Matrix-M™ adjuvant enhances immunogenicity of both protein- and modified vaccinia virus Ankara-based influenza vaccines in mice - PubMed (original) (raw)

Matrix-M™ adjuvant enhances immunogenicity of both protein- and modified vaccinia virus Ankara-based influenza vaccines in mice

Sofia E Magnusson et al. Immunol Res. 2018 Apr.

Abstract

Influenza viruses continuously circulate in the human population and escape recognition by virus neutralizing antibodies induced by prior infection or vaccination through accumulation of mutations in the surface proteins hemagglutinin (HA) and neuraminidase (NA). Various strategies to develop a vaccine that provides broad protection against different influenza A viruses are under investigation, including use of recombinant (r) viral vectors and adjuvants. The replication-deficient modified vaccinia virus Ankara (MVA) is a promising vaccine vector that efficiently induces B and T cell responses specific for the antigen of interest. It is assumed that live vaccine vectors do not require an adjuvant to be immunogenic as the vector already mediates recruitment and activation of immune cells. To address this topic, BALB/c mice were vaccinated with either protein- or rMVA-based HA influenza vaccines, formulated with or without the saponin-based Matrix-M™ adjuvant. Co-formulation with Matrix-M significantly increased HA vaccine immunogenicity, resulting in antigen-specific humoral and cellular immune responses comparable to those induced by unadjuvanted rMVA-HA. Of special interest, rMVA-HA immunogenicity was also enhanced by addition of Matrix-M, demonstrated by enhanced HA inhibition antibody titres and cellular immune responses. Matrix-M added to either protein- or rMVA-based HA vaccines mediated recruitment and activation of antigen-presenting cells and lymphocytes to the draining lymph node 24 and 48 h post-vaccination. Taken together, these results suggest that adjuvants can be used not only with protein-based vaccines but also in combination with rMVA to increase vaccine immunogenicity, which may be a step forward to generate new and more effective influenza vaccines.

Keywords: Immunogenicity; Influenza virus; MVA; Matrix-M™ adjuvant; Vaccine.

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Conflict of interest statement

Conflict of interest

SEM, KLB, and LS are employees of Novavax and hold stock and/or stock options in the company. Other authors report no conflict of interest.

Figures

Fig. 1

Fig. 1

HA-specific antibody responses induced after vaccination with HA protein or rMVA-HA with or without Matrix-M adjuvant IgG1 (a) and IgG2a (b) HA-specific antibody responses 21 days after the primary vaccination. c–d IgG1 and IgG2a HA-specific antibody responses 14 days after the booster vaccination. IgG1 (a, c) or IgG2a (b, d) serum antibodies were detected by ELISA using purified HA protein and anti-IgG1 or anti-IgG2a HRP-conjugated antibodies. Data is shown as mean ± 95% confidence interval (CI). *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001. MM = Matrix-M adjuvant

Fig. 2

Fig. 2

Induction of HA-specific HI antibody responses after vaccination with rMVA-HA adjuvanted with Matrix-M HI serum antibody responses against influenza virus A/Puerto Rico/8/34 (H1N1) was measured 21 days after the primary (a) or 14 days after the booster (b) vaccination. Data is shown as mean ± 95% CI. *p < 0.05; **p < 0.01; ***p < 0.001. MM = Matrix-M adjuvant

Fig. 3

Fig. 3

Enhanced HA-specific splenocyte responses by Matrix-M-adjuvanted vaccine spleens obtained 14 days after the booster vaccination were stimulated with purified HA protein and the number of IL-2 (a), IFN-γ (b), and IL-2/IFN-γ (c) producing splenocytes was determined in spot forming units (SFU)/106 cells by Fluorospot assay. Samples were tested in triplicate. The mean ± 95% CI of each group is indicated. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001. MM = Matrix-M adjuvant

Fig. 4

Fig. 4

Matrix-M-adjuvanted influenza vaccines induce influx of immune cells in the dLN with maintained composition of cellular subsets except for an increased monocyte population. a The total number of cells per dLN. b Contribution (%) of the indicated cellular subsets in the dLN was measured by flow cytometry at 4, 24, or 48 h after i.m. vaccination. c–d Total cell count of CD11b+Ly6C+ monocytes (c) and CD169+F4/80+ medullary sinus macrophages (d) were determined by flow cytometry. Data are shown as mean of 10 mice per group. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001. MM = Matrix-M adjuvant

Fig. 5

Fig. 5

Increased activation of APCs in the dLN 24 and 48 h after vaccination with Matrix-M-adjuvanted influenza HA vaccines. a–b The number of CD69+ or CD86+ DCs, monocytes, and B lymphocytes recruited to the dLN was measured by flow cytometry 4, 24, and 48 h after i.m. injection of the respective vaccine. c The mean fluorescence intensity (MFI) of MHC class II of on DCs, monocytes, and B lymphocytes in the dLN was measured by flow cytometry 4, 24, and 48 h post-injection. Data are shown as mean of 10 mice per group. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001. MM = Matrix-M adjuvant

Fig. 6

Fig. 6

Increased number of activated NK- and T lymphocytes in the dLN at 24 and 48 h post-vaccination with Matrix-M-adjuvanted influenza HA vaccines The number of CD69+ NK cells (a), CD4+ (b), and CD8+ (c) T lymphocytes in the dLN was measured by flow cytometry 4, 24, and 48 h after i.m. injection of the respective vaccines. Data are shown as mean of 10 mice per group. *p < 0.05; **p < 0.01; ***p < 0.001; ****p < 0.0001. MM = Matrix-M adjuvant

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References

    1. Koel BF, Burke DF, Bestebroer TM, van der Vliet S, Zondag GC, Vervaet G, et al. Substitutions near the receptor binding site determine major antigenic change during influenza virus evolution. Science. 2013;342(6161):976–979. doi: 10.1126/science.1244730. - DOI - PubMed
    1. Westgeest KB, de Graaf M, Fourment M, Bestebroer TM, van Beek R, Spronken MI, et al. Genetic evolution of the neuraminidase of influenza A (H3N2) viruses from 1968 to 2009 and its correspondence to haemagglutinin evolution. J Gen Virol. 2012;93(Pt 9):1996–2007. doi: 10.1099/vir.0.043059-0. - DOI - PMC - PubMed
    1. Wright PF, Neumann G, Kawaoka Y, et al. Orthomyxoviruses. In: Knipe DM, Howley PM, Cohen JI, Griffin DE, Lamb RA, Martin MA, et al., editors. Fields virology. 6. Philadelphia: Lippincott Williams & Wilkins; 2013. pp. 1186–1243.
    1. World Health Organization. Cumulative number of confirmed human cases for avian influenza A(H5N1) reported to WHO, 2003–2007. http://www.who.int/influenza/human_animal_interface/2017_07_25_tableH5N1... Accessed: 25/09/2017. http://www.who.int/influenza/human_animal_interface/2017_07_25_tableH5N1... Accessed 25/09/2017.
    1. World Health Organization. Human infections with avian influenza A(H5N6) virus. http://www.who.int/csr/don/07-december-2016-ah5n6-china/en/. Accessed: 25/09/2017. Accessed 25/09/2017.

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