Anti-neuraminidase immunity in the combat against influenza

Figures & data

Figure 1. Structure of neuraminidase and its catalytic sites. Reproduced with permission from Sarah Creytens et al. [113].

Figure 2. Eliciting NA-specific immunity. the anti-NA immunity can be induced by (i) pulmonary infection with influenza virus, (ii) immunization with variety of vaccines, and (iii) passive immunization with NA-specific polyclonal or monoclonal antibodies. NA-specific immunity provides protection against severe disease with reduced morbidity and mortality, decreased pulmonary virus titers and diminished lung lesions.

Table 1. NA-based vaccine studies.

Year	Vaccine	Model	Main Findings	Ref.
2014	Baculovirus- expressed rNA from either A/Beijing/262/95 (BJ/262) H1N1 or A/Hong Kong/483/97 (HK/483) H5N1 virus	Rabbits	Evaluated the antigenic relatedness and cross-protective immunity of the neuraminidase between human influenza A (H1N1) virus and highly pathogenic avian influenza A (H5N1) virus. The lack of cross-protective immunity correlates with low structural similarities of NA from a human seasonal H1N1 virus and an avian H5N1 influenza virus.	[121]
2016	Recombinant vaccinia viruses expressing the HA or NA from the influenza A/Anhui/1/2013 (H7N9) virus	BALB/c and ICR mice	The anti-HA and anti-NA antibodies showed activity against homosubtypic HA or NA, but not against heterosubtypic HA or NA	[122]
2017	N1 NA protein derived from A/California/04/2009 (A/Cal) H1N1 and N2 NA protein derived from A/Wisconsin/67/2005 (A/Wis) H3N2	BALB/c, C57BL/6, and C3KO mice	Anti-NA immune sera could confer better cross-protection against multiple heterologous influenza viruses correlating with NA inhibition activity compared to split vaccine immune sera.	[74]
2018	NA-expressing single-cycle vesicular stomatitis virus replicons	C57BL/6 mice and ferrets	Robust humoral and cellular immune responses and protected against challenge with the homologous influenza virus	[91]
2019	Seasonal inactivated influenza vaccines	Human*	Seasonal influenza immunization can induce a subset of NA-specific B cells with broad protective potential	[123]
2020	rNAs from A/Michigan/45/15 (N1), A/Viet- nam/1203/04 (N1), A/Philippines/2/82 (N2), A/Tanzania/205/10 (N2) or B/Florida/04/06 (BNA) were expressed in High Five insect cells	BALB/c mice	The enzymatically active NA is not required to induce protective anti- body responses as a vaccine; however a correctly folded NA is essential.	[87]
2020	Formalin-inactivated terminal packaging signals modified recombinant virus	BALB/c mice	Demonstrates the efficacy of rewiring influenza virus packaging signals for creating vaccines with more neuraminidase content which provide better NA-based protection.	[86]
2020	LAIVs	Human	Combining the traditional HI test with the detection of NI antibodies can provide a more complete assessment of LAIV immunogenicity.	[102]
2021	rNA with a Measles Virus Phosphoprotein Tetramerization Domain	BALB/c mice	Recombinant Influenza Virus Neuraminidase Vaccine Candidate Stabilized by a Measles Virus Phosphoprotein Tetramerization Domain Provides Robust Protection from Virus Challenge in the Mouse Model	[85]
2021	NA1 and NA2 neuraminidase virus-like particles	BALB/c mice	Vaccination with NA VLPs is protective against influenza challenge and supports, focusing on anti-NA responses in the development of future vaccination strategies.	[93]
2021	Baculovirus- expressed rNA from A/Brisbane/02/2018 (H1N1) with different tetramerization motifs	DBA/2 mice	Design of the Recombinant Influenza Neuraminidase Antigen is Crucial for its Biochemical Properties and Protective Efficacy	[84]
2021	Wild type or COBRA-based NA-expressing virus-like particles and rNA produced using EXPI293F cells expression system	BALB/c mice	The N1-I NA antigen described here protected mice from direct challenge of four distinct influenza viruses and inhibited the enzymatic activity of an N1 influenza virus panel.	[81]
2021	Baculovirus- expressed rNA from A/Michigan/45/2015 (H1N1) with additional Cysteines introduced in the Stalk Domain	BALB/c mice	The introduction of cysteines at certain positions led to the formation of stable N1 dimers, which are capable of inducing a strong antibody response characterized by neuraminidase inhibiting activity and protection of mice from high dose viral challenge.	[83]
2021	Soluble rHAs and rNAs from A/California/07/2009 (H1N1) were generated by using the Expi293 Expression System	C57BL/6J mice	Intranasal immunization with recombinant NA (rNA) plus adjuvant protected mice against not only homologous but also heterologous virus challenge in the upper respiratory tract, whereas intranasal immunization with rHA failed to protect against heterologous challenge.	[82]
2021	A/Chicken/Vietnam/G04/2004 (H5N1) N1 NA-expressing virus-like particles	BALB/c mice	The lowest bodyweight losses and lung virus titers were observed from HANA VLP immunization, and all of the immunized mice survived irrespective of the challenge dose.	[92]
2021	N1 from A/California/04/2009 (H1N1) and N2 from A/Switzerland/9715293/2013 (H3N2) rNA produced in baculovirus expression system	BALB/c mice	NAV-vaccinated mice showed robust antibody titers against N1 and N2, and after challenge with influenza A (H1N1) virus, decreased viral titers and decreased antiviral and inflammatory responses by transcriptomic analysis.	[24]
2021	AS03-adjuvanted pandemic H1N1pdm09 split virus vaccine (3.75 mg hemagglutinin A/California/7/2009 (H1N1)), trivalent seasonal inactivated influenza vaccine, or	Human (health care workers)	Durable NA-specific antibody responses can be induced by an adjuvanted influenza vaccine, which can be maintained and further boosted by TIVs. Although NA-specific antibody responses are boosted by annual influenza vaccines, high preexisting titers may negatively affect the magnitude of fold-increase in repeatedly vaccinated individuals.	[106]
2023	A split vaccine ‘Ultrix,’ a subunit vaccine ‘Grippol plus’ and a subunit vaccine ‘Sovigripp’	Human	The dynamics of the anti-NA antibody response differed depending on the virus subtype: antibodies to A/H3N2 virus neuraminidase increased later than antibodies to A/H1N1pdm09 subtype neuraminidase and persisted longer.	[101]
2023	Wild type or COBRA-based NA-expressing virus-like particles and rNA produced using EXPI293F cells expression system	Ferrets	The N1-I COBRA vaccine elicited protective immune responses against both H1N1 and H5N1 infections and partially mitigated disease in contact-transmission receiving ferrets.	[80]

*Clinical data in humans is listed in bold.

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