COVID-19 and Seasonal Influenza Vaccination

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1		Alexander Domnich	+ 2184 word(s)	2184	2022-03-15 07:46:02	\|
2	update layout and reference	Rita Xu	Meta information modification	2184	2022-03-23 04:54:29	\|

This entry is adapted from the peer-reviewed paper 10.3390/ph15030322

SARS-CoV-2 and influenza are the main respiratory viruses for which effective vaccines are currently available. Strategies in which COVID-19 and influenza vaccines are administered simultaneously or combined into a single preparation are advantageous and may increase vaccination uptake.

influenza COVID-19 vaccination vaccine co-administration

1. Introduction

Vaccination against COVID-19 is a cornerstone public health intervention to tackle the ongoing pandemic ^[1]. Analogously, seasonal influenza vaccination (SIV) is considered one of the most effective means of reducing the burden of disease, which in the pre-COVID-19 era caused on average 250,000–500,000 deaths worldwide each year ^[2]^[3]. Although circulation of the influenza virus has diminished drastically since 2020, the ongoing 2021/22 northern hemisphere winter season is characterized by the circulation of both SARS-CoV-2 and influenza ^[4]. Moreover, in the 2021/22 season, there is an overlap between the administration of booster doses of COVID-19 vaccines and the SIV campaign ^[5]^[6].

Very little is yet known about the interaction between SARS-CoV-2 and influenza viruses. Dadashi et al. ^[7] estimated a pooled prevalence of SARS-CoV-2 and influenza co-infection of 0.8% (95% confidence interval (CI): 0.4–1.3%) with marked regional heterogeneity, ranging from 0.4% in the Americas to 4.5% in Asia. A large study conducted in England ^[8] reported that, while individuals positive for influenza had 58% (95%: 44–69%) lower odds of also testing positive for SARS-CoV-2, co-infected individuals had worse clinical outcomes. Specifically, co-infected patients were approximately twice as likely to die (odds ratio (OR) 2.27; 95% CI: 1.23–4.19) as subjects positive only for SARS-CoV-2 ^[8]. Some experimental evidence has provided useful insights into these poorer outcomes in co-infected patients. Indeed, it has been observed ^[9] that prior infection with type A influenza virus promotes SARS-CoV-2 entry and infectiousness in both cell and animal models, probably owing to the ability of the former to increase the expression of angiotensin-converting enzyme 2 (ACE2).

2. Non-Specific Effects of Seasonal Influenza Vaccination on COVID-19-Related Outcomes

2.1. Real-World Evidence

Some early ecological studies ^[10]^[11], which are useful for hypothesis generation ^[12], found a negative correlation between SIV coverage rates and COVID-19-related outcomes. For instance, in Italy, which was the first western country where SARS-CoV-2 spread widely, a negative correlation (r = −0.59, p = 0.005) between regional SIV coverage rates in the elderly and COVID-19 deaths was demonstrated ^[10]. However, subsequent cohort studies on this non-specific effect of SIV yielded contrasting results: some ^[13]^[14]^[15] found a protective effect, while others did not find any significant association ^[16]^[17]. To summarize the body of available observational studies, Wang et al. ^[18] conducted a systematic review and meta-analysis of this non-specific association. In their random-effects model, a significant reduction in laboratory-confirmed cases of SARS-CoV-2 was found in subjects immunized with SIV, with a pooled (n = 9 studies) OR of 0.86 (95% CI: 0.79–0.94). On the other hand, the association between SIV and some other COVID-19-related outcomes, such as hospitalization (OR 0.74; 95% CI: 0.51–1.06), admission to intensive care units (OR 0.63; 95% CI: 0.22–1.81) or mortality (OR 0.89; 95% CI: 0.73–1.09) was not statistically significant ^[18].

2.2. Underlying Immunological Mechanisms

Different immunological mechanisms beyond the observed non-specific heterologous effects of SIV on COVID-19-related clinical endpoints, have been proposed. These mechanisms may involve either innate (the so-called “trained immunity”) or adaptive (bystander activation and cross-reactivity) compartments of the immune system ^[19]. Bystander activation refers to a type of heterologous response which is exerted by adjacent, but not relevant, T cells with different specificity. These heterologous T cells are probably activated by cytokines as a result of the activation of cells during the classical response ^[20]. By contrast, the cross-reactivity theory holds that T cells involved in the classical adaptive immune response may cross-react with an antigen presenting some degree of amino acid similarity ^[19]. Finally, the trained immunity hypothesis postulates that the innate immune cells may be primed upon encountering exogenous or endogenous insults, causing long-term metabolic and epigenetic reprogramming of these cells and leading to an enhanced response to a second challenge ^[21]^[22]^[23].

The available experimental data on influenza virus- and/or SIV-induced cross-reactive or even cross-protective antibodies against SARS-CoV-2 are controversial. For instance, with regard to T and B cell reactivity, Reche ^[24] concluded that influenza viruses do not have epitopes that cross-react with SARS-CoV-2. Murugavelu et al. ^[25] tested polyclonal sera obtained from SARS-CoV-2-positive subjects with high anti-spike neutralizing antibody titers and found some degree of cross-reactivity with influenza virus hemagglutinin in both enzyme-linked immunosorbent (ELISA) and Western blot assays. However, a subsequent analysis demonstrated that these hemagglutinin cross-reactive binding antibodies were not neutralizing. More recently, Almazán et al. ^[26] investigated the role of the small NGVEGF peptide—which is identical, or very similar, to a peptide found in most contemporary A(H1N1)pdm09 strains—in inducing cross-reactive antibodies. This peptide is present in the most critical part (N481–F486) of the receptor binding domain (RBD) of the SARS-CoV-2 spike protein, which interacts with the ACE2 receptor, while in influenza A(H1N1)pdm09 strains, the NGVEGF/NGVKGF peptide is located in an immunodominant region of the neuraminidase. Approximately two thirds of blood donors (n = 328) had detectable levels of antibodies to this peptide. Immunization with a quadrivalent egg-based influenza vaccine (QIVe) enhanced the anti-SARS-CoV-2 response: subjects with no recent influenza infection had low binding inhibitory activity (average of 32.7%), which was enhanced by QIVe administration (average of 55%) and further enhanced by the BNT162b2 (Comirnaty; Pfizer Inc., New York, NY, USA and BioNTech, Mainz, Germany) vaccine (average of 94%). The NGVEGF peptides also activated CD8+ cells in 20% of donors. Finally, the authors identified 11 additional CD8+ cell peptides that potentially cross-reacted with both SARS-CoV-2 and influenza viruses; depending on the type of human leukocyte antigen (HLA), these peptides may protect against SARS-CoV-2 in about 40–71% of individuals ^[26].

The bystander activation mechanism has been partially proven by Pallikkuth et al. ^[27]. Specifically, in their cohort of healthcare workers, A(H1N1) antigen-specific CD4+ cells were present in 92% and 76% of SARS-CoV-2-positive and -negative subjects, respectively. The A(H1N1) CD4+ response also showed a strong positive correlation with SARS-CoV-2-specific CD4+ cells ^[27].

The trained immunity hypothesis has recently drawn particular attention. It was first documented in the case of BCG (Bacillus Calmette–Guérin) vaccine, and then measles, oral polio and, more recently, SIV ^[19]^[20]. Experimental confirmation of SIV-induced trained immunity against SARS-CoV-2 was recently obtained in a Dutch study ^[28]. Following the demonstration of a 37–49% relative risk reduction of SARS-CoV-2 infection among healthcare workers vaccinated with QIVe (compared with non-vaccinated subjects), the authors investigated the biological plausibility of this observation in a well-established in vitro model. Specifically, following the stimulation of peripheral blood mononuclear cells with QIVe and BCG, an increase in the production of cytokines was observed. Re-stimulation of these cells with a heat-inactivated SARS-CoV-2 strain induced a higher production of interleukin (IL)-1 receptor antagonist (IL-1RA), while the production of pro-inflammatory IL-1β and IL-6 was reduced ^[28]. An Italian study ^[29] conducted among healthcare workers (n = 710) who received 2 doses of the BNT162b2 vaccine found that, in subjects previously vaccinated with the quadrivalent cell culture-based influenza vaccine (QIVc; Flucelvax Tetra, Seqirus Netherlands B.V., Amsterdam, The Netherlands) plus pneumococcal vaccines or with QIVc alone, microneutralization titers against SARS-CoV-2 were 58% (p = 0.01) and 42% (p = 0.07) higher, respectively, than in subjects who did not receive any vaccine. By contrast, no significant differences were found for the anti-spike and interferon-γ responses ^[29].

3. Safety, Immunogenicity and Efficacy of COVID-19 and Influenza Vaccine Co-Administration

As of February 2022, three randomized controlled trials (RCTs) ^[30]^[31]^[32] on COVID-19 and SIV vaccine co-administration are available. In a phase IV trial conducted in the United Kingdom (UK) ^[30], adults were randomized (1:1; n = 679) to receive either a second dose of ChAdOx1 (Vaxzevria, AstraZeneca, Cambridge, UK) or BNT162b2 vaccines, together with an age-appropriate SIV (QIVc, recombinant quadrivalent influenza vaccine (QIVr; Supemtek, Sanofi Pasteur, Lyon, France) for subjects aged 18–64 years and MF59-adjuvanted trivalent influenza vaccine (aTIV; Fluad, Seqirus) for those aged ≥65 years) or ChAdOx1/BNT162b2 together with placebo. Three weeks later, those who had received placebo received SIV, and vice versa. Toback et al. ^[31] reported the results of a phase III efficacy RCT, in which a subset of adults was randomized (1:1; n = 431) to receive the first dose of NVX-CoV2373 (Nuvaxovid, Novavax CZ a.s., Jevany, Czech Republic) plus SIV (QIVc and aTIV for subjects aged 18–64 and ≥65 years, respectively) or SIV alone. Finally, the interim results of a phase II RCT have recently been reported ^[32]; in this trial, elderly individuals (≥65 years) were randomized (1:1:1; n = 431) to receive a second dose of mRNA-1273 (Spikevax, Moderna, Cambridge, MA, USA) plus a high-dose quadrivalent influenza vaccine (hdQIV; Fluzone High-Dose Quadrivalent, Sanofi Pasteur, Lyon, France), a dose of hdQIV alone or a second dose of mRNA-1273 alone. In all three RCTs ^[31]^[32], vaccines were co-administered in opposite arms in each subject.

All three RCTs ^[31]^[32] reported no major safety concerns regarding COVID-19 + SIV co-administration. Specifically, as reported in Table 1, the overall rate of solicited local (especially pain in the injection site) and systemic adverse events was similar between subjects who received COVID-19 + SIV and those who received the COVID-19 vaccine alone. The adverse events reported were mostly mild-to-moderate and self-limiting. A similar picture was seen with regard to unsolicited adverse events.

Table 1. Rate (%) of solicited local and systemic adverse events in COVID-19 and influenza vaccine co-administration groups, as compared with groups to whom either vaccine was administered alone.

Adverse Event	Comparison		Vaccine Administration Pattern			Reference
Adverse Event	COVID-19 Vaccine	SIV	COVID-19 + SIV	COVID-19 Alone	SIV Alone	Reference
Any local, %	ChAdOx1 ¹	QIVc ¹	84	81	–	^[30]
	BNT162b2 ¹	QIVc ¹	96	94	–	^[30]
	ChAdOx1 ¹	QIVr ¹	85	86	–	^[30]
	BNT162b2 ¹	QIVr ¹	96	89	–	^[30]
	ChAdOx1 ²	aTIV ²	77	65	–	^[30]
	BNT162b2 ²	aTIV ²	76	79	–	^[30]
	mRNA-1273 ²	hdQIV ²	86	91	62	^[32]
	NVX-CoV2373 ¹	QIVc ¹	73	63	39	^[31]
	NVX-CoV2373 ²	aTIV ²	39	35	46	^[31]
Any systemic, %	ChAdOx1 ¹	QIVc ¹	81	83	–	^[30]
	BNT162b2 ¹	QIVc ¹	87	81	–	^[30]
	ChAdOx1 ¹	QIVr ¹	74	72	–	^[30]
	BNT162b2 ¹	QIVr ¹	89	82	–	^[30]
	ChAdOx1 ²	aTIV ²	72	62	–	^[30]
	BNT162b2 ²	aTIV ²	59	71	–	^[30]
	mRNA-1273 ²	hdQIV ²	80	84	49	^[32]
	NVX-CoV2373 ¹	QIVc ¹	62	50	47	^[31]
	NVX-CoV2373 ²	aTIV ²	39	28	55	^[31]

¹ Working-age adults (18–64 years); ² older adults (≥65 years); aTIV, MF59-adjuvanted trivalent influenza vaccine; hdQIV, high-dose quadrivalent influenza vaccine; QIVc, cell-based quadrivalent influenza vaccine; QIVr, recombinant quadrivalent influenza vaccine.

It has generally been found ^[30]^[31]^[32] that the humoral IgG response measured by means of the hemagglutination inhibition (HAI) assay approximately 3 weeks after immunization towards any SIV strain is preserved in COVID-19 + SIV co-administration groups. Indeed, apart from the statistical significance, geometric mean ratios of all pairwise comparisons have proved to be >0.67, which is the non-inferiority margin (Table 2). Lazarus et al. ^[30] did not observe any significant difference in geometric mean titers (GMTs) between most co-administration groups (ChAdOx1 + QIVc, ChAdOx1 + QIVr, ChAdOx1 + aTIV, BNT162b2 + QIVc or BNT162b2 + aTIV) and groups receiving SIVs alone. The only exception was the immune response to A(H1N1)pdm09, B/Victoria and B/Yamagata; in these cases, GMTs were 20–38% higher in the BNT162b2 + QIVr group than in individuals who received QIVr only. The IgG response to A(H3N2) was similar. Toback et al. ^[31] did not find any significant difference in HAI titers between COVID-19 + SIV and placebo + SIV groups, regardless of the strain or vaccine (QIVc or aTIV). Analogously, the humoral immune response towards all four SIV strains was similar in individuals who received mRNA-1273 + hdQIV or hdQIV alone ^[32].

Table 2. Hemagglutination inhibition IgG geometric mean ratios against influenza vaccine strains in COVID-19 + seasonal influenza vaccine co-administration groups, as compared with groups to whom either vaccine was administered alone.

Influenza Vaccine	Strain	COVID-19 Vaccine [Reference]
Influenza Vaccine	Strain	BNT162b2 ^[30]	mRNA-1273 ^[32]	ChAdOx1 ^[30]	NVX-CoV2373 ^[31]
QIVc ¹	A(H1N1)pdm09	1.05 (0.91–1.21) ⁴	–	1.05 (0.91–1.21) ⁴	1.09 (ns) ⁶
	A(H3N2)	1.06 (0.95–1.18) ⁴	–	1.08 (0.96–1.21) ⁴	1.08 (ns) ⁶
	B/Victoria	1.03 (0.93–1.14) ⁴	–	1.05 (0.94–1.18) ⁴	1.03 (ns) ⁶
	B/Yamagata	0.94 (0.85–1.05) ⁴	–	0.98 (0.88–1.10) ⁴	0.99 (ns) ⁶
QIVr ¹	A(H1N1)pdm09	1.38 (1.11–1.71) ⁴	–	0.86 (0.74–0.99) ⁴	–
	A(H3N2)	1.03 (0.87–1.23) ⁴	–	1.03 (0.91–1.15) ⁴	–
	B/Victoria	1.20 (1.02–1.42) ⁴	–	1.07 (0.96–1.19) ⁴	–
	B/Yamagata	1.24 (1.05–1.47) ⁴	–	1.06 (0.94–1.18) ⁴	–
aTIV ²	A(H1N1)pdm09	1.05 (0.87–1.27) ⁴	–	1.15 (1.01–1.32) ⁴	1.41 (ns) ⁶
	A(H3N2)	1.18 (1.02–1.37) ⁴	–	1.00 (0.89–1.11) ⁴	0.87 (ns) ⁶
	B/Victoria	1.08 (0.94–1.25) ⁴	–	1.01 (0.91–1.12) ⁴	0.54 (ns) ⁶
	B/Yamagata ³	1.00 (0.86–1.15) ⁴	–	0.92 (0.83–1.03) ⁴	0.81 (ns) ⁶
hdQIV ²	A(H1N1)pdm09	–	0.99 (ns) ⁵	–	–
	A(H3N2)	–	0.91 (ns) ⁵	–	–
	B/Victoria	–	0.97 (ns) ⁵	–	–
	B/Yamagata	–	0.91 (ns) ⁵	–	–

¹ Working-age adults (18–64 years); ² older adults (≥65 years); ³ strain was not present in the vaccine formulation; ⁴ seasonal influenza vaccine first vs. placebo first; ⁵ mRNA-1273 + hdQIV vs. hdQIV alone, geometric mean ratios were calculated from the geometric mean titers provided by the authors; ⁶ NVX-CoV2373 + seasonal influenza vaccine vs. placebo + seasonal influenza vaccine, geometric mean ratios were calculated from the geometric mean titers provided by the authors; aTIV, MF59-adjuvanted trivalent influenza vaccine; hdQIV, high-dose quadrivalent influenza vaccine; ns, non-significant (p > 0.05); QIVc, cell-based quadrivalent influenza vaccine; QIVr, recombinant quadrivalent influenza vaccine.

Similar results were reported with regard to anti-spike neutralizing antibody titers (Table 3). Lazarus et al. ^[30] and Izikson et al. ^[32] did not find any significant differences between the co-administration groups and individuals who received COVID-19 vaccines alone. By contrast, some immunological inference was reported in the RCT by Toback et al. ^[31] After adjustment for baseline titers, age and the treatment arm, the geometric mean ratio of the anti-spike humoral response in NVX-CoV2373 + QIVc/aTIV versus NVX-CoV2373 alone was 0.57 (95% CI: 0.47–0.70). On the other hand, this decrease did not seem to translate into a corresponding decrease in vaccine efficacy. For instance, absolute vaccine efficacy against laboratory-confirmed symptomatic COVID-19 in adults (18–64 years) was 87.5% (95% CI: −0.2–98.4%) and 89.8% (95% CI: 79.7–95.5%) in the influenza sub-study and main study, respectively ^[31].

Table 3. Anti-spike IgG geometric mean ratios in COVID-19/influenza vaccine co-administration groups, as compared with groups to whom either vaccine was administered alone.

Influenza Vaccine	COVID-19 Vaccine [Reference]
Influenza Vaccine	BNT162b2 ^[30]	mRNA-1273 ^[32]	ChAdOx1 ^[30]	NVX-CoV2373 ^[31]
QIVc ¹	0.90 (0.80–1.01) ³	–	0.92 (0.81–1.04) ³	0.66 (NA) ⁵
QIVr ¹	0.86 (0.72–1.03) ³	–	0.92 (0.81–1.04) ³	–
aTIV ²	0.97 (0.83–1.13) ³	–	1.02 (0.91–1.14) ³	0.71 (NA) ⁵
hdQIV ²	–	0.97 (0.79–1.19) ⁴	–	–

¹ Working-age adults (18–64 years); ² older adults (≥65 years); ³ COVID-19 vaccine + placebo vs. COVID-19 vaccine + seasonal influenza vaccine; ⁴ mRNA-1273 + hdQIV vs. hdQIV alone; ⁵ NVX-CoV2373 + seasonal influenza vaccine vs. placebo + NVX-CoV2373 alone, geometric mean ratios were calculated from the geometric mean titers provided by the authors; aTIV, MF59-adjuvanted trivalent influenza vaccine; hdQIV, high-dose quadrivalent influenza vaccine; NA, not available; QIVc, cell-based quadrivalent influenza vaccine; QIVr, recombinant quadrivalent influenza vaccine.

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Alexander Domnich

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Update Date: 23 Mar 2022

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