Seasonal influenza vaccine performance and the potential benefits of mRNA vaccines

Figures & data

Table 1. Northern Hemisphere vaccine composition and reports of antigenic drift or egg-adapted mutations in the literature analysis of Northern Hemisphere 2011–2020 influenza seasons.

Season (Northern Hemisphere)		WHO-recommended vaccine composition for the Northern Hemisphere^Citation32–41	Articles reporting evidence of antigenic drift and the potential impact on VE in the Northern Hemisphere	Articles reporting evidence of egg-adapted mutations and the potential impact on VE in the Northern Hemisphere
2011–2012	A/H1N1	A/California/7/2009	Antigenic drift of A/H3N2 as the season progressed. WHO recommended that the 2012–2013 Northern Hemisphere vaccine composition be updated to include the A/Victoria/361/2011 (H3N2)-like virus^Citation38	Six antigenic-site mutations (S45N, G186V, S214I, S228T, I260M, R261Q) from the reference strain were identified in the egg-passaged vaccine strain for A/H3N2, but whether this affected HAI titers against circulating strains was not assessed^Citation27
	A/H3N2	A/Perth/16/2009
	B/Victoria	B/Brisbane/60/2008
	B/Yamagata	Not applicable
2012–2013	A/H1N1	A/California/7/2009		Egg-adapted mutations were identified in the A/H3N2 vaccine strain (H156Q and G186V substitutions at antigenic site B, and S219Y mutation at antigenic site D), which reduced HAI titers to the WHO-recommended strain^Citation42 Recommendation that A/Texas/50/2012 be used in the 2013–2014 Northern Hemisphere vaccine composition due to egg-adapted mutations (H156Q, G186V, S219Y) in earlier A/Victoria/361/2011-like vaccine viruses^Citation33
	A/H3N2	A/Victoria/361/2011
	B/Victoria	B/Brisbane/60/2008 (if quadrivalent)
	B/Yamagata	B/Wisconsin/1/2010
2013–2014	A/H1N1	A/California/7/2009
	A/H3N2	A/Texas/50/2012
	B/Victoria	B/Brisbane/60/2008 (if quadrivalent)
	B/Yamagata	B/Massachusetts/2/2012
2014–2015	A/H1N1	A/California/7/2009	Reduced VE caused by antigenic drift of A/H3N2 virus: 3C.2a, 3C.3, and 3C.3a HA clades predominated, leading to mismatch with the H3N2 component of the vaccine (A/Texas/50/2012; 3C.1 HA clade); due to multiple mutations in the HA antigenic site B including F159S^Citation28,Citation29 WHO recommended that the 2015–2016 vaccine be updated to include A/Switzerland/9715293/2013^Citation40
	A/H3N2	A/Texas/50/2012
	B/Victoria	B/Brisbane/60/2008 (if quadrivalent)
	B/Yamagata	B/Massachusetts/2/2012
2015–2016	A/H1N1	A/California/7/2009		Single egg-adapted HA receptor binding site mutation (Q226R) in A/H1N1 viral strain (A/California/7/2009-X-179A), which in ~ 5% of vaccine recipients reduced antibody titers against wild-type HA^Citation43 Single egg-adapted substitution on HA (L194P) in A/H3N2 viral strain affecting the structural conformation of antigenic site B and leading to decreased neutralizing antibody binding^Citation44
	A/H3N2	A/Switzerland/9715293/2013
	B/Victoria	B/Brisbane/60/2008 (if quadrivalent)
	B/Yamagata	B/Phuket/3073/2013
2016–2017	A/H1N1	A/California/7/2009		Egg-adapted substitution (T160K) in HA antigenic site B of A/H3N2 virus causing loss of putative N-glycosylation site, which resulted in reduced antibody titers against circulating viruses^Citation16,Citation45
	A/H3N2	A/Hong Kong/4801/2014
	B/Victoria	B/Brisbane/60/2008
	B/Yamagata	B/Phuket/3073/2013 (if quadrivalent)
2017–2018	A/H1N1	A/Michigan/45/2015		Egg-adapted substitution (T160K) in antigenic site B of A/H3N2 virus may have contributed to low VE observed, which is attributed to loss of putative N-glycosylation site^Citation45 A study of hospitalized adults with infections from this season suggests that antibody responses among vaccinated individuals were specific to egg adaptations in the A/H3N2 vaccine strain that were not conserved in circulating strains including T160K and L194P (antigenic site B) and N96S (antigenic site D)^Citation46
	A/H3N2	A/Hong Kong/4801/2014
	B/Victoria	B/Brisbane/60/2008
	B/Yamagata	B/Phuket/3073/2013 (if quadrivalent)
2018–2019	A/H1N1	A/Michigan/45/2015	Antigenic drift of the A/H3N2 virus: 3C.3a HA clades predominated, leading to mismatch with the H3N2 component of the vaccine (A/Singapore/INFIMH-16–0019/2016; 3C.2a1 HA clade)^Citation30 WHO recommended that the 2019–2020 vaccine be updated to include A/Kansas/14/2017 (clade 3C.3a)^Citation30,Citation36	Egg-adapted mutations (T160K, L194P, and D225G) identified in the HA head of the A/H3N2 viral strain^Citation47 Antibodies collected from vaccinated individuals showed reduced neutralizing responses against the wild-type A/H3N2 virus versus the egg-propagated vaccine virus, which was likely attributed to the combination of 3 egg-adapted mutations in the HA head (T160K, L194P, and D225G)^Citation47
	A/H3N2	A/Singapore/INFIMH-16-0019/2016
	B/Victoria	B/Colorado/06/2017 (B/Victoria/2/87 lineage)
	B/Yamagata	B/Phuket/3073/2013 (B/Yamagata/16/88 lineage) (if quadrivalent)
2019–2020	A/H1N1	A/Brisbane/02/2018	Antigenically drifted A/H1N1 emerged over the course of the season; early in the season, clade 6B.1.A (which includes the vaccine strain) subclade 5A viruses genetically diversified and exhibited substitutions at D187A and Q189E in HA^Citation31; further amino acid changes (K130N, N156K, L161I, V250A, and E506D; termed 5A + 156K viruses) occurred and predominated by mid-season^Citation31 Genetic diversification in circulating A/H1N1 may have contributed to reduced VE, particularly for 6B.1A 5A + 156K viruses^Citation31 Antigenically drifted B/Victoria circulated throughout the season (V1A.3, containing a 3-amino acid deletion [162–164] in the HA protein, as opposed to a 2 amino-acid deletion [162–163] for V1A.1 in the vaccine), but this was not linked to a reduction in VE, possibly due to some cross-reactivity^Citation31
	A/H3N2	A/Kansas/14/2017
	B/Victoria	B/Colorado/06/2017 (B/Victoria/2/87 lineage)
	B/Yamagata	B/Phuket/3073/2013 (B/Yamagata/16/88 lineage) (if quadrivalent)

HA hemagglutinin; HAI hemagglutination inhibition; VE vaccine effectiveness; WHO World Health Organization.

For context, the findings of the targeted literature review are presented alongside the recommended vaccine compositions for each influenza season provided by the World Health Organization.^32-41.

Figure 1. Influenza vaccine effectiveness, vaccine match, and strain prevalence by Northern Hemisphere influenza season and geographic region.

Vaccine effectiveness estimates were based on information from the United States Centers for Disease Control and Prevention (CDC),⁴⁸ the Canadian Sentinel Practitioner Surveillance Network,⁴⁹ and I-MOVE (Influenza – Monitoring Vaccine Effectiveness in Europe; European Union primary care-based, multi-country cohort).^50–58 Overall vaccine effectiveness (across strains) is presented for the United States and Canada. Vaccine effectiveness for the predominant strain each season is presented for Europe.

Dotted line represents the overall percentage of antigenic match of the vaccine to circulating viruses in the United States, calculated as a sum of the antigenic match values for each of the four strains weighted by their relative prevalence during the season. Antigenic match values were published in the CDC’s Morbidity and Mortality Weekly Reports and were based on titers with ferret antisera,^59–68

Strain prevalence estimates were based on CDC’s Morbidity and Mortality Weekly Report,^59–67 the Canadian Sentinel Practitioner Surveillance Network,^{27,42,69–74} and the European Centre for Disease Prevention and Control.^75–83 The proportion of unknown influenza A or influenza B lineages is not shown.

Figure 2. Influenza vaccine manufacturing using egg-based, cell culture-based, and mRNA-based platforms.

HA hemagglutinin; mRNA messenger RNA.

Currently, egg- and cell culture-based technologies require approximately 6 months for vaccine manufacturing⁹⁸ after the World Health Organization releases the recommended vaccine composition in February/March ahead of the forthcoming Northern Hemisphere influenza season,^{32–35,37–41} By comparison, an mRNA-based influenza vaccine platform may only take 2–3 months to manufacture (based on the timeline for SARS-CoV-2 vaccine manufacturing).^99,100

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