVID-19 vaccine; d: days; ECLIA: electro-chemiluminescence immunoassay; ELISA: enzyme-linked immunosorbent assay; GMC: geometric mean concentration; GMT: geometric mean titer; HD-QIV: high dose quadrivalent influenza vaccine; HI: hemagglutinin inhibition; I: influenza vaccine; ISR: injection site reaction; MAAE: medically attended adverse event; P: placebo; QIVc: cellular quadrivalent influenza vaccine; QIVr: recombinant quadrivalent influenza vaccine; RCT: randomized clinical trials; SAE: serious/severe adverse event; y: years.

Figure 3. Proportion of vaccinees reporting at least one adverse reaction at injection site(s) through 7 d following mono or coadministration of influenza and COVID-19 vaccines.

(I) Izikson et al.³¹; (L) Lazarus et al.²⁰; (T) Toback et al.²¹

AR: adverse reaction; aTIV: adjuvanted trivalent influenza vaccine; CoAd: coadministration; HD-QIV: high-dose quadrivalent influenza vaccine; QIVc: cellular quadrivalent influenza vaccine; QIVr: recombinant quadrivalent influenza vaccine.

Figure 4. Proportion of vaccinees reporting at least one systemic adverse reaction through 7 d following mono or coadministration of influenza and COVID-19 vaccines.

(I) Izikson et al.³¹; (L) Lazarus et al.²⁰; (T) Toback et al.²¹

AR: adverse reaction; C: COVID-19 vaccine; C+I: coadministration of both vaccines; I: influenza vaccine; P: placebo.

*: Means the corresponding vaccine is administered 21 d after C+I for the COVID-19 vaccine and C+P for the influenza vaccine.

Table 2. Description of the acceptability & acceptance studies reviewed.

Ref.	Domnich et al. (2021)^Citation32	Domnich et al. (2022)^Citation33	Ma et al. (2022)^Citation35	COVIGIE (2022)^Citation34	Stefanizzi et al. (2022)^Citation29	Lazarus et al. (2021)^Citation20
STUDY INFORMATION
Country	Italy	Italy	China	France	Italy	UK
Study dates	May 2020/21	October/November 2021	September/October 2021	January/February 2022	October 2021	April/June 2021
STUDY DESIGN
	Survey CAWI	Survey CAWI	Survey 23-item online questionnaire	Survey Online questionnaire	Study Data collection about vaccination status	Study Interview during the study
Questioned participants	1979 adults: ≥18 y	2463 adults: ≥18 y	9424 adults: ≥18 y	975 HCPs: ≥18 y	2740 HCPs: ≥18 y	679 adults: ≥18 y Previously vaccinated with both vaccines concomitantly
OUTCOME
	Acceptability: willingness of being vaccinated concomitantly with both vaccines before concomitant administration	Acceptability: willingness of being vaccinated concomitantly with both vaccines before concomitant administration	Acceptability: willingness of being vaccinated concomitantly with both vaccines before concomitant administration	Acceptance: having agreed to vaccinate with both vaccines concomitantly (N = 529) or having agreed to be vaccinated with both vaccines concomitantly as reported by the HCPs (N = 719)	Acceptance(having agreed to be vaccinated concomitantly with both vaccines)	Acceptability (willingness of being vaccinated concomitantly with both vaccines before concomitant administration

CAWI: computer assisted web interview; d: days; HCPs: healthcare professionals; y: years.

Acceptability refers to the theoretical willing of participants to receive a concomitant injection of influenza and COVID-19 vaccines. Acceptance refers to the rate of participants who already chose the concomitant injection of both vaccines.

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